@article{FeldheimKesslerFeldheimetal.2023,
  author    = {Feldheim, Jonas and Kessler, Almuth F. and Feldheim, Julia J. and Schmitt, Dominik and Oster, Christoph and Lazaridis, Lazaros and Glas, Martin and Ernestus, Ralf-Ingo and Monoranu, Camelia M. and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {BRMS1 in gliomas — an expression analysis},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {11},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15112907},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319225},
  year      = {2023},
  abstract  = {The metastatic suppressor BRMS1 interacts with critical steps of the metastatic cascade in many cancer entities. As gliomas rarely metastasize, BRMS1 has mainly been neglected in glioma research. However, its interaction partners, such as NFκB, VEGF, or MMPs, are old acquaintances in neurooncology. The steps regulated by BRMS1, such as invasion, migration, and apoptosis, are commonly dysregulated in gliomas. Therefore, BRMS1 shows potential as a regulator of glioma behavior. By bioinformatic analysis, in addition to our cohort of 118 specimens, we determined BRMS1 mRNA and protein expression as well as its correlation with the clinical course in astrocytomas IDH mutant, CNS WHO grade 2/3, and glioblastoma IDH wild-type, CNS WHO grade 4. Interestingly, we found BRMS1 protein expression to be significantly decreased in the aforementioned gliomas, while BRMS1 mRNA appeared to be overexpressed throughout. This dysregulation was independent of patients' characteristics or survival. The protein and mRNA expression differences cannot be finally explained at this stage. However, they suggest a post-transcriptional dysregulation that has been previously described in other cancer entities. Our analyses present the first data on BRMS1 expression in gliomas that can provide a starting point for further investigations.},
  language  = {en}
}
@article{NicklEckGoedertetal.2023,
  author    = {Nickl, Vera and Eck, Juliana and Goedert, Nicolas and H{\"u}bner, Julian and Nerreter, Thomas and Hagemann, Carsten and Ernestus, Ralf-Ingo and Schulz, Tim and Nickl, Robert Carl and Keßler, Almuth Friederike and L{\"o}hr, Mario and Rosenwald, Andreas and Breun, Maria and Monoranu, Camelia Maria},
  title     = {Characterization and optimization of the tumor microenvironment in patient-derived organotypic slices and organoid models of glioblastoma},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {10},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15102698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319249},
  year      = {2023},
  abstract  = {While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.},
  language  = {en}
}
@article{FroehlichSassenrathNadjiOhletal.2022,
  author    = {Fr{\"o}hlich, Ellen and Sassenrath, Claudia and Nadji-Ohl, Minou and Unteroberd{\"o}rster, Meike and R{\"u}ckriegel, Stefan and Brelie, Christian von der and Roder, Constantin and Forster, Marie-Therese and Schommer, Stephan and L{\"o}hr, Mario and Pala, Andrej and Goebel, Simone and Mielke, Dorothee and Gerlach, R{\"u}diger and Renovanz, Mirjam and Wirtz, Christian Rainer and Onken, Julia and Czabanka, Marcus and Tatagiba, Marcos Soares and Rohde, Veit and Ernestus, Ralf-Ingo and Vajkoczy, Peter and Gansland, Oliver and Coburger, Jan},
  title     = {Resilience in lower grade glioma patients},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14215410},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297518},
  year      = {2022},
  abstract  = {Current data show that resilience is an important factor in cancer patients' well-being. We aim to explore the resilience of patients with lower grade glioma (LGG) and the potentially influencing factors. We performed a cross-sectional assessment of adult patients with LGG who were enrolled in the LoG-Glio registry. By phone interview, we administered the following measures: Resilience Scale (RS-13), distress thermometer, Montreal Cognitive Assessment Test for visually impaired patients (MoCA-Blind), internalized stigmatization by brain tumor (ISBI), Eastern Cooperative Oncological Group performance status (ECOG), patients' perspective questionnaire (PPQ) and typical clinical parameters. We calculated correlations and multivariate regression models. Of 74 patients who were assessed, 38\% of those showed a low level of resilience. Our results revealed significant correlations of resilience with distress (p < 0.001, -0.49), MOCA (p = 0.003, 0.342), ECOG (p < 0.001, -0.602), stigmatization (p < 0.001, -0.558), pain (p < 0.001, -0.524), and occupation (p = 0.007, 0.329). In multivariate analyses, resilience was negatively associated with elevated ECOG (p = 0.020, β = -0.383) and stigmatization levels (p = 0.008, β = -0.350). Occupation showed a tendency towards a significant association with resilience (p = 0.088, β = -0.254). Overall, low resilience affected more than one third of our cohort. Low functional status is a specific risk factor for low resilience. The relevant influence of stigmatization on resilience is a novel finding for patients suffering from a glioma and should be routinely identified and targeted in clinical routine.},
  language  = {en}
}
@article{SalvadorKesslerDomroeseetal.2022,
  author    = {Salvador, Ellaine and Kessler, Almuth F. and Domr{\"o}se, Dominik and H{\"o}rmann, Julia and Schaeffer, Clara and Giniunaite, Aiste and Burek, Malgorzata and Tempel-Brami, Catherine and Voloshin, Tali and Volodin, Alexandra and Zeidan, Adel and Giladi, Moshe and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and F{\"o}rster, Carola Y. and Hagemann, Carsten},
  title     = {Tumor Treating Fields (TTFields) reversibly permeabilize the blood-brain barrier in vitro and in vivo},
  series = {Biomolecules},
  volume    = {12},
  journal   = {Biomolecules},
  number    = {10},
  issn      = {2218-273X},
  doi       = {10.3390/biom12101348},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288057},
  year      = {2022},
  abstract  = {Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood-brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB's integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100-300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy.},
  language  = {en}
}
@article{FeldheimKesslerFeldheimetal.2022,
  author    = {Feldheim, Jonas and Kessler, Almuth F. and Feldheim, Julia J. and Schulz, Ellina and Wend, David and Lazaridis, Lazaros and Kleinschnitz, Christoph and Glas, Martin and Ernestus, Ralf-Ingo and Brandner, Sebastian and Monoranu, Camelia M. and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Effects of long-term temozolomide treatment on glioblastoma and astrocytoma WHO grade 4 stem-like cells},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23095238},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284417},
  year      = {2022},
  abstract  = {Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O\(^6\)-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.},
  language  = {en}
}
@article{SchulzMawambaLoehretal.2022,
  author    = {Schulz, Ellina and Mawamba, Viviane and L{\"o}hr, Mario and Hagemann, Carsten and Friedrich, Alexandra and Schatzschneider, Ulrich},
  title     = {Structure-activity relations of Pd(II) and Pt(II) thiosemicarbazone complexes on different human glioblastoma cell lines},
  series = {Zeitschrift f{\"u}r Anorganische und Allgemeine Chemie},
  volume    = {648},
  journal   = {Zeitschrift f{\"u}r Anorganische und Allgemeine Chemie},
  number    = {12},
  issn      = {0044-2313},
  doi       = {10.1002/zaac.202200073},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318281},
  year      = {2022},
  abstract  = {Ten thiosemicarbazone ligands obtained by condensation of pyridine-2-carbaldehyde, quinoline-2-carbaldehyde, 2-acetylpyridine, 2-acetylquinoline, or corresponding 2-pyridyl ketones with thiosemicarbazides RNHC(S)NHNH\(_{2}\) and R=CH\(_{3}\), C\(_{6}\)H\(_{5}\) were prepared in good yield. The reaction of [PdCl\(_{2}\)(cod)] with cod=1,5-cyclooctadiene or K\(_{2}\)[PtCl\(_{4}\)] resulted in a total of 17 Pd(II) and Pt(II) complexes isolated in excellent purity, as demonstrated by \(^{1}\)H, \(^{13}\)C, and, where applicable, \(^{195\)Pt NMR spectroscopy combined with CHNS analysis. The cytotoxicity of the title compounds was studied on four human glioblastoma cell lines (GaMG, U87, U138, and U343). The most active compound, with a Pd(II) metal centre, a 2-quinolinyl ring, and methyl groups on both the proximal C and distal N atoms exhibited an EC\(_{50}\) value of 2.1 μM on the GaMG cell lines, thus being slightly more active than cisplatin (EC\(_{50}\) 3.4 μM) and significantly more potent than temozolomide (EC\(_{50}\) 67.1 μM). Surprisingly, the EC\(_{50}\) values were inversely correlated with the lipophilicity, as determined with the "shake-flask method", and decreased with the length of the alkyl substituents (C\(_{1}\)>C\(_{8}\)>C\(_{10}\)). Correlation with the different structural motifs showed that for the most promising anticancer activity, a maximum of two aromatic rings (either quinolinyl or pyridyl plus phenyl) combined with one methyl group are favoured and the Pd(II) complexes are slightly more potent than their Pt(II) analogues.},
  language  = {en}
}
@article{PolatWohllebenKosmalaetal.2022,
  author    = {Polat, B{\"u}lent and Wohlleben, Gisela and Kosmala, Rebekka and Lisowski, Dominik and Mantel, Frederick and Lewitzki, Victor and L{\"o}hr, Mario and Blum, Robert and Herud, Petra and Flentje, Michael and Monoranu, Camelia-Maria},
  title     = {Differences in stem cell marker and osteopontin expression in primary and recurrent glioblastoma},
  series = {Cancer Cell International},
  volume    = {22},
  journal   = {Cancer Cell International},
  issn      = {1475-2867},
  doi       = {10.1186/s12935-022-02510-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-301240},
  year      = {2022},
  abstract  = {Background Despite of a multimodal approach, recurrences can hardly be prevented in glioblastoma. This may be in part due to so called glioma stem cells. However, there is no established marker to identify these stem cells. Methods Paired samples from glioma patients were analyzed by immunohistochemistry for expression of the following stem cell markers: CD133, Musashi, Nanog, Nestin, octamer-binding transcription factor 4 (Oct4), and sex determining region Y-box 2 (Sox2). In addition, the expression of osteopontin (OPN) was investigated. The relative number of positively stained cells was determined. By means of Kaplan-Meier analysis, a possible association with overall survival by marker expression was investigated. Results Sixty tissue samples from 30 patients (17 male, 13 female) were available for analysis. For Nestin, Musashi and OPN a significant increase was seen. There was also an increase (not significant) for CD133 and Oct4. Patients with mutated Isocitrate Dehydrogenase-1/2 (IDH-1/2) status had a reduced expression for CD133 and Nestin in their recurrent tumors. Significant correlations were seen for CD133 and Nanog between OPN in the primary and recurrent tumor and between CD133 and Nestin in recurrent tumors. By confocal imaging we could demonstrate a co-expression of CD133 and Nestin within recurrent glioma cells. Patients with high CD133 expression had a worse prognosis (22.6 vs 41.1 months, p = 0.013). A similar trend was seen for elevated Nestin levels (24.9 vs 41.1 months, p = 0.08). Conclusions Most of the evaluated markers showed an increased expression in their recurrent tumor. CD133 and Nestin were associated with survival and are candidate markers for further clinical investigation.},
  language  = {en}
}
@article{SalvadorKoepplHoermannetal.2023,
  author    = {Salvador, Ellaine and K{\"o}ppl, Theresa and H{\"o}rmann, Julia and Sch{\"o}nh{\"a}rl, Sebastian and Bugaeva, Polina and Kessler, Almuth F. and Burek, Malgorzata and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier},
  series = {Pharmaceutics},
  volume    = {15},
  journal   = {Pharmaceutics},
  number    = {1},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics15010185},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304830},
  year      = {2023},
  abstract  = {In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood-brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies.},
  language  = {en}
}
@article{NicklSchulzSalvadoretal.2022,
  author    = {Nickl, Vera and Schulz, Ellina and Salvador, Ellaine and Trautmann, Laureen and Diener, Leopold and Kessler, Almuth F. and Monoranu, Camelia M. and Dehghani, Faramarz and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Glioblastoma-derived three-dimensional ex vivo models to evaluate effects and efficacy of Tumor Treating Fields (TTFields)},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14215177},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290340},
  year      = {2022},
  abstract  = {Simple Summary In glioblastoma, tumor recurrence is inevitable and the prognosis of patients is poor, despite multidisciplinary treatment approaches involving surgical resection, radiotherapy and chemotherapy. Recently, Tumor Treating Fields (TTFields) have been added to the therapeutic set-up. These alternating electric fields are applied to glioblastoma at 200 kHz frequency via arrays placed on the shaved scalp of patients. Patients show varying response to this therapy. Molecular effects of TTFields have been investigated largely in cell cultures and animal models, but not in patient tissue samples. Acquisition of matched treatment-na{\"i}ve and recurrent patient tissues is a challenge. Therefore, we suggest three reliable patient-derived three-dimensional ex vivo models (primary cells grown as microtumors on murine organotypic hippocampal slices, organoids and tumor slice cultures) which may facilitate prediction of patients' treatment responses and provide important insights into clinically relevant cellular and molecular alterations under TTFields. Abstract Glioblastoma (GBM) displays a wide range of inter- and intra-tumoral heterogeneity contributing to therapeutic resistance and relapse. Although Tumor Treating Fields (TTFields) are effective for the treatment of GBM, there is a lack of ex vivo models to evaluate effects on patients' tumor biology or to screen patients for treatment efficacy. Thus, we adapted patient-derived three-dimensional tissue culture models to be compatible with TTFields application to tissue culture. Patient-derived primary cells (PDPC) were seeded onto murine organotypic hippocampal slice cultures (OHSC), and microtumor development with and without TTFields at 200 kHz was observed. In addition, organoids were generated from acute material cultured on OHSC and treated with TTFields. Lastly, the effect of TTFields on expression of the Ki67 proliferation marker was evaluated on cultured GBM slices. Microtumors exhibited increased sensitivity towards TTFields compared to monolayer cell cultures. TTFields affected tumor growth and viability, as the size of microtumors and the percentage of Ki67-positive cells decreased after treatment. Nevertheless, variability in the extent of the response was preserved between different patient samples. Therefore, these pre-clinical GBM models could provide snapshots of the tumor to simulate patient treatment response and to investigate molecular mechanisms of response and resistance.},
  language  = {en}
}
@article{LoehrHaertigSchulzeetal.2022,
  author    = {L{\"o}hr, Mario and H{\"a}rtig, Wolfgang and Schulze, Almut and Kroiß, Matthias and Sbiera, Silviu and Lapa, Constantin and Mages, Bianca and Strobel, Sabrina and Hundt, Jennifer Elisabeth and Bohnert, Simone and Kircher, Stefan and Janaki-Raman, Sudha and Monoranu, Camelia-Maria},
  title     = {SOAT1: A suitable target for therapy in high-grade astrocytic glioma?},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {7},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23073726},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284178},
  year      = {2022},
  abstract  = {Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.},
  language  = {en}
}