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Mixed PEGylated surfactant modifying system decrease the accelerated blood clearance phenomenon of nanoemulsions in rats

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Asian Journal of Pharmaceutical Sciences 2017年第1期12卷 28-36页

作者： Yuqing Su Wenya Tang Yanzhi Song Chunling Wang Qingjing Tian Xuling Wang Jingjing Quan Buoqun Li Shaoning Wang Yihui Deng School of Pharmacy Shenyang Pharmaceutical University103Wenhua RoadShenyang 110016China Beijing Sihuan-Pharm Company China School of Pharmaceutical Engineering Shenyang Pharmaceutical University103Wenhua RoadShenyang 110016China

The accelerated blood clearance(ABC) phenomenon which is induced by repeated injection of poly(ethylene glycol)(PEG)-coated colloidal carriers gives clinical challenge to the promising drug delivery system. It is necessary to decrease this unexpected immunological response.A novel 4-arm poly(ethylene glycol-5000)4-cholesteryl methyl amide(4-arm PEG5000-CHMA)has been synthesized. The structure of 4-arm PEG5000-CHMA was confirmed by IR and 1H-NMR spectrum. The pharmacokinetics of the tocopheryl nicotinate(TN)-loaded nanoemulsions modified with 4-arm PEG5000-CHMA or/and 1, 2-distearoyl-Sn-glycero-3-phosphoethanolamine-n-[methoxy(poly-ethyleneglycol)-2000](mPEG2000-DSPE) have been studied. Furthermore, the ABC phenomenon has been detailed investigated in rats by TN-loaded nanoemulsions modified with 4-arm PEG5000-CHMA and mPEG2000-DSPE(CPNE). The plasma levels of TN and anti-PEG IgM antibody were determined by HPLC and ELISA, respectively.The circulation time of the CPNEs were comparable to the mPEG2000-DSPE coated nanoemulsions. Moreover, the ABC phenomenon can be decreased by CPNEs. This study designs a method to decrease the ABC phenomenon and develops a clinical promising nanoemulsion for therapeutic or imaging purpose.

关键词： Accelerated blood clearance(ABC) phenomenon Repeated administration 4-arm PEG5000-CHMA Anti-PEG IgM

The effect of monosialylganglioside mix modifying the PEGylated liposomal epirubicin on the accelerated blood clearance phenomenon

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Asian Journal of Pharmaceutical Sciences 2017年第2期12卷 134-142页

作者： Ting Zhang Songlei Zhou Le Kang Xiang Luo Yang Liu Yanzhi Song Xinrong Liu Yihui Deng College of Pharmacy Shenyang Pharmaceutical University

PEGylated liposomes are potential candidates to improve the pharmacokinetic characteristics of encapsulated drugs, to extend their circulation half-life and facilitate their passive accumulation at tumour sites. However, PEG-modified liposomes can induce accelerated blood clearance(ABC) upon repeated administration, and the extent of ABC phenomenon on the cytotoxic drugs-containing PEGylated liposomes is related to the dose of the cytotoxic drugs.In this study, EPI served as a model cytotoxic drug, a hydrophilic surfactant molecule,monosialylganglioside(GM1) was chosen and modified on the liposomes together with PEG.It was shown that upon mixed modification, when GM1 contents reached 10% or 15% mol,the ABC phenomenon of the PEGylated liposomal EPI significantly reduced. We also found that GM1 played an important role in abrogating the ABC phenomenon in both the induction phase and the effectuation phase. The results suggested that GM1 incorporation unfortunately did not avoid occurrence of ABC phenomenon completely, but GM1 modification on PEGylated liposomes may provide a significant improvement in clinical practice of PEGylated liposomes. Further study must be necessary.

关键词： PEGylated liposomes Epirubicin Monosialylganglioside(GM1) Mixed modification Accelerated blood clearance (ABC) phenomenon

Anticipation phenomenon in familial adenomatous polyposis:an analysis of its origin

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World Journal of Gastroenterology 2000年第3期6卷 335-338页

作者： Takeo Iwama Joji Utsunomiya Department of Surgery Kyoundo HospitalSasaki Institute KandaSurugadai 1-8Chiyoda-KuTokyo 101-0062Japan Institute for Advanced Medical Sciences Hyogo Medical College Mukogawa 1-1NisinomiyaHyogo 663-8131Japan

AIM To analyze the origin of the anticipationphenomenon,which means earlier death insuccessive generation in familial adenomatouspolyposis.METHODS The study subjects were 2161patients with familial adenomatous polyposisand their 7465 first-degree relatives who weremembers of 750 families registered at ourPolyposis Registry.The ages at death andcumulative mortality rates in the parent,theproband,and the child generations werecompared for both all subjects and the patientsalone.RESULTS In the patients over 5 years of age,the mean age at death was 50.9 years for theparent,42.3 years for the proband,and 33.3years for the child generations,respectively(Pphenomenon was shown by anyparent-child pairing methods for the deceasedpatients.Other important causes of theanticipation were different proportion of causesof death between generations(P<0.001),and alow proportion of detected or deceased patients (P<0.001)in the child generation.CONCLUSION Anticipation in familialadenomatous polyposis may be caused byparent-child paring methods as well as severalintergenerational biases.

关键词： familial adenomatous apolyposis (FAP) anticipation phenomenon intergenerational bias child generations hereditary disorder mortality

Effect of Kupffer cells depletion on ABC phenomenon induced by Kupffer cells-targeted liposomes

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Asian Journal of Pharmaceutical Sciences 2019年第4期14卷 455-464页

作者： Chaoyang Lai Cong Li Mengyang Liu Qiujun Qiu Xiang Luo Xinrong Liu Ling Hu Yihui Deng Yanzhi Song Shenyang Pharmaceutical University

Accelerated blood clearance(ABC) phenomenon is common in many PEGylated nanocarriers, whose mechanism has not been completely elucidated yet. In this study, the correlation between Kupffer cells(KCs) and ABC phenomenon has been studied by KCs-targeted liposomes inducing ABC phenomenon and KCs depletion. In other words, the 4-aminophenyl-α-D-mannopyranoside(APM) lipid derivative DSPE-PEG 2000-APM(DPM), and 4-aminophenyl-β-L-fucopyranoside(APF) lipid derivative DSPE-PEG 2000-APF(DPF) were conjugated and modified on alendronate sodium(AD) liposomes to specifically target and deplete KCs. The dualligand modified PEGylated liposomes(MFPL) showed stronger ability to damage KCs in vitro and in vivo, which also could indirectly illustrate that dual-ligand modification could better target KCs. Besides, the hepatic biodistribution and pharmacokinetics could directly prove that MFPL had a stronger targeting ability to KCs. In addition, in depletion rats, plasma concentration and splenic biodistribution of MFPL and PEGylated liposomes(PL) were significantly elevated and hepatic biodistribution was significantly reduced, which demonstrated that KCs played an important role on elimination of nanoparticles. What’s more, ABC phenomenon of the secondary injection of PL was stronger in KCs depletion rats than that in normal rats, which indicated that depletion of KCs prolonged the circulation of PL in the first injection repeatedly stimulating B-cells in the marginal region of the spleen and causing it to secrete more IgM antibodies. This could also illustrate that anti-PEG IgM takes up a major station compared with KCs. Most important of all, KCs-targeted liposomes could induce a stronger ABC phenomenon than PL in normal rats, which declared that based on the same IgM concentration, the more the KCs were stimulated, the stronger ABC phenomenon was induced. However, in depletion rats, this difference of ABC phenomenon between PL and MFPL could no more exist, further demonstrating that KCs could participate and play a certain role

关键词： Accelerated blood clearance (ABC) phenomenon Kupffer cells Depletion Liposomes Bio-distribution

Precipitation seesaw phenomenon and its formation mechanism in the eastern and western parts of Northwest China during the flood season

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Science China Earth Sciences 2019年第12期62卷 2083-2098页

作者： Qiang ZHANG Jingjing LIN Weicheng LIU Lanying HAN Institute of Arid Meteorology China Meteorological AdministrationKey Laboratory of Arid Climatic Change and Reducing Disaster of Gansu ProvinceKey Open Laboratory of Arid Climatic Change and Disaster Reduction of CMALanzhou 730020China Gansu Provincial Meteorological Bureau Lanzhou 730020China Lanzhou Regional Climate Center Lanzhou 730020China Lanzhou Central Meteorological Observatory Lanzhou 730020China

Extending across three major plateaus,namely the Qinghai-Tibetan Plateau,the Inner Mongolia-Xinjiang Plateau and the Loess Plateau,Northwest China has the complex terrain and spatio-temporal climate variations,and is affected by the interactions among different circulation systems,such as the summer monsoon,the westerlies and the plateau monsoon.The understanding of the climate variability,as well as its characteristics and evolution mechanisms in this area has been limited so far.In this paper,the precipitation characteristics and mechanisms in the eastern and western parts of Northwest China during the flood season are compared and analyzed based on the data from 192 national meteorological observational sites in Northwest China in 1961-2016.The results show that,divided by the northern boundary of the East Asian summer monsoon,there are huge differences in the precipitation variation characteristics between the eastern and western parts.The inter-annual variations,interdecadal variations and total trends in the two parts all show a significant seesaw phenomenon.Moreover,it is found that the seesaw phenomenon of precipitation variation is closely related to the opposite variation between the East Asian summer monsoon index(MI)and the westerly circulation index(WI).In addition,the inverse variations on different time scales are only related to the contributions of precipitation at specific grades.Besides,in the two matching patterns of precipitation in the seesaw phenomenon,the middle and high latitudes are occupied by the"high-low-high"wave trains in the precipitation increases in the east of Northwest China(ENWC)and decreases in the west of Northwest China(WNWC)pattern,meaning precipitation increases in ENWC and decreases in WNWC.Whereas the opposite"low-high-low"wave trains at 500 hPa height are observed in the middle and high latitudes in the WH-EA pattern at 500 hPa height,meaning precipitation increases in WNWC and decreases in ENWC.Thus,the atmosphere circulation situation with two wave train types can su

关键词： Northwest China Precipitation changes Seesaw phenomenon Summer monsoon system Westerly circulation system South Asian High

A scaling phenomenon for the cross section of fragment produced in projectile fragmentation reactions

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Science China(Physics,Mechanics & Astronomy) 2019年第9期62卷 60-69页

作者： Yi-Dan Song Hui-Ling Wei Chun-Wang Ma Institute of Particle and Nuclear Physics Henan Normal University

A scaling phenomenon has been found for the cross section of a fragment, which is defined as a "square" cross section(SCS).This phenomenon can unify the cross sections of fragments in projectile fragmentation(PF) reactions. An empirical formula is proposed to calculate SCSfor a fragment with parameters determined by an extensive investigation of measured reactions ranging from Fermi energies to relativistic energies. The scaling phenomenon of SCShas been verified using different techniques,showing that the scaling of SCSgenerally exists in PF reactions. The concept of SCS, which can be assumed as a standard value for a fragment, is shown to accurately predict the cross sections of isotopes in PF reactions with incident energies ranging from tens of A MeV to approximately 1000 A MeV.

关键词： scaling phenomenon cross section prediction intermediate mass fragments projectile fragmentation

The accelerated blood clearance phenomenon of PEGylated nanoemulsion upon cross administration with nanoemulsions modified with polyglycerin

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Asian Journal of Pharmaceutical Sciences 2018年第1期13卷 44-53页

作者： Yuqing Su Lirong Wang Kaifan Liang Mengyang Liu Xinrong Liu Yanzhi Song Yihui Deng Shenyang Pharmaceutical University

For investigating the accelerated blood clearance(ABC) phenomenon of polyglycerin modified nanoemulsions upon cross administration with polyethylene glycol(PEG) covered nanoemulsion, we used the 1,2-distea-royl-sn-glycero-3-phosphoethanolamine-npolyglycerine-610 and the 1,2-distearoyl-n-glycero-3-phosphoethanolamine-n-[methoxy(polyethylene glycol)-2000] as modify materials, the dialkylcarbocyanines as fluorescence indicator. Exhausted macrophages rat model was established and new material containing polycarboxyl structure was synthesized. The microplate reader and the in vivo optical imaging system were applied to measure the concentration of nanoemulsions in tissues.The results show that the first dose of polyglycerin modified nanoemulsion can induce the ABC phenomenon of the second dose of PEGylated nanoemulsion. With the increase in the amount of the surface polyglycerin, the extent of the ABC phenomenon decreases. Liver accumulation has positive relationship with the ABC phenomenon. Furthermore, kupffer cells in liver can get more immune information from polyhydroxy structure than polycarboxyl group in the modify compound. The results of our work imply that the polycarboxyl structure has advantages to eliminate the ABC phenomenon.

关键词： ABC phenomenon Nanoemulsion Liver accumulation Kupffer cells Polyglycerin Polycarboxyl

A preliminary study on numerical simulation of microwave heating process for chemical reaction and discussion of hotspot and thermal runaway phenomenon

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Science China(Physics,Mechanics & Astronomy) 2009年第4期52卷 551-562页

作者： ZHAO Xiang HUANG KaMa YAN LiPing YAO Yuan College of Electronics and Information Engineering Sichuan UniversityChengdu 610064China Chengdu University of Information Technology Chengdu 610041China

The nonlinear process of microwave heating chemical reaction is studied by means of numerical simulation. Especially,the variation of temperature in terms of space and time,as well as the hotspot and thermal runaway phenomena are discussed. Suppose the heated object is a cylinder and the incident electromagnetic(EM) wave is plane wave,the problem turns out to be a coupling calculation of 2D multi-physical fields. The integral equation of EM field is solved using the method of moment(MoM) and the thermal conduction equation is solved using a semi-analysis method. Moreover,a method to determine the equivalent complex permittivity of reactant under the heating is presented in order to perform the calculation. The numerical results for water and a dummy chemical reaction(A) show that the hotspot is a ubiquitous phenomenon in microwave heating process. When the radius of the heated object is small,the highest temperature occurs somewhere inside the object due to the concentration of the EM wave. While the radius increases to a certain degree,the highest temperature occurs somewhere close to the surface due to the skin effect,and the whole high temperature area shows crescent-shaped. That is in accordance with basic physical principles. If the radius is kept the same in the heating process,the hotspot position of water does not change,while that of reaction A with several radius values varies. For either water or A,the thermal runaway phenomenon in which small difference of radius results in large difference of highest temperature,occurs easily when the radius is small. On the contrary,it is not evident when the radius is large. Moreover,it is notable that the highest temperature in water shows oscillating decreasing trend with the increase of radius,but in reaction A almost decreases monotonously. Further study should be performed to determine if this difference is only an occasional occurrence.

关键词： numerical simulation microwave heating chemical reaction hotspot phenomenon thermal runaway

Asymmetric Environmental Regulation:Mechanism and a Yardstick phenomenon

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China Economist 2023年第1期18卷 87-107页

作者： Yu Yazhuo Zhang Huilin Zhang Pingdan Business School Renmin University of ChinaBeijingChina School of Economics and Business Administration Beijing Normal UniversityBeijing

In discussing the policy effects of environmental regulation,we should focus not only on whether environmental regulation helps improve the environmental and economic performance of firms,but also on how such improvement is materialized,i.***.whether the obsolete mode of production is reversed.After matching the database of China’s industrial enterprises with that of pollution emissions from these industrial enterprises,this paper identifies the asymmetric scope of clean production standards to test the effect of environmental regulation on the total factor productivity(TFP)of the industrial enterprises.Our empirical research finds that the implementation of clean production standards may induce TFP improvement.However,such improvement only occurs for polluters who cannot or who barely meet clean production standards and does little to improve the production standards of polluters with low pollution emission,reflecting the yardstick phenomenon of the asymmetric environmental regulation policy effect:While polluters are forced to improve,clean enterprises that pollute less are more likely to take no action.Further research finds that such TFP improvement is materialized primarily by means of overall firm optimization;the compensation effect is insignificant and does not reverse the backward mode of production.Polluters cope with the implementation of clean production standards by purchasing more equipment and expanding capacity,which adds to the tension between the expansion of capacity and the abatement of pollution emission.

关键词： Environmental regulation clean production standards TFP asymmetry yardstick phenomenon