@article{BohnertTrellaPreissetal.2022,
  author    = {Bohnert, Simone and Trella, Stefanie and Preiß, Ulrich and Heinsen, Helmut and Bohnert, Michael and Zwirner, Johann and Tremblay, Marie-{\`E}ve and Monoranu, Camelia-Maria and Ondruschka, Benjamin},
  title     = {Density of TMEM119-positive microglial cells in postmortem cerebrospinal fluid as a surrogate marker for assessing complex neuropathological processes in the CNS},
  series = {International Journal of Legal Medicine},
  volume    = {136},
  journal   = {International Journal of Legal Medicine},
  number    = {6},
  doi       = {10.1007/s00414-022-02863-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325009},
  pages     = {1841-1850},
  year      = {2022},
  abstract  = {Routine coronal paraffin-sections through the dorsal frontal and parieto-occipital cortex of a total of sixty cases with divergent causes of death were immunohistochemically (IHC) stained with an antibody against TMEM119. Samples of cerebrospinal fluid (CSF) of the same cases were collected by suboccipital needle-puncture, subjected to centrifugation and processed as cytospin preparations stained with TMEM119. Both, cytospin preparations and sections were subjected to computer-assisted density measurements. The density of microglial TMEM119-positive cortical profiles correlated with that of cytospin results and with the density of TMEM119-positive microglial profiles in the medullary layer. There was no statistically significant correlation between the density of medullary TMEM119-positive profiles and the cytospin data. Cortical microglial cells were primarily encountered in supragranular layers I, II, and IIIa and in infragranular layers V and VI, the region of U-fibers and in circumscribed foci or spread in a diffuse manner and high density over the white matter. We have evidence that cortical microglia directly migrate into CSF without using the glympathic pathway. Microglia in the medullary layer shows a strong affinity to the adventitia of deep vessels in the myelin layer. Selected rapidly fatal cases including myocardial infarcts and drowning let us conclude that microglia in cortex and myelin layer can react rapidly and its reaction and migration is subject to pre-existing external and internal factors. Cytospin preparations proved to be a simple tool to analyze and assess complex changes in the CNS after rapid fatal damage. There is no statistically significant correlation between cytospin and postmortem interval. Therefore, the quantitative analyses of postmortem cytospins obviously reflect the neuropathology of the complete central nervous system. Cytospins provide forensic pathologists a rather simple and easy to perform method for the global assessment of CNS affliction.},
  language  = {en}
}
@article{HrudkaEisHeřmanetal.2019,
  author    = {Hrudka, Jan and Eis, V{\´a}clav and Heřman, Josef and Prouzov{\´a}, Zuzana and Rosenwald, Andreas and František, Duška},
  title     = {Panniculitis-like T-cell-lymphoma in the mesentery associated with hemophagocytic syndrome: autopsy case report},
  series = {Diagnostic Pathology},
  volume    = {14},
  journal   = {Diagnostic Pathology},
  doi       = {10.1186/s13000-019-0854-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322665},
  year      = {2019},
  abstract  = {Background Panniculitis-like T-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, occurring usually in the form of nodules within the subcutaneous fat tissue of the extremities or trunk. In the literature, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is described as a distinct type of T-cell lymphoma with a variable clinical behavior, depending on molecular phenotype of T-cell receptor (TCR) and on the presence or absence of hemophagocytic syndrome. Case presentation We present a bioptic and autoptic case of a 65-years old Caucasian man with panniculitic T-cell lymphoma with morphological and immunohistochemical features of SPTCL, limited to the retroperitoneal and mesenteric mass, i.e. without any cutaneous involvement, and associated with severe hemophagocytic lymphohistiocytosis. Conclusion A panniculitic T-cell lymphoma with morphological and molecular features of SPTCL, which is limited to mesentery, i.e. does not involve subcutaneous fat, seems to be exceedingly rare.},
  language  = {en}
}
@article{ZamoGerhardHartmannOttetal.2022,
  author    = {Zam{\`o}, Alberto and Gerhard-Hartmann, Elena and Ott, German and Anagnostopoulos, Ioannis and Scott, David W. and Rosenwald, Andreas and Rauert-Wunderlich, Hilka},
  title     = {Routine application of the Lymph2Cx assay for the subclassification of aggressive B-cell lymphoma: report of a prospective real-world series},
  series = {Virchows Archiv},
  volume    = {481},
  journal   = {Virchows Archiv},
  number    = {6},
  doi       = {10.1007/s00428-022-03420-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324686},
  pages     = {935-943},
  year      = {2022},
  abstract  = {The subclassification of diffuse large B-cell lymphoma (DLBCL) into germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes has become mandatory in the 2017 update of the WHO classification of lymphoid neoplasms and will continue to be used in the WHO 5\(^{th}\) edition. The RNA-based Lymph2Cx assay has been validated as a reliable surrogate of high-throughput gene expression profiling assays for distinguishing between GCB and ABC DLBCL and provides reliable results from formalin-fixed, paraffin-embedded (FFPE) material. This test has been previously used in clinical trials, but experience from real-world routine application is rare. We routinely applied the Lymph2Cx assay to day-to-day diagnostics on a series of 147 aggressive B-cell lymphoma cases and correlated our results with the immunohistochemical subclassification using the Hans algorithm and fluorescence in situ hybridization findings using break-apart probes for MYC, BCL2, and BCL6. The routine use of the Lymph2Cx assay had a high technical success rate (94.6\%) with a low rate of failure due to poor material and/or RNA quality. The Lymph2Cx assay was discordant with the Hans algorithm in 18\% (23 of 128 cases). Discordant cases were mainly classified as GCB by the Hans algorithm and as ABC by Lymph2Cx (n = 11, 8.6\%). Only 5 cases (3.9\%) were classified as non-GCB by the Hans algorithm and as GCB by Lymph2Cx. Additionally, 5.5\% of cases (n = 7) were left unclassified by Lymph2Cx, whereas they were defined as GCB (n = 4) or non-GCB (n = 3) by the Hans algorithm. Our data support the routine applicability of the Lymph2Cx assay.},
  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{VoelkerWeigelStrehletal.2018,
  author    = {V{\"o}lker, Hans-Ullrich and Weigel, Michael and Strehl, Annette and Frey, Lea},
  title     = {Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array},
  series = {Diagnostic Pathology},
  volume    = {13},
  journal   = {Diagnostic Pathology},
  number    = {67},
  doi       = {10.1186/s13000-018-0737-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176960},
  year      = {2018},
  abstract  = {Background: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX\(^{®}\), a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test. Methods: The results of Ki67, uPA/PAI-1 and OncotypeDX\(^{®}\) were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed. Results: With a proliferation index Ki67 of < 14\%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14\%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5\%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9\%); p = 0.054, Student's t-test. When Ki67 was > 14\% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14\% with non-raised uPA/PAI-1 (p < 0.03, Student's t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values. Conclusion: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).},
  language  = {en}
}
@article{FeldheimKesslerSchmittetal.2020,
  author    = {Feldheim, Jonas and Kessler, Almuth F. and Schmitt, Dominik and Salvador, Ellaine and Monoranu, Camelia M. and Feldheim, Julia J. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten},
  title     = {Ribosomal Protein S27/Metallopanstimulin-1 (RPS27) in Glioma — A New Disease Biomarker?},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {5},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12051085},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203648},
  year      = {2020},
  abstract  = {Despite its significant overexpression in several malignant neoplasms, the expression of RPS27 in the central nervous system (CNS) is widely unknown. We identified the cell types expressing RPS27 in the CNS under normal and disease conditions. We acquired specimens of healthy brain (NB), adult pilocytic astrocytoma (PA) World Health Organization (WHO) grade I, anaplastic PA WHO grade III, gliomas WHO grade II/III with or without isocitrate dehydrogenase (IDH) mutation, and glioblastoma multiforme (GBM). RPS27 protein expression was examined by immunohistochemistry and double-fluorescence staining and its mRNA expression quantified by RT-PCR. Patients' clinical and tumor characteristics were collected retrospectively. RPS27 protein was specifically expressed in tumor cells and neurons, but not in healthy astrocytes. In tumor tissue, most macrophages were positive, while this was rarely the case in inflamed tissue. Compared to NB, RPS27 mRNA was in mean 6.2- and 8.8-fold enhanced in gliomas WHO grade II/III with (p < 0.01) and without IDH mutation (p = 0.01), respectively. GBM displayed a 4.6-fold increased mean expression (p = 0.02). Although RPS27 expression levels did not affect the patients' survival, their association with tumor cells and tumor-associated macrophages provides a rationale for a future investigation of a potential function during gliomagenesis and tumor immune response.},
  language  = {en}
}
@article{PrietoGarciaHartmannReisslandetal.2022,
  author    = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Bozkurt, S{\"u}leyman and Pahor, Nikolett and Fuss, Carmina and Schirbel, Andreas and Sch{\"u}lein-V{\"o}lk, Christina and Buchberger, Alexander and Calzado Canale, Marco A. and Rosenfeldt, Mathias and Dikic, Ivan and M{\"u}nch, Christian and Diefenbacher, Markus E.},
  title     = {USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K},
  series = {Molecular Oncology},
  volume    = {16},
  journal   = {Molecular Oncology},
  number    = {17},
  doi       = {10.1002/1878-0261.13217},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312777},
  pages     = {3082-3106},
  year      = {2022},
  abstract  = {Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFR\(^{L858R}\)-, BRAF\(^{V600E}\)- or PI3K\(^{H1047R}\)-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.},
  language  = {en}
}
@article{WallaschekReuterSilkenatetal.2021,
  author    = {Wallaschek, Nina and Reuter, Saskia and Silkenat, Sabrina and Wolf, Katharina and Niklas, Carolin and {\"O}zge, Kayisoglu and Aguilar, Carmen and Wiegering, Armin and Germer, Christoph-Thomas and Kircher, Stefan and Rosenwald, Andreas and Shannon-Lowe, Claire and Bartfeld, Sina},
  title     = {Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids},
  series = {PLoS Pathogens},
  volume    = {17},
  journal   = {PLoS Pathogens},
  number    = {2},
  doi       = {10.1371/journal.ppat.1009210},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259206},
  pages     = {e1009210},
  year      = {2021},
  abstract  = {Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8\% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.},
  language  = {en}
}
@article{BohnertWirthSchmitzetal.2021,
  author    = {Bohnert, Simone and Wirth, Christoph and Schmitz, Werner and Trella, Stefanie and Monoranu, Camelia-Maria and Ondruschka, Benjamin and Bohnert, Michael},
  title     = {Myelin basic protein and neurofilament H in postmortem cerebrospinal fluid as surrogate markers of fatal traumatic brain injury},
  series = {International Journal of Legal Medicine},
  volume    = {135},
  journal   = {International Journal of Legal Medicine},
  number    = {4},
  issn      = {1437-1596},
  doi       = {10.1007/s00414-021-02606-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266929},
  pages     = {1525-1535},
  year      = {2021},
  abstract  = {The aim of this study was to investigate if the biomarkers myelin basic protein (MBP) and neurofilament-H (NF-H) yielded informative value in forensic diagnostics when examining cadaveric cerebrospinal fluid (CSF) biochemically via an enzyme-linked immunosorbent assay (ELISA) and comparing the corresponding brain tissue in fatal traumatic brain injury (TBI) autopsy cases by immunocytochemistry versus immunohistochemistry. In 21 trauma and 19 control cases, CSF was collected semi-sterile after suboccipital puncture and brain specimens after preparation. The CSF MBP (p = 0.006) and NF-H (p = 0.0002) levels after TBI were significantly higher than those in cardiovascular controls. Immunohistochemical staining against MBP and against NF-H was performed on cortical and subcortical samples from also biochemically investigated cases (5 TBI cases/5 controls). Compared to the controls, the TBI cases showed a visually reduced staining reaction against MBP or repeatedly ruptured neurofilaments against NF-H. Immunocytochemical tests showed MBP-positive phagocytizing macrophages in CSF with a survival time of > 24 h. In addition, numerous TMEM119-positive microglia could be detected with different degrees of staining intensity in the CSF of trauma cases. As a result, we were able to document that elevated levels of MBP and NF-H in the CSF should be considered as useful neuroinjury biomarkers of traumatic brain injury.},
  language  = {en}
}
@phdthesis{Hassler2023,
  author    = {Haßler, Markus Sebastian},
  title     = {NFATc3 in der akuten GvHD},
  doi       = {10.25972/OPUS-32368},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323681},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Bei Leuk{\"a}mien, Lymphomen und dem Multiplen Myelom stellt die allogene h{\"a}matopoetische Stammzelltransplantation (allo-HCT) oft die letzte kurative Therapieoption dar. Spender-T-Zellen (v.a. CD8+-T-Zellen), die im Transplantat enthalten sind, erkennen nach Chemo-/Strahlentherapie verbliebene Reste des entarteten Empf{\"a}ngergewebes, eradizieren dieses und verhindern somit ein Tumorrezidiv (Graft-versus-Leuk{\"a}mie Reaktion/GvL). H{\"a}ufig attackieren Spender-T-Zellen (v.a. CD4+-Th1-Zellen) aber auch nicht-malignes Gewebe (z.B. Haut, Leber und Darm), was bis zum Tod des Patienten f{\"u}hren kann (Graft-versus-Host Disease/GvHD). Calcineurin-Inhibitoren wie Cyclosporin A (CsA) und Tacrolimus, die oft schon prophylaktisch verabreicht werden, verhindern {\"u}ber eine unselektive Inhibition aller Mitglieder der NFAT-Transkriptionsfaktorfamilie (Nuclear factor of activated T-cells) die Aktivierung der Spender-T-Zellen. Es folgt eine klinische Besserung der GvHD-Symptomatik, w{\"a}hrend jedoch der GvL-Effekt ebenfalls supprimiert wird. Bisherige Untersuchungen unserer Arbeitsgruppe am Mausmodell hatten gezeigt, dass die selektive Inhibition eines NFAT-Familienmitgliedes (NFATc1 oder NFATc2) in den Donor-T-Zellen zu einer signifikanten Besserung der aGvHD bei jedoch erhaltener GvL f{\"u}hrt. Es wurde nun der Einfluss des dritten, in Lymphozyten exprimierten NFAT-Mitglieds NFATc3 im Kontext der aGvHD untersucht. Zur Basisanalyse der neu kreierten Nfatc3fl/fl.Cd4cre- und Nfatc1fl/fl.Nfatc3fl/fl.Cd4cre-Mauslinien erfolgten durchflusszytometrische und Western-Blot-Analysen. Anschließend wurden In-vivo-Untersuchungen unter Verwendung eines etablierten major-mismatch-aGvHD-Modells (H-2b→H-2d) durchgef{\"u}hrt. Es konnte gezeigt werden, dass durch eine NFATc3- (+/- NFATc1-) Defizienz direkt ex vivo die CD4+/CD8+-Ratio durch Abnahme der CD4+- hin zu den CD8+-T-Zellen verschoben wird. Auch zeigte sich in den entsprechenden Genotypen eine Abnahme der naiven- und daf{\"u}r vice versa eine Zunahme der Effektor-T-Zellen. In den wiederholt durchgef{\"u}hrten aGvHD-Versuchen zeigte sich in vivo als Korrelat der (ebenfalls erneut nachgewiesenen) Abnahme des CD4+/CD8+-Quotienten in den Zielorganen eine geringere Expansion der NFAT-defizienten als der wildtypischen T-Zellen. Leider spiegelte sich dies nicht in dem clinical score zur Quantifizierung der aGvHD-Symptomatik wider. Auch das K{\"o}rpergewicht der Versuchsgruppe nahm rapide ab. Urs{\"a}chlich hierf{\"u}r ist - als Korrelat zur direkt ex vivo nachgewiesenen Aktivierungsneigung - ein vermehrter Th1-Shift der NFATc3 (+/-NFATc1-) defizienten T-Zellen. Eine Inhibierung von NFATc3 - im Gegensatz zu NFATc1 und NFATc2 - ist demzufolge kein sinnvoller Ansatzpunkt f{\"u}r eine m{\"o}gliche, zielgerichtetere aGvHD-Therapie. Der positive Effekt der reduzierten Proliferationsneigung der NFATc3-defizienten Lymphozyten wird durch deren vermehrte Aktivierungsneigung mit erh{\"o}hter Sekretion von pro-inflammatorischen Zytokinen zunichte gemacht.},
  subject      = {Transplantat-Wirt-Reaktion},
  language  = {de}
}
@article{HagemannNeuhausDahlmannetal.2019,
  author    = {Hagemann, Carsten and Neuhaus, Nikolas and Dahlmann, Mathias and Kessler, Almuth F. and Kobelt, Dennis and Herrmann, Pia and Eyrich, Matthias and Freitag, Benjamin and Linsenmann, Thomas and Monoranu, Camelia M. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Stein, Ulrike},
  title     = {Circulating MACC1 transcripts in glioblastoma patients predict prognosis and treatment response},
  series = {Cancers},
  volume    = {11},
  journal   = {Cancers},
  number    = {6},
  issn      = {2072-6694},
  doi       = {10.3390/cancers11060825},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197327},
  year      = {2019},
  abstract  = {Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacksreliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associatedin colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinicaloutcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher inpatients compared to controls. Low MACC1 levels clustered together with other prognosticallyfavorable markers. It was associated with patients' prognosis in conjunction with the isocitratedehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable(median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (medianOS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months).No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levelsreceiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worstprognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulatingMACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcomeprediction and help define more precise risk categories of glioblastoma patients.},
  language  = {en}
}
@article{MuhammadRudolfPhametal.2018,
  author    = {Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Takata, Katsuyoshi and Matsushita, Nobuko and Ellenrieder, Volker and Kondo, Eisaku and  Serfling, Edgar},
  title     = {Induction of Short NFATc1/αA Isoform Interferes with Peripheral B Cell Differentiation},
  series = {Frontiers in Immunology},
  volume    = {9},
  journal   = {Frontiers in Immunology},
  number    = {32},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2018.00032},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197501},
  year      = {2018},
  abstract  = {In lymphocytes, immune receptor signals induce the rapid nuclear translocation of preformed cytosolic NFAT proteins. Along with co-stimulatory signals, persistent immune receptor signals lead to high levels of NFATc1/αA, a short NFATc1 isoform, in effector lymphocytes. Whereas NFATc1 is not expressed in plasma cells, in germinal centers numerous centrocytic B cells express nuclear NFATc1/αA. When overexpressed in chicken DT40 B cells or murine WEHI 231 B cells, NFATc1/αA suppressed their cell death induced by B cell receptor signals and affected the expression of genes controlling the germinal center reaction and plasma cell formation. Among those is the Prdm1 gene encoding Blimp-1, a key factor of plasma cell formation. By binding to a regulatory DNA element within exon 1 of the Prdm1 gene, NFATc1/αA suppresses Blimp-1 expression. Since expression of a constitutive active version of NFATc1/αA interfered with Prdm1 RNA expression, LPS-mediated differentiation of splenic B cells to plasmablasts in vitro and reduced immunoglobulin production in vivo, one may conclude that NFATc1/αA plays an important role in controlling plasmablast/plasma cell formation.},
  language  = {en}
}
@article{UpcinHenkeKleefeldtetal.2021,
  author    = {Upcin, Berin and Henke, Erik and Kleefeldt, Florian and Hoffmann, Helene and Rosenwald, Andreas and Irmak-Sav, Ster and Aktas, Huseyin Bertal and R{\"u}ckschloß, Uwe and Erg{\"u}n, S{\"u}leyman},
  title     = {Contribution of adventitia-derived stem and progenitor cells to new vessel formation in tumors},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {7},
  doi       = {10.3390/cells10071719},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242577},
  year      = {2021},
  abstract  = {Blocking tumor vascularization has not yet come to fruition to the extent it was hoped for, as angiogenesis inhibitors have shown only partial success in the clinic. We hypothesized that under- appreciated vascular wall-resident stem and progenitor cells (VW-SPCs) might be involved in tumor vascularization and influence effectiveness of anti-angiogenic therapy. Indeed, in patient samples, we observed that vascular adventitia-resident CD34\(^+\) VW-SPCs are recruited to tumors in situ from co-opted vessels. To elucidate this in detail, we established an ex vivo model using concomitant embedding of multi-cellular tumor spheroids (MCTS) and mouse aortic rings (ARs) into collagen gels, similar to the so-called aortic ring assay (ARA). Moreover, ARA was modified by removing the ARs' adventitia that harbors VW-SPCs. Thus, this model enabled distinguishing the contribution of VW-SPCs from that of mature endothelial cells (ECs) to new vessel formation. Our results show that the formation of capillary-like sprouts is considerably delayed, and their number and network formation were significantly reduced by removing the adventitia. Substituting iPSC-derived neural spheroids for MCTS resulted in distinct sprouting patterns that were also strongly influenced by the presence or absence of VW-SPCs, also underlying the involvement of these cells in non-pathological vascularization. Our data suggest that more comprehensive approaches are needed in order to block all of the mechanisms contributing to tumor vascularization.},
  language  = {en}
}
@article{FuhrHeidenreichSrivastavaetal.2022,
  author    = {Fuhr, Viktoria and Heidenreich, Shanice and Srivastava, Mugdha and Riedel, Angela and D{\"u}ll, Johannes and Gerhard-Hartmann, Elena and Rosenwald, Andreas and Rauert-Wunderlich, Hilka},
  title     = {CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma},
  series = {Cell Death Discovery},
  volume    = {8},
  journal   = {Cell Death Discovery},
  issn      = {2058-7716},
  doi       = {10.1038/s41420-022-01289-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300817},
  year      = {2022},
  abstract  = {Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.},
  language  = {en}
}
@article{SerflingZhiSchirbeletal.2021,
  author    = {Serfling, S. and Zhi, Y. and Schirbel, A. and Lindner, T. and Meyer, T. and Gerhard-Hartmann, E. and Lappa, C. and Hagen, R. and Hackenberg, S. and Buck, A. K. and Scherzad, A.},
  title     = {Improved cancer detection in Waldeyer's tonsillar ring by \(^{68}\)Ga-FAPI PET/CT imaging},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {48},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  issn      = {1619-7070},
  doi       = {10.1007/s00259-020-05055-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235271},
  pages     = {1178-1187},
  year      = {2021},
  abstract  = {Purpose In cancer of unknown primary (CUP), positron emission tomography/computed tomography (PET/CT) with the glucose analog [\(^{18}\)F]FDG represents the standard imaging approach for localization of the malignant primary. Frequently, however, [\(^{18}\)F]FDG PET/CT cannot precisely distinguish between small occult tumors and chronic inflammation, especially in Waldeyer's tonsillar ring. To improve the accuracy for detecting primary tumors in the Waldeyer's tonsillar ring, the novel PET tracer [\(^{68}\)Ga]Ga-FAPI-4 for specific imaging of fibroblast activation protein (FAP) expression was used as a more specific target for cancer imaging. Methods Eight patients with suspicion of a malignant tumor in Waldeyer's tonsillar ring or a CUP syndrome were examined. PET/CT scans with [\(^{18}\)F]-FDG and [\(^{68}\)Ga]Ga-FAPI-4 were performed for pre-operative tumor localization. After surgical resection, histopathological and immunohistochemical results were compared to PET/CT findings. Results Histopathology revealed a palatine or lingual tonsil carcinoma in all patients. In case of lymph node metastases smaller than 7 mm in size, the [\(^{18}\)F]FDG PET/CT detection rate of cervical lymph node metastases was higher than that of [\(^{68}\)Ga]FAPI PET/CT, while both tracers identified the primary tumors in all eight cases. The size of the primary and the lymph node metastases was directly correlated to the respective FAP expression, as detected by immunohistochemistry. The mean SUVmax for the primary tumors was 21.29 ± 7.97 for \(^{18}\)F-FDG and 16.06 ± 6.29 for \(^{68}\)Ga-FAPI, respectively (p = 0.2). The mean SUVmax for the healthy contralateral tonsils was 8.38 ± 2.45 for [\(^{18}\)F]FDG and 3.55 ± 0.47 for [\(^{68}\)Ga]FAPI (p < 0.001). The SUVmax ratio of [68Ga]FAPI was significantly different from [\(^{18}\)F] FDG (p = 0.03). Mean TBRmax for the [\(^{68}\)Ga]Ga-FAPI-4 tracer was markedly higher in comparison to [\(^{18}\)F]FDG (10.90 vs. 4.11). Conclusion Non-invasive imaging of FAP expression by [\(^{68}\)Ga]FAPI PET/CT resulted in a better visual detection of the malignant primary in CUP, as compared to [\(^{18}\)F]FDG imaging. However, the detection rate of lymph node metastases was inferior, presumably due to low FAP expression in small metastases. Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [\(^{68}\)Ga]FAPI PET/CT imaging.},
  language  = {en}
}
@article{AppeltshauserMessingerStarzetal.2022,
  author    = {Appeltshauser, Luise and Messinger, Julia and Starz, Katharina and Heinrich, David and Brunder, Anna-Michelle and Stengel, Helena and Fiebig, Bianca and Ayzenberg, Ilya and Birklein, Frank and Dresel, Christian and Dorst, Johannes and Dvorak, Florian and Grimm, Alexander and Joerk, Alexander and Leypoldt, Frank and M{\"a}urer, Mathias and Merl, Patrick and Michels, Sebastian and Pitarokoili, Kalliopi and Rosenfeldt, Mathias and Sperfeld, Anne-Dorte and Weihrauch, Marc and Welte, Gabriel Simon and Sommer, Claudia and Doppler, Kathrin},
  title     = {Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies},
  series = {Neurology: Neuroimmunology \& Neuroinflammation},
  volume    = {9},
  journal   = {Neurology: Neuroimmunology \& Neuroinflammation},
  number    = {3},
  doi       = {10.1212/NXI.0000000000001163},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300551},
  year      = {2022},
  abstract  = {Background and Objectives Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). Methods We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barr{\´e} syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. Results The frequency of DM was 33.3\% in seropositive patients and thus higher compared with seronegative patients (14.1\%, OR = 3.04, 95\% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. Discussion We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.},
  language  = {en}
}
@article{HaarmannSchuhmannSilwedeletal.2019,
  author    = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias},
  title     = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown},
  series = {International Journal of Molecular Science},
  volume    = {20},
  journal   = {International Journal of Molecular Science},
  number    = {3},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20030602},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297},
  year      = {2019},
  abstract  = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.},
  language  = {en}
}
@article{PeindlGoettlichCrouchetal.2022,
  author    = {Peindl, Matthias and G{\"o}ttlich, Claudia and Crouch, Samantha and Hoff, Niklas and L{\"u}ttgens, Tamara and Schmitt, Franziska and Pereira, Jes{\´u}s Guillermo Nieves and May, Celina and Schliermann, Anna and Kronenthaler, Corinna and Cheufou, Danjouma and Reu-Hofer, Simone and Rosenwald, Andreas and Weigl, Elena and Walles, Thorsten and Sch{\"u}ler, Julia and Dandekar, Thomas and Nietzer, Sarah and Dandekar, Gudrun},
  title     = {EMT, stemness, and drug resistance in biological context: a 3D tumor tissue/in silico platform for analysis of combinatorial treatment in NSCLC with aggressive KRAS-biomarker signatures},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14092176},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270744},
  year      = {2022},
  abstract  = {Epithelial-to-mesenchymal transition (EMT) is discussed to be centrally involved in invasion, stemness, and drug resistance. Experimental models to evaluate this process in its biological complexity are limited. To shed light on EMT impact and test drug response more reliably, we use a lung tumor test system based on a decellularized intestinal matrix showing more in vivo-like proliferation levels and enhanced expression of clinical markers and carcinogenesis-related genes. In our models, we found evidence for a correlation of EMT with drug resistance in primary and secondary resistant cells harboring KRAS\(^{G12C}\) or EGFR mutations, which was simulated in silico based on an optimized signaling network topology. Notably, drug resistance did not correlate with EMT status in KRAS-mutated patient-derived xenograft (PDX) cell lines, and drug efficacy was not affected by EMT induction via TGF-β. To investigate further determinants of drug response, we tested several drugs in combination with a KRAS\(^{G12C}\) inhibitor in KRAS\(^{G12C}\) mutant HCC44 models, which, besides EMT, display mutations in P53, LKB1, KEAP1, and high c-MYC expression. We identified an aurora-kinase A (AURKA) inhibitor as the most promising candidate. In our network, AURKA is a centrally linked hub to EMT, proliferation, apoptosis, LKB1, and c-MYC. This exemplifies our systemic analysis approach for clinical translation of biomarker signatures.},
  language  = {en}
}
@article{BarahonadeBritoKleinHesslingSerflingetal.2022,
  author    = {Barahona de Brito, Carlotta and Klein-Hessling, Stefan and Serfling, Edgar and Patra, Amiya Kumar},
  title     = {Hematopoietic stem and progenitor cell maintenance and multiple lineage differentiation is an integral function of NFATc1},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {13},
  issn      = {2073-4409},
  doi       = {10.3390/cells11132012},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278809},
  year      = {2022},
  abstract  = {Hematopoietic stem and progenitor cell (HSPC) maintenance and the differentiation of various lineages is a highly complex but precisely regulated process. Multiple signaling pathways and an array of transcription factors influence HSPC maintenance and the differentiation of individual lineages to constitute a functional hematopoietic system. Nuclear factor of activated T cell (NFAT) family transcription factors have been studied in the context of development and function of multiple mature hematopoietic lineage cells. However, until now their contribution in HSPC physiology and HSPC differentiation to multiple hematopoietic lineages has remained poorly understood. Here, we show that NFAT proteins, specifically NFATc1, play an indispensable role in the maintenance of HSPCs. In the absence of NFATc1, very few HSPCs develop in the bone marrow, which are functionally defective. In addition to HSPC maintenance, NFATc1 also critically regulates differentiation of lymphoid, myeloid, and erythroid lineage cells from HSPCs. Deficiency of NFATc1 strongly impaired, while enhanced NFATc1 activity augmented, the differentiation of these lineages, which further attested to the vital involvement of NFATc1 in regulating hematopoiesis. Hematopoietic defects due to lack of NFATc1 activity can lead to severe pathologies such as lymphopenia, myelopenia, and a drastically reduced lifespan underlining the critical role NFATc1 plays in HSPC maintenance and in the differentaion of various lineages. Our findings suggest that NFATc1 is a critical component of the myriad signaling and transcriptional regulators that are essential to maintain normal hematopoiesis.},
  language  = {en}
}
@article{PattschullWalzGruendletal.2019,
  author    = {Pattschull, Grit and Walz, Susanne and Gr{\"u}ndl, Marco and Schwab, Melissa and R{\"u}hl, Eva and Baluapuri, Apoorva and Cindric-Vranesic, Anita and Kneitz, Susanne and Wolf, Elmar and Ade, Carsten P. and Rosenwald, Andreas and von Eyss, Bj{\"o}rn and Gaubatz, Stefan},
  title     = {The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes},
  series = {Cell Reports},
  volume    = {27},
  journal   = {Cell Reports},
  number    = {12},
  doi       = {10.1016/j.celrep.2019.05.071},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202039},
  pages     = {3533-3546},
  year      = {2019},
  abstract  = {YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.},
  language  = {en}
}
@article{ReichelRuecklFenwicketal.2019,
  author    = {Reichel, Thomas and Rueckl, Kilian and Fenwick, Annabel and Vogt, Niklas and Rudert, Maximilian and Plumhoff, Piet},
  title     = {Hibernoma of the upper extremity: complete case of a rare but benign soft tissue tumor},
  series = {Case Reports in Orthopedics},
  volume    = {2019},
  journal   = {Case Reports in Orthopedics},
  doi       = {10.1155/2019/6840693},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201669},
  pages     = {6840693},
  year      = {2019},
  abstract  = {Hibernoma is a rare benign lipomatous tumor showing differentiation of brown fatty tissue. To the author's best knowledge, there is no known case of malignant transformation or metastasis. Due to their slow, noninfiltrating growth hibernomas are often an incidental finding in the third or fourth decade of life. The vast majority are located in the thigh, neck, and periscapular region. A diagnostic workup includes ultrasound and contrast-enhanced MRI. Differential diagnosis is benign lipoma, well-differentiated liposarcoma, and rhabdomyoma. An incisional biopsy followed by marginal resection of the tumor is the standard of care, and recurrence after complete resection is not reported. The current paper presents diagnostic and intraoperative findings of a hibernoma of the upper arm and reviews similar reports in the current literature.},
  language  = {en}
}
@article{MeirMaurusKuperetal.2021,
  author    = {Meir, Michael and Maurus, Katja and Kuper, Jochen and Hankir, Mohammed and Wardelmann, Eva and Rosenwald, Andreas and Germer, Christoph-Thomas and Wiegering, Armin},
  title     = {The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis, and seminoma development},
  series = {Genes, Chromosomes \& Cancer},
  volume    = {60},
  journal   = {Genes, Chromosomes \& Cancer},
  number    = {12},
  doi       = {10.1002/gcc.22988},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-257476},
  pages     = {827-832},
  year      = {2021},
  abstract  = {Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with exon 11 mutations.},
  language  = {en}
}
@phdthesis{Jaklin2023,
  author    = {Jaklin, Tamara},
  title     = {Nachweis von PD-1 und PD-L1 in Plattenepithelkarzinomen des Larynx und Hypopharynx},
  doi       = {10.25972/OPUS-31301},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313019},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {In der modernen Tumortherapie sind Checkpoint-Inhibitoren ein fester Bestandteil. Die Oberfl{\"a}chenproteine PD-L1 und PD-1 stellen die Angriffspunkte dieser spezifischen Therapie dar. Die Datenlage hinsichtlich PD-L1 in HNSCC ist sehr heterogen. Diese Arbeit besch{\"a}ftigte sich daher mit der Expression von PD-L1 und PD-1 in einem Kollektiv von 118 Plattenepithelkarzinomen in Larynx und Hypopharynx und einer prognostischen Aussagekraft hinsichtlich mehrerer histopathologischer und epidemiologischer Faktoren. Außerdem wurde ein m{\"o}glicher Zusammenhang zwischen der Expression von PD-L1, PD-1 und CD5 als T-Zell-Marker in besagtem Kollektiv untersucht. Die IHC-F{\"a}rbungen wurden lichtmikroskopisch an tissue micro arrays untersucht. F{\"u}r die Auswertung von PD-L1 wurde der bereits etablierte Cologne-Score verwendet, welcher zum einen zun{\"a}chst erweitert und anschließend zwecks einer fundierten statistischen Auswertung erg{\"a}nzend modifiziert wurde. F{\"u}r CD5 und PD-1 wurden eigene Cut-Off-Werte generiert. 48 \% der F{\"a}lle waren PD-L1+, die Spannweite im Literaturvergleich schwankt zwischen 30 - 90 \%. PD-1+ waren insgesamt 31\% der F{\"a}lle, auch hier zeigen sich deutliche Abweichungen zu den vorliegenden Publikationen. Hinsichtlich der prognostischen Aussagekraft konnte ein signifikanter Zusammenhang zwischen dem T-Stadium und der PD-L1-Expression aufgezeigt werden. Ob dies Einfluss auf m{\"o}gliche Behandlungsstrategien hat, bleibt Gegenstand weiterer Forschung. Auch im Literaturvergleich finden sich wiederholt signifikante prognostische Zusammenh{\"a}nge, jedoch beziehen sich diese auf differente Faktoren. Urs{\"a}chlich daf{\"u}r sind aller Wahrscheinlichkeit nach Diskrepanzen in der PD-L1-Expression sowie deren Schwankungen durch {\"a}ußere Einfl{\"u}sse und nicht standardisierte Testverfahren. Es zeigten sich weiterhin Korrelationen zwischen den Markern, welche sich abschließend nicht alle g{\"a}nzlich herleiten lassen. Zusammenfassend k{\"o}nnten einheitliche Testverfahren die Datenlage zu PD-L1 und PD-1 homogenisieren, auch m{\"o}gliche Vortherapien sollten dementsprechend ber{\"u}cksichtigt werden. Allerdings erscheint die prognostische Aussagekraft von PD-L1 und auch von PD-1 insgesamt aufgrund der inkonstanten Expression hochgradig eingeschr{\"a}nkt, sodass sich in Zukunft vermehrt auf andere Marker konzentriert werden sollte.},
  subject      = {Plattenepithelkarzinom},
  language  = {de}
}
@article{GschmackMonoranuMaroufetal.2022,
  author    = {Gschmack, Eva and Monoranu, Camelia-Maria and Marouf, Hecham and Meyer, Sarah and Lessel, Lena and Idris, Raja and Berg, Daniela and Maetzler, Walter and Steigerwald, Frank and Volkmann, Jens and Gerlach, Manfred and Riederer, Peter and Koutsilieri, Eleni and Scheller, Carsten},
  title     = {Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson's disease},
  series = {Journal of Neural Transmission},
  volume    = {129},
  journal   = {Journal of Neural Transmission},
  number    = {5-6},
  doi       = {10.1007/s00702-022-02495-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325161},
  pages     = {545-555},
  year      = {2022},
  abstract  = {Idiopathic Parkinson's disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus-subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood-brain barrier.},
  language  = {en}
}
@article{MadrahimovMutsenkoNatanovetal.2023,
  author    = {Madrahimov, Nodir and Mutsenko, Vitalii and Natanov, Ruslan and Radaković, Dejan and Klapproth, Andr{\´e} and Hassan, Mohamed and Rosenfeldt, Mathias and Kleefeldt, Florian and Aleksic, Ivan and Erg{\"u}n, S{\"u}leyman and Otto, Christoph and Leyh, Rainer G. and Bening, Constanze},
  title     = {Multiorgan recovery in a cadaver body using mild hypothermic ECMO treatment in a murine model},
  series = {Intensive Care Medicine Experimental},
  volume    = {11},
  journal   = {Intensive Care Medicine Experimental},
  doi       = {10.1186/s40635-023-00534-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357381},
  year      = {2023},
  abstract  = {Background Transplant candidates on the waiting list are increasingly challenged by the lack of organs. Most of the organs can only be kept viable within very limited timeframes (e.g., mere 4-6 h for heart and lungs exposed to refrigeration temperatures ex vivo). Donation after circulatory death (DCD) using extracorporeal membrane oxygenation (ECMO) can significantly enlarge the donor pool, organ yield per donor, and shelf life. Nevertheless, clinical attempts to recover organs for transplantation after uncontrolled DCD are extremely complex and hardly reproducible. Therefore, as a preliminary strategy to fulfill this task, experimental protocols using feasible animal models are highly warranted. The primary aim of the study was to develop a model of ECMO-based cadaver organ recovery in mice. Our model mimics uncontrolled organ donation after an "out-of-hospital" sudden unexpected death with subsequent "in-hospital" cadaver management post-mortem. The secondary aim was to assess blood gas parameters, cardiac activity as well as overall organ state. The study protocol included post-mortem heparin-streptokinase administration 10 min after confirmed death induced by cervical dislocation under full anesthesia. After cannulation, veno-arterial ECMO (V-A ECMO) was started 1 h after death and continued for 2 h under mild hypothermic conditions followed by organ harvest. Pressure- and flow-controlled oxygenated blood-based reperfusion of a cadaver body was accompanied by blood gas analysis (BGA), electrocardiography, and histological evaluation of ischemia-reperfusion injury. For the first time, we designed and implemented, a not yet reported, miniaturized murine hemodialysis circuit for the treatment of severe hyperkalemia and metabolic acidosis post-mortem. Results BGA parameters confirmed profound ischemia typical for cadavers and incompatible with normal physiology, including extremely low blood pH, profound negative base excess, and enormously high levels of lactate. Two hours after ECMO implantation, blood pH values of a cadaver body restored from < 6.5 to 7.3 ± 0.05, pCO2 was lowered from > 130 to 41.7 ± 10.5 mmHg, sO2, base excess, and HCO3 were all elevated from below detection thresholds to 99.5 ± 0.6\%, - 4 ± 6.2 and 22.0 ± 6.0 mmol/L, respectively (Student T test, p < 0.05). A substantial decrease in hyperlactatemia (from > 20 to 10.5 ± 1.7 mmol/L) and hyperkalemia (from > 9 to 6.9 ± 1.0 mmol/L) was observed when hemodialysis was implemented. On balance, the first signs of regained heart activity appeared on average 10 min after ECMO initiation without cardioplegia or any inotropic and vasopressor support. This was followed by restoration of myocardial contractility with a heart rate of up to 200 beats per minute (bpm) as detected by an electrocardiogram (ECG). Histological examinations revealed no evidence of heart injury 3 h post-mortem, whereas shock-specific morphological changes relevant to acute death and consequent cardiac/circulatory arrest were observed in the lungs, liver, and kidney of both control and ECMO-treated cadaver mice. Conclusions Thus, our model represents a promising approach to facilitate studying perspectives of cadaveric multiorgan recovery for transplantation. Moreover, it opens new possibilities for cadaver organ treatment to extend and potentiate donation and, hence, contribute to solving the organ shortage dilemma.},
  language  = {en}
}
@article{MeinertJessenHufnageletal.2024,
  author    = {Meinert, Madlen and Jessen, Christina and Hufnagel, Anita and Kreß, Julia Katharina Charlotte and Burnworth, Mychal and D{\"a}ubler, Theo and Gallasch, Till and Da Xavier Silva, Thamara Nishida and Dos Santos, Anc{\´e}ly Ferreira and Ade, Carsten Patrick and Schmitz, Werner and Kneitz, Susanne and Friedmann Angeli, Jos{\´e} Pedro and Meierjohann, Svenja},
  title     = {Thiol starvation triggers melanoma state switching in an ATF4 and NRF2-dependent manner},
  series = {Redox Biology},
  volume    = {70},
  journal   = {Redox Biology},
  doi       = {10.1016/j.redox.2023.103011},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350328},
  year      = {2024},
  abstract  = {The cystine/glutamate antiporter xCT is an important source of cysteine for cancer cells. Once taken up, cystine is reduced to cysteine and serves as a building block for the synthesis of glutathione, which efficiently protects cells from oxidative damage and prevents ferroptosis. As melanomas are particularly exposed to several sources of oxidative stress, we investigated the biological role of cysteine and glutathione supply by xCT in melanoma. xCT activity was abolished by genetic depletion in the Tyr::CreER; Braf\(^{CA}\); Pten\(^{lox/+}\) melanoma model and by acute cystine withdrawal in melanoma cell lines. Both interventions profoundly impacted melanoma glutathione levels, but they were surprisingly well tolerated by murine melanomas in vivo and by most human melanoma cell lines in vitro. RNA sequencing of human melanoma cells revealed a strong adaptive upregulation of NRF2 and ATF4 pathways, which orchestrated the compensatory upregulation of genes involved in antioxidant defence and de novo cysteine biosynthesis. In addition, the joint activation of ATF4 and NRF2 triggered a phenotypic switch characterized by a reduction of differentiation genes and induction of pro-invasive features, which was also observed after erastin treatment or the inhibition of glutathione synthesis. NRF2 alone was capable of inducing the phenotypic switch in a transient manner. Together, our data show that cystine or glutathione levels regulate the phenotypic plasticity of melanoma cells by elevating ATF4 and NRF2.},
  language  = {en}
}
@article{HungKasperkowitzKurzetal.2023,
  author    = {Hung, Sophia and Kasperkowitz, Amelie and Kurz, Florian and Dreher, Liane and Diessner, Joachim and Ibrahim, Eslam S. and Schwarz, Stefan and Ohlsen, Knut and Hertlein, Tobias},
  title     = {Next-generation humanized NSG-SGM3 mice are highly susceptible to Staphylococcus aureus infection},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1127709},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306966},
  year      = {2023},
  abstract  = {Humanized hemato-lymphoid system mice, or humanized mice, emerged in recent years as a promising model to study the course of infection of human-adapted or human-specific pathogens. Though Staphylococcus aureus infects and colonizes a variety of species, it has nonetheless become one of the most successful human pathogens of our time with a wide armory of human-adapted virulence factors. Humanized mice showed increased vulnerability to S. aureus compared to wild type mice in a variety of clinically relevant disease models. Most of these studies employed humanized NSG (NOD-scid IL2Rgnull) mice which are widely used in the scientific community, but show poor human myeloid cell reconstitution. Since this immune cell compartment plays a decisive role in the defense of the human immune system against S. aureus, we asked whether next-generation humanized mice, like NSG-SGM3 (NOD-scid IL2Rgnull-3/GM/SF) with improved myeloid reconstitution, would prove to be more resistant to infection. To our surprise, we found the contrary when we infected humanized NSG-SGM3 (huSGM3) mice with S. aureus: although they had stronger human immune cell engraftment than humanized NSG mice, particularly in the myeloid compartment, they displayed even more pronounced vulnerability to S. aureus infection. HuSGM3 mice had overall higher numbers of human T cells, B cells, neutrophils and monocytes in the blood and the spleen. This was accompanied by elevated levels of pro-inflammatory human cytokines in the blood of huSGM3 mice. We further identified that the impaired survival of huSGM3 mice was not linked to higher bacterial burden nor to differences in the murine immune cell repertoire. Conversely, we could demonstrate a correlation of the rate of humanization and the severity of infection. Collectively, this study suggests a detrimental effect of the human immune system in humanized mice upon encounter with S. aureus which might help to guide future therapy approaches and analysis of virulence mechanisms.},
  language  = {en}
}
@article{MurtiFenderGlatzleetal.2023,
  author    = {Murti, Krisna and Fender, Hendrik and Glatzle, Carolin and Wismer, Rhoda and Sampere-Birlanga, Salvador and Wild, Vanessa and Muhammad, Khalid and Rosenwald, Andreas and Serfling, Edgar and Avots, Andris},
  title     = {Calcineurin-independent NFATc1 signaling is essential for survival of Burkitt lymphoma cells},
  series = {Frontiers in Oncology},
  volume    = {13},
  journal   = {Frontiers in Oncology},
  doi       = {10.3389/fonc.2023.1205788},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323103},
  year      = {2023},
  abstract  = {In Burkitt lymphoma (BL), a tumor of germinal center B cells, the pro-apoptotic properties of MYC are controlled by tonic B cell receptor (BCR) signals. Since BL cells do not exhibit constitutive NF-κB activity, we hypothesized that anti-apoptotic NFATc1 proteins provide a major transcriptional survival signal in BL. Here we show that post-transcriptional mechanisms are responsible for the calcineurin (CN) independent constitutive nuclear over-expression of NFATc1 in BL and Eµ-MYC - induced B cell lymphomas (BCL). Conditional inactivation of the Nfatc1 gene in B cells of Eµ-MYC mice leads to apoptosis of BCL cells in vivo and ex vivo. Inhibition of BCR/SYK/BTK/PI3K signals in BL cells results in cytosolic re-location of NFATc1 and apoptosis. Therefore, NFATc1 activity is an integrated part of tonic BCR signaling and an alternative target for therapeutic intervention in BL.},
  language  = {en}
}
@article{LisowskiHartrampfHasenaueretal.2023,
  author    = {Lisowski, Dominik and Hartrampf, Philipp E. and Hasenauer, Natalie and Nickl, Vera and Monoranu, Camelia-Maria and Tamihardja, J{\"o}rg},
  title     = {Complete loss of E-cadherin expression in a rare case of metastatic malignant meningioma: a case report},
  series = {BMC Neurology},
  volume    = {23},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-023-03450-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357996},
  year      = {2023},
  abstract  = {Background Hematogenous tumor spread of malignant meningiomas occurs very rarely but is associated with very poor prognosis. Case presentation We report an unusual case of a patient with a malignant meningioma who developed multiple metastases in bones, lungs and liver after initial complete resection of the primary tumor. After partial hepatic resection, specimens were histologically analyzed, and a complete loss of E-cadherin adhesion molecules was found. No oncogenic target mutations were found. The patient received a combination of conventional radiotherapy and peptide receptor radionuclide therapy (PRRT). Due to aggressive tumor behavior and rapid spread of metastases, the patient deceased after initiation of treatment. Conclusions E-cadherin downregulation is associated with a higher probability of tumor invasion and distant metastasis formation in malignant meningioma. Up to now, the efficacy of systemic therapy, including PRRT, is very limited in malignant meningioma patients.},
  language  = {en}
}
@article{SealSchwabChiarollaetal.2023,
  author    = {Seal, Rishav and Schwab, Lara S. U. and Chiarolla, Cristina M. and Hundhausen, Nadine and Klose, Georg Heinrich and Reu-Hofer, Simone and Rosenwald, Andreas and Wiest, Johannes and Berberich-Siebelt, Friederike},
  title     = {Delayed and limited administration of the JAKinib tofacitinib mitigates chronic DSS-induced colitis},
  series = {Frontiers in Immunology},
  volume    = {14},
  journal   = {Frontiers in Immunology},
  doi       = {10.3389/fimmu.2023.1179311},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317815},
  year      = {2023},
  abstract  = {In inflammatory bowel disease, dysregulated T cells express pro-inflammatory cytokines. Using a chronic azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis model resembling ulcerative colitis, we evaluated whether and when treatment with the Janus kinase (JAK) inhibitor tofacitinib could be curative. Comparing the treatment with two and three cycles of tofacitinib medication in drinking water - intermittently with DSS induction - revealed that two cycles were not only sufficient but also superior over the 3-x regimen. The two cycles of the 2-x protocol paralleled the second and third cycles of the longer protocol. T cells were less able to express interferon gamma (IFN-γ) and the serum levels of IFN-γ, interleukin (IL)-2, IL-6, IL-17, and tumor necrosis factor (TNF) were significantly reduced in sera, while those of IL-10 and IL-22 increased under the 2-x protocol. Likewise, the frequency and effector phenotype of regulatory T cells (Tregs) increased. This was accompanied by normal weight gain, controlled clinical scores, and restored stool consistency. The general and histologic appearance of the colons revealed healing and tissue intactness. Importantly, two phases of tofacitinib medication completely prevented AOM-incited pseudopolyps and the hyper-proliferation of epithelia, which was in contrast to the 3-x regimen. This implies that the initial IBD-induced cytokine expression is not necessarily harmful as long as inflammatory signaling can later be suppressed and that time-restricted treatment allows for anti-inflammatory and tissue-healing cytokine activities.},
  language  = {en}
}
@article{BreunFlockFeldheimetal.2023,
  author    = {Breun, Maria and Flock, Katharina and Feldheim, Jonas and Nattmann, Anja and Monoranu, Camelia M. and Herrmann, Pia and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Hagemann, Carsten and Stein, Ulrike},
  title     = {Metastasis associated in colorectal cancer 1 (MACC1) mRNA expression is enhanced in sporadic vestibular schwannoma and correlates to deafness},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {16},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15164089},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362543},
  year      = {2023},
  abstract  = {Vestibular schwannoma (VS) are benign cranial nerve sheath tumors of the vestibulocochlear nerve. Their incidence is mostly sporadic, but they can also be associated with NF2-related schwannomatosis (NF2), a hereditary tumor syndrome. Metastasis associated in colon cancer 1 (MACC1) is known to contribute to angiogenesis, cell growth, invasiveness, cell motility and metastasis of solid malignant cancers. In addition, MACC1 may be associated with nonsyndromic hearing impairment. Therefore, we evaluated whether MACC1 may be involved in the pathogenesis of VS. Sporadic VS, recurrent sporadic VS, NF2-associated VS, recurrent NF2-associated VS and healthy vestibular nerves were analyzed for MACC1 mRNA and protein expression by quantitative polymerase chain reaction and immunohistochemistry. MACC1 expression levels were correlated with the patients' clinical course and symptoms. MACC1 mRNA expression was significantly higher in sporadic VS compared to NF2-associated VS (p \&lt; 0.001). The latter expressed similar MACC1 concentrations as healthy vestibular nerves. Recurrent tumors resembled the MACC1 expression of the primary tumors. MACC1 mRNA expression was significantly correlated with deafness in sporadic VS patients (p = 0.034). Therefore, MACC1 might be a new molecular marker involved in VS pathogenesis.},
  language  = {en}
}
@article{GerhardHartmannGoergenBroeckelmannetal.2022,
  author    = {Gerhard-Hartmann, Elena and Goergen, Helen and Br{\"o}ckelmann, Paul J. and Mottok, Anja and Steinm{\"u}ller, Tabea and Grund, Johanna and Zam{\`o}, Alberto and Ben-Neriah, Susana and Sasse, Stephanie and Borchmann, Sven and Fuchs, Michael and Borchmann, Peter and Reinke, Sarah and Engert, Andreas and Veldman, Johanna and Diepstra, Arjan and Klapper, Wolfram and Rosenwald, Andreas},
  title     = {9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial},
  series = {British Journal of Haematology},
  volume    = {196},
  journal   = {British Journal of Haematology},
  number    = {1},
  doi       = {10.1111/bjh.17793},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258358},
  pages     = {116-126},
  year      = {2022},
  abstract  = {High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed-Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97\%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50\% of HRSC, MHC-II expression in >50\% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.},
  language  = {en}
}
@article{SeilerEbertRudertetal.2022,
  author    = {Seiler, Jonas and Ebert, Regina and Rudert, Maximilian and Herrmann, Marietta and Leich, Ellen and Weißenberger, Manuela and Horas, Konstantin},
  title     = {Bone metastases of diverse primary origin frequently express the VDR (vitamin D receptor) and CYP24A1},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {21},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11216537},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297377},
  year      = {2022},
  abstract  = {Active vitamin D (1,25(OH)2D3) is known to exert direct anti-cancer actions on various malignant tissues through binding to the vitamin D receptor (VDR). These effects have been demonstrated in breast, prostate, renal and thyroid cancers, which all have a high propensity to metastasise to bone. In addition, there is evidence that vitamin D catabolism via 24-hydroxylase (CYP24A1) is altered in tumour cells, thus, reducing local active vitamin D levels in cancer cells. The aim of this study was to assess VDR and CYP24A1 expression in various types of bone metastases by using immunohistochemistry. Overall, a high total VDR protein expression was detected in 59\% of cases (39/66). There was a non-significant trend of high-grade tumours towards the low nuclear VDR expression (p = 0.07). Notably, patients with further distant metastases had a reduced nuclear VDR expression (p = 0.03). Furthermore, a high CYP24A1 expression was detected in 59\% (39/66) of bone metastases. There was a significant positive correlation between nuclear VDR and CYP24A1 expression (p = 0.001). Collectively, the VDR and CYP24A1 were widely expressed in a multitude of bone metastases, pointing to a potential role of vitamin D signalling in cancer progression. This is of high clinical relevance, as vitamin D deficiency is frequent in patients with bone metastases.},
  language  = {en}
}
@phdthesis{Marquardt2023,
  author    = {Marquardt, Andr{\´e}},
  title     = {Machine-Learning-Based Identification of Tumor Entities, Tumor Subgroups, and Therapy Options},
  doi       = {10.25972/OPUS-32954},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-329548},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {Molecular genetic analyses, such as mutation analyses, are becoming increasingly important in the tumor field, especially in the context of therapy stratification. The identification of the underlying tumor entity is crucial, but can sometimes be difficult, for example in the case of metastases or the so-called Cancer of Unknown Primary (CUP) syndrome. In recent years, methylome and transcriptome utilizing machine learning (ML) approaches have been developed to enable fast and reliable tumor and tumor subtype identification. However, so far only methylome analysis have become widely used in routine diagnostics. The present work addresses the utility of publicly available RNA-sequencing data to determine the underlying tumor entity, possible subgroups, and potential therapy options. Identification of these by ML - in particular random forest (RF) models - was the first task. The results with test accuracies of up to 99\% provided new, previously unknown insights into the trained models and the corresponding entity prediction. Reducing the input data to the top 100 mRNA transcripts resulted in a minimal loss of prediction quality and could potentially enable application in clinical or real-world settings. By introducing the ratios of these top 100 genes to each other as a new database for RF models, a novel method was developed enabling the use of trained RF models on data from other sources. Further analysis of the transcriptomic differences of metastatic samples by visual clustering showed that there were no differences specific for the site of metastasis. Similarly, no distinct clusters were detectable when investigating primary tumors and metastases of cutaneous skin melanoma (SKCM). Subsequently, more than half of the validation datasets had a prediction accuracy of at least 80\%, with many datasets even achieving a prediction accuracy of - or close to - 100\%. To investigate the applicability of the used methods for subgroup identification, the TCGA-KIPAN dataset, consisting of the three major kidney cancer subgroups, was used. The results revealed a new, previously unknown subgroup consisting of all histopathological groups with clinically relevant characteristics, such as significantly different survival. Based on significant differences in gene expression, potential therapeutic options of the identified subgroup could be proposed. Concludingly, in exploring the potential applicability of RNA-sequencing data as a basis for therapy prediction, it was shown that this type of data is suitable to predict entities as well as subgroups with high accuracy. Clinical relevance was also demonstrated for a novel subgroup in renal cell carcinoma. The reduction of the number of genes required for entity prediction to 100 genes, enables panel sequencing and thus demonstrates potential applicability in a real-life setting.},
  subject      = {Maschinelles Lernen},
  language  = {en}
}
@article{FeldheimWendLaueretal.2022,
  author    = {Feldheim, Jonas and Wend, David and Lauer, Mara J. and Monoranu, Camelia M. and Glas, Martin and Kleinschnitz, Christoph and Ernestus, Ralf-Ingo and Braunger, Barbara M. and Meybohm, Patrick and Hagemann, Carsten and Burek, Malgorzata},
  title     = {Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {15},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23158101},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284433},
  year      = {2022},
  abstract  = {Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects.},
  language  = {en}
}
@article{MarquardtHartrampfKollmannsbergeretal.2023,
  author    = {Marquardt, Andr{\´e} and Hartrampf, Philipp and Kollmannsberger, Philip and Solimando, Antonio G. and Meierjohann, Svenja and K{\"u}bler, Hubert and Bargou, Ralf and Schilling, Bastian and Serfling, Sebastian E. and Buck, Andreas and Werner, Rudolf A. and Lapa, Constantin and Krebs, Markus},
  title     = {Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15020392},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-305036},
  year      = {2023},
  abstract  = {(1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database — representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.},
  language  = {en}
}
@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{LinzBrandsKertelsetal.2021,
  author    = {Linz, Christian and Brands, Roman C. and Kertels, Olivia and Dierks, Alexander and Brumberg, Joachim and Gerhard-Hartmann, Elena and Hartmann, Stefan and Schirbel, Andreas and Serfling, Sebastian and Zhi, Yingjun and Buck, Andreas K. and K{\"u}bler, Alexander and Hohm, Julian and Lapa, Constantin and Kircher, Malte},
  title     = {Targeting fibroblast activation protein in newly diagnosed squamous cell carcinoma of the oral cavity - initial experience and comparison to [\(^{18}\)F]FDG PET/CT and MRI},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {48},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  number    = {12},
  issn      = {1619-7070},
  doi       = {10.1007/s00259-021-05422-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307246},
  pages     = {3951-3960},
  year      = {2021},
  abstract  = {Purpose While [\(^{18}\)F]-fluorodeoxyglucose ([\(^{18}\)F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT. Methods Ten consecutive, treatment-na{\"i}ve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [\(^{18}\)F]FDG and [\(^{68}\)Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV\(_{max}\)) and peak (SUV\(_{peak}\) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference. Results [\(^{18}\)F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([\(^{18}\)F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3\% vs. 87.5\%; P = 0.32) and specificity (93.3\% vs. 81.3\%; P = 0.16) to [\(^{18}\)F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples. Conclusion FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.},
  language  = {en}
}
@article{BoeckMaurusGerhardHartmannetal.2023,
  author    = {B{\"o}ck, Julia and Maurus, Katja and Gerhard-Hartmann, Elena and Br{\"a}ndlein, Stephanie and Kurz, Katrin S. and Ott, German and Anagnostopoulos, Ioannis and Rosenwald, Andreas and Zam{\`o}, Alberto},
  title     = {Targeted panel sequencing in the routine diagnosis of mature T- and NK-cell lymphomas},
  series = {Frontiers in Oncology},
  volume    = {13},
  journal   = {Frontiers in Oncology},
  issn      = {2234-943X},
  doi       = {10.3389/fonc.2023.1231601},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326478},
  year      = {2023},
  abstract  = {Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97\%) and could detect mutations in the majority (79\%) of tested T-cell lymphoma samples.},
  language  = {en}
}
@article{KressJessenHufnageletal.2023,
  author    = {Kreß, Julia Katharina Charlotte and Jessen, Christina and Hufnagel, Anita and Schmitz, Werner and Da Xavier Silva, Thamara Nishida and Ferreira Dos Santos, Anc{\´e}ly and Mosteo, Laura and Goding, Colin R. and Friedmann Angeli, Jos{\´e} Pedro and Meierjohann, Svenja},
  title     = {The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2},
  series = {Cell Reports},
  volume    = {42},
  journal   = {Cell Reports},
  number    = {7},
  doi       = {10.1016/j.celrep.2023.112724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350312},
  year      = {2023},
  abstract  = {Highlights • The integrated stress response leads to a general ATF4-dependent activation of NRF2 • ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization • An elevation of NRF2 transcript levels fosters this effect • NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply Summary The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.},
  language  = {en}
}
@article{BasslerKnoblichGerhardHartmannetal.2023,
  author    = {Bassler, Miriam C. and Knoblich, Mona and Gerhard-Hartmann, Elena and Mukherjee, Ashutosh and Youssef, Almoatazbellah and Hagen, Rudolf and Haug, Lukas and Goncalves, Miguel and Scherzad, Agmal and St{\"o}th, Manuel and Ostertag, Edwin and Steinke, Maria and Brecht, Marc and Hackenberg, Stephan and Meyer, Till Jasper},
  title     = {Differentiation of salivary gland and salivary gland tumor tissue via Raman imaging combined with multivariate data analysis},
  series = {Diagnostics},
  volume    = {14},
  journal   = {Diagnostics},
  number    = {1},
  issn      = {2075-4418},
  doi       = {10.3390/diagnostics14010092},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-355558},
  year      = {2023},
  abstract  = {Salivary gland tumors (SGTs) are a relevant, highly diverse subgroup of head and neck tumors whose entity determination can be difficult. Confocal Raman imaging in combination with multivariate data analysis may possibly support their correct classification. For the analysis of the translational potential of Raman imaging in SGT determination, a multi-stage evaluation process is necessary. By measuring a sample set of Warthin tumor, pleomorphic adenoma and non-tumor salivary gland tissue, Raman data were obtained and a thorough Raman band analysis was performed. This evaluation revealed highly overlapping Raman patterns with only minor spectral differences. Consequently, a principal component analysis (PCA) was calculated and further combined with a discriminant analysis (DA) to enable the best possible distinction. The PCA-DA model was characterized by accuracy, sensitivity, selectivity and precision values above 90\% and validated by predicting model-unknown Raman spectra, of which 93\% were classified correctly. Thus, we state our PCA-DA to be suitable for parotid tumor and non-salivary salivary gland tissue discrimination and prediction. For evaluation of the translational potential, further validation steps are necessary.},
  language  = {en}
}
@article{WilleSchuemannWreeetal.2015,
  author    = {Wille, Michael and Sch{\"u}mann, Antje and Wree, Andreas and Kreutzer, Michael and Glocker, Michael O. and Mutzbauer, Grit and Schmitt, Oliver},
  title     = {The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats-An Ontogenetic Study},
  series = {International Journal of Molecular Sciences},
  volume    = {16},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms160921454},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151347},
  pages     = {21454 -- 21485},
  year      = {2015},
  abstract  = {In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates.},
  language  = {en}
}
@article{AnStrisselAlAbboodietal.2022,
  author    = {An, Ran and Strissel, Pamela L. and Al-Abboodi, Majida and Robering, Jan W. and Supachai, Reakasame and Eckstein, Markus and Peddi, Ajay and Hauck, Theresa and B{\"a}uerle, Tobias and Boccaccini, Aldo R. and Youssef, Almoatazbellah and Sun, Jiaming and Strick, Reiner and Horch, Raymund E. and Boos, Anja M. and Kengelbach-Weigand, Annika},
  title     = {An innovative arteriovenous (AV) loop breast cancer model tailored for cancer research},
  series = {Bioengineering},
  volume    = {9},
  journal   = {Bioengineering},
  number    = {7},
  issn      = {2306-5354},
  doi       = {10.3390/bioengineering9070280},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-278919},
  year      = {2022},
  abstract  = {Animal models are important tools to investigate the pathogenesis and develop treatment strategies for breast cancer in humans. In this study, we developed a new three-dimensional in vivo arteriovenous loop model of human breast cancer with the aid of biodegradable materials, including fibrin, alginate, and polycaprolactone. We examined the in vivo effects of various matrices on the growth of breast cancer cells by imaging and immunohistochemistry evaluation. Our findings clearly demonstrate that vascularized breast cancer microtissues could be engineered and recapitulate the in vivo situation and tumor-stromal interaction within an isolated environment in an in vivo organism. Alginate-fibrin hybrid matrices were considered as a highly powerful material for breast tumor engineering based on its stability and biocompatibility. We propose that the novel tumor model may not only serve as an invaluable platform for analyzing and understanding the molecular mechanisms and pattern of oncologic diseases, but also be tailored for individual therapy via transplantation of breast cancer patient-derived tumors.},
  language  = {en}
}
@article{FringsRothRosenwaldetal.2021,
  author    = {Frings, Verena G. and Roth, Sabine and Rosenwald, Andreas and Goebeler, Matthias and Geissinger, Eva and Wobser, Marion},
  title     = {EBER in situ hybridization in subcutaneous aluminum granulomas/lymphoid hyperplasia: A diagnostic clue to differentiate injection-associated lymphoid hyperplasia from other forms of pseudolymphomas and cutaneous lymphomas},
  series = {Journal of Cutaneous Pathology},
  volume    = {48},
  journal   = {Journal of Cutaneous Pathology},
  number    = {5},
  doi       = {10.1111/cup.13972},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258405},
  pages     = {625-631},
  year      = {2021},
  abstract  = {Background Subcutaneous vaccination or desensitization may induce persistent nodules at the injection sites. Without the knowledge of prior injection, histopathological work-up may be challenging. Objective Aim of this study was to contribute to the histopathological work-up of unclear subcutaneous nodules, especially their differentiation from cutaneous lymphoma. Methods We retrospectively reviewed clinical data and histopathological slides of four patients with subcutaneous nodules, which were suspected to suffer from cutaneous T- or B-cell lymphoma. Sections of these cases and 12 negative controls were stained with hematoxylin and eosin and a standardized immunohistochemical panel of B- and T-cell markers including EBER in situ hybridization as well as electron microscopy. Results In all cases, large histiocytes with granular cytoplasm compatible with intracellular aluminum hydroxide were present. EBER in situ hybridization revealed positive staining of these granular histiocytes while staining was absent in negative controls. Limitations Post hoc completion of medical history revealed that vaccination or specific immunotherapy had been applied before at the biopsy site in only three out of four patients; one patient was lost to follow-up. Conclusion EBER in situ hybridization is an adjunctive tool to differentiate aluminum-induced granuloma/lymphoid hyperplasia from other forms of pseudolymphoma and cutaneous B- or T-cell lymphomas.},
  language  = {en}
}
@article{SbieraKircherAltierietal.2021,
  author    = {Sbiera, Iuliu and Kircher, Stefan and Altieri, Barbara and Lenz, Kerstin and Hantel, Constanze and Fassnacht, Martin and Sbiera, Silviu and Kroiss, Matthias},
  title     = {Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.795116},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251953},
  year      = {2021},
  abstract  = {Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95\%CI: 1.78 - 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95\%CI: 1.52 - 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.},
  language  = {en}
}
@article{ZamoJohnstonAttygalleetal.2020,
  author    = {Zam{\`o}, Alberto and Johnston, Peter and Attygalle, Ayoma D and Laurent, Camille and Arber, Daniel A and Fend, Falko},
  title     = {Aggressive B-cell lymphomas with a primary bone marrow presentation},
  series = {Histopathology},
  volume    = {77},
  journal   = {Histopathology},
  number    = {3},
  doi       = {10.1111/his.14124},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218327},
  pages     = {369 -- 379},
  year      = {2020},
  language  = {en}
}
@article{ZhouSteinhardtDuelletal.2020,
  author    = {Zhou, Xiang and Steinhardt, Maximilian Johannes and D{\"u}ll, Johannes and Krummenast, Franziska and Danhof, Sophia and Meckel, Katharina and Nickel, Katharina and Grathwohl, Denise and Leicht, Hans-Benno and Rosenwald, Andreas and Einsele, Hermann and Rasche, Leo and Kort{\"u}m, Martin},
  title     = {Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib-resistant non-nodal leukemic mantle cell lymphoma},
  series = {European Journal of Haematology},
  volume    = {104},
  journal   = {European Journal of Haematology},
  number    = {4},
  doi       = {10.1111/ejh.13382},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215513},
  pages     = {352 -- 355},
  year      = {2020},
  abstract  = {We herein report the case of a 73-year-old male patient who was diagnosed with leukemic non-nodal MCL. This patient had received six cycles of bendamustine, which resulted in a transient remission, and a second-line therapy with ibrutinib, which unfortunately failed to induce remission. We started a treatment with single-agent obinutuzumab at a dose of 20 mg on day 1, 50 mg on day 2-4, 330 mg on day 5, and 1000 mg on day 6. The laboratory analysis showed a rapid decrease of leukocyte count. Four weeks later, we repeated the treatment with obinutuzumab at a dose of 1000 mg q4w and started a therapy with venetoclax at a dose of 400 mg qd, which could be increased to 800 mg qd from the third cycle. This combination therapy was well tolerated. The patient achieved a complete remission (CR) after three cycles of obinutuzumab and venetoclax. To date, the patient has a progression-free survival of 17 months under ongoing obinutuzumab maintenance q4w. This is the first report about obinutuzumab and venetoclax induced CR in rituximab-intolerant patient with an ibrutinib-resistant MCL. This case suggests that obinutuzumab- and venetoclax-based combination therapy might be salvage therapy in patients with ibrutinib-resistant MCL.},
  language  = {en}
}
@article{BarahonadeBritoPatra2022,
  author    = {Barahona de Brito, Carlotta and Patra, Amiya Kumar},
  title     = {NFAT factors are dispensable for the development but are critical for the maintenance of Foxp3\(^+\) regulatory T cells},
  series = {Cells},
  volume    = {11},
  journal   = {Cells},
  number    = {9},
  issn      = {2073-4409},
  doi       = {10.3390/cells11091397},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270668},
  year      = {2022},
  abstract  = {The transcription factors of the nuclear factor of activated T cell (NFAT) family play a crucial role in multiple aspects of T cell function. It has recently been reported that NFATs play an important role in the suppressive function of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) regulatory T (T\(_{reg}\)) cells. In this study, we have investigated the role of NFATs in the thymic development of T\(_{reg}\) cells in mice. We show that NFAT factors are dispensable for the development of Foxp3\(^+\) T\(_{reg}\) cells in the thymus but are critical for the maintenance of both the phenotype and survival of T\(_{reg}\) cells in the thymus as well as in peripheral lymphoid organs. Specifically, the homeostasis of CD4\(^+\)CD25\(^+\)Foxp3\(^+\) but not the CD4\(^+\)CD25\(^-\)Foxp3\(^+\) fraction is severely perturbed when NFAT signaling is blocked, leading to a strongly reduced T\(_{reg}\) population. We underscored this intriguing effect of NFAT on CD4\(^+\)CD25\(^+\)Foxp3\(^+\) T\(_{reg}\) cells to the disruption of survival signals provided by interleukin 2 (IL-2). Accordingly, blocking T\(_{reg}\) cell death by abolishing the activity of pro-apoptotic Bcl-2 family member Bim, compensated for the survival defects induced due to a lack of NFAT-IL-2-IL-2R signaling. Inhibition of NFAT activity led to a strong reduction in the number of Foxp3\(^+\) T\(_{reg}\) cells; however, it did not influence the level of Foxp3 expression on an individual cell basis. In addition, we show a differential effect of IL-2 and IL-7 signaling on Foxp3\(^+\) T\(_{reg}\) versus CD4\(^+\)CD25\(^-\) T cell development, again underlining the dispensability of NFAT signaling in the development, but not in the maintenance of Foxp3\(^+\) T\(_{reg}\) cells.},
  language  = {en}
}
@article{BohnertGeorgiadesMonoranuetal.2021,
  author    = {Bohnert, Simone and Georgiades, Kosmas and Monoranu, Camelia-Maria and Bohnert, Michael and B{\"u}ttner, Andreas and Ondruschka, Benjamin},
  title     = {Quantitative evidence of suppressed TMEM119 microglial immunohistochemistry in fatal morphine intoxications},
  series = {International Journal of Legal Medicine},
  volume    = {135},
  journal   = {International Journal of Legal Medicine},
  number    = {6},
  issn      = {1437-1596},
  doi       = {10.1007/s00414-021-02699-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266934},
  pages     = {2315-2322},
  year      = {2021},
  abstract  = {The aim of this pilot study was to investigate the diagnostic potential of TMEM119 as a useful microglia-specific marker in combination with immunostainings for phagocytic function and infiltrating capacity of monocytes in cases of lethal monosubstance intoxications by morphine (MOR), methamphetamine (METH), and of ethanol-associated death (ETH) respectively. Human brain tissue samples were obtained from forensic autopsies of cases with single substance abuse (MOR, n = 8; ETH, n = 10; METH, n = 9) and then compared to a cohort of cardiovascular fatalities as controls (n = 9). Brain tissue samples of cortex, white matter, and hippocampus were collected and stained immunohistochemically with antibodies against TMEM119, CD68KiM1P, and CCR2. We could document the lowest density of TMEM119-positive cells in MOR deaths with highly significant differences to the control densities in all three regions investigated. In ETH and METH deaths, the expression of TMEM119 was comparable to cell densities in controls. The results indicate that the immunoreaction in brain tissue is different in these groups depending on the drug type used for abuse.},
  language  = {en}
}
@article{BohnertMonoranuSiauwetal.2020,
  author    = {Bohnert, S. and Monoranu, C. - M. and Siauw, C. and Al-Tinawi, F. and Bohnert, M.},
  title     = {T{\"o}dliche Hirnmassenblutung infolge Vitamin-K-Mangels bei einem 9 Wochen alten S{\"a}ugling},
  series = {Rechtsmedizin},
  volume    = {30},
  journal   = {Rechtsmedizin},
  issn      = {0937-9819},
  doi       = {10.1007/s00194-020-00387-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232475},
  pages     = {175-179},
  year      = {2020},
  abstract  = {Intrakranielle Blutungen sind im S{\"a}uglingsalter seltene, aber lebensbedrohende Ereignisse. Neben Gef{\"a}ßmissbildungen, Stoffwechseldefekten sowie St{\"o}rungen der Blutgerinnung kommen v. a. nichtakzidentielle Traumata, Sch{\"u}tteltrauma in Betracht. Die klinische Diagnostik umfasst hinsichtlich der Blutungsgenese neben Sonographie und MRT als apparatives Verfahren auch eine Fundoskopie sowie laborchemische Analysen, insbesondere der Gerinnungsparameter. F{\"u}r die Blutgerinnung ist das fettl{\"o}sliche Vitamin K essenziell: Fr{\"u}he, klassische und sp{\"a}te Vitamin-K-Mangel-Blutungen werden dabei unterschieden. Um ein geh{\"a}uftes Wiederauftreten von Vitamin-K-Mangel-Blutungen bei Neugeborenen und jungen S{\"a}uglingen zu verhindern, bedarf es einer hinreichenden Aufkl{\"a}rung der Eltern. Eine Verweigerung der Prophylaxe scheint Folge einer weltanschaulich begr{\"u}ndeten Ablehnung der Schulmedizin und ein zunehmendes Ph{\"a}nomen in wohlhabenden Industriel{\"a}ndern zu sein.},
  language  = {de}
}
@article{BellLenhartRosenwaldetal.2020,
  author    = {Bell, Luisa and Lenhart, Alexander and Rosenwald, Andreas and Monoranu, Camelia M. and Berberich-Siebelt, Friederike},
  title     = {Lymphoid aggregates in the CNS of progressive multiple sclerosis patients lack regulatory T cells},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  number    = {3090},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2019.03090},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-198130},
  year      = {2020},
  abstract  = {In gray matter pathology of multiple sclerosis, neurodegeneration associates with a high degree of meningeal inflammatory activity. Importantly, ectopic lymphoid follicles (eLFs) were identified at the inflamed meninges of patients with progressive multiple sclerosis. Besides T lymphocytes, they comprise B cells and might elicit germinal center (GC)-like reactions. GC reactions are controlled by FOXP3+ T-follicular regulatory cells (TFR), but it is unknown if they participate in autoantibody production in eLFs. Receiving human post-mortem material, gathered from autopsies of progressive multiple sclerosis patients, indeed, distinct inflammatory infiltrates enriched with B cells could be detected in perivascular areas and deep sulci. CD35+ cells, parafollicular CD138+ plasma cells, and abundant expression of the homing receptor for GCs, CXCR5, on lymphocytes defined some of them as eLFs. However, they resembled GCs only in varying extent, as T cells did not express PD-1, only few cells were positive for the key transcriptional regulator BCL-6 and ongoing proliferation, whereas a substantial number of T cells expressed high NFATc1 like GC-follicular T cells. Then again, predominant cytoplasmic NFATc1 and an enrichment with CD3+CD27+ memory and CD4+CD69+ tissue-resident cells implied a chronic state, very much in line with PD-1 and BCL-6 downregulation. Intriguingly, FOXP3+ cells were almost absent in the whole brain sections and CD3+FOXP3+ TFRs were never found in the lymphoid aggregates. This also points to less controlled humoral immune responses in those lymphoid aggregates possibly enabling the occurrence of CNS-specific autoantibodies in multiple sclerosis patients.},
  language  = {en}
}
@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{WeissbachHerediaGuerreroBarnsteineretal.2020,
  author    = {Weißbach, Susann and Heredia-Guerrero, Sofia Catalina and Barnsteiner, Stefanie and Großhans, Lukas and Bodem, Jochen and Starz, Hanna and Langer, Christian and Appenzeller, Silke and Knop, Stefan and Steinbrunn, Torsten and Rost, Simone and Einsele, Hermann and Bargou, Ralf Christian and Rosenwald, Andreas and St{\"u}hmer, Thorsten and Leich, Ellen},
  title     = {Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12020455},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200617},
  year      = {2020},
  abstract  = {Approximately 20\% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.},
  language  = {en}
}
@article{JahnDorbathKircheretal.2019,
  author    = {Jahn, Daniel and Dorbath, Donata and Kircher, Stefan and Nier, Anika and Bergheim, Ina and Lenaerts, Kaatje and Hermanns, Heike M. and Geier, Andreas},
  title     = {Beneficial effects of vitamin D treatment in an obese mouse model of non-alcoholic steatohepatitis},
  series = {Nutrients},
  volume    = {11},
  journal   = {Nutrients},
  number    = {1},
  doi       = {10.3390/nu11010077},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177222},
  pages     = {77},
  year      = {2019},
  abstract  = {Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut-liver axis.},
  language  = {en}
}
@article{BohnertSeiffertTrellaetal.2020,
  author    = {Bohnert, Simone and Seiffert, Anja and Trella, Stefanie and Bohnert, Michael and Distel, Luitpold and Ondruschka, Benjamin and Monoranu, Camelia-Marie},
  title     = {TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination},
  series = {International Journal of Legal Medicine},
  volume    = {134},
  journal   = {International Journal of Legal Medicine},
  issn      = {0937-9827},
  doi       = {10.1007/s00414-020-02384-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235346},
  pages     = {2167-2176},
  year      = {2020},
  abstract  = {The aim of the present study was a refined analysis of neuroinflammation including TMEM119 as a useful microglia-specific marker in forensic assessments of traumatic causes of death, e.g., traumatic brain injury (TBI). Human brain tissue samples were obtained from autopsies and divided into cases with lethal TBI (n = 25) and subdivided into three groups according to their trauma survival time and compared with an age-, gender-, and postmortem interval-matched cohort of sudden cardiovascular fatalities as controls (n = 23). Brain tissue samples next to cortex contusions and surrounding white matter as well as samples of the ipsilateral uninjured brain stem and cerebellum were collected and stained immunohistochemically with antibodies against TMEM119, CD206, and CCR2. We could document the highest number of TMEM119-positive cells in acute TBI death with highly significant differences to the control numbers. CCR2-positive monocytes showed a significantly higher cell count in the cortex samples of TBI cases than in the controls with an increasing number of immunopositive cells over time. The number of CD206-positive M2 microglial cells increased survival time-dependent. After 3 days of survival, the cell number increased significantly in all four regions investigated compared with controls. In sum, we validate a specific and robustly expressed as well as fast reacting microglia marker, TMEM119, which distinguishes microglia from resident and infiltrating macrophages and thus offers a great potential for the estimation of the minimum survival time after TBI.},
  language  = {en}
}
@article{FischerHartmannReisslandetal.2022,
  author    = {Fischer, Thomas and Hartmann, Oliver and Reissland, Michaela and Prieto-Garcia, Cristian and Klann, Kevin and Pahor, Nikolett and Sch{\"u}lein-V{\"o}lk, Christina and Baluapuri, Apoorva and Polat, B{\"u}lent and Abazari, Arya and Gerhard-Hartmann, Elena and Kopp, Hans-Georg and Essmann, Frank and Rosenfeldt, Mathias and M{\"u}nch, Christian and Flentje, Michael and Diefenbacher, Markus E.},
  title     = {PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy},
  series = {Cell \& Bioscience},
  volume    = {12},
  journal   = {Cell \& Bioscience},
  issn      = {2045-3701},
  doi       = {10.1186/s13578-022-00778-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-299865},
  year      = {2022},
  abstract  = {Background Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. Results We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. Conclusion PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.},
  language  = {en}
}
@article{AdamKircherSbieraetal.2021,
  author    = {Adam, Pia and Kircher, Stefan and Sbiera, Iuliu and Koehler, Viktoria Florentine and Berg, Elke and Kn{\"o}sel, Thomas and Sandner, Benjamin and Fenske, Wiebke Kristin and Bl{\"a}ker, Hendrik and Smaxwil, Constantin and Zielke, Andreas and Sipos, Bence and Allelein, Stephanie and Schott, Matthias and Dierks, Christine and Spitzweg, Christine and Fassnacht, Martin and Kroiss, Matthias},
  title     = {FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.712107},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244653},
  year      = {2021},
  abstract  = {Background Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising. Materials and Methods Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable. Results PD-L1 TPS≥50\% was observed in 42\% of ATC and 26\% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30\%) than in PDTC (5\%; p<0.01) and NT (0\%, p<0.001). 53\% of PDTC samples had PD-L1 expression ≤5\%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS. Conclusion High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.},
  language  = {en}
}
@article{RauertWunderlichBerberichRosenwaldetal.2018,
  author    = {Rauert-Wunderlich, Hilka and Berberich, Ingolf and Rosenwald, Andreas and Rudelius, Martina},
  title     = {CD40L mediated alternative NF kappa B-signaling induces resistance to BCR-inhibitors in patients with mantle cell lymphoma},
  series = {Cell Death \& Disease},
  journal   = {Cell Death \& Disease},
  number    = {9},
  doi       = {10.1038/s41419-017-0157-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225027},
  pages     = {86, 1-9},
  year      = {2018},
  abstract  = {Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NF kappa B) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NF kappa B signaling and illustrated the ability of CD40L to activate the alternative NF kappa B pathway in MCL. This activation leads to independency of classical NF kappa B signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NF kappa B pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NF kappa B signaling in MCL.},
  language  = {en}
}
@article{CadarJellingerRiedereretal.2021,
  author    = {Cadar, D{\´a}niel and Jellinger, Kurt A. and Riederer, Peter and Strobel, Sabrina and Monoranu, Camelia-Maria and Tappe, Dennis},
  title     = {No metagenomic evidence of causative viral pathogens in postencephalitic parkinsonism following encephalitis lethargica},
  series = {Microorganisms},
  volume    = {9},
  journal   = {Microorganisms},
  number    = {8},
  issn      = {2076-2607},
  doi       = {10.3390/microorganisms9081716},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245074},
  year      = {2021},
  abstract  = {Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP.},
  language  = {en}
}
@phdthesis{Witzig2018,
  author    = {Witzig, Raphael},
  title     = {Identifikation und Charakterisierung von Progressionsfaktoren Follikul{\"a}rer Non-Hodgkin Lymphome in einem Kollektiv des Verbundprojektes "Molekulare Mechanismen bei malignen Lymphomen (MMML)"},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174430},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2018},
  abstract  = {Das follikul{\"a}re Lymphom (FL) wird nach der aktuellen Klassifikation der WHO (World Health Organization Classification of Lymphoid Tumours) anhand der Zahl der Zentroblasten in drei Grade und der Grad 3 weiter in 3A und 3B eingeteilt. Bis heute ist die Rolle der FL3B aufgrund der morphologischen und genetischen Unterschiede zu den anderen FL umstritten, es wird eine eigene Entit{\"a}t und Pathogenese des FL3B diskutiert. Durch das Verbundprojekt „Molekulare Mechanismen in malignen Lymphomen" (MMML) Daten zu FISH-, Genexpressionsanalysen und immunhistochemischen F{\"a}rbungen bearbeitet werden. Diesen Daten zufolge sind FL3B in ihrer Genexpression nicht von FL3A trennbar. Es konnte jedoch eine Abgrenzung der FL1/2 zu den FL3A/B durch die erh{\"o}hte Expression von 13 Genen in den FL3A/B gefunden werden, von denen Homolog, double strand break repair nuclease (MRE11A), Topoisomerase II alpha (TOP2A) und Thioredoxin (TXN) schon zuvor im Rahmen von FL und NHL diskutiert wurden.},
  subject      = {Follikul{\"a}res Lymphom},
  language  = {de}
}
@article{WeigandRonchiRizkRabinetal.2017,
  author    = {Weigand, Isabel and Ronchi, Cristina L. and Rizk-Rabin, Marthe and Dalmazi, Guido Di and Wild, Vanessa and Bathon, Kerstin and Rubin, Beatrice and Calebiro, Davide and Beuschlein, Felix and Bertherat, J{\´e}r{\^o}me and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas},
  series = {Scientific Reports},
  volume    = {7},
  journal   = {Scientific Reports},
  number    = {49},
  doi       = {10.1038/s41598-017-00125-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157952},
  year      = {2017},
  abstract  = {Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40\% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.},
  language  = {en}
}
@article{WobserRothAppenzelleretal.2021,
  author    = {Wobser, Marion and Roth, Sabine and Appenzeller, Silke and Houben, Roland and Schrama, David and Goebeler, Matthias and Geissinger, Eva and Rosenwald, Andreas and Maurus, Katja},
  title     = {Targeted deep sequencing of mycosis fungoides reveals intracellular signaling pathways associated with aggressiveness and large cell transformation},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {21},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13215512},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250094},
  year      = {2021},
  abstract  = {Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and Methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling — together with epigenetic dysregulation — may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.},
  language  = {en}
}
@article{KaderAzeemJwayedetal.2021,
  author    = {Kader, Hidaya A. and Azeem, Muhammad and Jwayed, Suhib A. and Al-Shehhi, Aaesha and Tabassum, Attia and Ayoub, Mohammed Akli and Hetta, Helal F. and Waheed, Yasir and Iratni, Rabah and Al-Dhaheri, Ahmed and Muhammad, Khalid},
  title     = {Current insights into immunology and novel therapeutics of atopic dermatitis},
  series = {Cells},
  volume    = {10},
  journal   = {Cells},
  number    = {6},
  issn      = {2073-4409},
  doi       = {10.3390/cells10061392},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241008},
  year      = {2021},
  abstract  = {Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.},
  language  = {en}
}
@article{LoefflerWirthKreuzHoppetal.2019,
  author    = {Loeffler-Wirth, Henry and Kreuz, Markus and Hopp, Lydia and Arakelyan, Arsen and Haake, Andrea and Cogliatti, Sergio B. and Feller, Alfred C. and Hansmann, Martin-Leo and Lenze, Dido and M{\"o}ller, Peter and M{\"u}ller-Hermelink, Hans Konrad and Fortenbacher, Erik and Willscher, Edith and Ott, German and Rosenwald, Andreas and Pott, Christiane and Schwaenen, Carsten and Trautmann, Heiko and Wessendorf, Swen and Stein, Harald and Szczepanowski, Monika and Tr{\"u}mper, Lorenz and Hummel, Michael and Klapper, Wolfram and Siebert, Reiner and Loeffler, Markus and Binder, Hans},
  title     = {A modular transcriptome map of mature B cell lymphomas},
  series = {Genome Medicine},
  volume    = {11},
  journal   = {Genome Medicine},
  doi       = {10.1186/s13073-019-0637-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237262},
  year      = {2019},
  abstract  = {Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.},
  language  = {en}
}
@article{HeuserGototPiotrowskietal.2017,
  author    = {Heuser, Christoph and Gotot, Janine and Piotrowski, Eveline Christina and Philipp, Marie-Sophie and Courr{\`e}ges, Christina Johanna Felicia and Otte, Martin Sylvester and Guo, Linlin and Schmid-Burgk, Jonathan Leo and Hornung, Veit and Heine, Annkristin and Knolle, Percy Alexander and Garbi, Natalio and Serfling, Edgar and Evaristo, C{\´e}sar and Thaiss, Friedrich and Kurts, Christian},
  title     = {Prolonged IKK\(\beta\) Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells},
  series = {Cell Reports},
  volume    = {21},
  journal   = {Cell Reports},
  number    = {3},
  doi       = {10.1016/j.celrep.2017.09.082},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173643},
  pages     = {578-586},
  year      = {2017},
  abstract  = {Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-\(\kappa\)B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-\(\kappa\)B signaling through I\(\kappa\)B-kinase \(\beta\) (IKK\(\beta\)) after thymic egress. Mice lacking IKK\(\beta\) in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3\(^+\) Tregs. Also, pharmacological IKK\(\beta\) inhibition reduced Treg numbers in the circulation by ~50\% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKK\(\beta\) inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKK\(\beta\) inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKK\(\beta\) inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKK\(\beta\) represents a druggable checkpoint.},
  language  = {en}
}
@article{KleinHesslingMuhammadKleinetal.2017,
  author    = {Klein-Hessling, Stefan and Muhammad, Khalid and Klein, Matthias and Pusch, Tobias and Rudolf, Ronald and Fl{\"o}ter, Jessica and Qureischi, Musga and Beilhack, Andreas and Vaeth, Martin and Kummerow, Carsten and Backes, Christian and Schoppmeyer, Rouven and Hahn, Ulrike and Hoth, Markus and Bopp, Tobias and Berberich-Siebelt, Friederike and Patra, Amiya and Avots, Andris and M{\"u}ller, Nora and Schulze, Almut and Serfling, Edgar},
  title     = {NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells},
  series = {Nature Communications},
  volume    = {8},
  journal   = {Nature Communications},
  number    = {511},
  doi       = {10.1038/s41467-017-00612-6},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170353},
  year      = {2017},
  abstract  = {Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.},
  language  = {en}
}
@article{WilhelmSmetakReimeretal.2016,
  author    = {Wilhelm, M. and Smetak, M. and Reimer, P. and Geissinger, E. and Ruediger, T. and Metzner, B. and Schmitz, N. and Engert, A. and Schaefer-Eckart, K. and Birkmann, J.},
  title     = {First-line therapy of peripheral T-cell lymphoma: extension and long-term follow-up of a study investigating the role of autologous stem cell transplantation},
  series = {Blood Cancer Journal},
  volume    = {6},
  journal   = {Blood Cancer Journal},
  doi       = {10.1038/bcj.2016.63},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164506},
  pages     = {e452},
  year      = {2016},
  abstract  = {Current guidelines recommend consolidation with autologous stem cell transplantation (autoSCT) after induction chemotherapy for most patients with peripheral T-cell lymphoma (PTCL). This assumption is based on five prospective phase II studies, three of which included <50 patients with limited follow-up. Here we present the final analysis of the prospective German study. The treatment regimen consisted of four to six cycles of CHOP chemotherapy followed by mobilizing therapy and stem cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemo(radio)therapy and autoSCT. From January 2001 to July 2010, 111 patients were enrolled in the study. The main subgroups were PTCL not specified (n=42) and angioimmunoblastic T-cell lymphoma (n=37). Seventy-five (68\%) of the 111 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the complete response rate after myeloablative therapy was 59\%. The estimated 5-year overall survival, disease-free survival and progression-free survival rates were 44\%, 54\% and 39\%, respectively. The results of this study confirm that upfront autoSCT can result in long-term remissions in patients with all major subtypes of PTCL and therefore should be part of first-line therapy whenever possible.},
  language  = {en}
}
@article{EngelRudeliusSlawskaetal.2016,
  author    = {Engel, Katharina and Rudelius, Martina and Slawska, Jolanta and Jacobs, Laura and Abhari, Behnaz Ahangarian and Altmann, Bettina and Kurutz, Julia and Rathakrishnan, Abirami and Fern{\´a}ndez-S{\´a}iz, Vanesa and Brunner, Andr{\"a} and Targosz, Bianca-Sabrina and Loewecke, Felicia and Gloeckner, Christian Johannes and Ueffing, Marius and Fulda, Simone and Pfreundschuh, Michael and Tr{\"u}mper, Lorenz and Klapper, Wolfram and Keller, Ulrich and Jost, Philipp J. and Rosenwald, Andreas and Peschel, Christian and Bassermann, Florian},
  title     = {USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma},
  series = {EMBO Molecular Medicine},
  volume    = {8},
  journal   = {EMBO Molecular Medicine},
  doi       = {10.15252/emmm.201506047},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165016},
  pages     = {851-862},
  year      = {2016},
  abstract  = {The mitotic spindle assembly checkpoint (SAC) maintains genome stability and marks an important target for antineoplastic therapies. However, it has remained unclear how cells execute cell fate decisions under conditions of SAC-induced mitotic arrest. Here, we identify USP9X as the mitotic deubiquitinase of the X-linked inhibitor of apoptosis protein (XIAP) and demonstrate that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons. We find that primary human aggressive B-cell lymphoma samples exhibit high USP9X expression that correlate with XIAP overexpression. We show that high USP9X/XIAP expression is associated with shorter event-free survival in patients treated with spindle poison-containing chemotherapy. Accordingly, aggressive B-cell lymphoma lines with USP9X and associated XIAP overexpression exhibit increased chemoresistance, reversed by specific inhibition of either USP9X or XIAP. Moreover, knockdown of USP9X or XIAP significantly delays lymphoma development and increases sensitivity to spindle poisons in a murine Eμ-Myc lymphoma model. Together, we specify the USP9X-XIAP axis as a regulator of the mitotic cell fate decision and propose that USP9X and XIAP are potential prognostic biomarkers and therapeutic targets in aggressive B-cell lymphoma.},
  language  = {en}
}
@article{ElMeseryRosenthalRauertWunderlichetal.2019,
  author    = {El-Mesery, Mohamed and Rosenthal, Tina and Rauert-Wunderlich, Hilka and Schreder, Martin and St{\"u}hmer, Thorsten and Leich, Ellen and Schlosser, Andreas and Ehrenschwender, Martin and Wajant, Harald and Siegmund, Daniela},
  title     = {The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death},
  series = {Cell Death \& Disease},
  volume    = {10},
  journal   = {Cell Death \& Disease},
  doi       = {10.1038/s41419-019-1860-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226666},
  year      = {2019},
  abstract  = {The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.},
  language  = {en}
}
@article{RauschenbergerSchmittAzeemetal.2019,
  author    = {Rauschenberger, Tabea and Schmitt, Viola and Azeem, Muhammad and Klein-Hessling, Stefan and Murti, Krisna and Gr{\"a}n, Franziska and Goebeler, Matthias and Kerstan, Andreas and Klein, Matthias and Bopp, Tobias and Serfling, Edgar and Muhammad, Khalid},
  title     = {T cells control chemokine secretion by keratinocytes},
  series = {Frontiers in Immunology},
  volume    = {10},
  journal   = {Frontiers in Immunology},
  number    = {1917},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2019.01917},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195695},
  year      = {2019},
  abstract  = {The massive infiltration of lymphocytes into the skin is a hallmark of numerous human skin disorders. By co-culturing murine keratinocytes with splenic T cells we demonstrate here that T cells affect and control the synthesis and secretion of chemokines by keratinocytes. While pre-activated CD8\(^+\)T cells induce the synthesis of CXCL9 and CXCL10 in keratinocytes and keep in check the synthesis of CXCL1, CXCL5, and CCL20, keratinocytes dampen the synthesis of CCL3 and CCL4 in pre-activated CD8\(^+\)T cells. One key molecule is IFN-γ that is synthesized by CD8\(^+\)T cells under the control of NFATc1 and NFATc2. CD8\(^+\)T cells deficient for both NFAT factors are unable to induce CXCL9 and CXCL10 expression. In addition, CD8\(^+\)T cells induced numerous type I IFN-inducible "defense genes" in keratinocytes encoding the PD1 and CD40 ligands, TNF-α and caspase-1. The enhanced expression of type I IFN-inducible genes resembles the gene expression pattern at the dermal/epidermal interface in lichen planus, an inflammatory T lymphocyte-driven skin disease, in which we detected the expression of CXCL10 in keratinocytes in close vicinity to the infiltration front of T cells. These data reflect the multifaceted interplay of lymphocytes with keratinocytes at the molecular level.},
  language  = {en}
}
@article{KleinHesslingRudolfMuhammadetal.2016,
  author    = {Klein-Hessling, Stefan and Rudolf, Ronald and Muhammad, Khalid and Knobeloch, Klaus-Peter and Maqbool, Muhammad Ahmad and Cauchy, Pierre and Andrau, Jean-Christophe and Avots, Andris and Talora, Claudio and Ellenrieder, Volker and Screpanti, Isabella and Serfling, Edgar and Patra, Amiya Kumar},
  title     = {A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms11841},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172974},
  year      = {2016},
  abstract  = {NFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1β expression, preTCR-positive thymocytes express both Nfatc1β and P1 promoter-derived Nfatc1α transcripts. Inducing NFATc1α activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1β from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes.},
  language  = {en}
}
@article{PorubskyPopovicBadveetal.2021,
  author    = {Porubsky, Stefan and Popovic, Zoran V. and Badve, Sunil and Banz, Yara and Berezowska, Sabina and Borchert, Dietmar and Br{\"u}ggemann, Monika and Gaiser, Timo and Graeter, Thomas and Hollaus, Peter and Huettl, Katrin S. and Kotrova, Michaela and Kreft, Andreas and Kugler, Christian and L{\"o}tscher, Fabian and M{\"o}ller, Burkhard and Ott, German and Preissler, Gerhard and Roessner, Eric and Rosenwald, Andreas and Str{\"o}bel, Philipp and Marx, Alexander},
  title     = {Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: strong association with lymphomas and non-myasthenic autoimmune diseases},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13020315},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223049},
  year      = {2021},
  abstract  = {Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32-80; lesion diameter 7.0 cm, 1-14.5; median, range), five (14\%) showed associated lymphomas, including four (11\%) thymic MALT lymphomas and one (3\%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33\%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11\%), rheumatoid arthritis (n = 3, 8\%), myasthenia gravis (n = 2, 6\%), asthma (n = 2, 6\%), scleroderma, Sj{\"o}gren syndrome, pure red cell aplasia, Grave's disease and anti-IgLON5 syndrome (each n = 1, 3\%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18\%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.},
  language  = {en}
}
@article{SchuemannGrossBaueretal.2021,
  author    = {Sch{\"u}mann, Franziska Lea and Groß, Elisabeth and Bauer, Marcus and Rohde, Christian and Sandmann, Sarah and Terziev, Denis and M{\"u}ller, Lutz P. and Posern, Guido and Wienke, Andreas and Fend, Falko and Hansmann, Martin-Leo and Klapper, Wolfram and Rosenwald, Andreas and Stein, Harald and Dugas, Martin and M{\"u}ller-Tidow, Carsten and Wickenhauser, Claudia and Binder, Mascha and Weber, Thomas},
  title     = {Divergent effects of EZH1 and EZH2 protein expression on the prognosis of patients with T-cell lymphomas},
  series = {Biomedicines},
  volume    = {9},
  journal   = {Biomedicines},
  number    = {12},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines9121842},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252155},
  year      = {2021},
  abstract  = {T-cell lymphomas are highly heterogeneous and their prognosis is poor under the currently available therapies. Enhancers of zeste homologue 1 and 2 (EZH1/2) are histone H3 lysine-27 trimethyltransferases (H3K27me3). Despite the rapid development of new drugs inhibiting EZH2 and/or EZH1, the molecular interplay of these proteins and the impact on disease progression and prognosis of patients with T-cell lymphomas remains insufficiently understood. In this study, EZH1/2 mutation status was evaluated in 33 monomorphic epitheliotropic intestinal T-cell lymphomas by next generation sequencing and EZH1/2 and H3K27me3 protein expression levels were detected by immunohistochemistry in 46 T-cell lymphomas. Correlations with clinicopathologic features were analyzed and survival curves generated. No EZH1 mutations and one (3\%) EZH2 missense mutation were identified. In univariable analysis, high EZH1 expression was associated with an improved overall survival (OS) and progression-free survival (PFS) whereas high EZH2 and H3K27me3 expression were associated with poorer OS and PFS. Multivariable analysis revealed EZH1 (hazard ratio (HR) = 0.183; 95\% confidence interval (CI): 0.044-0.767; p = 0.020;) and EZH2 (HR = 8.245; 95\% CI: 1.898-35.826; p = 0.005) to be independent, divergent prognostic markers for OS. In conclusion, EZH1/2 protein expression had opposing effects on the prognosis of T-cell lymphoma patients.},
  language  = {en}
}
@article{AlrefaiMuhammadRudolfetal.2016,
  author    = {Alrefai, Hani and Muhammad, Khalid and Rudolf, Ronald and Pham, Duong Anh Thuy and Klein-Hessling, Stefan and Patra, Amiya K. and Avots, Andris and Bukur, Valesca and Sahin,, Ugur and Tenzer, Stefan and Goebeler, Matthias and Kerstan, Andreas and Serfling, Edgar},
  title     = {NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells},
  series = {Nature Communications},
  volume    = {7},
  journal   = {Nature Communications},
  doi       = {10.1038/ncomms11724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173053},
  year      = {2016},
  abstract  = {Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.},
  language  = {en}
}
@article{RichterHuettmannRekowskietal.2019,
  author    = {Richter, Julia and H{\"u}ttmann, Andreas and Rekowski, Jan and Schmitz, Christine and G{\"a}rtner, Selina and Rosenwald, Andreas and Hansmann, Martin-Leo and Hartmann, Sylvia and M{\"o}ller, Peter and Wacker, Hans-Heinrich and Feller, Alfred and Thorns, Christoph and M{\"u}ller, Stefan and D{\"u}hrsen, Ulrich and Klapper, Wolfram},
  title     = {Molecular characteristics of diffuse large B-cell lymphoma in the Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin lymphomas (PETAL) trial: correlation with interim PET and outcome},
  series = {Blood Cancer Journal},
  volume    = {9},
  journal   = {Blood Cancer Journal},
  doi       = {10.1038/s41408-019-0230-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226185},
  pages     = {67},
  year      = {2019},
  abstract  = {No abstract available},
  language  = {en}
}
@article{ShaikhVargasMokhtarietal.2021,
  author    = {Shaikh, Haroon and Vargas, Juan Gamboa and Mokhtari, Zeinab and Jarick, Katja J. and Ulbrich, Maria and Mosca, Josefina Pe{\~n}a and Viera, Estibaliz Arellano and Graf, Caroline and Le, Duc-Dung and Heinze, Katrin G. and B{\"u}ttner-Herold, Maike and Rosenwald, Andreas and Pezoldt, Joern and Huehn, Jochen and Beilhack, Andreas},
  title     = {Mesenteric Lymph Node Transplantation in Mice to Study Immune Responses of the Gastrointestinal Tract},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.689896},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244869},
  year      = {2021},
  abstract  = {Mesenteric lymph nodes (mLNs) are sentinel sites of enteral immunosurveillance and immune homeostasis. Immune cells from the gastrointestinal tract (GIT) are constantly recruited to the mLNs in steady-state and under inflammatory conditions resulting in the induction of tolerance and immune cells activation, respectively. Surgical dissection and transplantation of lymph nodes (LN) is a technique that has supported seminal work to study LN function and is useful to investigate resident stromal and endothelial cell biology and their cellular interactions in experimental disease models. Here, we provide a detailed protocol of syngeneic mLN transplantation and report assays to analyze effective mLN engraftment in congenic recipients. Transplanted mLNs allow to study T cell activation and proliferation in preclinical mouse models. Donor mLNs proved viable and functional after surgical transplantation and regenerated blood and lymphatic vessels. Immune cells from the host completely colonized the transplanted mLNs within 7-8 weeks after the surgical intervention. After allogeneic hematopoietic cell transplantation (allo-HCT), adoptively transferred allogeneic CD4+ T cells from FVB/N (H-2q) mice homed to the transplanted mLNs in C57BL/6 (H-2b) recipients during the initiation phase of acute graft-versus-host disease (aGvHD). These CD4+ T cells retained full proliferative capacity and upregulated effector and gut homing molecules comparable to those in mLNs from unmanipulated wild-type recipients. Wild type mLNs transplanted into MHCII deficient syngeneic hosts sufficed to activate alloreactive T cells upon allogeneic hematopoietic cell transplantation, even in the absence of MHCII+ CD11c+ myeloid cells. These data support that orthotopically transplanted mLNs maintain physiological functions after transplantation. The technique of LN transplantation can be applied to study migratory and resident cell compartment interactions in mLNs as well as immune reactions from and to the gut under inflammatory and non-inflammatory conditions.},
  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{HartmannPluetschowMottoketal.2019,
  author    = {Hartmann, Sylvia and Pl{\"u}tschow, Annette and Mottok, Anja and Bernd, Heinz-Wolfram and Feller, Alfred C. and Ott, German and Cogliatti, Sergio and Fend, Falko and Quintanilla-Martinez, Leticia and Stein, Harald and Klapper, Wolfram and M{\"o}ller, Peter and Rosenwald, Andreas and Engert, Andreas and Hansmann, Martin-Leo and Eichenauer, Dennis A.},
  title     = {The time to relapse correlates with the histopathological growth pattern in nodular lymphocyte predominant Hodgkin lymphoma},
  series = {American Journal of Hematology},
  volume    = {94},
  journal   = {American Journal of Hematology},
  number    = {11},
  doi       = {10.1002/ajh.25607},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212594},
  pages     = {1208 -- 1213},
  year      = {2019},
  abstract  = {Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first-line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67\% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.},
  language  = {en}
}
@phdthesis{Geiseler2019,
  author    = {Geiseler, Marina},
  title     = {Klinische, histopathologische und immunph{\"a}notypische Charakterisierung der CD4+ klein-/mittelgroßzelligen kutanen T-Zell-Lymphoproliferation},
  doi       = {10.25972/OPUS-18411},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-184112},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Innerhalb der Gruppe der kutanen T-Zell-Lymphome ist die CD4+ klein-/mittelgroßzellige T-Zell-Lymphoproliferation (SMTCL) eine seltene und bisher als provisorisch erfasste Entit{\"a}t. Um genauere Kenntnisse zu Klinik und Verlauf, Histologie und Immunph{\"a}notyp zu gewinnen, untersuchten wir in dieser Fallserie an 95 F{\"a}llen entsprechende Charakteristika. Dabei konnten alle der bisher provisorisch definierten Eigenschaften der SMTCL best{\"a}tigt werden. Lediglich die 5-Jahre-{\"U}berlebensrate zeigte sich mit 100\% weitaus h{\"o}her als die in der WHO-/EORTC-Klassifikation angegebenen 60-80\%. Diese Best{\"a}tigung der provisorisch definierten Eigenschaften an einem gr{\"o}ßeren Kollektiv kann dazu beitragen, dass die SMTCL in die n{\"a}chste Version der WHO-Klassifikation - durch ausreichende Daten gest{\"u}tzt - als definitive Entit{\"a}t aufgenommen werden kann. Insgesamt konnten in dieser Studie einige Faktoren, die mit einem weniger indolenten Krankheitsverlauf assoziiert sind, identifiziert werden. So zeigten klinisch ein initial bestehender generalisierter Hautbefall sowie eine extrafaziale Lokalisation der L{\"a}sion einen weniger indolenten Verlauf an. Auch Patienten, bei denen ein Verlust von CD2, CD3 oder CD5 bei den Tumorzellen festgestellt wurde, wiesen einen f{\"u}r die CD4+ SMTCL ungew{\"o}hnlichen und weniger indolenten Krankheitsverlauf mit h{\"a}ufigeren Rezidiven und seltenerem Erreichen einer kompletten Remission auf. Histopathologisch schien eine oberfl{\"a}chlichere Infiltrattiefe des Pr{\"a}parates sowie das Vorhandensein eines fokalen Epidermotropismus einen negativen prognostischen Wert zu besitzen. Bez{\"u}glich des Gesamt{\"u}berlebens hatten allerdings auch Patienten mit einem der identifizierten negativen prognostischen Faktoren eine exzellente Prognose. Bei Vorliegen eines dieser negativen Faktoren sollte jedoch eine engmaschigere klinische {\"U}berwachung erfolgen.},
  subject      = {Hautlymphom},
  language  = {de}
}
@article{GaritanoTrojaolaSanchoGoetzetal.2021,
  author    = {Garitano-Trojaola, Andoni and Sancho, Ana and G{\"o}tz, Ralph and Eiring, Patrick and Walz, Susanne and Jetani, Hardikkumar and Gil-Pulido, Jesus and Da Via, Matteo Claudio and Teufel, Eva and Rhodes, Nadine and Haertle, Larissa and Arellano-Viera, Estibaliz and Tibes, Raoul and Rosenwald, Andreas and Rasche, Leo and Hudecek, Michael and Sauer, Markus and Groll, J{\"u}rgen and Einsele, Hermann and Kraus, Sabrina and Kort{\"u}m, Martin K.},
  title     = {Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia},
  series = {Communications Biology},
  volume    = {4},
  journal   = {Communications Biology},
  number    = {1},
  doi       = {10.1038/s42003-021-02215-w},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260709},
  year      = {2021},
  abstract  = {The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.},
  language  = {en}
}
@article{RiedererMonoranuStrobeletal.2021,
  author    = {Riederer, P. and Monoranu, C. and Strobel, S. and Iordache, T. and Sian-H{\"u}lsmann, J.},
  title     = {Iron as the concert master in the pathogenic orchestra playing in sporadic Parkinson's disease},
  series = {Journal of Neural Transmission},
  volume    = {128},
  journal   = {Journal of Neural Transmission},
  number    = {10},
  issn      = {1435-1463},
  doi       = {10.1007/s00702-021-02414-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268539},
  pages     = {1577-1598},
  year      = {2021},
  abstract  = {About 60 years ago, the discovery of a deficiency of dopamine in the nigro-striatal system led to a variety of symptomatic therapeutic strategies to supplement dopamine and to substantially improve the quality of life of patients with Parkinson's disease (PD). Since these seminal developments, neuropathological, neurochemical, molecular biological and genetic discoveries contributed to elucidate the pathology of PD. Oxidative stress, the consequences of reactive oxidative species, reduced antioxidative capacity including loss of glutathione, excitotoxicity, mitochondrial dysfunction, proteasomal dysfunction, apoptosis, lysosomal dysfunction, autophagy, suggested to be causal for ɑ-synuclein fibril formation and aggregation and contributing to neuroinflammation and neural cell death underlying this devastating disorder. However, there are no final conclusions about the triggered pathological mechanism(s) and the follow-up of pathological dysfunctions. Nevertheless, it is a fact, that iron, a major component of oxidative reactions, as well as neuromelanin, the major intraneuronal chelator of iron, undergo an age-dependent increase. And ageing is a major risk factor for PD. Iron is significantly increased in the substantia nigra pars compacta (SNpc) of PD. Reasons for this finding include disturbances in iron-related import and export mechanisms across the blood-brain barrier (BBB), localized opening of the BBB at the nigro-striatal tract including brain vessel pathology. Whether this pathology is of primary or secondary importance is not known. We assume that there is a better fit to the top-down hypotheses and pathogens entering the brain via the olfactory system, then to the bottom-up (gut-brain) hypothesis of PD pathology. Triggers for the bottom-up, the dual-hit and the top-down pathologies include chemicals, viruses and bacteria. If so, hepcidin, a regulator of iron absorption and its distribution into tissues, is suggested to play a major role in the pathogenesis of iron dyshomeostasis and risk for initiating and progressing ɑ-synuclein pathology. The role of glial components to the pathology of PD is still unknown. However, the dramatic loss of glutathione (GSH), which is mainly synthesized in glia, suggests dysfunction of this process, or GSH uptake into neurons. Loss of GSH and increase in SNpc iron concentration have been suggested to be early, may be even pre-symptomatic processes in the pathology of PD, despite the fact that they are progression factors. The role of glial ferritin isoforms has not been studied so far in detail in human post-mortem brain tissue and a close insight into their role in PD is called upon. In conclusion, "iron" is a major player in the pathology of PD. Selective chelation of excess iron at the site of the substantia nigra, where a dysfunction of the BBB is suggested, with peripherally acting iron chelators is suggested to contribute to the portfolio and therapeutic armamentarium of anti-Parkinson medications.},
  language  = {en}
}
@article{WallstabeBussemerGroeberBeckeretal.2020,
  author    = {Wallstabe, Julia and Bussemer, Lydia and Groeber-Becker, Florian and Freund, Lukas and Alb, Mirian and Dragan, Mariola and Waaga-Gasser, Ana Maria and Jakubietz, Rafael and Kneitz, Hermann and Rosenwald, Andreas and Rebhan, Silke and Walles, Heike and Mielke, Stephan},
  title     = {Inflammation-Induced Tissue Damage Mimicking GvHD in Human Skin Models as Test Platform for Immunotherapeutics},
  series = {ALTEX},
  volume    = {37},
  journal   = {ALTEX},
  number    = {3},
  doi       = {10.14573/altex.1907181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229974},
  pages     = {429-440},
  year      = {2020},
  abstract  = {Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.},
  language  = {en}
}
@article{MainzSarhanRothetal.2022,
  author    = {Mainz, Laura and Sarhan, Mohamed A. F. E. and Roth, Sabine and Sauer, Ursula and Maurus, Katja and Hartmann, Elena M. and Seibert, Helen-Desiree and Rosenwald, Andreas and Diefenbacher, Markus E. and Rosenfeldt, Mathias T.},
  title     = {Autophagy blockage reduces the incidence of pancreatic ductal adenocarcinoma in the context of mutant Trp53},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {10},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2022.785252},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266005},
  year      = {2022},
  abstract  = {Macroautophagy (hereafter referred to as autophagy) is a homeostatic process that preserves cellular integrity. In mice, autophagy regulates pancreatic ductal adenocarcinoma (PDAC) development in a manner dependent on the status of the tumor suppressor gene Trp53. Studies published so far have investigated the impact of autophagy blockage in tumors arising from Trp53-hemizygous or -homozygous tissue. In contrast, in human PDACs the tumor suppressor gene TP53 is mutated rather than allelically lost, and TP53 mutants retain pathobiological functions that differ from complete allelic loss. In order to better represent the patient situation, we have investigated PDAC development in a well-characterized genetically engineered mouse model (GEMM) of PDAC with mutant Trp53 (Trp53\(^{R172H}\)) and deletion of the essential autophagy gene Atg7. Autophagy blockage reduced PDAC incidence but had no impact on survival time in the subset of animals that formed a tumor. In the absence of Atg7, non-tumor-bearing mice reached a similar age as animals with malignant disease. However, the architecture of autophagy-deficient, tumor-free pancreata was effaced, normal acinar tissue was largely replaced with low-grade pancreatic intraepithelial neoplasias (PanINs) and insulin expressing islet β-cells were reduced. Our data add further complexity to the interplay between Atg7 inhibition and Trp53 status in tumorigenesis.},
  language  = {en}
}
@article{BaeuerleinQureischiMokhtarietal.2021,
  author    = {B{\"a}uerlein, Carina A. and Qureischi, Musga and Mokhtari, Zeinab and Tabares, Paula and Brede, Christian and Jord{\´a}n Garrote, Ana-Laura and Riedel, Simone S. and Chopra, Martin and Reu, Simone and Mottok, Anja and Arellano-Viera, Estibaliz and Graf, Carolin and Kurzwart, Miriam and Schmiedgen, Katharina and Einsele, Hermann and W{\"o}lfl, Matthias and Schlegel, Paul-Gerhardt and Beilhack, Andreas},
  title     = {A T-Cell Surface Marker Panel Predicts Murine Acute Graft-Versus-Host Disease},
  series = {Frontiers in Immunology},
  volume    = {11},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2020.593321},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224290},
  year      = {2021},
  abstract  = {Acute graft-versus-host disease (aGvHD) is a severe and often life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). AGvHD is mediated by alloreactive donor T-cells targeting predominantly the gastrointestinal tract, liver, and skin. Recent work in mice and patients undergoing allo-HCT showed that alloreactive T-cells can be identified by the expression of α4β7 integrin on T-cells even before manifestation of an aGvHD. Here, we investigated whether the detection of a combination of the expression of T-cell surface markers on peripheral blood (PB) CD8\(^+\) T-cells would improve the ability to predict aGvHD. To this end, we employed two independent preclinical models of minor histocompatibility antigen mismatched allo-HCT following myeloablative conditioning. Expression profiles of integrins, selectins, chemokine receptors, and activation markers of PB donor T-cells were measured with multiparameter flow cytometry at multiple time points before the onset of clinical aGvHD symptoms. In both allo-HCT models, we demonstrated a significant upregulation of α4β7 integrin, CD162E, CD162P, and conversely, a downregulation of CD62L on donor T-cells, which could be correlated with the development of aGvHD. Other surface markers, such as CD25, CD69, and CC-chemokine receptors were not found to be predictive markers. Based on these preclinical data from mouse models, we propose a surface marker panel on peripheral blood T-cells after allo-HCT combining α4β7 integrin with CD62L, CD162E, and CD162P (cutaneous lymphocyte antigens, CLA, in humans) to identify patients at risk for developing aGvHD early after allo-HCT.},
  language  = {en}
}
@article{RosenfeldtHartmannLengetal.2021,
  author    = {Rosenfeldt, Mathias T. and Hartmann, Elena M. and Leng, Corinna and Rosenwald, Andreas and Anagnostopoulos, Ioannis},
  title     = {A case of nodular lymphocyte predominant Hodgkin lymphoma with unexpected EBV-latency type},
  series = {Annals of Hematology},
  volume    = {100},
  journal   = {Annals of Hematology},
  issn      = {0939-5555},
  doi       = {10.1007/s00277-020-04174-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232571},
  pages     = {2635-2637},
  year      = {2021},
  abstract  = {No abstract available.},
  language  = {en}
}
@phdthesis{Lu2020,
  author    = {Lu, Yunzhi},
  title     = {Kinetics of mouse and human muscle type nicotinic receptor channels},
  doi       = {10.25972/OPUS-19268},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-192688},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Acetylcholine (ACh) mediates transmission at vertebrate neuromuscular junctions and many other synapses. The postsynaptic ACh receptors at neuromuscular junctions are of the nicotinic subtype (nAChRs). They are among the best studied receptor channels and often serve as models or receptor prototypes. Despite a wealth of information on muscle type nAChRs so far little is known about species specific functional differences. In this work, mouse and human adult muscle type nAChRs are investigated. Cell attached recordings in the HEK293T heterologous expression system provided evidence that the ACh affinity of recombinant mouse and human adult muscle type nAChRs are different. To clarify this, I compared these receptors in outside-out patches employing a system for fast agonist application. Thus, the individual membrane patches with receptors can be exposed to various ligand concentrations. In response to 10 and 30 µM ACh normalized peak currents ({\^i}) were significantly larger and current rise-time (tr) shorter in human than in mouse receptors. Analyzing dose-response curves of {\^i} and tr and fitting them with a two-step equivalent binding-site kinetic mechanism revealed a two-fold higher ACh association rate constant in human compared to mouse receptors. Furthermore, human nAChRs were blocked faster in outside-out patches by superfusion of 300 nM α-Bungarotoxin (α-Bgtx) than mouse nAChRs. Finally, human nAChRs in outside-out patches showed higher affinity at 3 µM ACh than chimeric receptors consisting of mouse α- and human β-, γ- and ε-subunits. The higher affinity of human than mouse receptors for ACh and α-Bgtx is thus at least in part due to sequence difference in their α-subunits.},
  subject      = {Nicotinischer Acetylcholinrezeptor},
  language  = {en}
}
@article{Romero‐OlmedoSchulzHuberetal.2021,
  author    = {Romero-Olmedo, Addi J. and Schulz, Axel R. and Huber, Magdalena and Brehm, Corinna U. and Chang, Hyun-Dong and Chiarolla, Cristina M. and Bopp, Tobias and Skevaki, Chrysanthi and Berberich-Siebelt, Friederike and Radbruch, Andreas and Mei, Henrik E. and Lohoff, Michael},
  title     = {Deep phenotypical characterization of human CD3\(^{+}\)CD56\(^{+}\) T cells by mass cytometry},
  series = {European Journal of Immunology},
  volume    = {51},
  journal   = {European Journal of Immunology},
  number    = {3},
  doi       = {10.1002/eji.202048941},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225699},
  pages     = {672 -- 681},
  year      = {2021},
  abstract  = {CD56\(^{+}\) T cells are a group of pro-inflammatory CD3\(^{+}\) lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3\(^{+}\)CD56\(^{+}\) cells in peripheral blood of normal human donors and individuals sensitized to birch-pollen or/and house dust mite by high-dimensional mass cytometry combined with manual and computational data analysis. A co-regulation between major conventional T-cell subsets and their respective CD3\(^{+}\)CD56\(^{+}\) cell counterparts appeared restricted to CD8\(^{+}\), MAIT, and TCRγδ\(^{+}\) T-cell compartments. Interestingly, we find a co-regulation of several CD3\(^{+}\)CD56\(^{+}\) cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56\(^{+}\) T-cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3\(^{+}\)CD56\(^{+}\) subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3\(^{+}\)CD56\(^{+}\) FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.},
  language  = {en}
}
@article{WeberGlutschGeissingeretal.2020,
  author    = {Weber, J. and Glutsch, V. and Geissinger, E. and Haug, L. and Lock, J.F. and Schneider, F. and Kneitz, H. and Goebeler, M. and Schilling, B. and Gesierich, A.},
  title     = {Neoadjuvant immunotherapy with combined ipilimumab and nivolumab in patients with melanoma with primary or in transit disease},
  series = {British Journal of Dermatology},
  volume    = {183},
  journal   = {British Journal of Dermatology},
  number    = {3},
  doi       = {10.1111/bjd.18739},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213520},
  pages     = {559-563},
  year      = {2020},
  abstract  = {The introduction of new therapeutic agents has revolutionized the treatment of metastatic melanoma. The approval of adjuvant anti-programmed death-1 monotherapy with nivolumab or pembrolizumab, and dabrafenib plus trametinib has recently set a new landmark in the treatment of stage III melanoma. Now, clinical trials have shown that immune checkpoint blockade can be performed in a neoadjuvant setting, an approach established as a standard therapeutic approach for other tumour entities such as breast cancer. Recent studies suggest that a pathological response achieved by neoadjuvant immunotherapy is associated with long-term tumour control and that short neoadjuvant application of checkpoint inhibitors may be superior to adjuvant therapy. Most recently, neoadjuvant ipilimumab plus nivolumab in stage III melanoma was reported. With two courses of dose-optimized ipilimumab (1 mg kg-1) combined with nivolumab (3 mg kg-1), pathological responses were observed in 77\% of patients, while only 20\% of patients experienced grade 3 or 4 adverse events. However, the neoadjuvant trials employing combined immune checkpoint blockade conducted so far have excluded patients with in transit metastases, a common finding in stage III melanoma. Here we report four patients with in transit metastases or an advanced primary tumour who have been treated with neoadjuvant ipilimumab plus nivolumab according to the OpACIN-neo trial scheme (arm B). All patients achieved radiological disease control and a pathological response. None of the patients has relapsed so far.},
  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{LoehrKesslerMonoranuetal.2019,
  author    = {L{\"o}hr, Mario and Kessler, Almuth F. and Monoranu, Camelia-Maria and Grosche, Jens and Linsenmann, Thomas and Ernestus, Ralf-Ingo and H{\"a}rtig, Wolfgang},
  title     = {Primary brain amyloidoma, both a neoplastic and a neurodegenerative disease: a case report},
  series = {BMC Neurology},
  volume    = {19},
  journal   = {BMC Neurology},
  doi       = {10.1186/s12883-019-1274-x},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200341},
  pages     = {59},
  year      = {2019},
  abstract  = {Background Scattered extracellular deposits of amyloid within the brain parenchyma can be found in a heterogeneous group of diseases. Its condensed accumulation in the white matter without evidence for systemic amyloidosis is known as primary brain amyloidoma (PBA). Although originally considered as a tumor-like lesion by its space-occupying effect, this condition displays also common hallmarks of a neurodegenerative disorder. Case presentation A 50-year-old woman presented with a mild cognitive decline and seizures with a right temporal, irregular and contrast-enhancing mass on magnetic resonance imaging. Suspecting a high-grade glioma, the firm tumor was subtotally resected. Neuropathological examination showed no glioma, but distinct features of a neurodegenerative disorder. The lesion was composed of amyloid AL λ aggregating within the brain parenchyma as well as the adjacent vessels, partially obstructing the vascular lumina. Immunostaining confirmed a distinct perivascular inflammatory reaction. After removal of the PBA, mnestic impairments improved considerably, the clinical course and MRI-results are stable in the 8-year follow-up. Conclusion Based on our histopathological findings, we propose to regard the clinicopathological entity of PBA as an overlap between a neoplastic and neurodegenerative disorder. Since the lesions are locally restricted, they might be amenable to surgery with the prospect of a definite cure.},
  language  = {en}
}
@phdthesis{Schneider2022,
  author    = {Schneider, Alisa-Sophia Johanna Beatrice},
  title     = {Vergleich immunhistochemischer Markerprofile Her2/neu negativer, hormonrezeptorpositiver Mammakarzinome mit dem Recurrence-Score des OncotypeDX®},
  doi       = {10.25972/OPUS-27685},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-276858},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Zur Entscheidungshilfe in der Therapiefindung des Mammakarzinoms haben sich bez{\"u}glich der Indikation zur Chemotherapie neben den klinischen und histopathologischen Kriterien in den letzten Jahren vorrangig Multigentests etabliert. In der vorliegenden Arbeit wurden Zusammenh{\"a}nge zwischen dem Oncotyp DX® und 18 immunhistochemischen Markern aus der Tumorbiologie f{\"u}r 78 F{\"a}lle hormonrezeptorpositiver, Her2/neu negativer Mammafr{\"u}hkarzinome mit niedrigem Lymphknotenstatus untersucht. Es erfolgten immunhistochemische F{\"a}rbungen an Microtissue-Arrays der Tumorproben. F{\"u}r die Marker AMACR, Cyclin D1, p53, MDM2 und PDL1 ergab sich eine klare statistisch signifikante Korrelation zum Recurrence-Score®des Oncotyp DX® und mit Einschr{\"a}nkungen auch f{\"u}r CDK4. Die Marker p27, Bcl2 und Glut 1 erreichten ein etwas niedrigeres Signifikanzniveau in der statistischen Analyse. Der immunhistochemische Routinemarker Ki67\% zeigte eine hochsignifikante Korrelation mit dem Recurrence-Score®. Hierdurch ergeben sich neue Perspektiven zur Risikostratifizierung des Mammakarzinoms, wie beispielsweise die konsekutive Entwicklung eines immunhistochemischen Scores mit pr{\"a}diktivem Wert f{\"u}r den Recurrence-Score® mit klinischer Anwendung als Pr{\"a}test oder als eigenst{\"a}ndiges Stratifizierungstool bei Brustkrebs.},
  subject      = {Oncotype DX®},
  language  = {de}
}
@article{OttoKastnerSchmidtetal.2022,
  author    = {Otto, Christoph and Kastner, Carolin and Schmidt, Stefanie and Uttinger, Konstantin and Baluapuri, Apoorva and Denk, Sarah and Rosenfeldt, Mathias T. and Rosenwald, Andreas and Roehrig, Florian and Ade, Carsten P. and Schuelein-Voelk, Christina and Diefenbacher, Markus E. and Germer, Christoph-Thomas and Wolf, Elmar and Eilers, Martin and Wiegering, Armin},
  title     = {RNA polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells},
  series = {Molecular Oncology},
  volume    = {16},
  journal   = {Molecular Oncology},
  number    = {15},
  doi       = {10.1002/1878-0261.13265},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312806},
  pages     = {2788-2809},
  year      = {2022},
  abstract  = {Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.},
  language  = {en}
}
@article{MarquardtSolimandoKerscheretal.2021,
  author    = {Marquardt, Andr{\´e} and Solimando, Antonio Giovanni and Kerscher, Alexander and Bittrich, Max and Kalogirou, Charis and K{\"u}bler, Hubert and Rosenwald, Andreas and Bargou, Ralf and Kollmannsberger, Philip and Schilling, Bastian and Meierjohann, Svenja and Krebs, Markus},
  title     = {Subgroup-Independent Mapping of Renal Cell Carcinoma — Machine Learning Reveals Prognostic Mitochondrial Gene Signature Beyond Histopathologic Boundaries},
  series = {Frontiers in Oncology},
  volume    = {11},
  journal   = {Frontiers in Oncology},
  issn      = {2234-943X},
  doi       = {10.3389/fonc.2021.621278},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232107},
  year      = {2021},
  abstract  = {Background: Renal cell carcinoma (RCC) is divided into three major histopathologic groups—clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC). We performed a comprehensive re-analysis of publicly available RCC datasets from the TCGA (The Cancer Genome Atlas) database, thereby combining samples from all three subgroups, for an exploratory transcriptome profiling of RCC subgroups. Materials and Methods: We used FPKM (fragments per kilobase per million) files derived from the ccRCC, pRCC and chRCC cohorts of the TCGA database, representing transcriptomic data of 891 patients. Using principal component analysis, we visualized datasets as t-SNE plot for cluster detection. Clusters were characterized by machine learning, resulting gene signatures were validated by correlation analyses in the TCGA dataset and three external datasets (ICGC RECA-EU, CPTAC-3-Kidney, and GSE157256). Results: Many RCC samples co-clustered according to histopathology. However, a substantial number of samples clustered independently from histopathologic origin (mixed subgroup)—demonstrating divergence between histopathology and transcriptomic data. Further analyses of mixed subgroup via machine learning revealed a predominant mitochondrial gene signature—a trait previously known for chRCC—across all histopathologic subgroups. Additionally, ccRCC samples from mixed subgroup presented an inverse correlation of mitochondrial and angiogenesis-related genes in the TCGA and in three external validation cohorts. Moreover, mixed subgroup affiliation was associated with a highly significant shorter overall survival for patients with ccRCC—and a highly significant longer overall survival for chRCC patients. Conclusions: Pan-RCC clustering according to RNA-sequencing data revealed a distinct histology-independent subgroup characterized by strengthened mitochondrial and weakened angiogenesis-related gene signatures. Moreover, affiliation to mixed subgroup went along with a significantly shorter overall survival for ccRCC and a longer overall survival for chRCC patients. Further research could offer a therapy stratification by specifically addressing the mitochondrial metabolism of such tumors and its microenvironment.},
  language  = {en}
}
@article{MarquardtLandwehrRonchietal.2021,
  author    = {Marquardt, Andr{\´e} and Landwehr, Laura-Sophie and Ronchi, Cristina L. and di Dalmazi, Guido and Riester, Anna and Kollmannsberger, Philip and Altieri, Barbara and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {18},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13184671},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246245},
  year      = {2021},
  abstract  = {Simple Summary Using a visual-based clustering method on the TCGA RNA sequencing data of a large adrenocortical carcinoma (ACC) cohort, we were able to classify these tumors in two distinct clusters largely overlapping with previously identified ones. As previously shown, the identified clusters also correlated with patient survival. Applying the visual clustering method to a second dataset also including benign adrenocortical samples additionally revealed that one of the ACC clusters is more closely located to the benign samples, providing a possible explanation for the better survival of this ACC cluster. Furthermore, the subsequent use of machine learning identified new possible biomarker genes with prognostic potential for this rare disease, that are significantly differentially expressed in the different survival clusters and should be further evaluated. Abstract Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several "multiple-omics" studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.},
  language  = {en}
}
@article{MetznerHerzogHeckeletal.2022,
  author    = {Metzner, Valentin and Herzog, Gloria and Heckel, Tobias and Bischler, Thorsten and Hasinger, Julia and Otto, Christoph and Fassnacht, Martin and Geier, Andreas and Seyfried, Florian and Dischinger, Ulrich},
  title     = {Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {3},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11030753},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255244},
  year      = {2022},
  abstract  = {Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.},
  language  = {en}
}
@article{MajumderJugovicSauletal.2021,
  author    = {Majumder, Snigdha and Jugovic, Isabelle and Saul, Domenica and Bell, Luisa and Hundhausen, Nadine and Seal, Rishav and Beilhack, Andreas and Rosenwald, Andreas and Mougiakakos, Dimitrios and Berberich-Siebelt, Friederike},
  title     = {Rapid and Efficient Gene Editing for Direct Transplantation of Naive Murine Cas9\(^+\) T Cells},
  series = {Frontiers in Immunology},
  volume    = {12},
  journal   = {Frontiers in Immunology},
  issn      = {1664-3224},
  doi       = {10.3389/fimmu.2021.683631},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242896},
  year      = {2021},
  abstract  = {Gene editing of primary T cells is a difficult task. However, it is important for research and especially for clinical T-cell transfers. CRISPR/Cas9 is the most powerful gene-editing technique. It has to be applied to cells by either retroviral transduction or electroporation of ribonucleoprotein complexes. Only the latter is possible with resting T cells. Here, we make use of Cas9 transgenic mice and demonstrate nucleofection of pre-stimulated and, importantly, of naive CD3\(^+\) T cells with guideRNA only. This proved to be rapid and efficient with no need of further selection. In the mixture of Cas9\(^+\)CD3\(^+\) T cells, CD4\(^+\) and CD8\(^+\) conventional as well as regulatory T cells were targeted concurrently. IL-7 supported survival and naivety in vitro, but T cells were also transplantable immediately after nucleofection and elicited their function like unprocessed T cells. Accordingly, metabolic reprogramming reached normal levels within days. In a major mismatch model of GvHD, not only ablation of NFATc1 and/or NFATc2, but also of the NFAT-target gene IRF4 in na{\"i}ve primary murine Cas9\(^+\)CD3\(^+\) T cells by gRNA-only nucleofection ameliorated GvHD. However, pre-activated murine T cells could not achieve long-term protection from GvHD upon single NFATc1 or NFATc2 knockout. This emphasizes the necessity of gene-editing and transferring unstimulated human T cells during allogenic hematopoietic stem cell transplantation.},
  language  = {en}
}
@article{KarikariMcFlederRibechinietal.2022,
  author    = {Karikari, Akua A. and McFleder, Rhonda L. and Ribechini, Eliana and Blum, Robert and Bruttel, Valentin and Knorr, Susanne and Gehmeyr, Mona and Volkmann, Jens and Brotchie, Jonathan M. and Ahsan, Fadhil and Haack, Beatrice and Monoranu, Camelia-Maria and Keber, Ursula and Yeghiazaryan, Rima and Pagenstecher, Axel and Heckel, Tobias and Bischler, Thorsten and Wischhusen, J{\"o}rg and Koprich, James B. and Lutz, Manfred B. and Ip, Chi Wang},
  title     = {Neurodegeneration by α-synuclein-specific T cells in AAV-A53T-α-synuclein Parkinson's disease mice},
  series = {Brain, Behavior, and Immunity},
  volume    = {101},
  journal   = {Brain, Behavior, and Immunity},
  doi       = {10.1016/j.bbi.2022.01.007},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300600},
  pages     = {194 -- 210},
  year      = {2022},
  abstract  = {Background Antigen-specific neuroinflammation and neurodegeneration are characteristic for neuroimmunological diseases. In Parkinson's disease (PD) pathogenesis, α-synuclein is a known culprit. Evidence for α-synuclein-specific T cell responses was recently obtained in PD. Still, a causative link between these α-synuclein responses and dopaminergic neurodegeneration had been lacking. We thus addressed the functional relevance of α-synuclein-specific immune responses in PD in a mouse model. Methods We utilized a mouse model of PD in which an Adeno-associated Vector 1/2 serotype (AAV1/2) expressing human mutated A53T-α-Synuclein was stereotactically injected into the substantia nigra (SN) of either wildtype C57BL/6 or Recombination-activating gene 1 (RAG1)\(^{-/-}\) mice. Brain, spleen, and lymph node tissues from different time points following injection were then analyzed via FACS, cytokine bead assay, immunohistochemistry and RNA-sequencing to determine the role of T cells and inflammation in this model. Bone marrow transfer from either CD4\(^{+}\)/CD8\(^{-}\), CD4\(^{-}\)/CD8\(^{+}\), or CD4\(^{+}\)/CD8\(^{+}\) (JHD\(^{-/-}\)) mice into the RAG-1\(^{-/-}\) mice was also employed. In addition to the in vivo studies, a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay was utilized. Results AAV-based overexpression of pathogenic human A53T-α-synuclein in dopaminergic neurons of the SN stimulated T cell infiltration. RNA-sequencing of immune cells from PD mouse brains confirmed a pro-inflammatory gene profile. T cell responses were directed against A53T-α-synuclein-peptides in the vicinity of position 53 (68-78) and surrounding the pathogenically relevant S129 (120-134). T cells were required for α-synuclein-induced neurodegeneration in vivo and in vitro, while B cell deficiency did not protect from dopaminergic neurodegeneration. Conclusions Using T cell and/or B cell deficient mice and a newly developed A53T-α-synuclein-expressing neuronal cell culture/immune cell assay, we confirmed in vivo and in vitro that pathogenic α-synuclein peptide-specific T cell responses can cause dopaminergic neurodegeneration and thereby contribute to PD-like pathology.},
  language  = {en}
}
@article{HartmannReisslandMaieretal.2021,
  author    = {Hartmann, Oliver and Reissland, Michaela and Maier, Carina R. and Fischer, Thomas and Prieto-Garcia, Cristian and Baluapuri, Apoorva and Schwarz, Jessica and Schmitz, Werner and Garrido-Rodriguez, Martin and Pahor, Nikolett and Davies, Clare C. and Bassermann, Florian and Orian, Amir and Wolf, Elmar and Schulze, Almut and Calzado, Marco A. and Rosenfeldt, Mathias T. and Diefenbacher, Markus E.},
  title     = {Implementation of CRISPR/Cas9 Genome Editing to Generate Murine Lung Cancer Models That Depict the Mutational Landscape of Human Disease},
  series = {Frontiers in Cell and Developmental Biology},
  volume    = {9},
  journal   = {Frontiers in Cell and Developmental Biology},
  issn      = {2296-634X},
  doi       = {10.3389/fcell.2021.641618},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230949},
  year      = {2021},
  abstract  = {Lung cancer is the most common cancer worldwide and the leading cause of cancer-related deaths in both men and women. Despite the development of novel therapeutic interventions, the 5-year survival rate for non-small cell lung cancer (NSCLC) patients remains low, demonstrating the necessity for novel treatments. One strategy to improve translational research is the development of surrogate models reflecting somatic mutations identified in lung cancer patients as these impact treatment responses. With the advent of CRISPR-mediated genome editing, gene deletion as well as site-directed integration of point mutations enabled us to model human malignancies in more detail than ever before. Here, we report that by using CRISPR/Cas9-mediated targeting of Trp53 and KRas, we recapitulated the classic murine NSCLC model Trp53fl/fl:lsl-KRasG12D/wt. Developing tumors were indistinguishable from Trp53fl/fl:lsl-KRasG12D/wt-derived tumors with regard to morphology, marker expression, and transcriptional profiles. We demonstrate the applicability of CRISPR for tumor modeling in vivo and ameliorating the need to use conventional genetically engineered mouse models. Furthermore, tumor onset was not only achieved in constitutive Cas9 expression but also in wild-type animals via infection of lung epithelial cells with two discrete AAVs encoding different parts of the CRISPR machinery. While conventional mouse models require extensive husbandry to integrate new genetic features allowing for gene targeting, basic molecular methods suffice to inflict the desired genetic alterations in vivo. Utilizing the CRISPR toolbox, in vivo cancer research and modeling is rapidly evolving and enables researchers to swiftly develop new, clinically relevant surrogate models for translational research.},
  language  = {en}
}