Patrick N Harter

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

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Publications (35)149.46 Total impact

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    ABSTRACT: The transcription factor OCT4 is an established diagnostic marker for central nervous system (CNS) germinoma. However, no data are available to date concerning the expression of its downstream target undifferentiated embryonic cell transcription factor 1 (UTF1) in CNS germ cell tumours.We examined 21 CNS germinomas and two mixed CNS germ cell tumours for UTF1 and the post-transcriptional regulator LIN28 immunohistochemical expression. We compared the profile to established diagnostic germinoma markers and to the expression in six testicular and four metastatic germ cell tumours as well as 150 CNS tumours of various backgrounds.We found UTF1 expression in 23 of 23 and LIN28 in 20 of 23 CNS germ cell tumours. The established germinoma markers cKIT (23/23), OCT4 (21/23) and placental alkaline phosphatase (PLAP) (19/21) were also frequently expressed in our cohort. In terms of signal intensity and frequency, UTF1 showed similar results as cKIT but staining was superior to OCT4, PLAP and LIN28. OCT4 was absent in all CNS metastases and haemangioblastomas, while UTF1 was weakly observed in two metastases.With a sensitivity of 100% and a specificity of 97% in the detection of CNS germinomas, UTF1 serves as a new reliable alternative in the diagnostic setting of CNS germ cell tumours.
    Pathology 03/2014; · 2.66 Impact Factor
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    ABSTRACT: AimsThe prognosis of patients with malignant gliomas is still dismal despite maximum treatment. Novel therapeutic alternatives targeting tumorigenic pathways are, therefore, demanded. In murine glioma models, targeting of tumor necrosis factor receptor superfamily (TNFRSF) 9 led to complete tumor eradication. Thus, TNFRSF9 might also constitute a promising target in human diffuse gliomas. Since there is a lack of data, we aimed to define the expression pattern and cellular source of TNFRSF9 in human gliomas. Methods We investigated TNFRSF9 expression in normal human CNS tissue and glioma specimens using immunohistochemistry, immunofluorescence and western blotting techniques. ResultsOur results show that TNFRSF9 is considerably upregulated in human gliomas when compared to normal brain tissue. In addition, our data provides evidence for an immune cell-independent de novo expression pattern of TNFRSF9 in mainly non-neoplastic reactive astrocytes and excludes classic immunological cell types, namely lymphocytes and microglia as the source of TNFRSF9. Moreover, TNFRSF9 is predominantly expressed in a perivascular and peri-tumoral distribution with significantly higher expression in IDH1 mutant gliomas. Conclusions Our findings provide a novel, TNFRSF9-positive, reactive astrocytic phenotype and challenge the therapeutic suitability of TNFRSF9 as a promising target for human gliomas.
    Neuropathology and Applied Neurobiology 03/2014; · 4.84 Impact Factor
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    ABSTRACT: In the treatment of glioblastoma (GBM) the impact of radical tumor resection as first line therapy is beyond controversy. The significance of a second resection in case of tumor-recurrence remains unclear and is an issue of debate. Since GBMs always recur, it is important to determine whether or not patients will benefit from repeat surgery. We performed a retrospective analysis of our prospectively collected database and evaluated all re-resected patients with primary GBM who underwent second surgery during a 3 years period. All patients underwent early postoperative magnetic resonance imaging. We determined survival after re-resection with regard to possible prognostic factors using Kaplan-Meier estimates and Cox regression analyses. Forty patients were included in this study. Median age was 58 years and median KPS score was 80. Average tumor volume was 5.5 cm(3). A radiologically confirmed complete resection was achieved in 29 patients (72.5 %). Median follow-up was 18.8 months, and median survival after re-resection was 13.5 months. Only complete removal of contrast enhancing tumor was significantly correlated with survival after re-resection according to multivariate analysis. There was a statistical trend for KPS score influencing survival. In contrast, time between first diagnosis and tumor-recurrence, tumor volume at recurrence, MGMT status and MSM score were not significantly correlated with survival after second surgery. In the event of tumor recurrence, patients in good clinical condition with recurrent GBM amenable to complete resection should thus not be withheld second surgery as a treatment option.
    Journal of Neuro-Oncology 02/2014; · 3.12 Impact Factor
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    ABSTRACT: The multifunctional molecule netrin-1 is upregulated in various malignancies and has recently been presented as a major general player in tumorigenesis leading to tumor progression and maintenance in various animal models. However, there is still a lack of clinico-epidemiological data related to netrin-1 expression. Therefore, the aim of our study was to elucidate the association of netrin-1 expression and patient survival in brain metastases since those constitute one of the most limiting factors for patient prognosis. We investigated 104 brain metastases cases for netrin-1 expression using in-situ hybridization and immunohistochemistry with regard to clinical parameters such as patient survival and MRI data. Our data show that netrin-1 is strongly upregulated in most cancer subtypes. Univariate analyses revealed netrin-1 expression as a significant factor associated with poor patient survival in the total cohort of brain metastasis patients and in sub-entities such as non-small cell lung carcinomas. Interestingly, many cancer samples showed a strong nuclear netrin-1 signal which was recently linked to a truncated netrin-1 variant that enhances tumor growth. Nuclear netrin-1 expression was associated with poor patient survival in univariate as well as in multivariate analyses. Our data indicate both total and nuclear netrin-1 expression as prognostic factors in brain metastases patients in contrast to other prognostic markers in oncology such as patient age, number of brain metastases or Ki67 proliferation index. Therefore, nuclear netrin-1 expression constitutes one of the first reported molecular biomarkers for patient survival in brain metastases. Furthermore, netrin-1 may constitute a promising target for future anti-cancer treatment approaches in brain metastases.
    PLoS ONE 01/2014; 9(3):e92311. · 3.73 Impact Factor
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    ABSTRACT: The formation of new blood vessels is a major hallmark in the process of malignant transformation in human glioblastomas. In diffusely infiltrating gliomas, enhanced angiogenesis is associated with decreased patient survival rates and therefore serves as a central diagnostic criterion according to the WHO (World Health Organization) classification of tumors of the central nervous system (CNS). However, the assessment of what a newly built blood vessel really is and how the extent of glioma-associated angiogenesis can be estimated in vivo is often a highly subjective procedure with imprecise criteria depending on the experience of the neuropathologist. The increased interest in translational medicine and anti-angiogenic treatment strategies implies that basic researchers in glioma angiogenesis are frequently asked to validate their findings in patient material to provide evidence for potential clinical relevance of their results. Therefore, more precise methods and measurement techniques are needed to objectively measure the extent of angiogenesis in human glioblastoma samples. The present synopsis provides an overview about morphological methods to assess the formation of new blood vessels by quantitative imaging using histological and immunohistochemical marker profiles.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1135:187-203.
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    ABSTRACT: Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting D-Luciferin (molecular weight (MW) 320D) suggested tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244D) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated after 5weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27x10(-5)cm/s versus 1.12x10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55kD) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to D-Luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.
    Journal of Controlled Release 10/2013; · 7.63 Impact Factor
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    ABSTRACT: The Far Upstream Element [FUSE] Binding Protein 1 (FUBP1) regulates target genes, such as the cell cycle regulators MYC and p21. FUBP1 is up-regulated in many tumours and acts as an oncoprotein by stimulating proliferation and inhibiting apoptosis. Recently, FUBP1 mutations were identified in approximately 15% of oligodendrogliomas. To date, all reported FUBP1 mutations have been predicted to inactivate FUBP1, which suggests that in contrast to most other tumours FUBP1 may act as a tumour suppressor in oligodendrogliomas. As no data are currently available concerning FUBP1 protein levels in gliomas, we examined the FUBP1 expression profiles of human glial tumours by immunohistochemistry and immunofluorescence. We analysed FUBP1 expression related to morphological differentiation, IDH1 and FUBP1 mutation status, 1p/19q loss of heterozygosity (LOH) as well as proliferation rate. Our findings demonstrate that FUBP1 expression levels are increased in all glioma subtypes as compared to normal central nervous system (CNS) control tissue and are associated with increased proliferation. In contrast, FUBP1 immunonegativity predicted FUBP1 mutation with a sensitivity of 100% and a specificity of 90% in our cohort and was associated with oligodendroglial differentiation, IDH1 mutation and 1p/19q loss of heterozygosity (LOH). Using this approach, we detected a to-date undescribed FUBP1 mutation in an oligodendroglioma. In summary, our data indicate an association between of FUBP1 expression and proliferation in gliomas. Furthermore, our findings present FUBP1 immunohistochemical analysis as a helpful additional tool for neuropathological glioma diagnostics predicting FUBP1 mutation.
    Neuropathology and Applied Neurobiology 10/2013; · 4.84 Impact Factor
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    ABSTRACT: The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY® of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12α promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12α promoter methylation and markedly increased AKAP12α mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined.
    Journal of neuropathology and experimental neurology. 09/2013;
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    ABSTRACT: Familial Mediterranean fever (FMF) is an autoinflammatory autosomal recessive disease caused by mutations of the Mediterranean fever (MEFV) gene on chromosome 16p. Clinically, it is characterized by recurrent episodes of fever and painful polyserositis. An association of FMF with systemic vasculitis, namely Henoch-Schönlein purpura, polyarteritis nodosa and Behçet's disease has been described. Neurological manifestations of FMF occur rarely and include demyelinating (MS-like) lesions, posterior reversible encephalopathy syndrome, and pseudotumour cerebri. Hitherto hardly known, we herein present a young patient with a genetically proven FMF who suffered a brain stem infarction during a typical FMF attack. After a careful diagnostic workup including cerebrospinal fluid analysis, intra-arterial angiography and leptomeningeal biopsy, a FMF-associated central nervous system vasculitis was identified as the cause of stroke. The pathophysiological background and potential therapeutic strategies are discussed.
    Clinical and experimental rheumatology 05/2013; · 2.66 Impact Factor
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    ABSTRACT: Diffuse cerebral infiltration of primary brain tumors may be missed on conventional MRI. In glioblastomas it may be visible on MR-perfusion images as an elevated rCBV adjacent to the contrast enhancing area (penumbra). We aimed to evaluate whether penumbral rCBV of primary central nervous system lymphomas (PCNSL) is also increased and if PCNSL perfusion has different features than that of glioblastomas. We measured dynamic susceptibility contrast MR-perfusion at 3 Tesla in 38 presurgical patients with histopathological diagnosis of PCNSL (n = 19) and glioblastoma (n = 19). We compared normalized rCBV within and adjacent to the enhancing area and evaluated time-signal intensity curves (TSIC) in all patients. Histopathological comparison of patients with different TSIC patterns (with or without shoulder-like increase) was performed. Relative to the normal tissue, rCBV within and adjacent to the enhancing area was increased (p < 0.05) in both glioblastomas and PCNSL. In the penumbra the increase was moderate in both groups, with 1.4 ± 0.46 in PCNSL and 1.82 ± 0.82 in glioblastomas (p = 0.07 between groups). In the enhancing tumor the increase was moderate in PCNSL (1.46 ± 0.62) and marked in glioblastomas (4.13 ± 2.44) (p < 0.001 between groups). A shoulder-like TSIC increase was exclusively found in PCNSL (11/19) and was significantly associated with a less prominent reticulin fibre network compared to the PCNSL without a shoulder-like TSIC increase. The moderately increased penumbral rCBV in PCNSL and glioblastomas reveals tumor-related changes beyond the tumor borders which are invisible with conventional MRI. PCNSL can be differentiated from glioblastomas through their significantly lower rCBV and shoulder-like signal intensity changes inside the enhancing area.
    Journal of Neuro-Oncology 05/2013; · 3.12 Impact Factor
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    ABSTRACT: Aims: WHO grade III meningiomas are malignant neoplasms for which new and more targeted treatment strategies are urgently needed. Although clinical trials investigating anti-angiogenic vascular endothelial growth factor (VEGF) targeted therapies are currently recruiting, knowledge about the expression of VEGF and VEGF receptors remains to be determined. Methods: We investigated the expression of VEGF and its receptors VEGFR1 and VEGFR2 in 32 WHO grade III meningioma samples by immunohistochemistry. Furthermore, we performed in-situ hybridisation for VEGF. Results: We found low VEGF expression in tumor and endothelial cells. Highest VEGF expression levels were seen in peri-necrotic tumor cells potentially suffering from hypoxia. VEGFR1 and 2 were virtually absent on tumor cells, although endothelial cells displayed significantly higher levels reaching stronger expression for VEGFR2 than VEGFR1. Conclusions: Our findings showing constant expression levels of VEGFR2 in endothelial cells serve as a first indication that the use of small tyrosine kinase inhibitors such as Sunitinib directly targeting the VEGF-receptors might be worth testing, also in the clincial context in cases of therapy-refractory meningiomas. Further investigations are needed to study the response to drugs targeting the VEGF pathway in relation to the expression profile of VEGF and its receptors in high grade meningiomas.
    Histology and histopathology 03/2013; · 2.28 Impact Factor
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    ABSTRACT: In vitro and descriptive studies of human tissue samples revealed the pro-coagulant glycoprotein tissue factor (TF) as a potent player in glioma cell infiltration that is activated by hypoxia and has also been shown to be upregulated by mutations of TP53 or PTEN. Here we present the morphological and genetic characterization of a novel glioblastoma in vivo model and provide evidence that treatment with an antibody targeting TF leads to reduced glioma cell invasiveness. Therefore, we established a murine xenograft treatment model by transplanting the angiogenic and diffusely infiltrating human glioma cell line MZ-18 with endogenous TF expression into nude mice brains and treating these mice with an intracranial osmotic pump system continuously infusing a monoclonal antibody against TF (mAb TF9-10H10). The human MZ-18 cell line harbors two TP53 mutations resulting in a strong nuclear accumulation of p53, thereby facilitating the unambiguous identification of tumor cells in the xenograft model. Intracranial application of TF9-10H10 significantly reduced invasion of MZ-18 cells compared to mock-treated control animals. The extent of activated blood vessels was also reduced upon anti-TF treatment. Thus, targeting the TF pathway might be a promising treatment strategy for future glioblastoma therapies, by affecting both invading tumor cells and tumor vasculature.
    Neuropathology 02/2013; · 1.91 Impact Factor
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    ABSTRACT: Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin α(v)β(3). Here we identify the endothelial cell (EC)-secreted factor epidermal growth factor-like protein 7 (EGFL7) as a novel specific ligand of integrin α(v)β(3) thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the ECM and by its interaction with integrin α(v)β(3) increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads to a severe integrin-dependent malformation of the caudal venous plexus (CVP), pointing towards the significance of EGFL7 in vessel development. In biopsies of patients with neurological diseases, vascular EGFL7 expression rose with increasing EC proliferation. Further, EGFL7 became upregulated in vessels of the stroke penumbra using a mouse model of reversible middle cerebral artery occlusion (MCAO). Our data suggest that EGFL7 expression depends on the remodeling state of the existing vasculature rather than on the phenotype of neurological disease analyzed. In sum, our work sheds a novel light on the molecular mechanism EGFL7 engages to govern physiological and pathological angiogenesis.
    Blood 02/2013; · 9.06 Impact Factor
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    ABSTRACT: A disintegrin and metalloproteinase 17 (ADAM17) is a metalloprotease that is overexpressed in many cancer types, including renal cancers. However, the regulatory mechanisms of ADAM17 in cancer development and progression are poorly understood. In the present work, we provide evidence using overexpression and inhibition of microRNA 145 (miR-145) that miR-145 negatively regulates ADAM17 expression. Furthermore, we show that ADAM17 negatively regulates miR-145 through tumor necrosis factor-α, resulting in a reciprocal negative feedback loop. In this study, the expression of ADAM17 and miR-145 correlated negatively in renal cancer tumor tissues and cell lines, suggesting an important regulatory mechanism. Additionally, we showed that the regulation of ADAM17 is partly involved in the effects of miR-145 on proliferation and migration, whereas no involvement in chemosensitivity was observed. Importantly, in the healthy kidney, miR-145 was detected in different cell types including tubular cells, which are considered the origin of renal cancer. In renal cancer cell lines, miR-145 expression was strongly suppressed by methylation. In summary, miR-145 is downregulated in renal cancer patients, which leads to the up-regulation of ADAM17 in renal cancer. Importantly, miR-145 and ADAM17 are regulated in a reciprocal negative feedback loop.
    Neoplasia (New York, N.Y.) 02/2013; 15(2):218-30. · 5.48 Impact Factor
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    ABSTRACT: Because the onset of myocardial infarction and stroke has distinct circadian patterns, the disruption of circadian rhythms may contribute to cardiovascular disease. A recent clinical study, reporting that the severity of myocardial ischemia depends on the time-of-day when ischemia occurs, highlights the impact of circadian rhythms on cardiovascular disease. In support of these observations, we found a cardioprotective role of the circadian rhythm protein Period 2 (Per2) during myocardial ischemia in mice. In these studies, exposing mice to daylight induced cardiac Per2, which was associated with protection from myocardial ischemia. Recent epidemiological studies found sunlight as dominant regulator of the human circadian rhythm, suggesting sunlight cycles are critical for maintaining a healthy cardiovascular system. However, the impact of circadian rhythm proteins on human disease remains unclear. The current review aims to make a link to current and future clinical practice by targeting cardiac Per2.
    The international journal of biochemistry & cell biology 01/2013; · 4.89 Impact Factor
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    ABSTRACT: The migration of polymorphonuclear granulocytes (PMN) into the brain parenchyma and release of their abundant proteases are considered the main causes of neuronal cell death and reperfusion injury following ischemia. Yet, therapies targeting PMN egress have been largely ineffective. To address this discrepancy we investigated the temporo-spatial localization of PMNs early after transient ischemia in a murine transient middle cerebral artery occlusion (tMCAO) model and human stroke specimens. Using specific markers that distinguish PMN (Ly6G) from monocytes/macrophages (Ly6C) and that define the cellular and basement membrane boundaries of the neurovascular unit (NVU), histology and confocal microscopy revealed that virtually no PMNs entered the infarcted CNS parenchyma. Regardless of tMCAO duration, PMNs were mainly restricted to luminal surfaces or perivascular spaces of cerebral vessels. Vascular PMN accumulation showed no spatial correlation with increased vessel permeability, enhanced expression of endothelial cell adhesion molecules, platelet aggregation or release of neutrophil extracellular traps. Live cell imaging studies confirmed that oxygen and glucose deprivation followed by reoxygenation fail to induce PMN migration across a brain endothelial monolayer under flow conditions in vitro. The absence of PMN infiltration in infarcted brain tissues was corroborated in 25 human stroke specimens collected at early time points after infarction. Our observations identify the NVU rather than the brain parenchyma as the site of PMN action after CNS ischemia and suggest reappraisal of targets for therapies to reduce reperfusion injury after stroke.
    Acta Neuropathologica 12/2012; · 9.73 Impact Factor
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    ABSTRACT: Cardiac ischemia-reperfusion (I-R) injury represents a major cause of cardiac tissue injury. Adenosine signaling dampens inflammation during cardiac I-R. The authors investigated the role of the adenosine A2b-receptor (Adora2b) on inflammatory cells during cardiac I-R. To study Adora2b signaling on inflammatory cells, the authors transplanted wild-type (WT) bone marrow (BM) into Adora2b(-/-) mice or Adora2b(-/-) BM into WT mice. To study the role of polymorphonuclear leukocytes (PMNs), neutrophil-depleted WT mice were treated with an Adora2b agonist. After treatments, mice were exposed to 60 min of myocardial ischemia and 120 min of reperfusion. Infarct sizes and troponin I concentrations were determined by triphenyltetrazolium chloride staining and enzyme-linked immunosorbent assay, respectively. Transplantation of WT BM into Adora2b(-/-) mice decreased infarct sizes by 19 ± 4% and troponin I by 87.5 ± 25.3 ng/ml (mean ± SD, n = 6). Transplantation of Adora2b(-/-) BM into WT mice increased infarct sizes by 20 ± 3% and troponin I concentrations by 69.7 ± 17.9 ng/ml (mean ± SD, n = 6). Studies on the reperfused myocardium revealed PMNs as the dominant cell type. PMN depletion or Adora2b agonist treatment reduced infarct sizes by 30 ± 11% or 26 ± 13% (mean ± SD, n = 4); however, the combination of both did not produce additional cardioprotection. Cytokine profiling showed significantly higher cardiac tumor necrosis factor α concentrations in Adora2b(-/-) compared with WT mice (39.3 ± 5.3 vs. 7.5 ± 1.0 pg/mg protein, mean ± SD, n = 4). Pharmacologic studies on human-activated PMNs revealed an Adora2b-dependent tumor necrosis factor α release. Adora2b signaling on BM-derived cells such as PMNs represents an endogenous cardioprotective mechanism during cardiac I-R. The authors' findings suggest that Adora2b agonist treatment during cardiac I-R reduces tumor necrosis factor α release of PMNs, thereby dampening tissue injury.
    Anesthesiology 04/2012; 116(6):1245-57. · 5.16 Impact Factor
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    ABSTRACT: Glioblastoma (GBM), the most common malignant brain tumor, is among the most lethal neoplasms, with a median survival of approximately 1 year. Prognosis is poor since GBMs possess a strong migratory and highly invasive potential, making complete surgical resection impossible. Reduced expression of carboxypeptidase E (CPE), a neuropeptide-processing enzyme, in a cell death-resistant glioma cell line and lower CPE expression levels in the cohort of GBM samples of The Cancer Genome Atlas compared to normal brain control specimens prompted us to analyze the function of CPE as a putative tumor suppressor gene. In our samples, CPE was also reduced in GBM compared to normal brain with the strongest loss in cells surrounding hypoxic tumor areas as well as in most glioma cell lines and primary glioma cells. In our cohort of glioma patients, loss of CPE predominantly occurred in glioblastomas and was associated with worse prognosis. In glioma cells, CPE overexpression was significantly reduced, whereas knockdown or inhibition enhanced glioma cell migration and invasion. The decreased migratory potential following CPE overexpression was paralleled by altered cellular morphology, promoting a transition to focal adhesions and associated stress fibers. In contrast to the decreased migration, high CPE levels were associated with higher proliferative rates. As microenvironmental regulation cues, we identified CPE as being downregulated upon hypoxia or glucose deprivation. Our findings indicate an oxygen- and nutrition-dependent anti-migratory, but pro-proliferative role of CPE in gliomas with prognostic impact for patient survival, thereby contributing to the understanding of the "go or grow" hypothesis in gliomas.
    Acta Neuropathologica 01/2012; 124(1):83-97. · 9.73 Impact Factor
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    ABSTRACT: In Europe, commercially available extracts from the white-berry mistletoe (Viscum album L.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-β and matrix-metalloproteinases. Using in vitro glioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.
    Evidence-based Complementary and Alternative Medicine 01/2012; 2012:501796. · 1.72 Impact Factor

Publication Stats

158 Citations
149.46 Total Impact Points


  • 2012–2014
    • Goethe-Universität Frankfurt am Main
      • Institute of Neurology - Edinger Institute
      Frankfurt, Hesse, Germany
  • 2012–2013
    • University Hospital Frankfurt
      Frankfurt, Hesse, Germany
  • 2011
    • University of Tuebingen
      Tübingen, Baden-Württemberg, Germany
  • 2008
    • University of Zurich
      • Division of Neuropsychology
      Zürich, Zurich, Switzerland