G Weigel

Medical University of Vienna, Wien, Vienna, Austria

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Publications (112)328.04 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The short-term safety profile of recombinant human granulocyte–colony-stimulating factor (rHuG-CSF) in the allogeneic stem cell setting seems acceptable; only few data on long-term safety are available. To further study possible epigenetic alterations, we investigated prospectively the influence of rHuG-CSF on DNA methyltransferase (DNMT) activity and on changes in DNA methylation of candidate genes in peripheral blood cells of healthy unrelated stem cell donors within an observation period of 1 year.Study Design and Methods In this study, 20 stem cell donors (14 male/six female; median age, 40 years; range, 22-54 years) and 20 sex- and age-matched blood component donors (controls) were included. Sampling was performed before rHuG-CSF administration; at the time of donation; and on Days (+1), 7, 30, 100, 180, and 360 in both groups. Analysis of DNMT activity in nuclear extracts was performed using a modified radionuclide assay. We performed methylation-specific polymerase chain reaction to detect the methylation status of promoter CpG islands of the genes of the retinoic acid receptor beta (RAR-B) and the Ras association domain family 1A (RASSF1A).ResultsDNMT activity increased significantly on the day of donation and 1 day after (p < 0.05). By Day +7 baseline values were reached. No further significant alterations of DNMT activity in the treated group compared to the controls were observed. We could not detect any differences in the gene methylation of RAR-B and RASSF1A between both groups.Conclusion In our prospective study no evidence of long-lasting increased DNMT activity or enhanced DNA methylation in a limited panel of target genes after recombinant human G-CSF administration was observed in healthy stem cell donors.
    Transfusion 06/2014; · 3.53 Impact Factor
  • Immunohematology / American Red Cross 06/2012; 28(2):67-73.
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    ABSTRACT: Thermoplastic polyurethane (TPU) elastomers with biodegradable chain extenders were synthesized and tested for mechanical performance and biocompatibility. The design of the TPUs was based on structural modification of a mechanically appropriate aromatic isocyanate-based TPU. As the aromatic isocyanate was substituted with a less toxic but also less “hard” aliphatic isocyanate, the chain extender plays an important role on the mechanical properties. Here, the terephthalate ester chain extender was found to work better than hydroxyl ethyl lactate in providing polymers with mechanical properties similar to commercial aromatic isocyanate-based TPUs. The polymers were degraded in aqueous solutions at elevated temperatures and compared to polylactic acid (PLA) to partially simulate biodegradation. The lactate-based TPUs degraded about twice as fast as PLA while the terephthalate-based TPU degraded much more slowly. The latter material was processed by electrospinning to give a tubular graft approximately the size of a large rat blood vessel. Initial results from implantation of these TPUs into rats are promising and indicate that biodegradation occurs and is likely beneficial to cell proliferation. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011
    Journal of Polymer Science Part A Polymer Chemistry 04/2012; 50(7):1272-1280. · 3.54 Impact Factor
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    ABSTRACT: No small-diameter synthetic graft has yet shown comparable performance to autologous vessels. Synthetic conduits fail due to their inherent surface thrombogenicity and the development of intimal hyperplasia. In addressing these shortcomings, electrospinning offers an interesting alternative to other nanostructured, cardiovascular substitutes because of the close match of electrospun materials to the biomechanical and structural properties of native vessels. In this study, we investigated the in vivo behavior of electrospun, small-diameter conduits in a rat model. Vascular grafts composed of polyurethane were fabricated by electrospinning. Prostheses were implanted into the abdominal aorta in 40 rats for either 7 days, 4 weeks, 3 months, or 6 months. Retrieved specimens were evaluated by histology, immunohistochemical staining, confocal laser scanning microscopy, and scanning electron microscopy. At all time points, we found no evidence of foreign body reaction or graft degradation. The overall patency rate of the intravascular implants was 95%. Within 7 days, grafts revealed ingrowth of host cells. CD34+ cells increased significantly from 7 days up to 6 months of implantation (P < 0.05). Myofibroblasts and myocytes showed increasing cell numbers up to 3 months (P < 0.05). Ki67 staining indicated unaltered cell proliferation during the whole follow-up period. Besides biomechanical benefits, electrospun polyurethane grafts exhibit excellent biocompatibility in vivo. Cell immigration and differentiation seems to be promoted by the nanostructured artificial matrix.
    Artificial Organs 08/2011; 36(1):54-61. · 1.96 Impact Factor
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    ABSTRACT: The aim of this study was to design new resin formulations for blood vessel substitutes with small inner diameter that can be 3D-printed by Additive Manufacturing (AM). Commercially available urethane oligomer acrylates as crosslinking agents (CAs) with different reactive diluents (RDs) and/or thiol chain transfer agents (CTAs) were examined. It could be shown that the properties of photopolymers of carefully selected CA/RD/CTA combinations can be varied in a wide range, also to fit with those of natural blood vessels. Moreover, these materials showed good biocompatibility in in-vitro cell culture tests with endothelial cells. A new method to assess the tear resistance of the new materials in comparison with natural blood vessels was designed and established. The tear resistance of the developed photopolymers already approaches those of natural material, although there is still need of improvement. The 3D-structuring of optimized resin system succeeded. Hence AM has proven to be an ideal tool to manufacture parts with the complex structure of natural blood vessels.
    Macromolecular Symposia 11/2010; 296(1):121 - 126.
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    ABSTRACT: Heme oxygenase-1 (HO-1) is an antioxidative, antiinflammatory, and cytoprotective enzyme that is induced in response to cellular stress. The HO-1 promoter contains a (GT)n microsatellite DNA, and the number of GT repeats can influence the occurrence of cardiovascular diseases. We elucidated the effect of this polymorphism on endothelial cells isolated from newborns of different genotypes. On the basis of HO-1 expression, we classified the HO-1 promoter alleles into 3 groups: short (S) (most active, GT < or = 23), medium (moderately active, GT=24 to 28), and long (least active, GT > or = 29). The presence of the S allele led to higher basal HO-1 expression and stronger induction in response to cobalt protoporphyrin, prostaglandin-J(2), hydrogen peroxide, and lipopolysaccharide. Cells carrying the S allele survived better under oxidative stress, a fact associated with the lower concentration of oxidized glutathione and more favorable oxidative status, as determined by measurement of the ratio of glutathione to oxidized glutathione. Moreover, they proliferated more efficiently in response to vascular endothelial growth factor A, although the vascular endothelial growth factor-induced migration and sprouting of capillaries were not influenced. Finally, the presence of the S allele was associated with lower production of some proinflammatory mediators, such as interleukin-1beta, interleukin-6, and soluble intercellular adhesion molecule-1. The (GT)n promoter polymorphism significantly modulates a cytoprotective, proangiogenic, and antiinflammatory function of HO-1 in human endothelium.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2010; 30(8):1634-41. · 6.34 Impact Factor
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    ABSTRACT: After large volume bone marrow (BM) harvest, donors and patients can develop severe anaemia, because collected BM can contain up to 20% of their red cell mass. In a prospective analysis, we investigated the feasibility to recover red blood cells (RBCs) from the harvested BM and investigated whether these RBC units meet the quality requirements of the European Council. From 19 patients (median age 51 yrs, range 31-77) with acute myocardial infarction, who participated in the MYSTAR study, a median volume of 1299 ml (range, 700-1870 ml) BM was collected. During BM processing, mononuclear cells (MNC) were separated using the Cobe Spectra apheresis system and the residual RBCs were collected in a separate bag. The quality of the collected RBCs was assessed by measuring LDH, free haemoglobin, potassium and lactate. Haemolysis was calculated and the intracellular concentration of ATP, ADP, AMP was determined by HPLC. RBC units recovered from BM after MNC separation had a mean volume of 312 +/- 95 ml with a haematocrit of 47 +/- 8.9%, a haemoglobin content of 51 +/- 15 g per unit, a haemolysis of 0.15 +/- 0.005%, a pH of 6.8 +/- 0.007 and an intracellular ATP concentration of 135 pmol/10(6) RBC +/- 41, which is comparable with freshly collected packed red blood cells (PRBCs). RBCs, collected from bone marrow harvests, can be used for autologous blood support to minimize allogeneic blood transfusions in donors and patients after large volume BM donation.
    Vox Sanguinis 04/2010; 98(3 Pt 1):e284-9. · 2.85 Impact Factor
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    ABSTRACT: The mechanical properties of materials designated for vascular tissue replacement are of crucial importance. The elastic modulus, the tensile strength as well as the suture tear resistance have to be adjusted. Our approach is to use photopolymers for artificial vascular grafts. Via the layer-by-layer photopolymerization of suitable resin formulations as performed in additive manufacturing (AM) very complex structures are realizable. Hence AM offer the possibility to create cellular structures within the artificial grafts that might favor the ingrowth of new tissue. Commercially available urethane acrylates (UA) were chosen as base monomers since urethane groups are known to have good cell-adhesion behavior and poly-UAs show adequate mechanical performance. The mechanical properties of the photoelastomers can be tailored by addition of reactive diluents (e.g. 2-hydroxyethyl acrylate, HEA) and thiols (e.g. 3,6 dioxa-1,8-octane-dithiol) as chain transfer agents to comply with the mechanical properties of natural blood vessels. To examine the suture tear resistance a new testing method has been developed. Finally, a formulation containing 30 wt% UA and 70 wt% HEA complies with the mechanical properties of natural blood vessels, shows good biocompatibility in in-vitro tests and was successfully 3D-printed with digital light processing AM.
    2009 MRS Fall meeting, Boston; 03/2010
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    ABSTRACT: Electrospinning is a very powerful method to create cellular scaffolds for regenerative medicine – especially for artificial vascular grafts. Commercially available thermoplastic polyurethane elastomers (TPUs), like Pellethane™ are FDA approved and have already shown excellent biomechanical properties as electrospun vascular grafts. In order to induce the growth of a neo artery and hence increase the long-term patency of the graft, the use of biodegradable TPUs is beneficial. Therefore we aim for the development of degradable TPUs. In preliminary studies the mechanical properties of segmented TPUs were examined. The tendencies of the properties of the compression-molded bulk materials were also found for the electrospun materials. It could also be shown that the substitution of the aromatic 4,4′-methylene diphenyl diisocyanate building blocks in Pellethane™ with the aliphatic hexamethylene diisocyanate – to avoid toxic aromatic amines as degradation products - only causes minor loss of strength. To obtain degradable TPUs, our concept is to incorporate cleavable ester bonds into the polymer chain. For this purpose, lactic- and terephthalic ester-based cleavable chain extenders were used. The expected degradation products showed no cytotoxicity in-vitro. Degradation tests of polymer samples in phosphate buffered saline at elevated temperatures confirmed the degradability of the new polymers.
    2009 MRS Fall meeting, Boston; 12/2009
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    ABSTRACT: Mycophenolic acid (MPA) is a selective inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 micromol l(-1)) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 micromol l(-1) and 25 micromol l(-1). We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism.
    The Pharmacogenomics Journal 09/2009; 10(1):70-6. · 5.13 Impact Factor
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    ABSTRACT: Engineered small diameter vascular grafts must closely match mechanical characteristics of native vessels and exhibit stimulus-responsive bioactivity. In this study, mechanical homogeneity of electrospun small diameter polyurethane grafts as well as spontaneous attachment, proliferation, and adhesion molecule expression of endothelial cells (EC) in their presence was studied in vitro. Axial and circumferential tensile strengths were measured and found to be twofold higher in the circumferential direction. EC attachment was easily achieved without precoating the fiber matrix. Stimulation of EC with interleukin-1beta (IL-1beta) led to a statistically significant upregulation of the adhesion molecules E-Selectin, ICAM-1, and VCAM-1. Quantification of adhesion molecule expression by means of energy-dispersive X-ray microanalysis revealed no differences in the stimulatory responses of EC cultured on electrospun polyurethane when compared with cells grown on tissue culture-treated cover slips. Summarizing, highly uniform small diameter polyurethane grafts were fabricated and shown to allow spontaneous EC attachment. The synthetic graft surface neither impaired the endothelial response toward IL-1beta stimulation nor did it adversely affect the regulation of expression of endothelial adhesion molecules.
    Journal of Biomedical Materials Research Part A 08/2009; 93(2):716-23. · 2.83 Impact Factor
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    ABSTRACT: Platelets (PLTs) contain mRNA and synthesize proteins in response to activation. Most guidelines for PLT concentrates (PCs) recommend ambient temperature for storage but the impact of the storage temperature on PLT mRNA content has not yet been investigated. Ten leukoreduced apheresis PCs were split and stored at 22 and 4 degrees C. P-selectin mRNA, its expression on PLTs, and its soluble form were quantified. In parallel, cellular (cell count, mean PLT volume), metabolic (pH, pO(2), pCO(2), HCO(3), glucose), and functional markers (swirling, hypotonic shock response, aggregation to collagen) were analyzed. Rotation thrombelastography was used to monitor the hemostatic potential of PLTs. All measurements were performed on Days 1 and 5 of storage. After 5 days of storage at 4 degrees C, only 31 +/- 27 percent of P-selectin mRNA and 29 +/- 41 percent of glyceraldehyde-3-phosphate dehydrogenase mRNA were lost, while minute amounts of the mRNAs were detectable at 22 degrees C. In PCs stored at 4 degrees C the percentage of P-selectin-positive PLTs was significantly higher when compared to PCs stored at 22 degrees C. Soluble P-selectin concentrations did not significantly differ between both storage temperatures. Thrombelastography revealed significantly shorter reaction times in PLTs kept at 4 degrees C. Our data indicate that storage at 4 degrees C is accompanied by maintained mRNA levels. PLTs with intact mRNA levels and short reaction times in thrombelastography might be functionally superior to PLTs that are devoid of mRNA and show less augmented P-selectin surface expression. In therapeutic applications, that is, if PLTs are transfused to control acute bleeding, PLTs kept at 4 degrees C may be advantageous.
    Transfusion 02/2009; 49(5):921-7. · 3.53 Impact Factor
  • Lung Cancer. 01/2009; 64.
  • Lung Cancer. 01/2009; 64.
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    ABSTRACT: Gelatin-based monomers were considered as suitable base component for the 3D structuring of potential bone replacement materials by stereolithographic techniques. Different methacrylate-based gelatin derivatives were prepared, whereas a polyethylene glycol modified derivative GP4M turned out to have the highest tolerance toward other monomers. These are essential as they allow the tuning of the photoreactivity and the mechanical properties. Cell culture experiments with osteoblast- and endothelial-like cells confirmed negligible cytotoxicity of these monomers. Finally, we were able to show the possibility of producing arbitrary cellular structures with these gelatin-containing formulations using stereolithography. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2009
    Journal of Polymer Science Part A Polymer Chemistry 01/2009; 47(24):7078-7089. · 3.54 Impact Factor
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    ABSTRACT: The influence of an acellular porcine matrix on proinflammatory activation of endothelial cells (EC) during normoxia and hypoxia was investigated by a newly established semi-quantitative electron microscopic procedure. As a model, three adhesion molecules (E-selectin, ICAM-1, and VCAM-1) were localized by silver-enhanced immunogold staining and energy dispersive X-ray microanalysis after normoxic or hypoxic pretreatment of the cells and subsequent stimulation with IL-1beta. Morphology of EC grown on porcine matrix or coverslips was recorded simultaneously using secondary electron imaging. EC appeared tightly attached to the underlying surfaces with their typical cobblestone-like morphology. Statistically significant upregulations upon stimulation with IL-1beta were observed in both groups for all three adhesion molecules. Hypoxic pretreatment of the specimens with subsequent reoxygenation neither induced morphological changes nor caused an upregulation of adhesion molecule expression in cells grown on acellular porcine tissue. Unexpectedly, in cells seeded onto the acellular matrix, IL-1beta failed to upregulate ICAM-1 expression after a short period of hypoxia. The surface expression of VCAM-1 was also significantly lower even under normoxic conditions, which might indicate the development of functional impairment of cells in contact with acellular porcine tissue. The method presented in this study has proven valuable for the determination of antigen expression on scaffold materials in parallel with the characterization of surface morphology.
    Tissue Engineering Part C Methods 01/2009; 15(2):257-63. · 4.64 Impact Factor
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    ABSTRACT: Cardiovascular disease is one of the leading causes of morbidity and mortality in the western hemisphere. Currently available synthetic vascular conduits, like Dacron or ePTFE show excellent long-term results for large-caliber arterial reconstruction (aorta, iliac vessels) but when used for small diameter (<4 mm) vessel reconstruction, patency rates are extremely poor. We therefore aim at developing suitable blood vessel substitutes out of biocompatible photopolymer formulations, which can be printed by rapid prototyping. Rapid prototyping offers the possibility to create cellular structures within the grafts that favor the ingrowth of tissue. To meet the high requirements for artificial biomaterials, it is necessary to develop new resin formulations. Beside the biocompatibility, the mechanical properties—a low elastic modulus (500 kPa) at a relatively high tensile strength (1.0 MPa) and a high strain at break (130%)—play a central role. Resin systems containing cyanoethyl acrylate have shown to be highly reactive, have good mechanical properties and sufficient in vitro biocompatibility. Elastic modulus and tensile strength which should be similar to natural blood vessels were adjusted by the ratio of acrylate-based crosslinkers and—in case of hydrogels —the percentage of water. Finally, we were able to print small diameter conduits by microstereolithography. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2664–2676, 2009
    Journal of Polymer Science Part A Polymer Chemistry 01/2009; 47(10):2664-2676. · 3.54 Impact Factor
  • Lung Cancer. 01/2009; 64.
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    ABSTRACT: SLE is characterized by an increased cardiovascular risk. Since endothelial progenitor cells (EPCs) have been described to serve as a biomarker for the CV risk and are known to be depleted in various diseases, we were interested if SLE would also be associated with altered peripheral EPC levels or functional abnormalities of these cells. EPCs were quantified in 31 female SLE patients with different disease activity and in age-matched healthy controls (HCs) by FACS analysis and by colony forming unit (CFU) assay. Furthermore, EPC adhesion and migration capacity were tested. EPC levels were similar in HC and SLE when assessed by FACS (0.045 +/- 0.006% vs 0.036 +/- 0.007% within the lymphocyte gate) and by the CFU assay (18 +/- 3 vs 15 +/- 2 colonies/well). No correlation with disease activity could be observed, but SLE patients treated with chloroquine exhibited significantly decreased EPC levels (0.058 +/- 0.005% without vs 0.024 +/- 0.008% with chloroquine, P < 0.05). Addition of chloroquine to in vitro cultures also led to a decreased colony formation in SLE and in HC. When testing the adhesion and migration capacity of EPC on human umbilical vein endothelial cells (HUVEC), cells from SLE patients had reduced adhesion (19.2 +/- 3.5% vs 36.6 +/- 5.2% EPC/high power field, P < 0.02) and migratory activity (56 +/- 6 cells/random microscopic field in SLE vs 121 +/- 28 in controls, P < 0.02). The data reveal that EPCs are significantly affected in SLE. While circulating EPC levels are in the range of HC, they exhibit functional deficiencies that may lead to impaired tissue availability.
    Rheumatology (Oxford, England) 10/2008; 47(10):1476-83. · 4.24 Impact Factor
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    ABSTRACT: In an attempt to monitor the pharmacodynamics of mycophenolate mofetil (MMF) we investigated the association of inosine monophosphate dehydrogenase (IMPDH) activity in peripheral blood mononuclear cells with the expression of lymphocyte activation markers in stable cardiac transplant recipients treated with MMF. Twenty-four study patients were switched from azathioprine to MMF 7.2+/-4.1 years after heart transplantation. While the MPA trough level remained unchanged, the mean activity of IMPDH declined from 890 to 462 pmol/10(6)PBMC/h three months after onset of MMF therapy, was almost completely inhibited at six months and partially restored to 160 pmol/10(6)PBMC/h 12 months after switch to MMF (p< .0001). We detected also significant changes in a number of activated lymphocyte subsets: CD4+/25+, CD8+/38+, CD19+/69+, CD3+/16+/56+, natural killer (NK) cells, and monocytes. Moreover, the IMPDH activity profile correlated positively with the number of CD8+/38+ T cells (correlation coefficient (CC) +0.53), and inversely with NK cells (CC -0.52) and CD19+/69+ cells (CC -0.61). We revealed a close association of IMPDH baseline activity in mononuclear cells with the expression of lymphocyte activation markers in stable heart transplant patients after introduction of MMF therapy. This supports the assumption of a rather immunomodulatory than immunosuppressive effect of MMF.
    Clinica Chimica Acta 09/2008; 394(1-2):67-71. · 2.85 Impact Factor

Publication Stats

2k Citations
328.04 Total Impact Points

Institutions

  • 1997–2014
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 2008–2010
    • Ludwig Boltzmann-Cluster Oncology (LB-CO) | Medical University Vienna
      Wien, Vienna, Austria
  • 2004
    • Vienna General Hospital
      Wien, Vienna, Austria
  • 2003
    • Jagiellonian University
      • Department of Medical Biotechnology
      Kraków, Lesser Poland Voivodeship, Poland
  • 2001
    • Ludwig Boltzmann Institute for Osteology
      Wien, Vienna, Austria
  • 1998–2000
    • Ludwig Boltzmann Institute for Cancer Research
      Wien, Vienna, Austria
  • 1990–2000
    • University of Vienna
      • • Department of Cardio-Thoracic Surgery
      • • Department of Surgery
      Vienna, Vienna, Austria