Martin Hermann

University of Innsbruck, Innsbruck, Tyrol, Austria

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Publications (109)432.64 Total impact

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    ABSTRACT: Brain death (BD) has been associated with an immunological priming of donor organs and is thought to exacerbate ischemia reperfusion injury (IRI). Recently, we showed that the essential nitric oxide synthase co-factor tetrahydrobiopterin (BH4) abrogates IRI following experimental pancreas transplantation. We therefore studied the effects of BD in a murine model of syngeneic pancreas transplantation and tested the therapeutic potential of BH4 treatment. Compared with sham-operated controls, donor BD resulted in intragraft inflammation reflected by induced IL-1ß, IL-6, VCAM-1, and P-selectin mRNA expression levels and impaired microcirculation after reperfusion (p < 0.05), whereas pretreatment of the BD donor with BH4 significantly improved microcirculation after reperfusion (p < 0.05). Moreover, BD had a devastating impact on cell viability, whereas BH4-treated grafts showed a significantly higher percentage of viable cells (p < 0.001). Early parenchymal damage in pancreatic grafts was significantly more pronounced in organs from BD donors than from sham or non-BD donors (p < 0.05), but BH4 pretreatment significantly ameliorated necrotic lesions in BD organs (p < 0.05). Pretreatment of the BD donor with BH4 resulted in significant recipient survival (p < 0.05). Our data provide novel insights into the impact of BD on pancreatic isografts, further demonstrating the potential of donor pretreatment strategies including BH4 for preventing BD-associated injury after transplantation. © 2015 The Authors. American Journal of Transplantation Published by Wiley Periodicals, Inc. on behalf of American Society of Transplant Surgeons.
    American Journal of Transplantation 06/2015; DOI:10.1111/ajt.13364 · 6.19 Impact Factor
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    ABSTRACT: Total pancreatectomy is a last option for patients in whom all other efforts for managing intractable pain caused by chronic pancreatitis have failed. When performed with a simultaneous islet autotransplantation, endogenous insulin production can be preserved to some extent. Although it does not necessarily prevent any future need for exogenous insulin, the diabetic state of the patient is less severe compared to pancreatectomy alone. In contrast to islet allotransplantation, the patients do not require immunosuppressive drugs and are not at risk for autoimmune destruction or alloimmune rejection. Consequently, insulin independence is more likely to be preserved in autoislet-transplanted patients than in those patients who received alloislet transplants. Therefore, the setting of islet autotransplantation allows the study of the transplanted islets without interference from medication or immunological variables.
    Islets of Langerhans, 01/2015: pages 1229-1243; , ISBN: 978-94-007-6685-3
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    ABSTRACT: Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of male cancer death in Western nations. Thus, new treatment modalities are urgently needed. Elevated production of reactive oxygen species (ROS) by NADPH oxidase (Nox) enzymes is implicated in tumorigenesis of the prostate and other tissues. However, the identity of the Nox enzyme(s) involved in prostate carcinogenesis remains largely unknown. Analysis of radical prostatectomy tissue samples and benign and malignant prostate epithelial cell lines identified Nox5 as an abundantly expressed Nox isoform. Consistently, immunohistochemical staining of a human PCa tissue microarray revealed distinct Nox5 expression in epithelial cells of benign and malignant prostatic glands. shRNA-mediated knockdown of Nox5 impaired proliferation of Nox5-expressing (PC-3, LNCaP) but not Nox5-negative (DU145) PCa cell lines. Similar effects were observed upon ROS ablation via the antioxidant N-acetylcysteine confirming ROS as the mediators. In addition, Nox5 silencing increased apoptosis of PC-3 cells. Concomitantly, protein kinase C zeta (PKCζ) protein levels and c-Jun N-terminal kinase (JNK) phosphorylation were reduced. Moreover, the effect of Nox5 knockdown on PC-3 cell proliferation could be mimicked by pharmacological inhibition of JNK. Collectively, these data indicate that Nox5 is expressed at functionally relevant levels in the human prostate and clinical PCa. Moreover, findings herein suggest that Nox5-derived ROS and subsequent depletion of PKCζ and JNK inactivation play a critical role in modulating intracellular signaling cascades involved in the proliferation and survival of PCa cells. © 2014 The Authors. Molecular Carcinogenesis published by Wiley Periodicals, Inc.
    Molecular Carcinogenesis 12/2014; DOI:10.1002/mc.22255 · 4.77 Impact Factor
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    ABSTRACT: Aim of this study was to identify the nitric oxide synthase (NOS) isoform involved in early microcirculatory derangements following solid organ transplantation.
    PLoS ONE 11/2014; 9(11):e112570. DOI:10.1371/journal.pone.0112570 · 3.53 Impact Factor
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    ABSTRACT: Type 2 diabetes is associated with pancreatic α cell dysfunction, characterized by elevated fasting plasma glucagon concentrations and inadequate postprandial glucose- and insulin-induced suppression of glucagon secretion. The cause and the underlying mechanisms of α cell dysfunction are unknown.
    American Journal of Clinical Nutrition 11/2014; 100(5):1222-31. DOI:10.3945/ajcn.114.092023 · 6.92 Impact Factor
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    ABSTRACT: Background: Mitochondrial reactive oxygen species (ROS) produced during early reperfusion are important triggers for the development of ischemia/ reperfusion injury (IRI) in the course of solid organ transplantation. However, antioxidants yielded little clinical benefit in the prevention of IRI, most likely because of the failure to timely and efficiently target to the site of ROS production and action. In our work we are pursuing strategies to limit or prevent the early increase in ROS by targeting intracellular signaling pathways. Cytosolic p66SHC, which translocates to the mitochondria under stress to oxidize cytochrome c , is one of the main sources of ROS under stress conditions. Gene ablation experiments in mice also confirmed its important role in the development of IRI. Here we identified pathways essential for the activation of p66SHC, which may be targeted for therapeutic purposes. Methods: HL-1 cardiomyocytes and mouse embryonic fibroblasts (MEFs) were exposed to hypoxia/reoxygenation (HR) or pro-oxidant treatment. Intracellular signaling was monitored by phosphorylation-specific antibodies. ROS were detected by MitoTracker Red CM-H2XRos, DCF-DA, or protein- based ROS probes in vivo phosphorylation of p66SHC was analyzed by mass spectrometry. Results: Using MEFs and HL-1 cardiomyocytes we failed to detect the previously reported PKCß-dependent phosphorylation of p66SHC on S36 and instead identified S139 as critical target under oxidative stress. In p66SHC- deficient MEFs reconstituted with the S139A mutant of p66SHC we observed significantly reduced ROS levels. Also MAPK activities (ERK, JNK, p38), p66SHC S36 phosphorylation and ROS production were increased under prooxidant treatment and HR. Inhibition of signaling through MAPKs with specific inhibitors showed a pronounced decrease in p66SHC S36 phosphor- ylation only for JNK, which also directly interacted with p66SHC. Moreover, JNK inhibition resulted in decreased ROS production and reduced DNA damage. We further confirmed JNK-dependent regulation of p66SHC S36 phosphorylation, ROS production and cell death using JNK 1, 2 deficient MEFs. Finally, the low ROS phenotype of JNK 1, 2 knockout MEFs was reversed by introducing p66SHC mutated in S36E. Conclusion: Interference with p66SHC activation by targeting upstream pathways (PKCß, JNK) thus may provide a therapeutic approach for decreas- ing damage to cells and organs during ischemia/reperfusion.
    AUSTROTRANSPLANT, Bad Ischl; 10/2014
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    ABSTRACT: FOXO transcription factors control cellular levels of reactive oxygen species (ROS) which critically contribute to cell survival and cell death in neuroblastoma. In the present study we investigated the regulation of C10orf10/DEPP by the transcription factor FOXO3. As a physiological function of C10orf10/DEPP has not been described so far we analyzed its effects on cellular ROS detoxification and death sensitization in human neuroblastoma cells.
    Molecular Cancer 09/2014; 13(1):224. DOI:10.1186/1476-4598-13-224 · 5.40 Impact Factor
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    ABSTRACT: Premature birth represents a clinical situation of risk for brain injury. The diversity of pathophysiological processes complicates efforts to find effective therapeutic strategies. Excitotoxicity is one important factor in the pathogenesis of preterm brain injury. The observation that sigma-1 receptor agonists possess neuroprotective potential, at least partly mediated by a variety of anti-excitotoxic mechanisms, has generated great interest in targeting those receptors to counteract brain injury. The objective of this study was to evaluate the effect of the highly specific sigma-1 receptor agonist, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) to protect against excitotoxic developmental brain injury in vivo and in vitro. Primary hippocampal neurons were pre-treated with PPBP before glutamate was applied and subsequently analysed for cell death (PI/calcein AM), mitochondrial activity (TMRM) and morphology of the neuronal network (WGA) using confocal microscopy. Using an established neonatal mouse model we also determined whether systemic injection of PPBP significantly attenuates excitotoxic brain injury. PPBP significantly reduced neuronal cell death in primary hippocampal neurons exposed to glutamate. Neurons treated with PPBP showed a less pronounced loss of mitochondrial membrane potential and fewer morphological changes after glutamate exposure. A single intraperitoneal injection of PPBP given one hour after the excitotoxic insult significantly reduced microglial cell activation and lesion size in cortical gray and white matter. The present study provides strong support for the consideration of sigma-1 receptor agonists as a candidate therapy for the reduction of neonatal excitotoxic brain lesions and might offer a novel target to counteract developmental brain injury.
    Experimental Neurology 08/2014; 261. DOI:10.1016/j.expneurol.2014.07.022 · 4.62 Impact Factor
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    ABSTRACT: Background. The effect of cold ischemia (CI) in vascularized composite allotransplantation is unknown. We herein assess tissue-specific damage, acceptable CI time, and the effect of preservation solutions in a syngenic rat hindlimb transplant model. Methods. Lewis rat limbs were flushed and stored for 2, 10, or 30 hr CI in saline, histidine-tryptophan-ketoglutarate or University of Wisconsin preservation solution before transplantation. Morphologic alterations, inflammation, and damage of the individual tissues were analyzed on day 10 using histomorphology, confocal, light, and transmission-electron microscopy. Results. Two-hour CI led to mild inflammation of tissues on day 10, whereas 10-hr and 30-hr CI resulted in massive inflammation and tissue damage. Although muscle was mainly affected after prolonged CI (>= 10 hr), nerve was affected in all CI groups. A perineural cell infiltrate, hypercellular appearance, pronounced vacuolization, and mucoid degeneration, appearing as Wallerian degeneration, were observed. Staining with propidium iodide and Syto 16 revealed a decrease in viable muscle cell nuclei in the anterior tibial muscle on day 10 in all groups, which was most pronounced in 10-hr and 30-hr CI animals. Transmission-electron microscopy indicated that a large number of mitochondria were degenerated in the 10-hr and 30-hr CI groups. Histidine-tryptophan-ketoglutarate preservation solution slightly decreased inflammation and tissue damage compared to University of Wisconsin-treated and saline-treated animals, especially in skin and muscle when CI times did not exceed 10 hr. Conclusion. Severe inflammation and tissue damage are observed after prolonged CI in muscle and nerve. Ischemia times in vascularized composite allotransplantation should be kept as short as possible and certainly below 10 hr.
    Transplantation 07/2014; 98(7). DOI:10.1097/TP.0000000000000300 · 3.78 Impact Factor
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    ABSTRACT: Prolonged Ischemia (I) times caused by organ procurement and transport are main contributors to a decrease in organ function, which is further enhanced during early reperfusion (R). This combined damage, referred to as ischemia-reperfusion injury (IRI), is a main contributor to delayed graft function, which leads to costly and lengthy follow-up treatments or even organ loss. Methods to monitor the status of a graft prior to transplantation are, therefore, highly desirable to optimize the clinical outcome. Here we propose the use of fine needle biopsies, which are analyzed by real time live confocal microscopy. Such a combination provides information about the functional and structural integrity of an organ within a few minutes. To confirm the feasibility of this approach, we obtained fine needle biopsies from rodent kidneys and exposed them to various stress conditions. Following the addition of a range of live stains, biopsies were monitored for mitochondrial function, cell viability and tissue integrity using confocal live cell imaging. Our data demonstrate that this procedure requires minimal time for sample preparation and data acquisition and is well suitable to record organ damage resulting from unphysiological stress. This article is protected by copyright. All rights reserved.
    Transplant International 04/2014; 27(8). DOI:10.1111/tri.12338 · 3.16 Impact Factor
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    ABSTRACT: Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects. Here we identified p38MAPKalpha as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKalpha signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death. These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.
    Cell Communication and Signaling 01/2014; 12(1):6. DOI:10.1186/1478-811X-12-6 · 4.67 Impact Factor
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    ABSTRACT: Islet transplantation is a valid treatment option for patients suffering from type 1 diabetes mellitus. To assure optimal islet cell quality, specialized islet isolation facilities have been developed. Utilization of such facilities necessitates transportation of islet cells to distant institutions for transplantation. Despite its importance, a clinically feasible solution for the transport of islets has still not been established. We here compare the functionality of isolated islets from C57BL/6 mice directly after the isolation procedure as well as after two simulated transport conditions, static versus rotation. Islet cell quality was assessed using real-time live confocal microscopy. In vivo islet function after syngeneic transplantation was determined by weight and blood sugar measurements as well as by intraperitoneal glucose tolerance tests. Vascularization of islets was documented by fluorescence microscopy and immunohistochemistry. All viability parameters documented comparable cell viability in the rotary group and the group transplanted immediately after isolation. Functional parameters assessed in vivo displayed no significant difference between these two groups. Moreover, vascularization of islets was similar in both groups. In conclusion, rotary culture conditions allows the maintenance of highest islet quality for at least 15 h, which is comparable to that of freshly isolated islets.
    11/2013; 2013:975608. DOI:10.1155/2013/975608
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    ABSTRACT: Langerhans cells (LCs) are dendritic cells (DCs) residing in epithelia, where they critically regulate immunity and tolerance. The p14 adaptor molecule is part of the late endosomal/lysosomal adaptor and MAPK and mTOR activator/regulator (LAMTOR) complex, thereby contributing to the signal transduction of the "extracellular signaling-regulated kinase" (ERK) and the "mammalian target of rapamycin" (mTOR) cascade. Furthermore, p14 represents an important regulator for endosomal sorting processes within the cell. Mutated, dysfunctional p14 leads to a human immunodeficiency disorder with endosomal/lysosomal defects in immune cells. Since p14 participates in the regulation of endosomal trafficking, growth factor signaling and cell proliferation, we investigated the role of p14 in mouse DCs/LCs using a conditional knock out mouse model. p14-deficient animals displayed a virtually complete loss of LCs in the epidermis early after birth due to impaired proliferation and increased apoptosis of LCs. Repopulation analysis after application of contact sensitizer leads to the recruitment of a transient LC population, predominantly consisting of short-term LCs. The underlying molecular mechanism involves the p14-mediated disruption of the LAMTOR complex which results in the malfunction of both ERK and mTOR signal pathways. Hence, we conclude that p14 acts as a novel and essential regulator of LC homeostasis in vivo.
    Blood 10/2013; 123(2). DOI:10.1182/blood-2013-08-518555 · 10.43 Impact Factor
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    ABSTRACT: Ischemia-reperfusion injury is a primarily non-allospecific event leading to the depletion of the essential nitric oxide synthase cofactor and potent antioxidant tetrahydrobiopterin. Suboptimal concentrations of tetrahydrobiopterin result in a reduced biosynthesis of nitric oxide leading to vascular endothelial dysfunction. Tetrahydrobiopterin supplementation has been shown to protect from this pathological state in a plethora of cardiovascular diseases including transplant-related ischemia-reperfusion injury. Even though still controversially discussed, there is increasing evidence emerging from both human as well as animal studies that tetrahydrobiopterin-mediated actions rely on its nitric oxide synthase cofactor activity rather than on its antioxidative properties. Herein, we review the current literature regarding the role of tetrahydrobiopterin in ischemia-reperfusion injury including our experience acquired in a murine pancreas transplantation model.
    06/2013; 24(1). DOI:10.1515/pterid-2013-0006
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    ABSTRACT: Dysregulation of the insulin-like growth factor (IGF) axis is implicated in the development of benign prostatic hyperplasia (BPH) and prostate cancer (PCa), two of the most common diseases affecting elderly males. PCa is the second leading cause of male-related cancer death in Western societies. Although distinct pathologies, BPH and PCa are both characterized by extensive stromal remodeling, in particular fibroblast-to-myofibroblast differentiation thought to be induced by elevated local production of transforming growth factor beta 1 (TGFβ1). We previously showed that TGFβ1-mediated fibroblast-to-myofibroblast differentiation of primary human prostatic stromal cells (PrSCs) resulted in dsyregulation of several components of the IGF axis, including induction of IGF binding protein 3 (IGFBP3). Using isoform-specific lentiviral-mediated knockdown, we demonstrate herein that IGFBP3 is essential for TGFβ1-mediated differentiation. Whilst recombinant human IGFBP3 alone was not sufficient to induce differentiation, IGFBP3 synergistically potentiated TGFβ1-mediated stromal remodeling predominantly via an IGF-independent mechanism. Consistent with these in vitro findings, IGFBP3 immunohistochemistry revealed elevated levels of IGFBP3 in the hyperplastic fibromuscular stroma of BPH specimens and in the tumor-adjacent stroma of high-grade PCa. Collectively, these data indicate that dysregulation of the stromal IGF axis, in particular elevated IGFBP3, plays a crucial role in fibroblast-to-myofibroblast differentiation in the diseased prostatic stroma and indicate the therapeutic potential of inhibiting stromal remodeling and the resulting dysregulation of the stromal IGF axis as a novel strategy for the treatment of advanced PCa and BPH.
    Endocrinology 05/2013; 154(8). DOI:10.1210/en.2012-2259 · 4.64 Impact Factor
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    ABSTRACT: Infections with enterohemorrhagic Escherichia coli (EHEC) are a primary cause of hemolytic uremic syndrome (HUS). Recently, Shiga toxin 2 (Stx2), the major virulence factor of EHEC, was reported to interact with complement, implying that the latter is involved in the pathogenesis of EHEC-induced HUS.The aim of the present study was to investigate the effect of Stx2 on the expression of membrane-bound complement regulators CD46, CD55 and CD59 on proximal tubular epithelial (HK-2) and glomerular endothelial (GEnC) cells, derived from human kidney cells that are involved in HUS.Incubation with Stx2 did not influence the amount of CD46 and CD55 on the surface of HK-2 and GEnC cells, as determined by FACS. In contrast, CD59 was significantly reduced by half on GEnC cells, but less pronounced on HK-2 cells. With increasing amounts of Stx2 reduction of CD59 also reached significance in HK-2 cells. ELISA analyses showed that CD59 was not present in supernatant of Stx2-treated cells, implying that CD59 reduction was not caused by cleavage from the cell surface. In fact, RT-qPCR analyses showed downregulation of CD59 mRNA as likely reason for CD59 cell surface reduction. In addition, a significant increase in terminal complement complex deposition on HK-2 cells was observed after treatment with Stx2, as possible consequence of CD59 downregulation.In summary, Stx2 downregulates CD59 on mRNA and protein levels on tubular epithelial and glomerular endothelial cells, which likely contributes to complement activation and kidney destruction in EHEC-associated HUS.
    Infection and immunity 05/2013; DOI:10.1128/IAI.01079-12 · 4.16 Impact Factor
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    ABSTRACT: Lipocalin-2 (Lcn2) expression contributes to ischemia and reperfusion injury (IRI) by enhancing pro-inflammatory responses. The aim of this work was to elucidate the regulation of Lcn2 during hypoxia and its effects on the expression of key chemokines and adhesion molecules. Lcn2 wt and Lcn2(-/-) mice were used in a heterotopic heart transplantation model. Quantitative RT-PCR was applied for chemokine gene expression analysis. Reporter gene studies were used to elucidate the regulation of the Lcn2 promoter by hypoxia. HIF-1β expression led to a 2.4-fold induction of the Lcn2 promoter. Apart from an earlier onset of granulocyte infiltration in the Lcn2 wt setting after 2 h of reperfusion compared with the Lcn2(-/-) setting (P < 0.013), exogenous application of recombinant Lcn2 revealed a trend toward increase of granulocyte infiltration. Analyzed chemokines were expressed significantly higher in the Lcn2 wt setting at 2 h of reperfusion (P ≤ 0.05). The number of apoptotic cells observed in Lcn2(-/-) grafts was significantly higher than in the Lcn2 wt setting. Our results indicate that Lcn2 affects granulocyte infiltration in the reperfused graft by modulating the expression of chemokines, their receptors and the apoptotic rate.
    Transplant International 05/2013; DOI:10.1111/tri.12116 · 3.16 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) generated by NADPH oxidases play an important role in cellular signal transduction regulating cell proliferation, survival and differentiation. NADPH oxidase 4 (Nox4) induces cellular senescence in human endothelial cells; however, intracellular targets for Nox4 remained elusive. Here we show that Nox4 induces mitochondrial dysfunction in human endothelial cells. Nox4 depletion induced alterations in mitochondrial morphology, stabilized mitochondrial membrane potential, and decreased production of hydrogen peroxide in mitochondria. High-resolution respirometry in permeabilized cells combined with native polyacrylamide gel electrophoresis demonstrated that Nox4 specifically inhibits the activity of mitochondrial electron transport chain complex I, and this was associated with a decreased concentration of complex I subunits. These data suggest a new pathway by which sustained Nox4 activity decreases mitochondrial function.
    Biochemical Journal 03/2013; 452. DOI:10.1042/BJ20121778 · 4.78 Impact Factor
  • 36. Seminar für Chirurgische Forschung, Vienna, Austria; 11/2012
  • 26. Tagung der Österreichischen Gesellschaft für Transplantation, Transfusion und Genetik, Rust am Neusiedlersee, Austria; 10/2012