Leonie E. Paulis

Radboud University Nijmegen

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Gustav J. Strijkers

Health & Safety in Sports

Tessa Geelen

Medtronic (Netherlands)

Klaas Nicolay

Salem State University

Bram F. Coolen

Amsterdam University Medical Centers

Joachim E. Wildberger

Maastricht University

Cécile R. L. P. N. Jeukens

Maastricht University Medical Centre

Laura Vergoossen

Maastricht University

Carl G. Figdor

Radboud University Medical Center

Anna M. Sailer

Stanford University

Ulrich Lalji

Maastricht University

Cooperative Institutions

University Medical Center

Maastricht University

Maastricht University Medical Centre

Radboud University Nijmegen

University Medical Center Utrecht

Eindhoven University of Technology

University of Cologne

Radboud University Medical Center

Utrecht University

Radboud Institute for Molecular Life Sciences

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Passive targeting of lipid‐based nanoparticles to mouse cardiac ischemia–reperfusion injury

Contrast Media & Molecular Imaging (2012)

Tessa Geelen Leonie E. Paulis Bram F. Coolen Klaas Nicolay Gustav J. Strijkers

Reperfusion therapy is commonly applied after a myocardial infarction. Reperfusion, however, causes secondary damage. An emerging approach for treatment of ischemia-reperfusion (IR) injury involves the delivery of therapeutic nanoparticles to the myocardium to promote cell survival and constructively influence scar formation and myocardial remodeling. The aim of this study was to provide detailed understanding of the in vivo accumulation and distribution kinetics of lipid-based nanoparticles (micelles and liposomes) in a mouse model of acute and chronic IR injury. Both micelles and liposomes contained paramagnetic and fluorescent lipids and could therefore be visualized with magnetic resonance imaging (MRI) and confocal laser scanning microscopy (CLSM). In acute IR injury both types of nanoparticles accumulated massively and specifically in the infarcted myocardium as revealed by MRI and CLSM. Micelles displayed faster accumulation kinetics, probably owing to their smaller size. Liposomes occasionally co-localized with vessels and inflammatory cells. In chronic IR injury only minor accumulation of micelles was observed with MRI. Nevertheless, CLSM revealed specific accumulation of both micelles and liposomes in the infarct area 3 h after administration. Owing to their specific accumulation in the infarcted myocardium, lipid-based micelles and liposomes are promising vehicles for (visualization of) drug delivery in myocardial infarction.

10.1002/cmmi.1501

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Embryonic Cardiomyocyte, but Not Autologous Stem Cell Transplantation, Restricts Infarct Expansion, Enhances Ventricular Function, and Improves Long-Term Survival

PLoS ONE (2013)

Leonie E. Paulis A. Кlеіn Alexander Ghanem Tessa Geelen Bram F. Coolen

Aims Controversy exists in regard to the beneficial effects of transplanting cardiac or somatic progenitor cells upon myocardial injury. We have therefore investigated the functional short- and long-term consequences after intramyocardial transplantation of these cell types in a murine lesion model. Methods and Results Myocardial infarction (MI) was induced in mice (n = 75), followed by the intramyocardial injection of 1−2×105 luciferase- and GFP-expressing embryonic cardiomyocytes (eCMs), skeletal myoblasts (SMs), mesenchymal stem cells (MSCs) or medium into the infarct. Non-treated healthy mice (n = 6) served as controls. Bioluminescence and fluorescence imaging confirmed the engraftment and survival of the cells up to seven weeks postoperatively. After two weeks MRI was performed, which showed that infarct volume was significantly decreased by eCMs only (14.8±2.2% MI+eCM vs. 26.7±1.6% MI). Left ventricular dilation was significantly decreased by transplantation of any cell type, but most efficiently by eCMs. Moreover, eCM treatment increased the ejection fraction and cardiac output significantly to 33.4±2.2% and 22.3±1.2 ml/min. In addition, this cell type exclusively and significantly increased the end-systolic wall thickness in the infarct center and borders and raised the wall thickening in the infarct borders. Repetitive echocardiography examinations at later time points confirmed that these beneficial effects were accompanied by better survival rates. Conclusion Cellular cardiomyoplasty employing contractile and electrically coupling embryonic cardiomyocytes (eCMs) into ischemic myocardium provoked significantly smaller infarcts with less adverse remodeling and improved cardiac function and long-term survival compared to transplantation of somatic cells (SMs and MSCs), thereby proving that a cardiomyocyte phenotype is important to restore myocardial function.

Ventricular remodeling

Stem Cell Therapy

Cell therapy

10.1371/journal.pone.0061510

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Citations (19)

Radiation dose of step-and-shoot digital breast tomography in comparison to full field digital mammography

Leonie E. Paulis Ulrich Lalji Ramona W. Bouwman Nicky Gelissen Joachim E. Wildberger

Poster: ECR 2015 / C-0933 / Radiation dose of step-and-shoot digital breast tomography in comparison to full field digital mammography by: L. Paulis1, U. Lalji1, R. Bouwman2, N. N. Gelissen1, J. E. Wildberger1, M. Lobbes1, C. R. Jeukens1; 1Maastricht/NL, 2Nijmegen/NL

Digital Mammography

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The right touch: design of artificial antigen-presenting cells to stimulate the immune system

Chemical Science (2014)

J. van der Weijden Leonie E. Paulis Martijn Verdoes Jan C. M. van Hest Carl G. Figdor

With the ever expanding possibilities to build supramolecular structures, chemists are challenged to mimic nature including the construction of artificial cells or functions thereof. Within the field of immunology, effective immunotherapy critically depends on efficient production of antigen-specific cytotoxic T-cells. Herein lies an opportunity for chemists to design and synthesize so-called artificial antigen presenting cells (aAPCs) that can promote T-cell activation and their subsequent expansion. In this review we discuss the current status of aAPC development, also focusing on developments in nanoscience which might improve future designs. As synthetic mimics of natural antigen-presenting cells, aAPCs encompass three basic signals required for T-cell activation: MHC–antigen complexes, costimulatory molecules and soluble immune modulating compounds. Both spatial and temporal organization of these signals during aAPC/T-cell contact is important for efficient T-cell activation. We discuss how signals have been incorporated in several aAPC designs, but also how physical properties such as size and shape are essential for targeting the aAPCs to T-cell rich areas in vivo.

Artificial cell

10.1039/c4sc01112k

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Evaluation of cardiac function by high resolution MRI after cellular cardiomyoplasty

The Thoracic and Cardiovascular Surgeon (2011)

AM Klein Leonie E. Paulis Tessa Geelen Gustav J. Strijkers Armin Welz

Objective: We performed cellular cardiomyoplasty employing embryonic cardiomyocytes (eCM) in a murine lesion model. To assess the therapeutic efficacy of transplanted cells we performed in vivo contrast enhanced cardiac MRI to assess left ventricular (LV) function.

Cardiomyoplasty

10.1055/s-0030-1269111

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Towards efficient cancer immunotherapy: advances in developing artificial antigen-presenting cells

Trends in biotechnology (2014)

Loek J. Eggermont Leonie E. Paulis Jurjen Tel Carl G. Figdor

Active anti-cancer immune responses depend on efficient presentation of tumor antigens and co-stimulatory signals by antigen-presenting cells (APCs). Therapy with autologous natural APCs is costly and time-consuming and results in variable outcomes in clinical trials. Therefore, development of artificial APCs (aAPCs) has attracted significant interest as an alternative. We discuss the characteristics of various types of acellular aAPCs, and their clinical potential in cancer immunotherapy. The size, shape, and ligand mobility of aAPCs and their presentation of different immunological signals can all have significant effects on cytotoxic T cell activation. Novel optimized aAPCs, combining carefully tuned properties, may lead to efficient immunomodulation and improved clinical responses in cancer immunotherapy.

Cancer Immunotherapy

10.1016/j.tibtech.2014.06.007

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Quantitative T₂ mapping of the mouse heart by segmented MLEV phase‐cycled T₂ preparation

Magnetic Resonance in Medicine (2013)

Bram F. Coolen Frank F.J. Simonis Tessa Geelen Rik P. M. Moonen Fatih Arslan

A high-quality, reproducible, multi-slice T2-mapping protocol for the mouse heart is presented.A T2-prepared sequence with composite 90° and 180° radiofrequency pulses in a segmented MLEV phase cycling scheme was developed. The T2-mapping protocol was optimized using simulations and evaluated with phantoms.Repeatability for determination of myocardial T2 values was assessed in vivo in n = 5 healthy mice on 2 different days. The average baseline T2 of the left ventricular myocardium was 22.5 ± 1.7 ms. The repeatability coefficient for R2 = 1/T2 for measurements at different days was ΔR2 = 6.3 s(−1). Subsequently, T2 mapping was applied in comparison to late-gadolinium-enhancement (LGE) imaging, to assess 1-day-old ischemia/reperfusion (IR) myocardial injury in n = 8 mice. T2 in the infarcts was significantly higher than in remote tissue, whereas remote tissue was not significantly different from baseline. Infarct sizes based on T2 versus LGE showed strong correlation. To assess the time-course of T2 changes in the infarcts, T2 mapping was performed at day 1, 3, and 7 after IR injury in a separate group of mice (n = 16). T2 was highest at day 3, in agreement with the expected time course of edema formation and resolution after myocardial infarction.T2 prepared imaging provides high quality reproducible T2 maps of healthy and diseased mouse myocardium.

Repeatability

10.1002/mrm.24952

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Citations (34)

Personalized Feedback on Staff Dose in Fluoroscopy-Guided Interventions: A New Era in Radiation Dose Monitoring

CardioVascular and Interventional Radiology (2017)

Anna M. Sailer Laura Vergoossen Leonie E. Paulis Willem H. van Zwam Marco Das

Radiation safety and protection are a key component of fluoroscopy-guided interventions. We hypothesize that providing weekly personal dose feedback will increase radiation awareness and ultimately will lead to optimized behavior. Therefore, we designed and implemented a personalized feedback of procedure and personal doses for medical staff involved in fluoroscopy-guided interventions. Medical staff (physicians and technicians, n = 27) involved in fluoroscopy-guided interventions were equipped with electronic personal dose meters (PDMs). Procedure dose data including the dose area product and effective doses from PDMs were prospectively monitored for each consecutive procedure over an 8-month period (n = 1082). A personalized feedback form was designed displaying for each staff individually the personal dose per procedure, as well as relative and cumulative doses. This study consisted of two phases: (1) 1–5th months: Staff did not receive feedback (n = 701) and (2) 6–8th months: Staff received weekly individual dose feedback (n = 381). An anonymous evaluation was performed on the feedback and occupational dose. Personalized feedback was scored valuable by 76% of the staff and increased radiation dose awareness for 71%. 57 and 52% reported an increased feeling of occupational safety and changing their behavior because of personalized feedback, respectively. For technicians, the normalized dose was significantly lower in the feedback phase compared to the prefeedback phase: [median (IQR) normalized dose (phase 1) 0.12 (0.04–0.50) µSv/Gy cm2 versus (phase 2) 0.08 (0.02–0.24) µSv/Gy cm2, p = 0.002]. Personalized dose feedback increases radiation awareness and safety and can be provided to staff involved in fluoroscopy-guided interventions.

10.1007/s00270-017-1690-5

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Contrast‐enhanced MRI of murine myocardial infarction – Part I

NMR in Biomedicine (2012)

Tessa Geelen Leonie E. Paulis Bram F. Coolen Klaas Nicolay Gustav J. Strijkers

The use of contrast agents has added considerable value to the existing cardiac MRI toolbox that can be used to study murine myocardial infarction, as it enables detailed in vivo visualization of the molecular and cellular processes that occur in the infarcted and remote tissue. A variety of non‐targeted and targeted contrast agents to study myocardial infarction are available and under development. Manganese, which acts as a calcium analogue, can be used to assess cell viability. Traditionally, low‐molecular‐weight Gd‐containing contrast agents are employed to measure infarct size in a late gadolinium enhancement experiment. Gd‐based blood‐pool agents are used to study the vascular status of the myocardium. The use of targeted contrast agents facilitates more detailed imaging of pathophysiological processes in the acute and chronic infarct. Cell death was visualized by contrast agents functionalized with annexin A5 that binds specifically to phosphatidylserine accessible on dying cells and with an agent that binds to the exposed DNA of dead cells. Inflammation in the myocardium was depicted by contrast agents that target cell adhesion molecules expressed on activated endothelium, by contrast agents that are phagocytosed by inflammatory cells, and by using a probe that targets enzymes excreted by inflammatory cells. Cardiac remodeling processes were visualized with a contrast agent that binds to angiogenic vasculature and with an MR probe that specifically binds to collagen in the fibrotic myocardium. These recent advances in murine contrast‐enhanced cardiac MRI have made a substantial contribution to the visualization of the pathophysiology of myocardial infarction, cardiac remodeling processes and the progression to heart failure, which helps to design new treatments. This review discusses the advances and challenges in the development and application of MRI contrast agents to study murine myocardial infarction. Copyright © 2012 John Wiley & Sons, Ltd.

Molecular Imaging

10.1002/nbm.2768

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SU‐G‐IeP3‐13: Real‐Time Patient and Staff Dose Monitoring in Fluoroscopy Guided Interventions

Medical Physics (2016)

Laura Vergoossen Anna M. Sailer Leonie E. Paulis Joachim E. Wildberger Cécile R. L. P. N. Jeukens

Purpose: Interventional radiology procedures involve the use of X‐rays, which can pose a large radiation burden on both patients and staff. Although some reports on radiation dose are available, most studies focus on limited types of procedures and only report patient dose. In our cathlabs a dedicated real‐time patient and staff monitoring system was installed in November 2015. The aim of this study was to investigate the patient and staff dose exposure for different types of interventions. Methods: Radiologists involved in fluoroscopy guided interventional radiology procedures wore personal dose meters (PDM, DoseAware, Philips) on their lead‐apron that measured the personal dose equivalent Hp(10), a measure for the effective dose (E). Furthermore, reference PDMs were installed in the C‐arms of the fluoroscopy system (Allura XPer, Philips). Patient dose‐area‐product (DAP) and PDM doses were retrieved from the monitoring system (DoseWise, Philips) for each procedure. A total of 399 procedures performed between November 2015 and February 2016 were analyzed with respect to the type of intervention. Interventions were grouped by anatomy and radiologist position. Results: The mean DAP for the different types of interventions ranged from 2.86±2.96 Gycm 2 (percutaneous gastrostomy) to 147±178 Gycm 2 (aortic repair procedures). The radiologist dose (E) ranged from 5.39±7.38 µSv (cerebral interventions) to 84.7±106 µSv (abdominal interventions) and strongly correlated with DAP (R 2 =0.83). The E normalized to DAP showed that the relative radiologist dose was higher for interventions in larger body parts (e.g. abdomen) compared to smaller body parts (e.g. head). Conclusion: Using a real‐time dose monitoring system we were able to assess the staff and patient dose revealing that the relative staff dose strongly depended on the type of procedure and patient anatomy. This could be explained by the position of the radiologist with respect to the patient and X‐ray tube. To facilitate this study L Vergoossen received a scholarship from Philips Medical Systems.

Interventional radiology

10.1118/1.4957062

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