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| 1 | Antibacterial photodynamic therapy:overview of a promising approach to fight antibiotic-resistant bacterial infections显示文摘Antibacterial photodynamic therapy(APDT)has drawn increasing attention from the scientific society for its potential to effectively kill multidrug-resistant pathogenic bacteria and for its low tendency to induce drug resistance that bacteria can rapidly develop against traditional antibiotic therapy.The review summarizes the mechanism of action of APDT,the photosensitizers,the barriers to PS localization,the targets,the in vitro-,in vivo-,and clinical evidence,the current developments in terms of treating Gram-positive and Gram-negative bacteria,the limitations,as well as future perspectives.Relevance for patients:A structured overview of all important aspects of APDT is provided in the context of resistant bacterial species.The information presented is relevant and accessible for scientists as well as clinicians,whose joint effort is required to ensure that this technology benefits patients in the post-antibiotic era. | Yao Liu Rong Qin Sebastian A.J.Zaat Eefjan Breukink Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，3： | 8 |
| 2 | Site-specific pharmaco-laser therapy:A novel treatment modality for refractory port wine stains显示文摘Despite extensive efforts to optimize laser therapy,i.e.,the current gold standard treatment,a majority of port wine stain(PWS)patients responds suboptimally to laser therapy.This paper describes the niceties of a novel PWS treatment modality termed site-specific pharmaco-laser therapy(SSPLT).In contrast to the classic approach of enhancing the extent of intravascular photocoagulation(the photothermal response),SSPLT focuses on optimization of post-irradiation thrombus formation(i.e.,the hemodynamic response)by combining conventional laser therapy with the administration of thermosensitive drug delivery systems that encapsulate prothrombotic and antifibrinolytic drugs.The aim of SSPLT is to instill complete lumenal occlusion in target vessels,which has been linked to optimal PWS blanching.Relevance for patients:The current treatment options for PWS patients are limited in efficacy.Novel therapeutic modalities are needed to more effectively treat patients with recalcitrant PWSs.SSPLT is an experimental-stage treatment modality that could serve as an adjuvant to pulsed dye laser therapy for a selected group of patients whose PWS is ill-responsive to standard treatment.The expected clinical result of SSPLT is improved lesional blanching. | M.Ingmar van Raath Jojanneke E.van Amesfoort Martin Hermann Yasin Ince Maurice J.Zwart Agustina V.Echague Yan Chen Baoyue Ding Xuan Huang Gert Storm Michal Heger | 2019 | Journal of Clinical & Translational Research2019，5，1： | 4 |
| 3 | Inhibition of hypoxia-inducible factor 1 with acriflavine sensitizes hypoxic tumor cells to photodynamic therapy with zinc phthalocyanine-encapsulating cationic liposomes显示文摘光力学的治疗(太平洋夏季时间) 是 tumorlocalized photosensitizer 与光是激动的一种肿瘤治疗在形式,它导致反应的氧种类,肿瘤 vasculature 的破坏,肿瘤组织缺氧,肿瘤房间死亡,和反肿瘤免疫者回答的正式就职的本地生产。然而,先存在肿瘤组织缺氧可以减少肿瘤到由激活组织缺氧可诱导的因素的太平洋夏季时间 1 (HIF-1 ) 幸存小径。因此,我们与吖啶黄(ACF ) 假设了 HIF-1 的那抑制将在人的表皮状的癌(A431 ) 加重房间死亡房间。A431 肿瘤房间的太平洋夏季时间用包含 photosensitizer 锌酞毒(ZnPC ) 的最新发达并且优化的 PEGylated cationic liposomes 被执行。分子的停靠表明 ACF 绑在 HIF-1 的 dimerization 领域,并且共焦的显微镜学在组织缺氧下面从 cytosol 证实了 ACF 的 translocation 到原子核。HIF-1 在 hypoxic,然而并非 normoxic 被稳定, A431 房间列在后面太平洋夏季时间。有 ACF 的 HIF-1 的抑制在 hypoxic 条件下面增加了导致太平洋夏季时间的房间死亡的程度并且减少了 HIF-1 目标基因 VEGF, PTGS2,和 EDN1 的表示。而且,在包含 ZnPC liposomes 的水的核心的 ACF 的合作封装在比得上非包含的 ACF 的太平洋夏季时间功效上产出辅助效果。在结论, HIF-1 与 liposomal ZnPC 贡献 A431 肿瘤房间幸存追随者太平洋夏季时间。HIF-1 与的抑制免费或 liposomal ACF 改进太平洋夏季时间功效。 | Mans Broekgaarden Ruud Weijer Massis Krekorian Bas van den IJssel Milan Kos Lindy K. Alles Albert C. van Wijk1 Zsolt Bikadi Eszter Hazai Thomas M. van Gulik Michal Heger | 2016 | Nano Research2016，9，6： | 4 |
| 4 | Importance of intellectual property generated by biomedical research at universities and academic hospitals显示文摘Biomedical research has many different facets.Researchers and clinicians study disease biology and biochemistry to discover novel therapeutic targets,unravel biochemical pathways and identify biomarkers to improve diagnosis,or devise new approaches to clinically manage diseases more effectively.In all instances,the overall goal of biomedical research is to ensure that results thereof(such as a therapy,a device,or a method which may be broadly referred to as“inventions”)are clinically implemented.Most of the researchers’efforts are centered on the advance of technical and scientific aspects of an invention.The development and implementation of an invention can be arduous and very costly.Historically,it has proven to be crucial to protect intellectual property rights(IPR)to an invention(i.e.,a patent)to ensure that companies can obtain a fair return on their investment that is needed to develop an academic invention into a product for the benefit of patients.However,the importance of IPR is not generally acknowledged among researchers at academic institutions active in biomedical research.Therefore this paper aims to(1)raise IP awareness amongst clinical and translational researchers;(2)provide a concise overview of what the patenting trajectory entails;and(3)highlight the importance of patenting for research and the researcher.Importance for patients:Adequate patent protection of inventions generated through biomedical research at academic institutions increases the probability that patients will benefit from these inventions,and indirectly enables the financing of clinical studies,mainly by opening up funding opportunities(e.g.specific grants aimed at start-ups,pre-seed and seed capital)that otherwise would not be accessible.As a consequence,patented inventions are more likely to become clinically tested and reach the market,providing patients with more treatment options. | Joris J.Heus Elmar S.de Pauw Mirjam Leloux Margherita Morpurgo Michael R Hamblin Michal Heger | 2017 | Journal of Clinical & Translational Research2017，3，2： | 3 |
| 5 | Physiological and Biochemical Basis of Clinical Liver Function Tests: A Review显示文摘 | Lisette T. Hoekstra Wilmar de Graaf Geert A. A. Nibourg Michal Heger Roelof J. Bennink Bruno Stieger Thomas M. van Gulik | 2013 | Annals of Surgery2013，，1： | 3 |
| 6 | Platelet aggregation but not activation and degranulation during the acute post-ischemic reperfusion phase in livers with no underlying disease显示文摘Background:Platelets and P-selectin(CD62P)play an unequivocal role in the pathology of hepatic ischemia/reperfusion(I/R)injury.Inhibition or knock-out of P-selectin or immunodepletion of platelets results in amelioration of post-ischemic inflammation,reduced hepatocellular damage,and improved survival.However,P-selectin expression on platelets and endothelial cells,which concurs with platelet activation,has never been clearly demonstrated in I/R-subjected livers.Aims:To determine whether platelets become activated and degranulate in the acute phase of liver I/R and whether the platelets interact with neutrophils.Methods:Hepatic I/R was induced in male C57BL/6J mice(N=12)using 37.5-min ischemia time.Platelets,endothelial cells,and neutrophils were fluorescently labeled by systemic administration of non-blocking antibodies.Cell kinetics were monitored by intravital spinning disk confocal microscopy during 90 min of reperfusion.Image analysis and quantification was performed with dedicated software.Results:Platelets adhered to sinusoids more extensively in post-ischemic livers compared to livers not subjected to I/R and formed aggregates,which occurred directly after ischemia.Platelets and endothelial cells did not express P-selectin in post-ischemic livers.There was no interaction between platelets and neutrophils.Conclusions:Platelets aggregate but do not become activated and do not degranulate in post-ischemic livers.There is no platelet-neutrophil interplay during the early reperfusion phase in a moderate model of hepatic I/R injury.The mechanisms underlying the biological effects of platelets and P-selectin in this setting warrant further investigation.Relevance for patients:I/R in surgical liver patients may compromise outcome due to post-ischemic oxidative stress and sterile inflammation.Both processes are mediated in part by platelets.Understanding platelet function during I/R is key to developing effective interventions for I/R injury and improving clinical outcomes. | Rowan F.van Golen Katarzyna M.Stevens Pina Colarusso Hartmut Jaeschke Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，2： | 2 |
| 7 | Editor’s inaugural issue foreword: perspectives on translational and clinical research显示文摘1. Introduction The efficacy with which human maladies can be treated by medical intervention generally depends on the extent of translational and clinical research conducted on the given illness before the diagnosis. This may be the reason why, for example, human immunodeficiency virus infections (~300,000 studies on “human immunodeficiency virus” indexed on PubMed) can nowadays be controlled with a cocktail of well-tolerated antiviral medication, while Ebola virus infections (~4,000 studies on “Ebola” indexed on PubMed) still kill ~50% of the infected individuals. | Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，1： | 2 |
| 8 | Potential therapeutic benefits stemming from the thermal nature of irreversible electropora tion of solid cancers显示文摘To the Editor:Irreversible electroporation(IRE)is a CE-and FDAapproved treatment modality for pancreatic and liver tumors that is based on the site-confined destruction of tumor tissue by multiple short,high-intensity electrical pulses.^([1])Currently there is a heated debate about whether the therapy is thermal or non-thermal.The'non-thermal proponents'advocate | Michal Heger Allard C van der Wal Gert Storm Martin J van Gemert | 2015 | Hepatobiliary & Pancreatic Diseases International2015，14，3： | 2 |
| 9 | Post-hepatectomy liver regeneration in the context of bile acid homeostasis and the gut-liver signaling axis显示文摘Background:Liver regeneration following partial hepatectomy(PHx)is a complicated process involving multiple organs and several types of signaling networks.The bile acid-activated metabolic pathways occupy an auxiliary yet important chapter in the entire biochemical story.PHx is characterized by rapid but transient bile acid overload in the liver,which constitutes the first wave of proliferative signaling in the remnant hepatocytes.Bile acids trigger hepatocyte proliferation through activation of several nuclear receptors.Following biliary passage into the intestines,enterocytes reabsorb the bile acids,which results in the activation of farnesoid X receptor(FXR),the consequent excretion of fibroblast growth factor(FGF)19/FGF15,and its release into the enterohepatic circulation.FGF19/FGF15 subsequently binds to its cognate receptor,fibroblast growth factor receptor 4(FGFR4)complexed withβ-klotho,on the hepatocyte membrane,which initiates the second wave of proliferative signaling.Because some bile acids are toxic,the remnant hepatocytes must resolve the potentially detrimental state of bile acid excess.Therefore,the hepatocytes orchestrate a bile acid detoxification and elimination response as a protective mechanism in concurrence with the proliferative signaling.The response in part results in the excretion of(biotransformed)bile acids into the canalicular system,causing the bile acids to end up in the intestines.Relevance for patients:Recently,FXR agonists have been shown to promote regeneration via the gut-liver axis.This type of pharmacological intervention may prove beneficial for patients with hepatobiliary tumors undergoing PHx.In light of these developments,the review provides an in-depth account of the pathways that underlie post-PHx liver regeneration in the context of bile acid homeostasis in the liver and the gut-liver signaling axis. | Lianne de Haan Sarah Jvan der Lely Anne-Loes K.Warps Quincy Hofsink Pim B.Olthof Mark J.de Keijzer Daniel A.Lionarons Lionel Mendes-Dias Bote G.Bruinsma Korkut Uygun Hartmut Jaeschke Geoffrey C.Farrell Narci Teoh Rowan Fvan Golen Tiangang Li Michal Heger | 2018 | Journal of Clinical & Translational Research2018，4，1： | 2 |
| 10 | Enhanced tumor growth after portal vein embolization in a rabbit tumor model显示文摘 | Lisette T. Hoekstra Krijn P. van Lienden Joanne Verheij Chris M. van der Loos Michal Heger Thomas M. van Gulik | 2012 | Journal of Surgical Research2012，，： | 1 |
| 11 | Effect of Preoperative Biliary Drainage on Coagulation and Fibrinolysis in Severe Obstructive Cholestasis显示文摘 | Jaap J. Kloek Michal Heger Niels A. van der Gaag Ulrich Beuers Thomas M. van Gulik Dirk J. Gouma Marcel Levi | 2010 | Journal of Clinical Gastroenterology2010，，9： | 1 |
| 12 | Accretion in strong field gravity with eXTP显示文摘In this paper we describe the potential of the enhanced X-ray Timing and Polarimetry(eXTP) mission for studies related to accretion flows in the strong field gravity regime around both stellar-mass and supermassive black-holes. eXTP has the unique capability of using advanced 'spectral-timing-polarimetry' techniques to analyze the rapid variations with three orthogonal diagnostics of the flow and its geometry, yielding unprecedented insight into the inner accreting regions, the effects of strong field gravity on the material within them and the powerful outflows which are driven by the accretion process. | Alessandra De Rosa Phil Uttley LiJun Gou Yuan Liu Cosimo Bambi Didier Barret Tomaso Belloni Emanuele Berti Stefano Bianchi Ilaria Caiazzo Piergiorgio Casella Marco Feroci Valeria Ferrari Leonardo Gualtieri Jeremy Heyl Adam Ingram Vladimir Karas FangJun Lu Bin Luo Giorgio Matt Sara Motta Joseph Neilsen Paolo Pani Andrea Santangelo XinWen Shu JunFeng Wang Jian-Min Wang YongQuan Xue YuPeng Xu WeiMin Yuan YeFei Yuan Shuang-Nan Zhang Shu Zhang Ivan Agudo Lorenzo Amati Nils Andersson Cristina Baglio Pavel Bakala Altan Baykal Sudip Bhattacharyya Ignazio Bombaci NiccolóBucciantini Fiamma Capitanio Riccardo Ciolfi Wei K.Cui Filippo D'Ammando Thomas Dauser Melania Del Santo Barbara De Marco Tiziana Di Salvo Chris Done Michal Dovciak Andrew C.Fabian Maurizio Falanga Angelo Francesco Gambino Bruce Gendre Victoria Grinberg Alexander Heger Jeroen Homan Rosario Iaria JiaChen Jiang ChiChuan Jin Elmar Koerding Manu Linares Zhu Liu Thomas J.Maccarone Julien Malzac Antonios Manousakis Frédéric Marin Andea Marinucci Missagh Mehdipour Mariano Méndez Simone Migliari Cole Miller Giovanni Miniutti Emanuele Nardini Paul T.O'Brien Julian P.Osborne Pierre Olivier Petrucci Andrea Possenti Alessandro Riggio Jerome Rodriguez Andrea Sanna LiJing Shao Malgosia Sobolewska Eva Sramkova Abigail L.Stevens Holger Stiele Giulia Stratta Zdenek Stuchlik Jiri Svoboda Fabrizio Tamburini Thomas M.Tauris Francesco Tombesi Gabriel Torok Martin Urbanec Frederic Vincent QingWen Wu Feng Yuan Jean J.M.in't Zand Andrzej A.Zdziarski XinLin Zhou | 2019 | Science China(Physics,Mechanics & Astronomy)2019，62，2： | 1 |
| 13 | Liver Regeneration After Portal Vein Embolization Using Absorbable and Permanent Embolization Materials in a Rabbit Model显示文摘 | Jacomina W. van den Esschert Krijn P. van Lienden Lindy K. Alles Albert C. van Wijk Michal Heger Joris J. Roelofs Thomas M. van Gulik | 2012 | Annals of Surgery2012，，2： | 1 |
| 14 | Survey and critical appraisal of pharmacological agents with potential thermo-modulatory properties in the context of artificially induced hypometabolism显示文摘A reduction in body temperature can be achieved by a downward adjustment of the termoneutral zone, a process also described as anapyrexia. Pharmacological induction of anapyrexia could enable numerous applications in medicine. However, little is known about the potential of pharmacological agents to induce anapyrexic signaling. Therefore, a review of literature was performed and over a thousand pharmacologically active compounds were analyzed for their ability to induce anapyrexia in animals. Based on this analysis, eight agents (helium, dimethyl sulfoxide, reserpine,(oxo)tremorine, pentobarbital,(chlor) promazine, insulin, and acetaminophen) were identified as potential anapyrexia-inducing compounds and discussed in detail. The translational pitfalls were also addressed for each candidate compound. Of the agents that were discussed, reserpine,(oxo)tremorine, and (chlor) promazine may possess true anapyrexic properties based on their ability to either affect the thermoneutral zone or its effectors and facilitate hypothermic signaling. However, these properties are currently not unequivocal and warrant further examination in the context of artificially-induced hypometabolism. | Marcel C. Dirkes Thomas M. van Gulik Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，1： | 0 |
| 15 | Laser-assisted vascular welding: optimization of acute and post-hydration welding strength显示文摘Background: Liquid solder laser-assisted vascular welding using biocompatible polymeric scaffolds (ssLAVW) is a novel technique for vascular anastomoses. Although ssLAVW has pronounced advantages over conventional suturing, drawbacks include low welding strength and extensive thermal damage. Aim: To determine optimal ssLAVW parameters for maximum welding strength and minimal thermal damage. Methods: Substudy 1 compared breaking strength (BS) of aortic strips welded with electrospun poly(ε-caprolactone)(PCL) or poly(lactic-co-glycolic acid)(PLGA) scaffold, 670-nm laser, 50-s single-spot continuous lasing (SSCL), and semi-solid solder (48% bovine serum albumin (BSA)/0.5% methylene blue (MB)/3% hydroxypropylmethylcellulose (HPMC)). Substudy 2 compared the semi-solid solder to 48% BSA/0.5% MB/0.38% genipin and 48% BSA/0.5% MB/3% HPMC/0.38% genipin solder. Substudy 3 compared SSCL to single-spot pulsed lasing (SSPL).Results: PCL-ssLAVW yielded an acute BS of 248.0 ± 54.0 N/cm^2 and remained stable up to 7d of hydration. PLGA-ssLAVW obtained higher acute BS (408.6 ± 78.8 N/cm^2) but revealed structural defects and a BS of 109.4 ± 42.6 N/cm2 after 14 d of hydration. The addition of HPMC and genipin improved the 14-d BS of PLGA- sLAVW (223.9 ± 19.1 N/cm^2). Thermal damage was reduced with SSPL compared with SSCL.Conclusions: PCL-ssLAVW yielded lower but more stable welds than PLGA-ssLAVW. The addition of HPMC and genipin to the solder increased the post-hydration BS of PLGA-ssLAVW. SSPL regimen reduced thermal damage. PLGA-ssLAVW using 48% BSA/0.5% MB/3% HPMC/0.38% genipin solder and SSPL constitutes the most optimal welding modality. Relevance for patients: Surgical patients requiring vascular anastomoses may benefit from the advantages that ssLAVW potentially offers over conventional sutures (gold standard). These include no needle trauma and remnant suture materials in the patient, reduction of foreign body reaction, immediate liquid-tight sealing, and the possibility of a faster and easier procedure for minimally invasive and endoscopic anastomotic techniques. | Dara R. Pabittei Michal Heger Marc Simonet Sjoerd van Tuijl Allard C. van der Wal Ed van Bavel Ron Balm Bas A. J. M. de Mol | 2015 | Journal of Clinical & Translational Research2015，1，1： | 0 |
| 16 | Laser-assisted vessel welding:state of the art and future outlook显示文摘Laser-assisted vascular welding(LAVW)is an experimental technique being developed as an alternative to suture anastomosis.In comparison to mechanical anastomosis,LAVW is less traumatic,non-immunogenic,provides immediate water tight sealant,and possibly a faster and easier procedure for minimally invasive surgery.This review focuses on technical advances to improve welding strength and to reduce thermal damage in LAVW.In terms of welding strength,LAVW has evolved from the photothermally-induced microvascular anastomosis,requiring stay sutures to support welding strength,to sutureless anastomoses of medium-sized vessels,withstanding physiological and supraphysiological pressure.Further improvements in anastomotic strength could be achieved by the use of chromophore-containing albumin solder and the employment of(biocompatible)polymeric scaffolds.The anastomotic strength and the stability of welds achieved with such a modality,referred to as scaffold-and solder-enhanced LAVW(ssLAVW),are dependent on the intermolecular bonding of solder molecules(cohesive bonding)and the bonding between solder and tissue collagen(adhesive bonding).Presently,the challenges of ssLAVW include(1)obtaining an optimal balance between cohesive and adhesive bonding and(2)minimizing thermal damage.The modulation of thermodynamics during welding,the application of semi-solid solder,and the use of a scaffold that supports both cohesive and adhesive strength are essential to improve welding strength and to limit thermal damage. | Dara R.Pabittei Wadim de Boon Michal Heger Rowan F.van Golen Ron Balm Dink A.Legemate Bas A.de Mol | 2015 | Journal of Clinical & Translational Research2015，1，2： | 0 |
| 17 | The physiology of artificial hibernation显示文摘Incomplete understanding of the mechanisms responsible for induction of hibernation prevent translation of natural hibernation to its artificial counterpart.To facilitate this translation,a model was developed that identifies the necessary physiological changes for induction of artificial hibernation.This model encompasses six essential components:metabolism(anabolism and catabolism),body temperature,thermoneutral zone,substrate,ambient temperature,and hibernation-inducing agents.The individual components are interrelated and collectively govern the induction and sustenance of a hypometabolic state.To illustrate the potential validity of this model,various pharmacological agents(hibernation induction trigger,delta-opioid,hydrogen sulfide,5’-adenosine monophosphate,thyronamine,2-deoxyglucose,magnesium)are described in terms of their influence on specific components of the model and corollary effects on metabolism.Relevance for patients:The ultimate purpose of this model is to help expand the paradigm regarding the mechanisms of hibernation from a physiological perspective and to assist in translating this natural phenomenon to the clinical setting. | Marcel C.Dirkes Thomas M.van Gulik Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，2： | 0 |
| 18 | IL-23 and IL-17A are not involved in hepatic/ischemia reperfusion injury in mouse and man显示文摘Background:Hepatic ischemia and reperfusion(I/R)is common in liver surgery and transplantation and compromises postoperative liver function.Hepatic I/R injury is characterized by sterile inflammation that contributes to hepatocellular necrosis.Many immune cells and cytokines have been implicated in hepatic I/R injury.However,the role and relevance of IL-23 and IL-17A remains controversial in literature.Aim:To determine whether the IL-23/IL-17A signaling axis is activated in hepatic I/R using a triple-level experimental approach(in vitro,in vivo,and clinical).Methods:IL-23 and IL-17A were assayed by ELISA in the supernatant fractions of cultured murine(RAW 264.7)macrophages that were activated by supernatant fractions of necrotic cultured mouse(AML12)hepatocytes.Similarly,levels of these cytokines were determined in plasma samples and liver tissue of mice(N=85)subjected to partial(70%)liver I/R.Finally,IL-23 and IL-17A were assayed in plasma samples obtained from a controlled cohort of liver resection patients who were either subjected to I/R(N=27)or not(N=13).Results:Activated macrophages did not produce IL-23 in response to supernatant of necrotic AML12 hepatocytes.IL-23 and IL-17A were not elevated in mice subjected hepatic I/R and were not elevated in serum from patients subjected to I/R during liver resection.Conclusion:IL-23 and IL-17A are not involved in hepatic I/R injury in mouse and man.Relevance for patients:If IL-23 and IL-17A were to mediate hepatocellular injury following I/R,these cytokines would constitute potential therapeutic targets.Since this study has revealed that IL-23 and IL-17A do not play a role in hepatic I/R,other pathways and therapeutic targets should be considered when developing modalities aimed at reducing hepatic I/R injury. | Pim B.Olthof Rowan F.van Golen Megan J.Reiniers Milan Kos Lindy K.Alles Martinus A.Maas Joanne Verheij Thomas M.van Gulik Michal Heger | 2015 | Journal of Clinical & Translational Research2015，1，3： | 0 |
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