Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-14241 Wissenschaftlicher Artikel Müller-Sienerth, Nicole; Dietz, Lena; Holtz, Philipp; Kapp, Markus; Grigoleit, Götz Ulrich; Schmuck, Carsten; Wajant, Harald; Siegmund, Daniela SMAC Mimetic BV6 Induces Cell Death in Monocytes and Maturation of Monocyte-Derived Dendritic Cells Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NF kappa B system and TNF signaling. In view of the overwhelming importance of the NF kappa B transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings: BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NF kappa B pathway, but it also diminished the stronger NF kappa B-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12. Significance: The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies. 2011 e21556 PLoS ONE 6 6 urn:nbn:de:bvb:20-opus-142415 10.1371/journal.pone.0021556 Medizinische Klinik und Poliklinik II OPUS4-6415 Wissenschaftlicher Artikel Müller-Sienerth, Nicole; Dietz, Lena; Holtz, Philipp; Kapp, Markus; Grigoleit, Götz Ulrich; Schmuck, Carsten; Wajant, Harald; Siegmund, Siegmund SMAC Mimetic BV6 Induces Cell Death in Monocytes and Maturation of Monocyte-Derived Dendritic Cells Background: Compounds mimicking the inhibitory effect of SMAC / DIABLO on X-linked inhibitor of apoptosis (XIAP) have been developed with the aim to achieve sensitization for apoptosis of tumor cells resistant due to deregulated XIAP expression. It turned out that SMAC mimetics also have complex effects on the NFkB system and TNF signaling. In view of the overwhelming importance of the NFkB transcription factors in the immune system, we analyzed here the effects of the SMAC mimetic BV6 on immune cells. Principal Findings: BV6 induced apoptotic and necrotic cell death in monocytes while T-cells, dendritic cells and macrophages were largely protected against BV6-induced cell death. In immature dendritic cells BV6 treatment resulted in moderate activation of the classical NFkB pathway, but it also diminished the stronger NFkB-inducing effect of TNF and CD40L. Despite its inhibitory effect on TNF- and CD40L signaling, BV6 was able to trigger maturation of immature DCs as indicated by upregulation of CD83, CD86 and IL12. Significance: The demonstrated effects of SMAC mimetics on immune cells may complicate the development of tumor therapeutic concepts based on these compounds but also arise the possibility to exploit them for the development of immune stimulatory therapies. 2011 urn:nbn:de:bvb:20-opus-76106 Medizinische Klinik und Poliklinik II OPUS4-23259 Wissenschaftlicher Artikel Luber, Verena; Lutz, Mathias; Thiede, Christian; Haferlach, Claudia; Dürk, Heinz Albert; Einsele, Hermann; Grigoleit, Götz Ulrich; Mielke, Stephan Donor-cell leukemia with novel genetic features 2 years after sex-mismatched T cell-depleted haploidentical stem cell transplantation No abstract available. 2020 899–901 Annals of Hematology 99 urn:nbn:de:bvb:20-opus-232596 10.1007/s00277-020-03905-x Medizinische Klinik und Poliklinik II OPUS4-26647 Wissenschaftlicher Artikel Isberner, Nora; Kraus, Sabrina; Grigoleit, Götz Ulrich; Aghai, Fatemeh; Kurlbaum, Max; Zimmermann, Sebastian; Klinker, Hartwig; Scherf-Clavel, Oliver Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity. 2021 973-983 Cancer Chemotherapy and Pharmacology 88 6 urn:nbn:de:bvb:20-opus-266476 10.1007/s00280-021-04351-w Abteilung für Molekulare Innere Medizin (in der Medizinischen Klinik und Poliklinik II) OPUS4-23231 Wissenschaftlicher Artikel Gierlich, Philipp; Lex, Veronika; Technau, Antje; Keupp, Anne; Morper, Lorenz; Glunz, Amelie; Sennholz, Hanno; Rachor, Johannes; Sauer, Sascha; Marcu, Ana; Grigoleit, Götz Ulrich; Wölfl, Matthias; Schlegel, Paul G.; Eyrich, Matthias Prostaglandin E\(_2\) in a TLR3‑ and 7/8‑agonist‑based DC maturation cocktail generates mature, cytokine‑producing, migratory DCs but impairs antigen cross‑presentation to CD8\(^+\) T cells Mature dendritic cells (DCs) represent cellular adjuvants for optimal antigen presentation in cancer vaccines. Recently, a combination of prostaglandin E\(_2\) (PGE\(_2\)) with Toll-like receptor agonists (TLR-P) was proposed as a new standard to generate superior cytokine-producing DCs with high migratory capacity. Here, we compare TLR-P DCs with conventional DCs matured only with the proinflammatory cytokines TNFα and IL-1ß (CDCs), focussing on the interaction of resulting DCs with CD8\(^+\) T-cells. TLR-P matured DCs showed elevated expression of activation markers such as CD80 and CD83 compared to CDCs, together with a significantly higher migration capacity. Secretion of IL-6, IL-8, IL-10, and IL-12 was highest after 16 h in TLR-P DCs, and only TLR-P DCs secreted active IL-12p70. TLR-P DCs as well as CDCs successfully primed multifunctional CD8\(^+\) T-cells from naïve precursors specific for the peptide antigens Melan-A, NLGN4X, and PTP with comparable priming efficacy and T-cell receptor avidity. CD8\(^+\) T-cells primed by TLR-P DCs showed significantly elevated expression of the integrin VLA-4 and a trend for higher T-cell numbers after expansion. In contrast, TLR-P DCs displayed a substantially reduced capability to cross-present CMVpp65 protein antigen to pp65-specific T cells, an effect that was dose-dependent on PGE2 during DC maturation and reproducible with several responder T-cell lines. In conclu-sion, TLR-P matured DCs might be optimal presenters of antigens not requiring processing such as short peptides. However, PGE\(_2\) seems less favorable for maturation of DCs intended to process and cross-present more complex vaccine antigens such as lysates, proteins or long peptides. 2020 1029–1042 Cancer Immunology, Immunotherapy 69 urn:nbn:de:bvb:20-opus-232311 10.1007/s00262-019-02470-1 Kinderklinik und Poliklinik OPUS4-15898 Wissenschaftlicher Artikel Lapa, Constantin; Kircher, Malte; Hänscheid, Heribert; Schirbel, Andreas; Grigoleit, Götz Ulrich; Klinker, Erdwine; Böck, Markus; Samnick, Samuel; Pelzer, Theo; Buck, Andreas K Peptide receptor radionuclide therapy as a new tool in treatment-refractory sarcoidosis - initial experience in two patients Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that can involve virtually all organ systems. Whereas most patients present without symptoms, progressive and disabling organ failure can occur in up to 10% of subjects. Somatostatin receptor (SSTR)-directed peptide receptor radionuclide therapy (PRRT) has recently received market authorization for treatment of SSTR-positive neuroendocrine tumors. Methods: We describe the first case series comprising two patients with refractory multi-organ involvement of sarcoidosis who received 4 cycles of PRRT. Results: PRRT was well-tolerated without any acute adverse effects. No relevant toxicities could be recorded during follow-up. Therapy resulted in partial response accompanied by a pronounced reduction in pain (patient #1) and stable disease regarding morphology as well as disease activity (patient #2), respectively. Conclusion: Peptide receptor radionuclide therapy in sarcoidosis is feasible and might be a new valuable tool in patients with otherwise treatment-refractory disease. Given the long experience with and good tolerability of PRRT, further evaluation of this new treatment option for otherwise treatment-refractory sarcoidosis in larger patient cohorts is warranted. 2018 644–649 Theranostics 8 3 urn:nbn:de:bvb:20-opus-158983 10.7150/thno.22161 Klinik und Poliklinik für Nuklearmedizin OPUS4-15757 Wissenschaftlicher Artikel Zeller, Daniel; Heidemeier, Anke; Grigoleit, Götz Ulrich; Müllges, Wolfgang Case report: subacute tetraplegia in an immunocompromised patient Background: Clinical reasoning in Neurology is based on general associations which help to deduce the site of the lesion. However, even "golden principles" may occasionally be deceptive. Here, we describe the case of subacute flaccid tetraparesis due to motor cortical lesions. To our knowledge, this is the first report to include an impressive illustration of nearly symmetric motor cortical involvement of encephalitis on brain MRI. Case presentation: A 51 year old immunocompromized man developed a high-grade pure motor flaccid tetraparesis over few days. Based on clinical presentation, critical illness polyneuromyopathy was suspected. However, brain MRI revealed symmetrical hyperintensities strictly limited to the subcortical precentral gyrus. An encephalitis, possibly due to CMV infection, turned out to be the most likely cause. Conclusion: While recognition of basic clinical patterns is indispensable in neurological reasoning, awareness of central conditions mimicking peripheral nervous disease may be crucial to detect unsuspected, potentially treatable conditions. 2017 BMC Neurology 17 31 urn:nbn:de:bvb:20-opus-157576 10.1186/s12883-017-0814-5 Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) OPUS4-21960 Wissenschaftlicher Artikel Luber, Verena; Lutz, Mathias; Abele-Horn, Marianne; Einsele, Hermann; Grigoleit, Götz Ulrich; Mielke, Stephan Excretion of Ascaris lumbricoides following reduced-intensity allogeneic hematopoietic stem cell transplantation and consecutive treatment with mebendazole Here, we present the unique case of a 51-year-old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three-day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post-transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed. 2019 1-4 Transplant Infectious Disease 22 1 urn:nbn:de:bvb:20-opus-219608 10.1111/tid.13224 Institut für Hygiene und Mikrobiologie OPUS4-29726 Wissenschaftlicher Artikel Gerner, Bettina; Aghai-Trommeschlaeger, Fatemeh; Kraus, Sabrina; Grigoleit, Götz Ulrich; Zimmermann, Sebastian; Kurlbaum, Max; Klinker, Hartwig; Isberner, Nora; Scherf-Clavel, Oliver A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug-drug interaction frequently observed in graft versus host disease patients Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes. 2022 Pharmaceutics 14 12 urn:nbn:de:bvb:20-opus-297261 10.3390/pharmaceutics14122556 Medizinische Klinik und Poliklinik I