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Randomized Trial of Ciclosporin with 2-h Monitoring *** with Trough Monitoring in Liver Transplantation:DELTA Study

journal of Clinical and Translational Hepatology 2023年第4期11卷 839-849页

作者： Bastian N.Ruijter Akin Inderson Aad Pvan den Berg herold j.metselaar jeroen Dubbeld Maarten E.Tushuizen Robert j.Porte Wojciech Polak Danny van der Helm Marjolein van Reeven Mar Rodriguez-Girondo Bart van Hoek Department of Gastroenterology and Hepatology LUMC Transplantation CenterLeiden University Medical CenterLeidenThe Netherlands Department of Gastroenterology and Hepatology University Medical Center GroningenGroningenThe Netherlands Department of Gastroenterology and Hepatology Erasmus MC Transplant InstituteErasmus Medical CenterRotterdamThe Netherlands Department of Surgery LUMC Transplantation CenterLeiden University Medical CenterLeidenThe Netherlands Department of Surgery Section HPB Surgery and Liver TransplantationUniversity of GroningenUniversity Medical Center GroningenGroningenThe Netherlands Department of Surgery Division of HPB and Transplant SurgeryErasmus MC Transplant InstituteErasmus Medical CenterRotterdamThe Netherlands Department of Biomedical Data Sciences Leiden University Medical CenterLeidenThe Netherlands.

Background and Aims:Previous trials comparing cyclosporine and tacrolimus after liver transplantation(LT)showed conflicting *** used trough monitoring for cyclosporine(C0),leading to less accurate dosing than with 2-h monitoring(C2).Only one larger trial compared C2 with tacrolimus based on trough level(T0)after LT,with similar treated biopsy-proven acute rejection(tBPAR)and graft loss,while a smaller trial had less tBPAR with C2 compared to ***,it is still unclear which calcineurin inhibitor is preferred after *** aimed to demonstrate superior efficacy(tBPAR),tolerability,and safety of C2 or T0 after first ***:Patients after first LT were randomized to C2 or ***,patient-and graft survival,safety and tolerability were the main endpoints,with analysis by Fisher test,Kaplan-Meier survival analysis and log-rank ***:In intention-totreat analysis 84 patients on C2 and 85 on T0 were *** incidence of tBPAR C2 vs.T0 was 17.7%vs.8.4%at 3 months(p=0.104),and 21.9%vs.9.7%at 6 and 12 months(p=0.049).One-year cumulative mortality C2 vs.T0 was 15.5%vs.5.9%(p=0.049)and graft loss 23.8%vs.9.4%(p=0.015).Serum triglyceride and LDL-cholesterol was lower with T0 than with *** of diarrhea in T0 vs,C2 was 64%vs.31%(p≤0.001),with no other differences in safety and ***:In the first year after LT immunosuppression with T0 leads to less tBPAR and better patient-/re-transplant-free survival as compared to C2.

关键词： Adverse effects Ciclosporin Liver transplantation Outcome Randomized controlled trial Rejection Survival Renal function Tacrolimus

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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

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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 < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver 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

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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 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

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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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Measure of Segments which Intersect a Convex Body from Rotational Formulae

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Acta Mathematica Sinica,English Series 2015年第2期31卷 345-352页

作者： Ximo GUAL-ARNAU Silena herold-GARCA Departament de Matemàtiques-INIT Universitat Jaume I. 12071-CastellSpain Departamento de Computacin Universidad de Oriente. 90900-Santiago de CubaCuba

Classical problems in integral geometry and geometric probability involve the kinematic measure of congruent segments of fixed length within a convex body in R3. We give this measure from rotational formulae; that is, from isotropic plane sections through a fixed point. From this result we also obtain a new rotational formula for the volume of a convex body; which is proved to be equivalent to the wedge formula for the volume.

关键词： Convex body flower integral geometry stereology rotational formulae segment supportset

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Experimental Investigation on Prototype Latent Heat Thermal Battery Charging and Discharging Function Integrated with Solar Collector

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Energy Engineering 2022年第4期119卷 1587-1610页

作者： Farhood Sarrafzadeh javadi Hendrik Simon Cornelis metselaar Poo Balan Ganesan Department of Mechanical Engineering Faculty of EngineeringUniversity of MalayaKuala Lumpur50603Malaysia Center of Advanced Materials Faculty of EngineeringUniversity of MalayaKuala Lumpur50603Malaysia

This paper reports the performance investigation of a newly developed Latent Heat Thermal Battery(LHTB)integrated with a solar collector as the main source of *** LHTB is a new solution in the field of thermal storage and developed based on the battery concept in terms of recharge ability,portability and usability as a standalone *** is fabricated based on the thermal battery storage concept and consists of a plate-fin and tube heat exchanger located inside the battery casing and paraffin wax which is used as a latent heat storage *** thermal energy is absorbed by solar collector and transferred to the LHTB using water as Heat Transfer Fluid(HTF).Charging experiments have been conducted with a HTF at three different temperatures of 68°C,88°C and 108°C and three different flow rates of 30,60 and 120 l/*** is followed by discharging experiments on fully charged LHTB at three different temperatures of 68°C,88°C and 108°C using HTF at three different flow rates of 30,60 and 120 l/*** is found that both higher HTF inlet temperature and flow rate have a positive impact on stored thermal ***,charging efficiency was decreased by increasing the HTF flow *** highest charging efficiency of 29%was achieved using HTF of 108°C at a flow rate of 30 l/*** of paraffin melted in this case,while part of the paraffin remained solid in other *** the other hand,the results from discharging experiments revealed that both recovered thermal energy and recovery efficiency increased by either increasing the LHTB temperature or HTF flow *** recovered thermal energy of 5,825 Kj at 35%recovery efficiency achieved at LHTB of 108°C using 120 l/h of HTF.

关键词： Latent heat thermal battery phase change materials solar thermal latent heat storage thermal battery thermal storage

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Apples to oranges:environmentally derived,dynamic regulation of serotonin neuron subpopulations in adulthood?

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Neural Regeneration Research 2025年第9期20卷 2596-2597页

作者： Christopher j.O’Connell Matthew j.Robson Department of Genetics College of MedicineHarvard UniversityBostonMAUSA james L.Winkle College of Pharmacy Division of Pharmaceutical SciencesUniversity of CincinnatiCincinnatiOHUSA Neuroscience Graduate Program College of MedicineUniversity of CincinnatiCincinnatiOHUSA

Traumatic brain injury(TBI)is a public health problem with an undue economic burden that impacts nearly every age,ethnic,and gender group across the globe(Capizzi et al.,2020).TBIs are often sustained during a dynamic range of exposures to energetic environmental forces and as such outcomes are typically heterogeneous regarding severity and pathology(Capizzi et al.,2020).

关键词： sustained orange dynamic

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Longitudinal changes in personalized platelet count metrics are good indicators of initial 3-year outcome in colorectal cancer

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World journal of Clinical Cases 2022年第20期10卷 6825-6844页

作者： Zoltan herold Magdolna herold julia Lohinszky Attila Marcell Szasz Magdolna Dank Aniko Somogyi Division of Oncology Department of Internal Medicine and OncologySemmelweis UniversityBudapest 1083Hungary Department of Internal Medicine and Hematology Semmelweis UniversityBudapest 1088Hungary

BACKGROUND Platelet count or complete blood count(CBC)-based ratios including lymphocyteto-monocyte(LMR),neutrophil-to-lymphocyte(NLR),hemoglobin-to-platelet(HPR),red blood cell count distribution width-to-platelet(RPR),and platelet-tolymphocyte(PLR)ratio are good predictors of colorectal cancer(CRC)*** change in time is not well documented,*** To investigate the effect of longitudinal CBC ratio changes on CRC survival and their possible associations with clinicopathological properties,comorbidities,and anamnestic *** A retrospective longitudinal observational study was conducted with the inclusion of 835 CRC patients,who attended at Semmelweis University,*** ratios and two additional newly defined personalized platelet count metrics(pPLT_(D)and pPLT_(S),the platelet counts relative to the measurement at the time of CRC diagnosis and to the one 4-6 wk after tumor removal surgery,respectively)were *** The 835 CRC patients had a total of 4608 measurements(5.52 visits/patient,in average).Longitudinal survival models revealed that the increases/decreases in LMR[hazard ratio(HR):0.4989,Pjust as well as the former,while the use of RPR and PLR with the course of the disease is not *** detection of the abnormal changes in pPLT_(D),pPLT_(S),LMR,NLR,or HPR may alert the practicing oncologist for further therapy decisions in a timely manner.

关键词： Personalized platelet count Lymphocyte-to-monocyte ratio Neutrophil-to-lymphocyte ratio Hemoglobin-to-platelet ratio Platelet-to-lymphocyte ratio Colorectal neoplasms

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Evidence based tools to improve efficiency of currently administered oncotherapies for tumors of the hepatopancreatobiliary system

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World journal of Gastrointestinal Oncology 2021年第9期13卷 1109-1120页

作者： Zoltan herold A Marcell Szasz Magdolna Dank Division of Oncology Department of Internal Medicine and OncologySemmelweis UniversityBudapest H-1083Hungary

Hepatopancreatobiliary tumors are challenging to treat,and the advanced or metastatic forms have a very low 5-year survival *** drug combinations have been tested,and new therapeutic approaches have been introduced in the last decades,including radiofrequency and heat based *** is the artificial heating of tumors by various biophysical methods that may possess immunostimulant,tumoricidal,and chemoradiotherapy sensitizer *** whole-body and regional hyperthermia studies have been conducted since the 1980s after the introduction of deep-seated tumor hyperthermia *** of the effects of hyperthermia in hepatocellular and pancreatic cancer are known from several *** in biliary cancers is a less investigated *** local and overall responses to treatment,increased progression-free and overall survival,and improved laboratory and quality-of-life results are associated with hyperthermia in all three tumor *** the evolution of chemotherapeutic agents and the introduction of newer techniques,the combination of adjuvant hyperthermia with those therapies is advantageous and has not been associated with an increase in alarming adverse ***,despite the many positive effects of hyperthermia,its use is still only known at the experimental level,and its concomitant utilization in routine cancer treatment is not certain because of the lack of thorough clinical studies.

关键词： Hyperthermia induced Carcinoma hepatocellular Cholangiocarcinoma Gallbladder neoplasms Pancreatic neoplasms

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