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Port Integration in China: Temporal Pathways, Spatial Patterns and Dynamics 被引量:8
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作者 WANG Chengjin César DUCRUET WANG Wei 《Chinese Geographical Science》 SCIE CSCD 2015年第5期612-628,共17页
Over the past two decades, numerous ports located in China have participated in port integration strategies, thus influencing the entire port system. The current research is initiated in order to examine the nature of... Over the past two decades, numerous ports located in China have participated in port integration strategies, thus influencing the entire port system. The current research is initiated in order to examine the nature of port integration in China, including associated temporal pathways, spatial patterns and dynamics. Results indicate that port integration in China has been characterized by a significant increase at the turn of the 21 st century, comprising thirteen distinguishable pathways typified by differing dynamics, particularly between the northern and southern ports. Pathways were found to include 44 seaports and river ports, chiefly concentrated in the Bohai Rim, Yangtze(Changjiang) River Delta, Beibu Gulf and the southeastern Fujian, thus representing significant spatial regions. Categorically larger seaports have become the primary beneficiaries of port integration. Integration cases were divided into four categories based upon quantified dynamic magnitude including the government-driven mode, market-driven mode, government/market-driven mode and strategic alliance, and into five further categories based upon spatial extent including port internal integration, jurisdictional port integration, port integration across neighbor region, regional port integration and hub-feeder port integration. Results suggest that several factors have effectively driven port integration in China, including legislative tools and spatial planning, optimization of shoreline resources and port functionality, and port competition with the same hinterland. 展开更多
关键词 中国港口 空间格局 整合 路径 时间 市场驱动 一体化 港口体系
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Peripheral Challenge in Container Port System:A Case Study of Pearl River Delta 被引量:1
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作者 WANG Chengjin WANG Jiao'e Cesar DUCRUET 《Chinese Geographical Science》 SCIE CSCD 2012年第1期97-108,共12页
The growth of peripheral ports to dominant hubs has been well documented in North America and Europe,and has led to the elaboration of several theoretical models.However,although changes in containerization growth hav... The growth of peripheral ports to dominant hubs has been well documented in North America and Europe,and has led to the elaboration of several theoretical models.However,although changes in containerization growth have been taking place in the South and East Asia in recent years,particularly in China,only a few studies have fo-cused on this region.The Pearl(Zhujiang) River Delta(PRD) has a typical port system with hub and peripheral ports,and provides an excellent case for studying the Peripheral Challenge.This paper introduces the theoretical evidence of the Hayuth model and analyzes the evolution of the container port system in the PRD with five phases:1) phase I:preconditions for change and phase II:initial container port development in the 1970s and early 1980s;2) phase III:diffusion,consolidation,and port concentration in the middle and late 1980s;3) phase IV:the load center in the 1990s;and(4) phase V:the Peripheral Challenge since the late 1990s.The results illustrate that the Shenzhen port presents mounting challenges to the Hong Kong port,descending from a transshipment hub of China to a regional load center of Southeast China.Furthermore,this paper explores five points that have led to the evolution of the port system in the PRD:1) competition in the regional port systems;2) different interested parties;3) shift of investment strategies of in-ternational terminal operators;4) integration of shipping networks and reorganization of carriers;and 5) cost-based competition. 展开更多
关键词 珠江三角洲 集装箱运输 港口体系 中国东南地区 负荷中心 珠三角 周边港口 港口发展
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Genetic Variability of the Mitochondrial DNA in Honeybees (Apis mellifera L.) from Benin
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作者 Aude Kelomey Armand Paraiso +4 位作者 Haziz Sina Helene Legout Adolphe Adjanohoun Lionel Gamery Lamine Baba-Moussa 《Journal of Agricultural Science and Technology(A)》 2017年第8期557-566,共10页
关键词 DNA 可变性 蜜蜂 基因 PCR-RFLP 细胞色素 APIS 亚种
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High Frequency Roughness Scattering from Various Rough Surfaces: Theory and Laboratory Experiments
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作者 Virginie Jaud Jean-Pierre Sessarego +1 位作者 Cedric Gervaise Yann Stephan 《Open Journal of Acoustics》 2012年第1期50-59,共10页
The scattering strength of isotropic and anisotropic rough surfaces was experimentally and theoretically investigated for high frequencies about 500 kHz. Emphasis was placed on studying the response from three two-dim... The scattering strength of isotropic and anisotropic rough surfaces was experimentally and theoretically investigated for high frequencies about 500 kHz. Emphasis was placed on studying the response from three two-dimensional rough surfaces which roughness was either isotropic (characterized by a Gaussian distribution) or anisotropic (characterized by a modified-sine surface). Theoretical predictions rely on the first-order small slope approximation either including a Gaussian structure function or a quasi-periodic structure function. The combination of true data and theoretical results indicates the importance of taking into account the anisotropy of a surface in a scattering prediction process. It is shown that the scattering strength varies a lot depending on the propagation plane. In the longitudinal direction of ripples, scattering strength is mostly in the specular direction, whereas in the transversal direction of the ripples, the scattering strength is spread in a very different way related to the particular features of the ripples, with several maxima and minima independent of the specular direction. Contrary to the isotropic surface, the scattering strength from an anisotropic rough surface is modified from one propagation plane to another, which explains why the entire rough surface should be taken into account without any simplification as it is often seen when dealing with scattering models. Compared to such a surface, positions of the emitter and of the receiver are naturally significant when measuring scattering strength. 展开更多
关键词 BISTATIC SCATTERING TANK Experiment ANISOTROPIC and ISOTROPIC ROUGHNESS
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Modelling of High-Frequency Roughness Scattering from Various Rough Surfaces through the Small Slope Approximation of First Order
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作者 Virginie Jaud Cedric Gervaise +1 位作者 Yann Stephan Ali Khenchaf 《Open Journal of Acoustics》 2012年第1期1-11,共11页
The first-order small slope approximation is applied to model the scattering strength from a rough surface in underwater acoustics to account for seafloor for high frequencies from 10 kHz to hundreds of kilohertz. Emp... The first-order small slope approximation is applied to model the scattering strength from a rough surface in underwater acoustics to account for seafloor for high frequencies from 10 kHz to hundreds of kilohertz. Emphasis is placed on simulating the response from two-dimensional anisotropic rough surfaces. Several rough surfaces are described based on structure functions such as the particular sandy ripples shape. The scattering strength is predicted by the small slope approximation and is first compared to a well known bistatic method, interpolating the Kirchhoff approximation and the small perturbations model, assuming that the rough interface is isotropic. Results obtained from the two different models are similar and show a higher level in the specular direction than in the other directions. For an isotropic surface, changing the propagation plane gives similar results. Then, SSA, which lets us adapt the structure function of the roughness straight away, is tested trough several anisotropic surfaces. In a longitudinal direction of ripples, the scattering strength is mostly in the specular direction, whereas in the transversal direction of ripples, the scattering strength prediction shows high values for different angular directions. Thus the scattering strength is spread in a very different way strictly related to the particular features of the ripples. Combine our results, indicates the importance of taking into account the anisotropy of a surface in a scattering prediction process, taking into account the positions of the emitter and of the receiver which are naturally significant when predicting scattering strength. 展开更多
关键词 Anisotropy ROUGHNESS SCATTERING SMALL SLOPE APPROXIMATION
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孔历纪元法是在中国先使用还是在南洋先使用?(英文)
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作者 苏尔梦 《海洋史研究》 2014年第2期266-282,共17页
学者一般认为孔子纪年的设想初步形成于1891年前后。康有为首次使用孔子纪年则是在1895年创立的《强学报》第一期上,1898年他提倡把孔历当作国历。同年在新加坡,邱菽园在其创立的《天南新报》上也开始使用孔子纪年。然而在南洋,当时孔... 学者一般认为孔子纪年的设想初步形成于1891年前后。康有为首次使用孔子纪年则是在1895年创立的《强学报》第一期上,1898年他提倡把孔历当作国历。同年在新加坡,邱菽园在其创立的《天南新报》上也开始使用孔子纪年。然而在南洋,当时孔教和孔子纪元的观念却并非新鲜事物。根据一些华文碑铭和马来文的回忆录的记载,1880年前后出生于爪哇泗水的一位改革者周[平为],已经开始使用孔子纪年,其带有双重目的:一是提醒国人中国文化的本位意识,二是引进西洋的思想。因此,不仅关于孔子纪年的起始时间、起源地区需要重新检讨,而且对于处在多元文化交融与碰撞前沿的南洋华人在近代东西方文化交流中的地位与作用也需要郑重关注。 展开更多
关键词 孔历纪元 南洋 康有为 周平为
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火山喷发对陆地植被与碳循环影响的研究进展 被引量:1
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作者 张原 梁尔源 +1 位作者 汪涛 朴世龙 《科学通报》 EI CAS CSCD 北大核心 2024年第2期160-168,共9页
1991年,Pinatubo火山喷发导致全球大气二氧化碳浓度上升态势出现停滞,这一现象揭示了地球内部系统可以通过火山活动对地表生物地球化学循环产生重大影响.近些年,火山喷发对陆地生态系统的影响及其驱动机制引起科学界的广泛讨论.本文系... 1991年,Pinatubo火山喷发导致全球大气二氧化碳浓度上升态势出现停滞,这一现象揭示了地球内部系统可以通过火山活动对地表生物地球化学循环产生重大影响.近些年,火山喷发对陆地生态系统的影响及其驱动机制引起科学界的广泛讨论.本文系统梳理了火山喷发对陆地生态系统影响的研究,总结了火山活动的辐射效应和气候效应对树木生长和陆地碳循环产生影响的机制.大型火山喷发形成的平流层气溶胶一方面引起散射辐射增加促进光合作用,另一方面,还引起总辐射减弱抑制光合作用,由于散射辐射的影响相比更强,总体上火山辐射效应有利于陆地碳汇的增加.火山的气候效应体现在全球尺度的降温和区域降水的改变.降温作用在低纬地区促进植被的光合作用,在高纬地区抑制光合作用,同时在全球尺度减弱生态系统的呼吸作用,总体上也有利于增加碳汇.对火山造成降水变化影响的评估目前还存在较大不确定性.在对这些机制总结的基础上,本文评述了当前的认识盲点和研究难点,以期为未来进一步推进火山喷发影响的研究、完善地球内外系统联动机制的认识提供参考. 展开更多
关键词 火山爆发 陆地生态系统 火山冷却效应 散射辐射 碳循环
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Reliability-based settlement analysis of embankments over soft soils reinforced with T-shaped deep cement mixing piles 被引量:1
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作者 Chana PHUTTHANANON Pornkasem JONGPRADIST +3 位作者 Daniel DIAS Xiangfeng GUO Pitthaya JAMSAWANG Julien BAROTH 《Frontiers of Structural and Civil Engineering》 SCIE EI CSCD 2022年第5期638-656,共19页
This paper presents a reliability-based settlement analysis of T-shaped deep cement mixing(TDM)pile-supported embankments over soft soils.The uncertainties of the mechanical properties of the in-situ soil,pile,and emb... This paper presents a reliability-based settlement analysis of T-shaped deep cement mixing(TDM)pile-supported embankments over soft soils.The uncertainties of the mechanical properties of the in-situ soil,pile,and embankment,and the effect of the pile shape are considered simultaneously.The analyses are performed using Monte Carlo Simulations in combination with an adaptive Kriging(using adaptive sampling algorithm).Individual and system failure probabilities,in terms of the differential and maximum settlements(serviceability limit state(SLS)requirements),are considered.The reliability results for the embankments supported by TDM piles,with various shapes,are compared and discussed together with the results for conventional deep cement mixing pile-supported embankments with equivalent pile volumes.The influences of the inherent variabilities in the material properties(mean and coefficient of variation values)on the reliability of the piled embankments,are also investigated.This study shows that large TDM piles,particularly those with a shape factor of greater than 3,can enhance the reliability of the embankment in terms of SLS requirements,and even avoid unacceptable reliability levels caused by variability in the material properties. 展开更多
关键词 T-shaped deep cement mixing piles piled embankments SETTLEMENT reliability analysis soil uncertainties
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Millimeter gap contrast as a probe for turbulence level in protoplanetary disks
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作者 Yao Liu Gesa H.-M.Bertrang +7 位作者 Mario Flock Giovanni P.Rosotti Ewine F.van Dishoeck Yann Boehler Stefano Facchini Can Cui Sebastian Wolf Min Fang 《Science China(Physics,Mechanics & Astronomy)》 SCIE EI CAS CSCD 2022年第12期131-144,共14页
Turbulent motions are believed to regulate angular momentum transport and influence dust evolution in protoplanetary disks.Measuring the strength of turbulence is challenging through gas line observations because of t... Turbulent motions are believed to regulate angular momentum transport and influence dust evolution in protoplanetary disks.Measuring the strength of turbulence is challenging through gas line observations because of the requirement for high spatial and spectral resolution data,and an exquisite determination of the temperature.In this work,taking the well-known HD 163296 disk as an example,we investigated the contrast of gaps identified in high angular resolution continuum images as a probe for the level of turbulence.With self-consistent radiative transfer models,we simultaneously analyzed the radial brightness profiles along the disk major and minor axes,and the azimuthal brightness profiles of the B67 and B100 rings.By fitting all the gap contrasts measured from these profiles,we constrained the gas-to-dust scale height ratioΛto be 3.0^(+0.3)_(−0.8),1.2^(+0.1)_(−0.1),and≥6.5 for the D48,B67,and B100 regions,respectively.The varying gas-to-dust scale height ratios indicate that the degree of dust settling changes with radius.The inferred values forΛtranslate into a turbulence level of α_(turb)<3×10^(−3) in the D48 and B100 regions,which is consistent with previous upper limits set by gas line observations.However,turbulent motions in the B67 ring are strong with α_(turb)∼1.2×10^(−2).Due to the degeneracy betweenΛand the depth of dust surface density drops,the turbulence strength in the D86 gap region is not constrained. 展开更多
关键词 protoplanetary disks radiative transfer planet formation
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MHD and kinetic analysis of flow bursts in the Earth's plasma sheet 被引量:7
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作者 MA YuDuan CAO JinBin +6 位作者 FU HuiShan REME H. DANDOURAS I. YANG JunYing WANG ZhiQiang TAO Dan YANG Jian 《Science China(Technological Sciences)》 SCIE EI CAS 2014年第1期55-66,共12页
In an attempt to study the flow bursts in the Earth’s plasma sheet we select an event that took place on August 7,2004 in the expansion phase of a substorm,using data from the geomagnetic index,solar wind data,plasma... In an attempt to study the flow bursts in the Earth’s plasma sheet we select an event that took place on August 7,2004 in the expansion phase of a substorm,using data from the geomagnetic index,solar wind data,plasma and magnetic field observations from C1 Cluster satellite(the Cluster mission has 4 satellites)and from Double Star TC-1 satellite.In MHD approach,TC-1 firstly observed the tailward flow,then the earthward,and finally the flow alternated in two directions.C1 firstly observed the earthward plasma flow,and then the tailward plasma flow.Before flow bursts are observed by TC-1 and C1,there are disturbances in local entropy with their tailward local entropy larger than those of the earthward.The kinetic features of the plasma flow observed by C1 are similar to those in MHD.However,kinetic characteristics of the plasma flow observed by TC-1 are far more than the description in MHD.The inadequacy mainly exists in two cases:(i)the firstly enhanced tailward flows given in MHD are found without significant increase of the energetic tailward flux;(ii)the almost stagnant flow in MHD is composed of the enhanced energetic ion flux in both earthward and tailward directions.The earthward flow burst observed by TC-1 might be multiple overshoots and rebounds.The earthward flow burst observed by C1 might be simply rebounded in the near-Earth.The pulsation observed by C1 is earlier than that observed by TC-1 with the former intensity less than that of the latter.After the energetic ion flux in the tailward direction is significantly enhanced,the power spectrum intensity of the ULF wave commences to increase obviously,which may suggest that the stream instability is closely correlated with ULF pulsations. 展开更多
关键词 等离子体片 磁流体 出流量 动力学分析 地球 爆发 TC-1卫星 等离子体流
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Evolution, accessibility and dynamics of road networks in China from 1600 BC to 1900 AD 被引量:5
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作者 WANG Chengjin DUCRUET Cesar WANG Wei 《Journal of Geographical Sciences》 SCIE CSCD 2015年第4期451-484,共34页
Before the emergence of modern modes of transport, the traditional road infra structure was the major historical means of carrying out nationwide socioeconomic exchange However, the history of transport infrastructure... Before the emergence of modern modes of transport, the traditional road infra structure was the major historical means of carrying out nationwide socioeconomic exchange However, the history of transport infrastructure has received little attention from researchers. Given this background, the work reported here examined the longterm development of transport networks in China. The national road network was selected for study and the 3500 years from 1600 BC to 1900 AD was chosen as the study period. Indicators were designed for the maturity level of road networks and an accessibility model was developed for the paths of the shortest distance. The evolution of the road network in China since the Shang Dynasty (1600 BC) was described and its major features were summarized to reveal longterm regu larities. The maturity level of the road network and its accessibility was assessed and regions with good and poor networks were identified. The relationship between China's natural, social and economic systems and the road network were discussed. Our analysis shows that the road network in China has a number of longterm regularities. The continuously expanding road network follows a path of inland expansion especially towards the border areas. How ever, its coverage and accessibility are characterized by a coreperipheral configuration, which has close relationships with, not only the natural conditions, but also national defense and warfare. The centralization of national power, national land governance, postal transport, the transport of specialized cargos, and international trade are also related to the develop ment of the road network. This research draws attention to the evolving regularities of trans port networks. 展开更多
关键词 China road networks historical evolution ACCESSIBILITY dynamic mechanisms
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Nonadiabatic acceleration of plasma sheet ions related to ion cyclotron waves 被引量:3
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作者 WANG Zhi Qiang CAO Jin Bin +2 位作者 RME Henri DANDOURAS Iannis MA Yu Duan 《Science China(Technological Sciences)》 SCIE EI CAS 2014年第12期2434-2440,共7页
The nonadiabatic acceleration of plasma sheet ions is important to the understanding of substorm energetic injections and the formation of ring current. Previous studies show that nonadiabatic acceleration of protons ... The nonadiabatic acceleration of plasma sheet ions is important to the understanding of substorm energetic injections and the formation of ring current. Previous studies show that nonadiabatic acceleration of protons by magnetic field dipolarization is hard to occur at X>–10 RE because the time-scale of dipolarization(several minutes) is much larger than the gyroperiod of protons there(several seconds). In this paper, we present a case of nonadiabatic acceleration of plasma sheet ions observed by Cluster on October 30, 2006 at(XGSM, YGSM)=(-7.7, 4.7) RE. The nonadiabatic acceleration of ions is caused not by previously reported magnetospheric dipolarization but by the ultra low frequency(ULF) waves during magnetospheric dipolarization. The nonadiabatic acceleration of ions generates a new energy flux structure of ions, which is characterized by the usual energy flux increase of ions(28–80 ke V) and a concurrent energy flux decrease of ions in a lower energy range(10 e V–20 ke V). These new observations constitute a complete physical picture: The lower energy ions absorb the wave energy, and thus get accelerated to higher energy. We use a nonadiabatic model to interpret the ion energy flux variations. Both analytic and simulation results are in good agreement with the observations. This indicates that the nonadiabatic acceleration associated with ULF waves superposed on dipolarized magnetic field is an effective mechanism for ion energization in the near-Earth plasma sheet. The presented energy flux structures can be used as a proxy to identify the similar dynamic process. 展开更多
关键词 离子回旋波 等离子体片 非绝热 能量通量 加速度 高能注入 时间尺度 能量范围
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Precipitation strengthening of nano-scale TiC in a duplex low-density steel under near-rapid solidification 被引量:1
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作者 Jian-lei Zhang Cong-hui Hu +4 位作者 Yu-xiang Liu Yang Yang Gang Ji Chang-jiang Song Qi-jie Zhai 《Journal of Iron and Steel Research(International)》 SCIE EI CSCD 2021年第9期1141-1148,共8页
Precipitation strengthening of nano-scale TiC is a promising method to improve mechanical properties of Fe–16Mn–9Al–0.8C (wt.%) low-density steel. This work attempted to introduce nano-scale TiC precipitates by add... Precipitation strengthening of nano-scale TiC is a promising method to improve mechanical properties of Fe–16Mn–9Al–0.8C (wt.%) low-density steel. This work attempted to introduce nano-scale TiC precipitates by adding 1 wt.% Ti element. The experimental results show that these precipitates with the total fraction of about 2 vol.% were formed and no coarse precipitates were observed despite the high Ti addition. It was interesting that the polygonal and needle-shaped TiC precipitates were observed in γ-austenite and δ-ferrite, respectively. Ti addition also decreased the volume fraction of γ-austenite significantly. Correspondingly, the yield strength was increased, but the elongation was significantly decreased due to the significant decrease of γ-austenite. Comparing with the Ti-free steel, the formation of TiC precipitates was the main reason for the increase in yield strength of Ti-bearing steel, and TiC precipitates also led to a higher strain hardening index at the first deformation stage. TiC precipitates promoted the Orowan strengthening, resulting in a higher strain hardening capability than Ti-free steel reinforced by shearable κ-carbide. 展开更多
关键词 Precipitation strengthening Nano-scale TiC precipitate Low-density steel Yield strength Strain hardening
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Bubbles and incentives:an experiment on asset markets
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作者 Stéphane Robin Katerina Stráznická Marie Claire Villeval 《Economic and Political Studies》 2021年第1期68-89,共22页
We explore the effects of competitive incentives and of their time horizon on the evolution of both asset prices and trading activity in experimental asset markets.We compare(i)a no-bonus treatment;(ii)a short-term bo... We explore the effects of competitive incentives and of their time horizon on the evolution of both asset prices and trading activity in experimental asset markets.We compare(i)a no-bonus treatment;(ii)a short-term bonus treatment in which bonuses are assigned to the best performers at the end of each trading period;(iii)a long-term bonus treatment in which bonuses are assigned to the best performers at the end of the 15 periods of the market.We find that the existence of bonus contracts does not increase the likelihood of bubbles but it affects their severity,depending on the time horizon of bonuses.Markets with longterm bonus contracts experience lower price deviations and a lower turnover of assets than markets with either no bonuses or long-term bonus contracts.Short-term bonus contracts increase price deviations but only when markets include a higher share of male traders.At the individual level,the introduction of bonus contracts increases the trading activity of males,probably due to their higher competitiveness. 展开更多
关键词 Asset market BUBBLES INCENTIVES bonuses risk attitudes EXPERIMENT
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Introduction
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作者 Marie Claire Villeval 《Economic and Political Studies》 2021年第1期1-3,共3页
Behavioural and experimental economics constitutes a dynamic field of research that has produced new and perhaps more realistic theoretical models of human behaviour,and allowed researchers to test empirically these m... Behavioural and experimental economics constitutes a dynamic field of research that has produced new and perhaps more realistic theoretical models of human behaviour,and allowed researchers to test empirically these models in laboratory and/or field settings.This field is based on models of preferences,beliefs,and decision rules that contrast with standard economic theories assuming selfish individual preferences,perfect and immediate information processing,and rational decision-making.By hybridising knowledge from other social and cognitive sciences with economics,behavioural and experimental economics models and tests how cognitive biases and non-standard preferences affect the way people process information,update their beliefs,and make decisions. 展开更多
关键词 BEHAVIOUR RATIONAL ECONOMICS
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Constructing and Cleaning Identity Graphs in the LOD Cloud
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作者 Joe Raad Wouter Beek +3 位作者 Frank van Harmelen Jan Wielemaker Nathalie Pernelle Fatiha Saïs 《Data Intelligence》 2020年第3期323-352,共30页
In the absence of a central naming authority on the Semantic Web,it is common for different data sets to refer to the same thing by different names.Whenever multiple names are used to denote the same thing,owl:sameAs ... In the absence of a central naming authority on the Semantic Web,it is common for different data sets to refer to the same thing by different names.Whenever multiple names are used to denote the same thing,owl:sameAs statements are needed in order to link the data and foster reuse.Studies that date back as far as 2009,observed that the owl:sameAs property is sometimes used incorrectly.In our previous work,we presented an identity graph containing over 500 million explicit and 35 billion implied owl:sameAs statements,and presented a scalable approach for automatically calculating an error degree for each identity statement.In this paper,we generate subgraphs of the overall identity graph that correspond to certain error degrees.We show that even though the Semantic Web contains many erroneous owl:sameAs statements,it is still possible to use Semantic Web data while at the same time minimising the adverse effects of misusing owl:sameAs. 展开更多
关键词 Linked Open Data IDENTITY Quality REASONING
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Genomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells
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作者 Kevin G.Chen George E.Duran +8 位作者 Mark J.Mogul Yan C.Wang Kevin L.Ross Jean-Pierre Jaffrézou Lyn M.Huff Kory R.Johnson Tito Fojo Norman J.Lacayo Branimir I.Sikic 《Cancer Drug Resistance》 2020年第4期959-979,共21页
Aim:Despite considerable efforts to reverse clinical multidrug resistance(MDR),targeting the predominant multidrug transporter ABCB1/P-glycoprotein(P-gp)using small molecule inhibitors has been unsuccessful,possibly d... Aim:Despite considerable efforts to reverse clinical multidrug resistance(MDR),targeting the predominant multidrug transporter ABCB1/P-glycoprotein(P-gp)using small molecule inhibitors has been unsuccessful,possibly due to the emergence of alternative drug resistance mechanisms.However,the non-specific P-gp inhibitor cyclosporine(CsA)showed significant clinical benefits in patients with acute myeloid leukemia(AML),which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors.Nevertheless,the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models.In this study,our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs.Methods:Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay,rhodamine-123 accumulation,[3H]-labeled drug export,ABCB1 cDNA sequencing,and RNase protection assay.The genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human populations.Moreover,the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas(TCGA)at the National Cancer Institute.Results:We report the development of two erythroleukemia variants,RVC and RDC,which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations,respectively.Interestingly,both RVC and RDC cell lines,which retained P-gp expression,showed altered multidrug-resistant phenotypes that were resistant to CsA modulation.Strikingly,no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug selection.Genomically,ABCB1 displayed relatively low variant allele frequencies in human populations when compared with several ABC superfamily members.Moreover,ABCB1 also exhibited a very low mutational frequency in AMLs compared with all types of human cancer.In addition,we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low-level and unstable drug resistance.Conclusion:Our data indicate that ABCB1 coding regions are genomically stable and relatively resistant to drug-induced mutations.Non-ABCB1 mutational mechanisms are responsible for the drug-resistant phenotypes in both RVC and RDC cell lines,which are also prevalent in clinical AML patients.Accordingly,we propose several relevant models that account for the development of alternative drug resistance mechanisms in the absence of ABCB1 mutations. 展开更多
关键词 Cancer LEUKEMIA multidrug resistance ABCB1 P-GLYCOPROTEIN CYCLOSPORINE mutation
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