@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} } @article{SteinhardtKrummenastRosenwaldetal.2022, author = {Steinhardt, Maximilian J. and Krummenast, Franziska C. and Rosenwald, Andreas and Gerhard-Hartmann, Elena and Heidemeier, Anke and Einsele, Hermann and Topp, Max S. and Duell, Johannes}, title = {R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement}, series = {Journal of Cancer Research and Clinical Oncology}, volume = {148}, journal = {Journal of Cancer Research and Clinical Oncology}, number = {1}, issn = {1432-1335}, doi = {10.1007/s00432-021-03663-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267731}, pages = {205-214}, year = {2022}, abstract = {Purpose Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. Methods We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. Results Overall response rate to Ping-Pong was 100\% measured by CT/MRI, including 93.75\% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75\% after a 4.8-year follow-up currently. Conclusion Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population.}, language = {en} } @article{DetomasAltieriSchloetelburgetal.2021, author = {Detomas, Mario and Altieri, Barbara and Schl{\"o}telburg, Wiebke and Appenzeller, Silke and Schlaffer, Sven and Coras, Roland and Schirbel, Andreas and Wild, Vanessa and Kroiss, Matthias and Sbiera, Silviu and Fassnacht, Martin and Deutschbein, Timo}, title = {Case Report: Consecutive Adrenal Cushing's Syndrome and Cushing's Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations}, series = {Frontiers in Endocrinology}, volume = {12}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2021.731579}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244596}, year = {2021}, abstract = {The occurrence of different subtypes of endogenous Cushing's syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing's disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.}, language = {en} } @article{ChifuHeinzeFussetal.2020, author = {Chifu, Irina and Heinze, Britta and Fuss, Carmina T. and Lang, Katharina and Kroiss, Matthias and Kircher, Stefan and Ronchi, Cristina L. and Altieri, Barbara and Schirbel, Andreas and Fassnacht, Martin and Hahner, Stefanie}, title = {Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.597878}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216494}, year = {2020}, abstract = {Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50\% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=-0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.}, language = {en} } @article{MarquardtKollmannsbergerKrebsetal.2022, author = {Marquardt, Andr{\´e} and Kollmannsberger, Philip and Krebs, Markus and Argentiero, Antonella and Knott, Markus and Solimando, Antonio Giovanni and Kerscher, Alexander Georg}, title = {Visual clustering of transcriptomic data from primary and metastatic tumors — dependencies and novel pitfalls}, series = {Genes}, volume = {13}, journal = {Genes}, number = {8}, issn = {2073-4425}, doi = {10.3390/genes13081335}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281872}, year = {2022}, abstract = {Personalized oncology is a rapidly evolving area and offers cancer patients therapy options that are more specific than ever. However, there is still a lack of understanding regarding transcriptomic similarities or differences of metastases and corresponding primary sites. Applying two unsupervised dimension reduction methods (t-Distributed Stochastic Neighbor Embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP)) on three datasets of metastases (n = 682 samples) with three different data transformations (unprocessed, log10 as well as log10 + 1 transformed values), we visualized potential underlying clusters. Additionally, we analyzed two datasets (n = 616 samples) containing metastases and primary tumors of one entity, to point out potential familiarities. Using these methods, no tight link between the site of resection and cluster formation outcome could be demonstrated, or for datasets consisting of solely metastasis or mixed datasets. Instead, dimension reduction methods and data transformation significantly impacted visual clustering results. Our findings strongly suggest data transformation to be considered as another key element in the interpretation of visual clustering approaches along with initialization and different parameters. Furthermore, the results highlight the need for a more thorough examination of parameters used in the analysis of clusters.}, language = {en} } @article{StaussBrunnerBerberichSiebeltetal.2016, author = {Stauss, Dennis and Brunner, Cornelia and Berberich-Siebelt, Friederike and H{\"o}pken, Uta E. and Lipp, Martin and M{\"u}ller, Gerd}, title = {The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6}, series = {Embo Journal}, volume = {35}, journal = {Embo Journal}, number = {8}, doi = {10.15252/embj.201591459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189506}, pages = {881-898}, year = {2016}, abstract = {Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4\(^+\) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses.}, language = {en} } @article{KressJessenMarquardtetal.2021, author = {Kreß, Julia Katharina Charlotte and Jessen, Christina and Marquardt, Andr{\´e} and Hufnagel, Anita and Meierjohann, Svenja}, title = {NRF2 enables EGFR signaling in melanoma cells}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {8}, issn = {1422-0067}, doi = {10.3390/ijms22083803}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260222}, year = {2021}, abstract = {Receptor tyrosine kinases (RTK) are rarely mutated in cutaneous melanoma, but the expression and activation of several RTK family members are associated with a proinvasive phenotype and therapy resistance. Epidermal growth factor receptor (EGFR) is a member of the RTK family and is only expressed in a subgroup of melanomas with poor prognosis. The insight into regulators of EGFR expression and activation is important for the understanding of the development of this malignant melanoma phenotype. Here, we describe that the transcription factor NRF2, the master regulator of the oxidative and electrophilic stress response, mediates the expression and activation of EGFR in melanoma by elevating the levels of EGFR as well as its ligands EGF and TGFα. ChIP sequencing data show that NRF2 directly binds to the promoter of EGF, which contains a canonical antioxidant response element. Accordingly, EGF is induced by oxidative stress and is also increased in lung adenocarcinoma and head and neck carcinoma with mutationally activated NRF2. In contrast, regulation of EGFR and TGFA occurs by an indirect mechanism, which is enabled by the ability of NRF2 to block the activity of the melanocytic lineage factor MITF in melanoma. MITF effectively suppresses EGFR and TGFA expression and therefore serves as link between NRF2 and EGFR. As EGFR was previously described to stimulate NRF2 activity, the mutual activation of NRF2 and EGFR pathways was investigated. The presence of NRF2 was necessary for full EGFR pathway activation, as NRF2-knockout cells showed reduced AKT activation in response to EGF stimulation compared to controls. Conversely, EGF led to the nuclear localization and activation of NRF2, thereby demonstrating that NRF2 and EGFR are connected in a positive feedback loop in melanoma. In summary, our data show that the EGFR-positive melanoma phenotype is strongly supported by NRF2, thus revealing a novel maintenance mechanism for this clinically challenging melanoma subpopulation.}, language = {en} } @article{GroebnerWorstWeischenfeldtetal.2018, author = {Gr{\"o}bner, Susanne N. and Worst, Barbara C. and Weischenfeldt, Joachim and Buchhalter, Ivo and Kleinheinz, Kortine and Rudneva, Vasilisa A. and Johann, Pascal D. and Balasubramanian, Gnana Prakash and Segura-Wang, Maia and Brabetz, Sebastian and Bender, Sebastian and Hutter, Barbara and Sturm, Dominik and Pfaff, Elke and H{\"u}bschmann, Daniel and Zipprich, Gideon and Heinold, Michael and Eils, J{\"u}rgen and Lawerenz, Christian and Erkek, Serap and Lambo, Sander and Waszak, Sebastian and Blattmann, Claudia and Borkhardt, Arndt and Kuhlen, Michaela and Eggert, Angelika and Fulda, Simone and Gessler, Manfred and Wegert, Jenny and Kappler, Roland and Baumhoer, Daniel and Stefan, Burdach and Kirschner-Schwabe, Renate and Kontny, Udo and Kulozik, Andreas E. and Lohmann, Dietmar and Hettmer, Simone and Eckert, Cornelia and Bielack, Stefan and Nathrath, Michaela and Niemeyer, Charlotte and Richter, G{\"u}nther H. and Schulte, Johannes and Siebert, Reiner and Westermann, Frank and Molenaar, Jan J. and Vassal, Gilles and Witt, Hendrik and Burkhardt, Birgit and Kratz, Christian P. and Witt, Olaf and van Tilburg, Cornelis M. and Kramm, Christof M. and Fleischhack, Gudrun and Dirksen, Uta and Rutkowski, Stefan and Fr{\"u}hwald, Michael and Hoff, Katja von and Wolf, Stephan and Klingebeil, Thomas and Koscielniak, Ewa and Landgraf, Pablo and Koster, Jan and Resnick, Adam C. and Zhang, Jinghui and Liu, Yanling and Zhou, Xin and Waanders, Angela J. and Zwijnenburg, Danny A. and Raman, Pichai and Brors, Benedikt and Weber, Ursula D. and Northcott, Paul A. and Pajtler, Kristian W. and Kool, Marcel and Piro, Rosario M. and Korbel, Jan O. and Schlesner, Matthias and Eils, Roland and Jones, David T. W. and Lichter, Peter and Chavez, Lukas and Zapatka, Marc and Pfister, Stefan M.}, title = {The landscape of genomic alterations across childhood cancers}, series = {Nature}, volume = {555}, journal = {Nature}, organization = {ICGC PedBrain-Seq Project, ICGC MMML-Seq Project,}, doi = {10.1038/nature25480}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229579}, pages = {321-327}, year = {2018}, abstract = {Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8\% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50\% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.}, language = {en} } @article{GiampaoloWojcikKleinHesslingetal.2019, author = {Giampaolo, Sabrina and W{\´o}jcik, Gabriela and Klein-Hessling, Stefan and Serfling, Edgar and Patra, Amiya K.}, title = {B cell development is critically dependent on NFATc1 activity}, series = {Cellular \& Molecular Immunology}, volume = {16}, journal = {Cellular \& Molecular Immunology}, doi = {10.1038/s41423-018-0052-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233006}, pages = {508-520}, year = {2019}, abstract = {B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.}, language = {en} } @phdthesis{Koch2024, author = {Koch, Hanna Ulrike}, title = {Funktionelle Untersuchung von IGF1R Mutationen im Multiplen Myelom}, doi = {10.25972/OPUS-37040}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-370406}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das Mutationsspektrum einzelner Gene beziehungsweise zusammengefasster Gengruppen innerhalb von Signalwegen bei Patienten mit Multiplem Myelom wurde in den letzten Jahren eingehend untersucht und charakterisiert. Die Herausforderung besteht nun in der Interpretation der erhobenen Daten, insbesondere der Bewertung einzelner durch Sequenzierung identifizierter Biomarker bez{\"u}glich deren prognostischer Aussagekraft und konkreter therapeutischer Relevanz. Als {\"u}bergeordnetes Ziel gilt die Ableitung von klinischen (Therapie-) Ans{\"a}tzen. Auf dem Weg zu einem individualisierten Therapieansatz ist entscheidend, dass wir unser Wissen {\"u}ber die funktionelle Relevanz einzelner Mutationen wie hier im IGF1R im Hinblick auf deren Einbettung in Signalnetzwerke und auf das Proliferationsverhalten der MM Zellen erweitern. Konkret wurde im Rahmen der vorliegende Doktorarbeit der Einfluss von zwei IGF1R Punktmutationen, n{\"a}mlich D1146N (Punktmutation des IGF1R der HMCL L-363) und N1129S (Punktmutation des IGF1R eines Patienten der DSMM XI Kohorte) auf die Proliferation und das nachgeschaltete Signalling in IGF1R-{\"U}berexpressionsmodellen der MM Zelllinien AMO-1 und U-266 untersucht. Zur stabilen Transfektion der HMCLs mit IGF1RWT und den zwei IGF1R Mutanten wurde ein Protokoll auf Grundlage des Sleeping Beauty (SB) Transposase Systems genutzt. In dieser und anderen assoziierten Arbeit konnte unter zu Hilfenahme von insgesamt vier verschiedenen gentechnisch ver{\"a}nderter HMCLs gezeigt werden, dass funktionelle Mutationen im IGF1R Effekte auf das Downstream Signalling zum Beispiel die Aktivierung von AKT und ERK, jedoch nicht auf die Zellproliferation haben. Im Vergleich der untersuchten HMCLs konnten jedoch keine verallgemeinerbaren Schl{\"u}sse gezogen werden, was die Heterogenit{\"a}t der Erkrankung und die Wichtigkeit der Einzelfallbetrachtung unterstreicht.}, subject = {Plasmozytom}, language = {de} } @article{SolimandoBrandlMattenheimeretal.2018, author = {Solimando, A G and Brandl, A and Mattenheimer, K and Graf, C and Ritz, M and Ruckdeschel, A and St{\"u}hmer, T and Mokhtari, Z and Rudelius, M and Dotterweich, J and Bittrich, M and Desantis, V and Ebert, R and Trerotoli, P and Frassanito, M A and Rosenwald, A and Vacca, A and Einsele, H and Jakob, F and Beilhack, A}, title = {JAM-A as a prognostic factor and new therapeutic target in multiple myeloma}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, doi = {10.1038/leu.2017.287}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239069}, pages = {736-743}, year = {2018}, abstract = {Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.}, language = {en} } @article{WegertVokuhlCollordetal.2018, author = {Wegert, Jenny and Vokuhl, Christian and Collord, Grace and Del Castillo Velasco-Herrera, Martin and Farndon, Sarah J. and Guzzo, Charlotte and Jorgensen, Mette and Anderson, John and Slater, Olga and Duncan, Catriona and Bausenwein, Sabrina and Streitenberger, Heike and Ziegler, Barbara and Furtw{\"a}ngler, Rhoikos and Graf, Norbert and Stratton, Michael R. and Campbell, Peter J. and Jones, David TW and Koelsche, Christian and Pfister, Stefan M. and Mifsud, William and Sebire, Neil and Sparber-Sauer, Monika and Koscielniak, Ewa and Rosenwald, Andreas and Gessler, Manfred and Behjati, Sam}, title = {Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants}, series = {Nature Communications}, volume = {9}, journal = {Nature Communications}, doi = {10.1038/s41467-018-04650-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233446}, year = {2018}, abstract = {Soft tissue tumors of infancy encompass an overlapping spectrum of diseases that pose unique diagnostic and clinical challenges. We studied genomes and transcriptomes of cryptogenic congenital mesoblastic nephroma (CMN), and extended our findings to five anatomically or histologically related soft tissue tumors: infantile fibrosarcoma (IFS), nephroblastomatosis, Wilms tumor, malignant rhabdoid tumor, and clear cell sarcoma of the kidney. A key finding is recurrent mutation of EGFR in CMN by internal tandem duplication of the kinase domain, thus delineating CMN from other childhood renal tumors. Furthermore, we identify BRAF intragenic rearrangements in CMN and IFS. Collectively these findings reveal novel diagnostic markers and therapeutic strategies and highlight a prominent role of isolated intragenic rearrangements as drivers of infant tumors.}, language = {en} } @article{LopezKleinheinzAukemaetal.2019, author = {L{\´o}pez, Cristina and Kleinheinz, Kortine and Aukema, Sietse M. and Rohde, Marius and Bernhart, Stephan H. and H{\"u}bschmann, Daniel and Wagener, Rabea and Toprak, Umut H. and Raimondi, Francesco and Kreuz, Markus and Waszak, Sebastian M. and Huang, Zhiqin and Sieverling, Lina and Paramasivam, Nagarajan and Seufert, Julian and Sungalee, Stephanie and Russell, Robert B. and Bausinger, Julia and Kretzmer, Helene and Ammerpohl, Ole and Bergmann, Anke K. and Binder, Hans and Borkhardt, Arndt and Brors, Benedikt and Claviez, Alexander and Doose, Gero and Feuerbach, Lars and Haake, Andrea and Hansmann, Martin-Leo and Hoell, Jessica and Hummel, Michael and Korbel, Jan O. and Lawerenz, Chris and Lenze, Dido and Radlwimmer, Bernhard and Richter, Julia and Rosenstiel, Philip and Rosenwald, Andreas and Schilhabel, Markus B. and Stein, Harald and Stilgenbauer, Stephan and Stadler, Peter F. and Szczepanowski, Monika and Weniger, Marc A. and Zapatka, Marc and Eils, Roland and Lichter, Peter and Loeffler, Markus and M{\"o}ller, Peter and Tr{\"u}mper, Lorenz and Klapper, Wolfram and Hoffmann, Steve and K{\"u}ppers, Ralf and Burkhardt, Birgit and Schlesner, Matthias and Siebert, Reiner}, title = {Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, organization = {ICGC MMML-Seq Consortium}, doi = {10.1038/s41467-019-08578-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-237281}, year = {2019}, abstract = {Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing.}, language = {en} } @article{WaszakNorthcottBuchhalteretal.2018, author = {Waszak, Sebastian M and Northcott, Paul A and Buchhalter, Ivo and Robinson, Giles W and Sutter, Christian and Groebner, Susanne and Grund, Kerstin B and Brugi{\`e}res, Laurence and Jones, David T W and Pajtler, Kristian W and Morrissy, A Sorana and Kool, Marcel and Sturm, Dominik and Chavez, Lukas and Ernst, Aurelie and Brabetz, Sebastian and Hain, Michael and Zichner, Thomas and Segura-Wang, Maia and Weischenfeldt, Joachim and Rausch, Tobias and Mardin, Balca R and Zhou, Xin and Baciu, Cristina and Lawerenz, Christian and Chan, Jennifer A and Varlet, Pascale and Guerrini-Rousseau, Lea and Fults, Daniel W and Grajkowska, Wiesława and Hauser, Peter and Jabado, Nada and Ra, Young-Shin and Zitterbart, Karel and Shringarpure, Suyash S and De La Vega, Francisco M and Bustamante, Carlos D and Ng, Ho-Keung and Perry, Arie and MacDonald, Tobey J and Driever, Pablo Hern{\´a}iz and Bendel, Anne E and Bowers, Daniel C and McCowage, Geoffrey and Chintagumpala, Murali M and Cohn, Richard and Hassall, Timothy and Fleischhack, Gudrun and Eggen, Tone and Wesenberg, Finn and Feychting, Maria and Lannering, Birgitta and Sch{\"u}z, Joachim and Johansen, Christoffer and Andersen, Tina V and R{\"o}{\"o}sli, Martin and Kuehni, Claudia E and Grotzer, Michael and Kjaerheim, Kristina and Monoranu, Camelia M and Archer, Tenley C and Duke, Elizabeth and Pomeroy, Scott L and Shelagh, Redmond and Frank, Stephan and Sumerauer, David and Scheurlen, Wolfram and Ryzhova, Marina V and Milde, Till and Kratz, Christian P and Samuel, David and Zhang, Jinghui and Solomon, David A and Marra, Marco and Eils, Roland and Bartram, Claus R and von Hoff, Katja and Rutkowksi, Stefan and Ramaswamy, Vijay and Gilbertson, Richard J and Korshunov, Andrey and Taylor, Michael D and Lichter, Peter and Malkin, David and Gajjar, Amar and Korbel, Jan O and Pfister, Stefan M}, title = {Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort}, series = {The Lancet Oncology}, volume = {19}, journal = {The Lancet Oncology}, doi = {10.1016/S1470-2045(18)30242-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233425}, pages = {785-798}, year = {2018}, abstract = {Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6\% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20\% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5\% of medulloblastoma diagnoses, with the highest prevalence [14\%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71\%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57\%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52\% (95\% CI 40-69) and 5-year overall survival was 65\% (95\% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.}, language = {en} } @phdthesis{Pickert2024, author = {Pickert, Julia Felicia}, title = {Untersuchungen zum Einfluss des Insulin-like growth factor Rezeptors auf Signalnetzwerke im Multiplen Myelom}, doi = {10.25972/OPUS-36981}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-369815}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Das MM ist eine maligne Erkrankung, die von biologischer und klinischer Heterogenit{\"a}t gepr{\"a}gt ist. Sie ist durch die monoklonale Vermehrung von Plasmazellen charakterisiert. In vorangegangenen Studien wurde eine H{\"a}ufung von Mutationen in RTK nachgewiesen. Diese gingen mit einem negativen Einfluss auf das {\"U}berleben von MM Patientinnen und Patienten einher. Im Rahmen dieser Arbeit wurde der Einfluss des IGF1R an HMZL mittels siRNA-vermitteltem IGF1R-Knockdown untersucht und dessen Effekt auf das Signalnetzwerk mittels Western Blot Analysen ermittelt. Um die Heterogenit{\"a}t des MM besser abzubilden, wurden sechs verschiedenen HMZL ausgew{\"a}hlt. Der IGF1R-Knockdown war in allen HMZL sowohl anhand der Reduktion der IGF1R-Expression als auch der IGF1R-Aktivierung deutlich nachweisbar. Stellvertretend f{\"u}r den PI3K/AKT Signalweg wurde die AKT-Aktivierung untersucht, welche nach IGF1R-Knockdown in allen Linien abnahm. Im Ras/Raf/MEK/ERK Signalweg fiel eine deutliche Reduktion der ERK1/2- und MEK-Aktivierung in den von PCL stammenden HMZL L-363 und MM.1S, sowie in JJN-3 mit der Hochrisikotranslokation t(14;16) auf. Entsprechend der Beobachtungen f{\"u}r die AKT-Aktivierung, nahm die PYK2-Aktivierung in allen HMZL nach IGF1R-Knockdown ab, was auf ein Zusammenspiel von IGF1R, PYK2 und AKT in allen HMZL hindeutet. Zuk{\"u}nftige Untersuchungen werden zeigen, ob IGF1R Inhibitoren alleine oder in Kombination mit z.B. AKT, PYK2 oder Proteasomen-Inhibitoren in bestimmten molekularen MM Subgruppen ein effektives therapeutisches Ziel sind.}, subject = {Plasmozytom}, language = {de} }