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世界最新医学信息文摘 2016年第11期 8-8页

作者： Qiuwei Pan Scot D.Henry Herold j.Metselaar Bob Scholte jaap Kwekkeboom Hugo w.Tilanus Harry L.A.janssen auc j.w.van der laan

The current standard interferon-alpha(IFN-α)-based therapy for chronic hepatitis C virus(HCV) infection is only effective in approximately half of the patients, prompting the need for alternative treatments. RNA interference(RNAi) represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in infection. Monotherapy of RNAi, however, may lead to therapeutic resistance by mutational escape of the virus. Here, we proposed that combining lentiviral vector-mediated RNAi and IFN-α could be more effective and avoid therapeutic resistance. In this study, we found that IFN-α treatment did not interfere with RNAi-mediated gene silencing. RNAi and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or sequentially. Transduction ofmouse hepatocytes in vivo and in vitro was not effected by IFN-α treatment. In conclusion, RNAi and IFN-α can be effectively combined without crossinterference and may represent a promising combinational strategy for the treatment of hepatitis c.

关键词： RNAi IFN-α Gene therapy Lentiviral vector HCV

Melting of hydrous pyroxenites with alkali amphiboles in the continental mantle:*** relations and major element compositions of melts

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Geoscience Frontiers 2022年第4期13卷 48-74页

作者： Stephen F.Foley Isra S.Ezad Sieger R.van der laan Maik Pertermann School of Natural Sciences Macquarie UniversityNorth RydeNew South Wales 2109Australia Research School of Earth Sciences Australian National UniversityCanberraACT 2601Australia Tata Steel Europe Research and DevelopmentIjmuidenThe Netherlands Coos Bay OregonUSA

Melting experiments on ultramafic rocks rich in the hydrous minerals phlogopite or phlogopite+K-rich terite,some including 5%of accessory phases,have been conducted at 15 and 50 *** assemblages represent probable source components that contribute to melts in cratonic regions,but whose melt compositions are poorly known.A main series of starting compositions based on MARID xenoliths consisted of a third each of clinopyroxene(CPX),phlogopite(PHL)and K-richterite(KR)with or without 5%ilmenite,rutile or *** experiments were run without KR and with higher proportions of accessory *** traps were used at near-solidus temperatures to facilitate accurate analysis of wellquenched melts,for which reversal experiments demonstrate *** show that KR melts rapidly and completely within 50°C of the solidus,so that melts reflect the composition of the amphibole and its melting *** have high SiO_(2) and especially K_(2)O but low CaO and Al_(2)O_(3) relative to basaltic melts produced from peridotites at similar *** have no counterparts amongst natural rocks,but most closely resemble leucite lamproites at 15 *** and PHL melt incongruently to form olivine(OL)and CPX at 15 kbar,promoting SiO2 contents of the melt,whereas orthopyroxene OPX is increasingly stable at lower lithosphere pressures,leading to an increase in Mg O and decrease in SiO_(2) in melts,which resemble olivine *** of mica pyroxenites without KR are richer in CaO and Al_(2)O_(3) and do not resemble *** experiments show that low CaO and Al_(2)O_(3) in igneous rocks is not necessarily a sign of a depleted peridotite *** phases produce melts exceptionally rich in P_(2)O_(5) or TiO_(2) depending on the phases present and are unlike any melts seen at the Earth’s surface,but may be important agents of metasomatism seen in *** addition of the 5%accessory phases ilmenite,rutile or apatite result in melting temper

关键词： Hydrous pyroxenite Experimental petrology Mantle melts Phlogopite Lamproite Mantle metasomatism

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New therapeutic opportunities for Hepatitis C based on small RNA

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world journal of Gastroenterology 2007年第33期13卷 4431-4436页

作者： Qiu-wei Pan Scot D Henry Bob j Scholte Hugo w Tilanus Harry LA janssen Luc jw van der laan Departments of Gastroenterology & Hepatology and Surgery Erasmus MC-University Medical Centre Rotterdam The Netherlands Department of Surgery Erasmus MC-University Medical Centre Rotterdam The Netherlands Department of Cell Biology Erasmus MC- University Medical Centre Rotterdam The Netherlands Department of Gastroenterology & Hepatology Erasmus MC-University Medical Centre Rotterdam The Netherlands

Hepatitis C virus （HCV） infection is one of the major causes of chronic liver disease, including cirrhosis and liver cancer and is therefore, the most common indication for liver transplantation. Conventional antiviral drugs such as pegylated interferon-alpha, taken in combination with ribavirin, represent a milestone in the therapy of this disease. However, due to different viral and host factors, clinical success can be achieved only in approximately half of patients, making urgent the requirement of exploiting alternative approaches for HCV therapy. Fortunately, recent advances in the understanding of HCV viral replication and host cell interactions have opened new possibilities for therapeutic intervention. The most recent technologies, such as small interference RNA mediated gene-silencing, antisense oligonucleotides （ASO）, or viral vector based gene delivery systems, have paved the way to develop novel therapeutic modalities for HCV. In this review, we outline the application of these technologies in the context of HCV therapy. In particular, we will focus on the newly defined role of cellular microRNA （miR-222） in viral replication and discuss its potential for HCV molecular therapy.

关键词： Hepatitis C virus therapy miR-122 RNAi Antisense oligonucleotides Viral vectors

It's all about timing, early treatment with hyperbaric oxygen therapy and corticosteroids is essential in acute acoustic trauma

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journal of Otology 2021年第4期16卷 237-241页

作者： A.B.Bayoumy R.P.weenink E.Lvan der Veen F.S.Besseling-Hansen A.D.M.Hoedemaeker F.j.Mde jong M.Hvan der laan R.Swenker R.Avan Hulst j.Ade Ru Department of Otolaryngology Central Military HospitalMinistry of DefenseUtrechtthe Netherlands Department of Anesthesiology and Department of Hyperbaric Medicine Amsterdam University Medical CentersLocation AMCAmsterdamthe Netherlands Department of Otolaryngology-Head and Neck Surgery University Medical Centre UtrechtUtrechtthe Netherlands Diving Medical Centre Royal Netherlands NavyMinistry of DefenseDen Helderthe Netherlands

Background: Acute acoustic trauma (AAT) is an acute hearing impairment caused by intense noiseimpact. The current management strategy for AAT with substantial hearing loss in the Dutch militaryis the combination therapy with corticosteroids and hyperbaric oxygen therapy (HBOT). In a previousstudy, early initiation of the combination therapy was associated with better outcomes. Therefore, weperformed a new analysis to assess the difference in hearing outcome between patients in whomcombination therapy was started within two days, versus after more than two ***: A retrospective analysis was performed on military patients diagnosed with AAT with substantial hearing loss who presented between February 2018 and March 2020. Absolute and relativehearing improvement between first and last audiograms were calculated for all affected frequencies(defined as loss of 20 dB on initial audiogram). we also determined the amount of patients whorecovered to the level of Dutch military requirement, and performed speech discrimination ***: In this analysis, 30 male patients (49 ears) with AAT were included. The median age was 24.5years (IQR 23e29). The median time to initiation of therapy with corticosteroids and HBOT were one andtwo days, respectively. HBOT was started within two days in 31 ears, and after more than two days in 18ears. The mean absolute and relative hearing gains were 18.8 dB (SD 14.6) and 46.8% (SD 31.3) on allaffected frequencies. The 100% discrimination/speech perception level improved from 64.0 dB to 51.7 dB(gain 12.3 dB ± 14.1). There was significantly more improvement in absolute and relative hearingimprovement when HBOT was started in 2 days, compared to >2 ***: Our analysis shows results in favor of early initiation ( 2 days) of the combination treatmentof HBOT and corticosteroids in patients with AAT.

关键词： Hyperbaric oxygen therapy Acute acoustic trauma Hearing loss Corticosteroids Blast injury Noise-induced hearing loss

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Interaction of immunosuppressants with HCV antivirals daclatasvir and asunaprevir: combined effects with mycophenolic acid

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world journal of Transplantation 2018年第5期8卷 156-166页

作者： Petra E de Ruiter Yashna Gadjradj Robert j de Knegt Herold j Metselaar jan NM Ijzermans Luc jw van der laan Department of Surgery Erasmus MC-University Medical Center Department of Gastroenterology and Hepatology Erasmus MC-University Medical Center

AIM To investigate the specific effects of immunosuppressants on the antiviral action of daclatasvir and *** The antiviral activity of daclatasvir(DCV) and asunaprevir(ASV) combined with immunosuppressants was tested using two in vitro models for hepatitis C virus(HCV) *** Tacrolimus, rapamycin and cyclosporine did not negatively affect the antiviral action of DCV or ASV. Mycophenolic acid(MPA) showed additive antiviral effects combined with these direct acting antivirals(DAAs). MPA induces interferon-stimulated genes(ISGs) and is a potent GTP synthesis inhibitor. DCV or ASV did not induce ISGs expression nor affected ISG induction by MPA. Rather, the combined antiviral effect of MPA with DCV and ASV was partly mediated via inhibition of GTP *** Immunosuppressants do not negatively affect the antiviral activity of DAAs. MPA has additive effect on the antiviral action of DCV and ASV. This combined benefit needs to be confirmed in prospective clinical trials.

关键词： Immunosuppressant Hepatitis C Daclatasvir Asunaprevir Liver Transplantation

m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

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world journal of Transplantation 2013年第3期3卷 36-47页

作者： Suomi MG Fouraschen Petra E de Ruiter jaap Kwekkeboom Ron wF de Bruin Geert Kazemier Herold j Metselaar Hugo w Tilanus Luc jw van der laan jeroen de jonge Department of Surgery and Laboratory of Experimental Transplantation and Intestinal Surgery Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands Department of Gas-troenterology and Hepatology Erasmus MC-University Medical Center 3015 CE Rotterdam The Netherlands

AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection ***: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical ***: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased infl

关键词： Hepatocyte proliferation Autophagy Microtubule-associated protein 1 light chain 3 Partial hepatectomy Rapamycin

Drug repurposing screen identifies vidofludimus calcium and pyrazofurin as novel chemical entities for the development of hepatitis E interventions

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Virologica Sinica 2024年第1期39卷 123-133页

作者： Hongbo Guo Dan Liu Kuan Liu Yao Hou Chunyang Li Qiudi Li Xiaohui Ding Monique M.A.Verstegen jikai Zhang Lingli wang Yibo Ding Renxian Tang Xiucheng Pan Kuiyang Zheng Luc j.wvan der laan Qiuwei Pan wenshi wang Department of Pathogen Biology and Immunology Jiangsu Key Laboratory of Immunity and MetabolismJiangsu International Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhou221004China Department of Gastroenterology and Hepatology Erasmus MC-University Medical CenterRotterdamNL-3015 CNthe Netherlands Department of Surgery Erasmus MC Transplant InstituteUniversity Medical CenterRotterdam3015CENL-3015 CNthe Netherlands Department of Infectious Diseases The Affiliated Hospital of Xuzhou Medical UniversityXuzhou221002China

Hepatitis E virus(HEV)infection can cause severe complications and high mortality,particularly in pregnant women,organ transplant recipients,individuals with pre-existing liver disease and immunosuppressed ***,there are still unmet needs for treating chronic HEV ***,we screened a best-in-class drug repurposing library consisting of 262 drugs/*** screening,we identified vidofludimus calcium and pyrazofurin as novel anti-HEV *** calcium is the next-generation dihydroorotate dehydrogenase(DHODH)inhibitor in the phase 3 pipeline to treat autoimmune diseases or SARS-CoV-2 *** selectively targets uridine monophosphate synthetase(UMPS).Their anti-HEV effects were further investigated in a range of cell culture models and human liver organoids models with wild type HEV strains and ribavirin treatment failure-associated HEV ***,both drugs exhibited a sizeable therapeutic window against *** instance,the IC50 value of vidofludimus calcium is 4.6–7.6-fold lower than the current therapeutic doses in ***,their anti-HEV mode of action depends on the blockage of pyrimidine ***,two drugs robustly inhibited ribavirin treatment failure-associated HEV mutants(Y1320H,G1634R).Their combination with IFN-αresulted in synergistic antiviral *** conclusion,we identified vidofludimus calcium and pyrazofurin as potent candidates for the treatment of HEV *** on their antiviral potency,and also the favorable safety profile identified in clinical studies,our study supports the initiation of clinical studies to repurpose these drugs for treating chronic hepatitis E.

关键词： Hepatitis Evirus(HEV) Drug repurposing Vidofludimus calcium Pyrazofurin Pyrimidine biosynthesis

Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing

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世界最新医学信息文摘 2017年第30期 281-281页

作者： Qiuwei Pan Scot D.Henry Herold j.Metselaar Bob Scholte jaap Kwekkeboom Hugo w.Tilanus Harry L.A.janssen Luc j.w.van der laan

The current standard interferon-alpha(IFN-α)-based therapy for chronic hepatitis C virus(HCV) infection is only effective in approximately half of the patients,prompting the need for alternative *** interference(RNAi)represents novel approach to combat HCV by sequence-specific targeting of viral or host factors involved in *** of RNAi,however,may lead to therapeutic resistance by mutational escape of the ***,we proposed that combining lentiviral vector-mediated RNAi and IFN-a could be more effective and avoid therapeutic *** this study,we found that IFN-α treatment did not interfere with RNAi-mediated gene *** and IFN-α act independently on HCV replication showing combined antiviral activity when used simultaneously or *** ofmouse hepatocytes in vivo and in vitro was not effected by IFN-α *** conclusion,RNAi and IFN-a can be effectively combined without crossinterference and may represent a promising combinational strategy for the treatment of hepatitis C.

关键词： RNAi IFN-α Gene therapy Lentiviral vector HCV

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荷兰不同来源耐多药结核病例中二线耐药情况

国际结核病与肺部疾病杂志 2009年第2期4卷 47-51页

作者： j. van Ingen M. j. Boeree A. wright T. van der laan P. N. R. Dekhuijzen D. vanSoolingen 刘青(译) 何广学(审校) Department of Pulmonary Diseases Radboud University Nijmegen Medical Centre Nijmegen National Mycobacteria Reference Laboratory National Institute for Public Health and the Environment Bilthoven The Netherlands Stop TB Department World Health Organization Geneva Switzerland 不详

背景:荷兰。目的:调查不同地理来源的耐多药结核病人耐二线药情况及其相关因素。方法:对荷兰1993年1月至2007年10月间耐多药结核病人分离菌株的实验室数据进行回顾性研究。结果:发现的153例耐多药结核病人中,18例(12%)为荷兰本国人。对... 详细信息

背景:荷兰。目的:调查不同地理来源的耐多药结核病人耐二线药情况及其相关因素。方法:对荷兰1993年1月至2007年10月间耐多药结核病人分离菌株的实验室数据进行回顾性研究。结果:发现的153例耐多药结核病人中,18例(12%)为荷兰本国人。对其中的131例进行二线药物敏感性实验,有28例(21%)为耐二线药,且大部分为单一耐药(24/28(86%));9例耐丙硫异烟胺(PTH),6例耐对氨基水杨酸,4例耐阿米卡星(ASK),4例耐环丙沙星,1例耐环丝氨酸)。有4例耐多药结核病人耐多种二线药;2例为广泛耐药的牛型结核分枝杆菌。在所有耐多药结核病人中,来自欧洲和中亚者二线耐药较普遍,且涉及的药物也较广泛。来自非洲和美洲者主要耐PTH,而来自东南亚者主要耐AMK。结论:在荷兰,耐多药结核病人中二线耐药情况并不普遍。大部分二线耐药发生在移民当中,来源于不同的地域,病人耐药情况也不同。

关键词：结核耐多药广泛耐药结核病

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仰卧位椎骨骨折的评估:常规半定量X线片与目视X线片的对比

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国际医学放射学杂志 2009年第4期 394-395页

作者： I.C.Hospers j.G.van der laan C.j.Zeebregts P.Nieboer B.H.R.wolffenbuttel R.A.Dierckx 关祥祯 Nuclear Medicine and Molecular Imaging University Medical Center GroningenUniversity of Groningen

目的以常规目视X线片作为参考标准,回顾性评价病人仰卧位时行脊柱常规半定量X线片评估椎骨骨折(VFA)的准确性。方法该回顾性研究得到机构伦理审查委员会批准,并获得病人知情同意。

关键词：椎骨骨折 VFA 仰卧位半定量常规