TY - JOUR A1 - Breun, Maria A1 - Monoranu, Camelia M. A1 - Kessler, Almuth F. A1 - Matthies, Cordula A1 - Löhr, Mario A1 - Hagemann, Carsten A1 - Schirbel, Andreas A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Buck, Andreas K. A1 - Wester, Hans-Jürgen A1 - Ernestus, Ralf-Ingo A1 - Lapa, Constantin T1 - [\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas JF - Frontiers in Oncology N2 - We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor. Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients. Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors. Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression. KW - vestibular schwannoma KW - CXCR4 KW - PET/CT KW - molecular imaging KW - Pentixafor Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201863 VL - 9 IS - 503 ER - TY - JOUR A1 - Lapa, Constantin A1 - Lückerath, Katharina A1 - Kleinlein, Irene A1 - Monoranu, Camelia Maria A1 - Linsenmann, Thomas A1 - Kessler, Almuth F. A1 - Rudelius, Martina A1 - Kropf, Saskia A1 - Buck, Andreas K. A1 - Ernestus, Ralf-Ingo A1 - Wester, Hans-Jürgen A1 - Löhr, Mario A1 - Herrmann, Ken T1 - \(^{68}\)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma JF - Theranostics N2 - Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. \(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy. KW - imaging KW - chemokine receptor-4 KW - glioblastoma KW - positron emission tomography/computed tomography KW - \(^{68}\)Ga-Pentixafor Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168174 VL - 6 IS - 3 ER - TY - JOUR A1 - Hagemann, Carsten A1 - Anacker, Jelena A1 - Ernestus, Ralf-Ingo A1 - Vince, Giles H. T1 - A complete compilation of matrix metalloproteinase expression in human malignant gliomas JF - World Journal of Clinical Oncology N2 - Glioblastomas are characterized by an aggressive local growth pattern, a marked degree of invasiveness and poor prognosis. Tumor invasiveness is facilitated by the increased activity of proteolytic enzymes which are involved in destruction of the extracellular matrix of the surrounding healthy brain tissue. Elevated levels of matrix metalloproteinases (MMPs) were found in glioblastoma (GBM) cell-lines, as well as in GBM biopsies as compared with low-grade astrocytoma (LGA) and normal brain samples, indicating a role in malignant progression. A careful review of the available literature revealed that both the expression and role of several of the 23 human MMP proteins is controversely discussed and for some there are no data available at all. We therefore screened a panel of 15 LGA and 15 GBM biopsy samples for those MMPs for which there is either no, very limited or even contradictory data available. Hence, this is the first complete compilation of the expression pattern of all 23 human MMPs in astrocytic tumors. This study will support a better understanding of the specific expression patterns and interaction of proteolytic enzymes in malignant human glioma and may provide additional starting points for targeted patient therapy. KW - glioblastoma cell-lines KW - matrix metalloproteinase KW - glioblastoma multiforme KW - astrocytic tumor KW - expression pattern Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123982 VL - 3 IS - 5 ER - TY - JOUR A1 - Adeyemo, O. M. A1 - Shapira, S. A1 - Tombaccini, D. A1 - Pollard, H. A1 - Feuerstein, G. A1 - Sirén, Anna-Leena T1 - A goldfish model for evaluation of the neurotoxicit of \(\omega\)-conotoxin GVIA and screening of monoclonal antibodies N2 - A Goldfish Model for Evaluation of the Neurotaxicity of \(\omega\)-Conotoxin GVI A and Screening of Monoclonal Antibodies. ADEYEMO, 0. M .. SHAPIRA, S., TOMBACCINI, D., POLLARD, H. 8 .• FEUERSTEIN, G .. AND SIREN, A-L. ( 1991 ). Toxicol. App/. Pharmaco/. 108, 489-496. The neurotoxicity of \(\omega\)-conotoxin (\(\omega\)-CgTx), a potent neuronal voltage-sensitive calcium channel blocker, was measured using a new bioassay. \(\omega\)-CgTx was administered intraperitoneally (ip) to goldfish weighing approximately 1.6 g, and dose-related changes were observed over a 2-hr period. \(\omega\)CgTx induced time- and dose-dependent abnormal swimming behavior (ASB) and mortality. The antitoxin activity of the antiborlies was investigated in vivo by either ( l) preincubation of the antibody with w-CgTx at 4°C overnight, or (2) pretreatment with antibody, 30 min before \(\omega\)CgTx injection in a 10:1 antibody/\(\omega\)-CgTx molar ratio. The LD50 dose of \(\omega\)-CgTx in goldfish was 5 nmol/kg ip, and preincubation of monoclonal antibody (50 nmol/kg ip) with \(\omega\)-CgTx (5 nmol/kg ip) significantly (p < 0.05) reduced mortality. ASB, and toxicity time. The antitoxin activity of the monoclonal antiborlies evidenced in the goldfish bioassay was further tested in the conscious rat. In the rat, the increases in mean arterial pressure and heart rate induced by \(\omega\)-CgTx (0.03 nmol/rat icv) were significantly (p < 0.02 and p < 0.0 l, respectively) attenuated by preincubation of the toxin with the antibody (0.3 nmol/rat). We conclude that the goldfish bioassay provides a simple. accurate, and inexpensive in vivo model for the study of the toxicity of \(\omega\)CgTx KW - Neurobiologie Y1 - 1991 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63087 ER - TY - JOUR A1 - Conrads, Nora A1 - Grunz, Jan-Peter A1 - Huflage, Henner A1 - Luetkens, Karsten Sebastian A1 - Feldle, Philipp A1 - Grunz, Katharina A1 - Köhler, Stefan A1 - Westermaier, Thomas T1 - Accuracy of pedicle screw placement using neuronavigation based on intraoperative 3D rotational fluoroscopy in the thoracic and lumbar spine JF - Archives of Orthopaedic and Trauma Surgery N2 - Introduction In spinal surgery, precise instrumentation is essential. This study aims to evaluate the accuracy of navigated, O-arm-controlled screw positioning in thoracic and lumbar spine instabilities. Materials and methods Posterior instrumentation procedures between 2010 and 2015 were retrospectively analyzed. Pedicle screws were placed using 3D rotational fluoroscopy and neuronavigation. Accuracy of screw placement was assessed using a 6-grade scoring system. In addition, screw length was analyzed in relation to the vertebral body diameter. Intra- and postoperative revision rates were recorded. Results Thoracic and lumbar spine surgery was performed in 285 patients. Of 1704 pedicle screws, 1621 (95.1%) showed excellent positioning in 3D rotational fluoroscopy imaging. The lateral rim of either pedicle or vertebral body was protruded in 25 (1.5%) and 28 screws (1.6%), while the midline of the vertebral body was crossed in 8 screws (0.5%). Furthermore, 11 screws each (0.6%) fulfilled the criteria of full lateral and medial displacement. The median relative screw length was 92.6%. Intraoperative revision resulted in excellent positioning in 58 of 71 screws. Follow-up surgery due to missed primary malposition had to be performed for two screws in the same patient. Postsurgical symptom relief was reported in 82.1% of patients, whereas neurological deterioration occurred in 8.9% of cases with neurological follow-up. Conclusions Combination of neuronavigation and 3D rotational fluoroscopy control ensures excellent accuracy in pedicle screw positioning. As misplaced screws can be detected reliably and revised intraoperatively, repeated surgery for screw malposition is rarely required. KW - pedicle screws KW - vertebral pedicles KW - fluoroscopy KW - neuronavigation KW - spine Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324966 VL - 143 IS - 6 ER - TY - JOUR A1 - Mrestani, Achmed A1 - Pauli, Martin A1 - Kollmannsberger, Philip A1 - Repp, Felix A1 - Kittel, Robert J. A1 - Eilers, Jens A1 - Doose, Sören A1 - Sauer, Markus A1 - Sirén, Anna-Leena A1 - Heckmann, Manfred A1 - Paul, Mila M. T1 - Active zone compaction correlates with presynaptic homeostatic potentiation JF - Cell Reports N2 - Neurotransmitter release is stabilized by homeostatic plasticity. Presynaptic homeostatic potentiation (PHP) operates on timescales ranging from minute- to life-long adaptations and likely involves reorganization of presynaptic active zones (AZs). At Drosophila melanogaster neuromuscular junctions, earlier work ascribed AZ enlargement by incorporating more Bruchpilot (Brp) scaffold protein a role in PHP. We use localization microscopy (direct stochastic optical reconstruction microscopy [dSTORM]) and hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to study AZ plasticity during PHP at the synaptic mesoscale. We find compaction of individual AZs in acute philanthotoxin-induced and chronic genetically induced PHP but unchanged copy numbers of AZ proteins. Compaction even occurs at the level of Brp subclusters, which move toward AZ centers, and in Rab3 interacting molecule (RIM)-binding protein (RBP) subclusters. Furthermore, correlative confocal and dSTORM imaging reveals how AZ compaction in PHP translates into apparent increases in AZ area and Brp protein content, as implied earlier. KW - active zone KW - Bruchpilot KW - RIM-binding protein KW - compaction KW - homeostasis KW - presynaptic plasticity KW - super-resolution microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265497 VL - 37 IS - 1 ER - TY - THES A1 - Nattmann, Anja Maria T1 - ADAM9 und CXCR4 – neue Angriffspunkte in der Pathogenese des Vestibularisschwannoms T1 - ADAM9 and CXCR4 – new targets in vestibular schwannoma pathogenesis N2 - Obwohl es sich bei Vestibularisschwannomen (VS) um benigne Tumoren handelt, können sie die Lebensqualität der betroffenen Patienten deutlich beeinträchtigen. Gerade bei Patienten, die an einer NF 2 leiden und sich daher wiederholt operativen Eingriffen unterziehen müssen, ist es notwendig, eine medikamentöse Therapiealternative anbieten zu können, die ohne die Notwendigkeit einer operativen Intervention auskommt und gleichzeitig schwerwiegenden Folgen der Tumorerkrankung – wie dem drohenden Hörverlust – Einhalt gebietet. Die vorliegende Arbeit hatte zum Ziel, sich dieser medikamentösen Therapiealternative einen Schritt anzunähern, indem molekulare Pathomechanismen, die dem VS zugrunde liegen könnten, untersucht wurden. Im Mittelpunkt standen der Chemokinrezeptor CXCR4, das Tumorsuppressorprotein Merlin und die Metalloprotease ADAM9. Für CXCR4 ließen sich keine Effekte in Bezug auf die Aktivierung der ERK- und AKT-Signalwege erkennen. Auch beeinflusste eine Merlinüberexpression in VS-Zellen die CXCR4- und ADAM9-Proteinexpression nicht. Für ADAM9 zeigte sich eine potenzielle Relevanz für die Pathogenese des VS: Wurde die ADAM9-Konzentration durch einen knock-down reduziert, hatte dies eine verminderte VS-Zellzahl zur Folge. Des Weiteren scheint Integrin α6 ein Substrat von ADAM9 zu sein, das möglicherweise in die Zytoskelettmodifikation durch ADAM9 involviert ist. Somit stellt die ADAM9-Inhibition einen interessanten Angriffspunkt für eine mögliche medikamentöse Behandlung von VS dar. Ferner wurden Cytokine gefunden, die bisher nicht in einen Zusammenhang mit dem VS gebracht worden waren. Vor allem die Bedeutung der Cytokine TIMP-2 und CXCL7 sollte für das VS näher untersucht werden. Somit konnte diese Arbeit weitere Aspekte aufdecken, die für die Pathogenese des VS relevant sein könnten und an die zukünftige Forschung anknüpfen sollte. N2 - Although they are benign tumors, vestibular schwannomas have the potential to noticeably impair the patients’ quality of life. Especially patients suffering from neurofibromatosis type 2 develop multiple schwannomas and therefore often require repeated surgery. Thus, a non-invasive and effective pharmacotherapy is urgently needed to prevent severe consequences of vestibular schwannoma such as hearing loss. The aim of this thesis was to investigate pathological mechanisms of vestibular schwannoma to identify potential druggable targets. Especially the chemokine receptor CXCR4, the tumor suppressor protein Merlin and the metalloproteinase ADAM9 were in the focus of interest. Neither inhibition, nor stimulation of CXCR4 affected the activity of ERK and AKT signaling pathways, respectively. Similarly, Merlin overexpression did not change CXCR4 or ADAM9 protein expression in vestibular schwannoma. However, ADAM9 appeared to be potentially important for the pathogenesis of vestibular schwannoma: An ADAM9 knock-down led to reduced vestibular schwannoma cell numbers. Moreover, integrin α6 appeared to be a substrate of ADAM9 and might be involved in its mediation of cytoskeleton alterations. Thus, pharmacological inhibition of ADAM9 could be a promising therapeutic strategy to target vestibular schwannoma. In addition, a cytokine screen revealed the tissue inhibitor of metalloproteinases 2 (TIMP-2) and the chemokine ligand CXCL7 as hitherto unknown factors with putative relevance for the vestibular schwannoma pathogenesis. To conclude, this thesis revealed new perspectives on pathological mechanisms of vestibular schwannoma which deserve further investigation. KW - Akustikustumor KW - Vestibularisschwannom KW - ADAM9 KW - CXCR4 KW - Merlin KW - vestibular schwannoma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-278086 ER - TY - JOUR A1 - Luger, Sebastian A1 - Hohmann, Carina A1 - Niemann, Daniela A1 - Kraft, Peter A1 - Gunreben, Ignaz A1 - Neumann-Haefelin, Tobias A1 - Kleinschnitz, Christoph A1 - Steinmetz, Helmuth A1 - Foerch, Christian A1 - Pfeilschifter, Waltraud T1 - Adherence to oral anticoagulant therapy in secondary stroke prevention - impact of the novel oral anticoagulants JF - Patient Preference and Adherence N2 - Background: Oral anticoagulant therapy (OAT) potently prevents strokes in patients with atrial fibrillation. Vitamin K antagonists (VKA) have been the standard of care for long-term OAT for decades, but non-VKA oral anticoagulants (NOAC) have recently been approved for this indication, and raised many questions, among them their influence on medication adherence. We assessed adherence to VKA and NOAC in secondary stroke prevention. Methods: All patients treated from October 2011 to September 2012 for ischemic stroke or transient ischemic attack with a subsequent indication for OAT, at three academic hospitals were entered into a prospective registry, and baseline data and antithrombotic treatment at discharge were recorded. At the 1-year follow-up, we assessed the adherence to different OAT strategies and patients' adherence to their respective OAT. We noted OAT changes, reasons to change treatment, and factors that influence persistence to the prescribed OAT. Results: In patients discharged on OAT, we achieved a fatality corrected response rate of 73.3% (n=209). A total of 92% of these patients received OAT at the 1-year follow-up. We observed good adherence to both VKA and NOAC (VKA, 80.9%; NOAC, 74.8%; P=0.243) with a statistically nonsignificant tendency toward a weaker adherence to dabigatran. Disability at 1-year follow-up was an independent predictor of lower adherence to any OAT after multivariate analysis, whereas the choice of OAT did not have a relevant influence. Conclusion: One-year adherence to OAT after stroke is strong (>90%) and patients who switch therapy most commonly switch toward another OAT. The 1-year adherence rates to VKA and NOAC in secondary stroke prevention do not differ significantly between both therapeutic strategies. KW - transient ischemic attack KW - adherence KW - non-VKA oral anticoagulants KW - vitamin K antagonists KW - prevention KW - stroke KW - atrial fibrillation KW - warfarin KW - guidelines KW - scale Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-144477 VL - 9 ER - TY - JOUR A1 - McCarron, R. M. A1 - Wang, L. A1 - Sirén, Anna-Leena A1 - Spatz, M. A1 - Hallenbeck, J. M. T1 - Adhesion molecules on normotensive and hypertensive rat brain endothelial cells N2 - The intercellular adhesion of circulating leukocytes to vascular endothellum ls a prerequisite for leukocyte emigration from the blood to extravascular tlssues. This process is facllltated by adhesion molecules on the surfaces of both the vascular endothelial cells and the leukocytes. The experiments presented here demonstrate for the first time that the leukocyte adhesion receptor, intercellular adhesion molecule-1, is constitutively expressed on cultured cerebromicrovascular endothelial cell lines derived from both spontaneously hypertensive (SHR) rats and normotensive WistarKyoto (WKY) rats. Both cultures contained simliar numbers of cells constitutively expressing this adhesion molecule (31.4% and 29.6%, respectlvely). Adhesion molecule expression was up-regulated by interleukin-1 ß, tumor necrosis factor-a, interferon-y and lipopolysaccharide in a dose- and time-dependent manner. Both cultures exhibited similar maximum levels of adhesion molecule up-regulation to optimal concentrations of all three cytokines. However, SHR endothelial cells were moresensitive to all three cytokines; significantly higher levels of intercellular adhesion molecule-1 expresslon were seen on SHR as opposed to WKY endothelial cells cultured with sub-optimal cytokine concentrations. It was also observed that lipopolysaccharide up-regulated intercellular adhesion molecule-1 expression on SHR endothelial cells to a greater extent than on WKY endothelial cells. The findings that intercellular adhesion molecule-1 can be up-regulated to a greater degree on SHR endothelial cells may have important implications for in vivo perivascular leukocyte accumulation under hypertensive conditions. These observations indicate a possible mechanism by which hypertension may predispose to the development of disorders such as atherosclerosis and stroke. KW - Endothelzelle KW - Zell-Adhäsionsmolekül Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-86819 ER - TY - RPRT A1 - McCarron, R. M. A1 - Doron, D. A. A1 - Sirén, Anna-Leena A1 - Feuerstein, G. Z. A1 - Heldman, E. A1 - Pollard, H. B. A1 - Spatz, M. A1 - Hallenbeck, J. M. T1 - Agonist-stimulated release of von Willebrand factor and procoagulant factor VIII in rats with and without risk factors for stroke [Research Report] N2 - Lipopolysaccharidc (LPS)-induced (i.v. or i.c.v., 1.8 mg/kg) release of von Willebrand factor (vWF) ·was examined in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. SHR rats releascd significantly (P < 0.05) more vWF than WKY rats in response to LPS. LPS also inhibited factor VIII procoagulant activity (FVIII: c) which may indicate an increase in thrombin activity. Cultured cerebrovascular endothelial cells (EC) derived from both SHR and WKY rats, as weil as human umbilical vein EC (HUVEC) cultures constitutively released vWF. Treatment with agonists including LPS, thrombin and tumor necrosis factor-a (TNFa) did not affect the in vitro secretion of vWF by cerebrovascular EC cultures but significantly upregulated vWF release by HUVEC cultur~s. Preincubation of cerebrovascular EC cultures with interleukin-1 OL-l) ± TNFa or co-culturing in the presence of LPS-activated syngeneic monocytes had no effect on vWF secretion. The findings demoostrate that conditions of hypertension may affect endothelial cells and make them more responsive to agonist Stimulation and thereby increase secretion of vWF, an important factqr in hemostasis as weil as thrombosis. The capacity of LPS to significantly affect the in vivo secretion of vWF in SHR and WKY rats but not cultured cerebrovascular EC indicates that observed elevations in plasma vWF were not derived from cerebrovascular EC. lt is suggested that hypertension may function as a risk factor for thrombotic stroke by influencing factors involved in coagulation processes, such as vWF and factor VIII : c. KW - Neurobiologie KW - von Willebrand factor KW - Hypertension KW - Lipopolysaccharide KW - Endothelial cell KW - Stroke KW - Monocyte Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62945 ER -