@article{NattmannBreunMonoranuetal.2020, author = {Nattmann, Anja and Breun, Maria and Monoranu, Camelia M. and Matthies, Cordula and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Analysis of ADAM9 regulation and function in vestibular schwannoma primary cells}, series = {BMC Research Notes}, volume = {13}, journal = {BMC Research Notes}, doi = {10.1186/s13104-020-05378-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231213}, year = {2020}, abstract = {Objective Recently, we described a disintegrin and metalloproteinase 9 (ADAM9) overexpression by Schwann cells of vestibular schwannoma (VS) and suggested that it might be a marker for VS tumor growth and invasiveness. This research note provides additional data utilizing a small cohort of VS primary cultures and tissue samples. We examined whether reconstitution of Merlin expression in VS cells regulates ADAM9 protein expression and performed lentiviral ADAM9 knock down to investigate possible effects on VS cells numbers. Moreover, the co-localization of ADAM9 and Integrins α6 and α2β1, respectively, was examined by immunofluorescence double staining. Results ADAM9 expression was not regulated by Merlin in VS. However, ADAM9 knock down led to 58\% reduction in cell numbers in VS primary cell cultures (p < 0.0001). While ADAM9 and Integrin α2β1 were co-localized in only 22\% (2 of 9) of VS, ADAM9 and Integrin α6 were co-localized in 91\% (10 of 11) of VS. Therefore, we provide first observations on possible regulatory functions of ADAM9 expression in VS.}, language = {en} } @article{BreunMonoranuKessleretal.2019, author = {Breun, Maria and Monoranu, Camelia M. and Kessler, Almuth F. and Matthies, Cordula and L{\"o}hr, Mario and Hagemann, Carsten and Schirbel, Andreas and Rowe, Steven P. and Pomper, Martin G. and Buck, Andreas K. and Wester, Hans-J{\"u}rgen and Ernestus, Ralf-Ingo and Lapa, Constantin}, title = {[\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas}, series = {Frontiers in Oncology}, volume = {9}, journal = {Frontiers in Oncology}, number = {503}, doi = {10.3389/fonc.2019.00503}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201863}, year = {2019}, abstract = {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.}, language = {en} } @article{FeldheimKesslerMonoranuetal.2019, author = {Feldheim, Jonas and Kessler, Almuth F. and Monoranu, Camelia M. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Changes of O\(^6\)-Methylguanine DNA Methyltransferase (MGMT) promoter methylation in glioblastoma relapse—a meta-analysis type literature review}, series = {Cancers}, volume = {11}, journal = {Cancers}, number = {12}, issn = {2072-6694}, doi = {10.3390/cancers11121837}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193040}, year = {2019}, abstract = {Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter has emerged as strong prognostic factor in the therapy of glioblastoma multiforme. It is associated with an improved response to chemotherapy with temozolomide and longer overall survival. MGMT promoter methylation has implications for the clinical course of patients. In recent years, there have been observations of patients changing their MGMT promoter methylation from primary tumor to relapse. Still, data on this topic are scarce. Studies often consist of only few patients and provide rather contrasting results, making it hard to draw a clear conclusion on clinical implications. Here, we summarize the previous publications on this topic, add new cases of changing MGMT status in relapse and finally combine all reports of more than ten patients in a statistical analysis based on the Wilson score interval. MGMT promoter methylation changes are seen in 115 of 476 analyzed patients (24\%; CI: 0.21-0.28). We discuss potential reasons like technical issues, intratumoral heterogeneity and selective pressure of therapy. The clinical implications are still ambiguous and do not yet support a change in clinical practice. However, retesting MGMT methylation might be useful for future treatment decisions and we encourage clinical studies to address this topic}, language = {en} } @article{SalvadorBurekLoehretal.2021, author = {Salvador, Ellaine and Burek, Malgorzata and L{\"o}hr, Mario and Nagai, Michiaki and Hagemann, Carsten and F{\"o}rster, Carola Y.}, title = {Senescence and associated blood-brain barrier alterations in vitro}, series = {Histochemistry and Cell Biology}, volume = {156}, journal = {Histochemistry and Cell Biology}, number = {3}, issn = {1432-119X}, doi = {10.1007/s00418-021-01992-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267435}, pages = {283-292}, year = {2021}, abstract = {Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within.}, language = {en} } @article{KesslerFeldheimSchmittetal.2020, author = {Kessler, Almuth F. and Feldheim, Jonas and Schmitt, Dominik and Feldheim, Julia J. and Monoranu, Camelia M. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Monopolar Spindle 1 Kinase (MPS1/TTK) mRNA Expression is Associated with Earlier Development of Clinical Symptoms, Tumor Aggressiveness and Survival of Glioma Patients}, series = {Biomedicines}, volume = {8}, journal = {Biomedicines}, number = {7}, doi = {10.3390/biomedicines8070192}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236105}, year = {2020}, abstract = {Inhibition of the protein kinase MPS1, a mitotic spindle-checkpoint regulator, reinforces the effects of multiple therapies against glioblastoma multiforme (GBM) in experimental settings. We analyzed MPS1 mRNA-expression in gliomas WHO grade II, III and in clinical subgroups of GBM. Data were obtained by qPCR analysis of tumor and healthy brain specimens and correlated with the patients' clinical data. MPS1 was overexpressed in all gliomas on an mRNA level (ANOVA, p < 0.01) and correlated with tumor aggressiveness. We explain previously published conflicting results on survival: high MPS1 was associated with poorer long term survival when all gliomas were analyzed combined in one group (Cox regression: t < 24 months, p = 0.009, Hazard ratio: 8.0, 95\% CI: 1.7-38.4), with poorer survival solely in low-grade gliomas (LogRank: p = 0.02, Cox regression: p = 0.06, Hazard-Ratio: 8.0, 95\% CI: 0.9-66.7), but not in GBM (LogRank: p > 0.05). This might be due to their lower tumor volume at the therapy start. GBM patients with high MPS1 mRNA-expression developed clinical symptoms at an earlier stage. This, however, did not benefit their overall survival, most likely due to the more aggressive tumor growth. Since MPS1 mRNA-expression in gliomas was enhanced with increasing tumor aggressiveness, patients with the worst outcome might benefit best from a treatment directed against MPS1.}, language = {en} } @article{KesslerFroemblingGrossetal.2018, author = {Kessler, Almuth F. and Fr{\"o}mbling, Greta E. and Gross, Franziska and Hahn, Mirja and Dzokou, Wilfrid and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten}, title = {Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition}, series = {Cell Death Discovery}, volume = {4}, journal = {Cell Death Discovery}, doi = {10.1038/s41420-018-0079-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325744}, year = {2018}, abstract = {Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (-78.6\% vs. TTFields, P = 0.0337; -52.6\% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62\% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44\% (TTFields 14\%, P = 0.0002; IN-3 4\%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92\% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.}, language = {en} }