TY - JOUR A1 - Werner, Rudolf A. A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Schmid, Jan S. A1 - Schirbel, Andreas A1 - Lassmann, Michael A1 - Wild, Vanessa A1 - Rudelius, Martina A1 - Kudlich, Theodor A1 - Herrmann, Ken A1 - Scheurlen, Michael A1 - Buck, Andreas K. A1 - Kropf, Saskia A1 - Wester, Hans-Jürgen A1 - Lapa, Constantin T1 - Imaging of Chemokine Receptor 4 Expression in Neuroendocrine Tumors - a Triple Tracer Comparative Approach JF - Theranostics N2 - C-X-C motif chemokine receptor 4 (CXCR4) and somatostatin receptors (SSTR) are overexpressed in gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). In this study, we aimed to elucidate the feasibility of non-invasive CXCR4 positron emission tomography/computed tomography (PET/CT) imaging in GEP-NET patients using [\(^{68}\)Ga]Pentixafor in comparison to \(^{68}\)Ga-DOTA-D-Phe-Tyr3-octreotide ([\(^{68}\)Ga]DOTATOC) and \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG). Twelve patients with histologically proven GEP-NET (3xG1, 4xG2, 5xG3) underwent [\(^{68}\)Ga]DOTATOC, [\(^{18}\)F]FDG, and [\(^{68}\)Ga]Pentixafor PET/CT for staging and planning of the therapeutic management. Scans were analyzed on a patient as well as on a lesion basis and compared to immunohistochemical staining patterns of CXCR4 and somatostatin receptors SSTR2a and SSTR5. [\(^{68}\)Ga]Pentixafor visualized tumor lesions in 6/12 subjects, whereas [\(^{18}\)F]FDG revealed sites of disease in 10/12 and [\(^{68}\)Ga]DOTATOC in 11/12 patients, respectively. Regarding sensitivity, SSTR-directed PET was the superior imaging modality in all G1 and G2 NET. CXCR4-directed PET was negative in all G1 NET. In contrast, 50% of G2 and 80% of G3 patients exhibited [\(^{68}\)Ga]Pentixafor-positive tumor lesions. Whereas CXCR4 seems to play only a limited role in detecting well-differentiated NET, increasing receptor expression could be non-invasively observed with increasing tumor grade. Thus, [\(^{68}\)Ga]Pentixafor PET/CT might serve as non-invasive read-out for evaluating the possibility of CXCR4-directed endoradiotherapy in advanced dedifferentiated SSTR-negative tumors. KW - SSTR KW - peptide receptor radionuclide therapy KW - neuroendocrine tumor KW - [\(^{68}\)Ga]Pentixafor KW - CXCR4 KW - chemokine receptor KW - PET/CT KW - DOTATOC KW - PRRT KW - Positronen-Emissions-Tomografie Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158008 VL - 7 IS - 6 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Beykan, Seval A1 - Higuchi, Takahiro A1 - Lückerath, Katharina A1 - Weich, Alexander A1 - Scheurlen, Michael A1 - Bluemel, Christina A1 - Herrmann, Ken A1 - Buck, Andreas K. A1 - Lassmann, Michael A1 - Lapa, Constantin A1 - Hänscheid, Heribert T1 - The impact of \(^{177}\)Lu-octreotide therapy on \(^{99m}\)Tc-MAG3 clearance is not predictive for late nephropathy JF - Oncotarget N2 - Peptide Receptor Radionuclide Therapy (PRRT) for the treatment of neuroendocrine tumors may lead to kidney deterioration. This study aimed to evaluate the suitability of \(^{99m}\)Tc-mercaptoacetyltriglycine (\(^{99m}\)Tc-MAG3) clearance for the early detection of PRRT-induced changes on tubular extraction (TE). TE rate (TER) was measured prior to 128 PRRT cycles (7.6±0.4 GBq \(^{177}\)Lu-octreotate/octreotide each) in 32 patients. TER reduction during PRRT was corrected for age-related decrease and analyzed for the potential to predict loss of glomerular filtration (GF). The GF rate (GFR) as measure for renal function was derived from serum creatinine. The mean TER was 234 ± 53 ml/min/1.73 m² before PRRT (baseline) and 221 ± 45 ml/min/1.73 m² after a median follow-up of 370 days. The age-corrected decrease (mean: -3%, range: -27% to +19%) did not reach significance (p=0.09) but significantly correlated with the baseline TER (Spearman p=-0.62, p<0.001). Patients with low baseline TER showed an improved TER after PRRT, high decreases were only observed in individuals with high baseline TER. Pre-therapeutic TER data were inferior to plasma creatinine-derived GFR estimates in predicting late nephropathy. TER assessed by \(^{99m}\)Tc-MAG3­clearance prior to and during PRRT is not suitable as early predictor of renal injury and an increased risk for late nephropathy. KW - renal scintigraphy KW - neuroendocrine tumor KW - 177Lu KW - MAG3 KW - PRRT Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177318 VL - 7 IS - 27 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Adam, Elisabeth Hannah A1 - Notz, Quirin A1 - Helmer, Philipp A1 - Sonntagbauer, Michael A1 - Ungemach-Papenberg, Peter A1 - Sanns, Andreas A1 - Zausig, York A1 - Steinfeldt, Thorsten A1 - Torje, Iuliu A1 - Schmid, Benedikt A1 - Schlesinger, Tobias A1 - Rolfes, Caroline A1 - Reyher, Christian A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Brack, Alexander A1 - Wurmb, Thomas A1 - Gill-Schuster, Daniel A1 - Kranke, Peter A1 - Weismann, Dirk A1 - Klinker, Hartwig A1 - Heuschmann, Peter A1 - Rücker, Viktoria A1 - Frantz, Stefan A1 - Ertl, Georg A1 - Muellenbach, Ralf Michael A1 - Mutlak, Haitham A1 - Meybohm, Patrick A1 - Zacharowski, Kai A1 - Lotz, Christopher T1 - COVID-19 Induced Acute Respiratory Distress Syndrome — A Multicenter Observational Study JF - Frontiers in Medicine N2 - Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients. KW - COVID-19 KW - ARDS (acute respiratory distress syndrome) KW - intensive care medicine KW - pandemia KW - Germany Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219834 SN - 2296-858X VL - 7 ER - TY - JOUR A1 - Kleinschnitz, Christoph A1 - Grund, Henrike A1 - Wingler, Kirstin A1 - Armitage, Melanie E. A1 - Jones, Emma A1 - Mittal, Manish A1 - Barit, David A1 - Schwarz, Tobias A1 - Geis, Christian A1 - Kraft, Peter A1 - Barthel, Konstanze A1 - Schuhmann, Michael K. A1 - Herrmann, Alexander M. A1 - Meuth, Sven G. A1 - Stoll, Guido A1 - Meurer, Sabine A1 - Schrewe, Anja A1 - Becker, Lore A1 - Gailus-Durner, Valerie A1 - Fuchs, Helmut A1 - Klopstock, Thomas A1 - de Angelis, Martin Hrabe A1 - Jandeleit-Dahm, Karin A1 - Shah, Ajay M. A1 - Weissmann, Norbert A1 - Schmidt, Harald H. H. W. T1 - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration N2 - Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy. KW - Schlaganfall Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416 ER - TY - JOUR A1 - Buder, Kristina A1 - Lapa, Constantin A1 - Kreissl, Michael C. A1 - Schirbel, Andreas A1 - Herrmann, Ken A1 - Schnack, Alexander A1 - Bröcker, Eva-Bettina A1 - Goebeler, Matthias A1 - Buck, Andreas K. A1 - Becker, Jürgen C. T1 - "Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging" N2 - Background Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. Methods To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). Results SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73% for nodal metastases, 100% for bone, and 67% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13%). Conclusion SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management. KW - Merkel cell carcinoma KW - Molecular imaging KW - Somatostatin receptor expression KW - Positron emission tomography Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110326 ER - TY - THES A1 - Herrmann, Alexander Michael T1 - CD8+ Lymphozyten mediierter Angriff auf Neuronen des ZNS: Relevanz von Granzym B und Perforin für akute elektrophysiologische Veränderungen T1 - CD8+ lymphocyte-mediated attack on neurons of the CNS: Relevance on granzyme B and perforin for acute electrophysiological alterations N2 - Zytotoxische CD8+ T-Lymphozyten spielen in vielen inflammatorischen, aber auch primär neurodegenerativen Erkrankungen eine wichtige Rolle. Daher besitzt die Fragestellung inwiefern CD8+ ZTL Neurone direkt schädigen und ggf. welche mechanistischen Aspekte dieser Schädigung zugrunde liegen, eine hohe Relevanz. Um diese Fragestellung eingehender zu beleuchten, wurde mit dem OT-I-System gearbeitet. Dieses gut vorcharakterisierte CD8+ T-Zell-Modell besitzt den Vorteil, dass diese transgenen Zellen nur eine Peptidsequenz des Ovalbumin (OVA) Protein als spezifisches Antigen erkennen. Zunächst wurden in der vorliegenden Arbeit Co-Kultivierungs-Experimente durchgeführt. Hierzu wurden akut isolierte murine Hippokampus-Neurone unter verschiedenen Bedingungen mit OT-I Lymphozyten co-kultiviert. Hierbei konnte gezeigt werden, dass unter Antigenpräsentation der Neurone signifikant mehr Neurone in die Apoptose/Nekrose geführt werden, als unter Kontroll-Bedingungen, in denen entweder kein Antigen oder ein Antigen, das nicht von OT-I Lymphozyten erkannt wird, präsentiert wird. Nachdem die Antigen-abhängigen zytotoxischen Effekte auf Neurone gezeigt werden konnten, wurde mithilfe elektrophysiologischer Techniken die mechanistischen und funktionellen Konsequenzen des direkten neuronalen/OT-I-vermittelten Zellkontakts untersucht. Bei diesem experimentellen Ansatz wurde durch elektrisches Auslenken eines Neurons nach Kontakt mit einem OT-I Lymphozyt die passiven elektrischen Parameter der Neuronenmembran gemessen. In diesen Messungen konnte gezeigt werden, dass nach unmittelbarem Kontakt eines Neurons mit einem OT-I Lymphozyt der neuronale Membranwiderstand reduziert wird bzw. die Leitfähigkeit der Zellmembran erhöht wird. Diese Änderung der neuronalen Membran-Leitfähigkeit findet in einem Zeitraum von 10 min nach dem Zell-Zell-Kontakt statt. Auch hier konnte gezeigt werden, dass dieser Einfluss von OT-I Lymphozyten auf Neurone strikt Antigen-abhängig ist. Zur Untersuchung des Mechanismus der OT-I T-Lymphozyten auf Neurone wurde das Augenmerk auf verschiedene T-Zell-induzierte Apoptosewegegelegt. Es konnte gezeigt werden, dass durch Blockieren der Fas/FasL-Interaktion mittels eines Antikörpers kein Unterschied, weder in der neuronalen Apoptoserate nach Co-Kultivierung, noch eine Änderung der passiven neuronalen Membran-Leitfähigkeit auftritt. Weiterhin wurde die Rolle der von T-Zellen sezernierten Granula Perforin und Granzym B untersucht. Um den Einfluss dieser Granula aufzuklären, wurden OT-I Lymphozyten verwendet, die entweder defizient für Perforin oder Granzym B waren. In diesem experimentellen Ansatz wurde gezeigt, dass ausschließlich Perforin für die Erniedrigung des passiven neuronalen Membran-Widerstandes verantwortlich ist. Diese Erhöhung der neuronalen Membranleitfähigkeit führte aber nicht direkt zum neuronalen Zelltod. Vielmehr wurde durch die einhergehende Depolarisation des Neurons die elektrische Aktivität der Zelle vermindert, sodass es zu einem sogenannten „electrical silencing“ kommt. Dieser Umstand konnte auch in der Betrachtung der spontanen Netzwerkaktivität von Neuronenkulturen gezeigt werden. Hierfür wurden hoch dichte Neuronenkulturen auf MEA-Chips kultiviert. Mit Hilfe dieser MEA konnten die Summenfeldpotentiale der Neuronenkulturen detektiert werden. Hierbei wurde beobachtet, dass nach Beladung der Neuronen mit dem spezifischen OT-I-Antigen und OT-I Zellen eine Verringerung der spontanen Netzwerkaktivität einhergeht. Auch in diesem Effekt konnte eine Antigen-Spezifität nachgewiesen werden. Da der Prozess der zellulären Apoptose mit einem Anstieg der intrazellulären Ca2+-Konzentration einhergeht, und Perforin als Ca2+-durchlässiger unselektiver Porenbildner fungiert, wurden zur Überprüfung der Hypothese calcium imaging-Experimente durchgeführt. Analog zu den elektrophysiologischen Messungen wurde gezeigt, dass nach direktem Zell-Zell-Kontakt zwischen Neuron und OT-I Lymphozyt eine Erhöhung der intrazellulären Ca2+-Konzentration zu messen ist. Dass diese Änderung des neuronalen Ca2+-Einstroms durch Perforin-abhängige Membranporen hervorgerufen wird, konnte durch die Verwendung von Perforin-defizienten OT-I Lymphozyten bewiesen werden. Unter Verwendung von Perforin-defizienten OT-I Lymphozyten wurde keine Änderung der neuronalen Ca2+-Konzentration ermittelt. Weiterhin wurde in diesem experimentellen Ansatz gezeigt, dass auch der OT-I-vermittelte neuronale Ca2+-Anstieg strikt Antigen-abhängig ist.Zusammengefasst konnte in dieser Arbeit gezeigt werden, dass MHC-I/Antigen-vermittelte CD8+ Lymphozyten-Interaktion mit einem Neuron zu „electrical silencing“ des Neurons führt. Dieser Prozess ist klar Perforin-abhängig, führt jedoch nicht zum unmittelbaren Zelltod des Neurons. N2 - Cytotoxic CD8+ T cells are considered as important effector cells contributing to neuronal damage in inflammatory and primary degenerative disorders in the CNS. Hence, it is highly relevant to know to what extent CD8+ T-lymphocytes can contribute to neuronal damage in these disorders. To challenge this question, we used the murine OT-I system. The advantage of this well-characterized transgenic model is that OT-I CD8+ T-lymphocytes are restricted to one single antigen – one peptide sequence of Ovalbumin (Ova). In a first set of experiments, OT-I lymphocytes were co-cultured with neurons that presented Ova in a MHC-I specific context on their surface. As control, neurons without any antigen or neurons that presented a scrambled peptide form (SIY) were used. These co-culture experiments indicates that neuronal killing by OT-I lymphocytes is a MHC-I and antigen-dependent mechanism. To clarify the underlying mechanism and the functionally consequences in this OT-I/neuron interaction, we performed electrophysiological patch-clamp analysis to measure the influence from one single OT-I T-cell on a single neuron. For this purpose, we established a special protocol to stimulate the neuronal membrane to measure the passive electrical parameters after a direct OT-I contact. These measurements revealed a significant antigen restricted reduction in neuronal membrane resistance. This effect could be detected within 10 min after the direct cell-cell contact. To challenge the underlying cellular mechanisms we analyzed several known apoptosis pathways. In a first set of experiments, we investigated the Fas/FasL interaction. To answer this question, we used a blocking FasL antibody, to interrupt this pathway. These experiments showed no changes in neuronal apoptosis, neither in co-cultivation experiments nor in the electrophysiological situation. As next step we investigate the role of CD8+ lymphocyte derived granula perforin and granzyme B. Therefore we used OT-I T-cells that are either deficient for perforin or granzyme B. Using these experimental conditions, we could show that only perforin is responsible for changing passive electrical parameters. However, these reductions in neuronal membrane resistance did not lead immediately in neuronal cell death, but rather led to a depolarization and therefore to an electrical silencing of the neuron. This electrical silencing was also shown to occur in the spontaneous network activity in a neuronal network. The network activity was measured on a high density neuron network cultivated on a MEA. These MEA measurements revealed a decrease in the total spike activity after loading of OT-I lymphocytes on an antigen presenting neuronal network. Due to the increase of the intracellular Ca2+ level in the process of cell death and the Ca2+ selectivity of perforin membrane pores, we hypothesized that neuronal silencing and neuronal cell death elicited by perforin pores might lead to an intracellular Ca2+ increase. To proof this hypothesis we established a calcium imaging experiment in an OT-I/neuron contact situation. These measurements were done in the same manner as the electrophysiological measurements. Ca2+ imaging indicated increasing Ca2+ levels in neurons after application of perforin releasing OT-I lymphocytes. Furthermore, these experiments revealed a strictly antigen dependence for Ca2+ increase in target cells. In conclusion, we could show that MHC-I/antigen-mediated CD8+ lymphocyte interactions with neurons led to their electrical silencing. This process was perforin dependent. However this process was not causally linked to neuronal cell death. KW - Antigen CD8 KW - T-Lymphozyt KW - Lymphozyten mediierter Angriff auf Neurone KW - Nervendegeneration KW - Lymphozyten KW - neurone Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-109124 ER - TY - JOUR A1 - Göbel, Kerstin A1 - Pankratz, Susann A1 - Asaridou, Chloi-Magdalini A1 - Herrmann, Alexander M. A1 - Bittner, Stefan A1 - Merker, Monika A1 - Ruck, Tobias A1 - Glumm, Sarah A1 - Langhauser, Friederike A1 - Kraft, Peter A1 - Krug, Thorsten F. A1 - Breuer, Johanna A1 - Herold, Martin A1 - Gross, Catharina C. A1 - Beckmann, Denise A1 - Korb-Pap, Adelheid A1 - Schuhmann, Michael K. A1 - Kuerten, Stefanie A1 - Mitroulis, Ioannis A1 - Ruppert, Clemens A1 - Nolte, Marc W. A1 - Panousis, Con A1 - Klotz, Luisa A1 - Kehrel, Beate A1 - Korn, Thomas A1 - Langer, Harald F. A1 - Pap, Thomas A1 - Nieswandt, Bernhard A1 - Wiendl, Heinz A1 - Chavakis, Triantafyllos A1 - Kleinschnitz, Christoph A1 - Meuth, Sven G. T1 - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells JF - Nature Communications N2 - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders. KW - blood coagulation KW - factor XII KW - neuroinflammation KW - dendric cells Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165503 VL - 7 IS - 11626 ER -