TY - JOUR A1 - Dix, Andreas A1 - Czakai, Kristin A1 - Springer, Jan A1 - Fliesser, Mirjam A1 - Bonin, Michael A1 - Guthke, Reinhard A1 - Schmitt, Anna L. A1 - Einsele, Hermann A1 - Linde, Jörg A1 - Löffler, Jürgen T1 - Genome-Wide Expression Profiling Reveals S100B as Biomarker for Invasive Aspergillosis JF - Frontiers in Microbiology N2 - Invasive aspergillosis (IA) is a devastating opportunistic infection and its treatment constitutes a considerable burden for the health care system. Immunocompromised patients are at an increased risk for IA, which is mainly caused by the species Aspergillus fumigatus. An early and reliable diagnosis is required to initiate the appropriate antifungal therapy. However, diagnostic sensitivity and accuracy still needs to be improved, which can be achieved at least partly by the definition of new biomarkers. Besides the direct detection of the pathogen by the current diagnostic methods, the analysis of the host response is a promising strategy toward this aim. Following this approach, we sought to identify new biomarkers for IA. For this purpose, we analyzed gene expression profiles of hematological patients and compared profiles of patients suffering from IA with non-IA patients. Based on microarray data, we applied a comprehensive feature selection using a random forest classifier. We identified the transcript coding for the S100 calcium-binding protein B (S100B) as a potential new biomarker for the diagnosis of IA. Considering the expression of this gene, we were able to classify samples from patients with IA with 82.3% sensitivity and 74.6% specificity. Moreover, we validated the expression of S100B in a real-time reverse transcription polymerase chain reaction (RT-PCR) assay and we also found a down-regulation of S100B in A. fumigatus stimulated DCs. An influence on the IL1B and CXCL1 downstream levels was demonstrated by this S100B knockdown. In conclusion, this study covers an effective feature selection revealing a key regulator of the human immune response during IA. S100B may represent an additional diagnostic marker that in combination with the established techniques may improve the accuracy of IA diagnosis. KW - human biomarker KW - invasive aspergillosis KW - allogeneic stem cell transplantation KW - gene expression data KW - fungal infection Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165386 IS - 7 ER - TY - JOUR A1 - Zhou, Xiang A1 - Steinhardt, Maximilian Johannes A1 - Düll, Johannes A1 - Krummenast, Franziska A1 - Danhof, Sophia A1 - Meckel, Katharina A1 - Nickel, Katharina A1 - Grathwohl, Denise A1 - Leicht, Hans‐Benno A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Rasche, Leo A1 - Kortüm, Martin T1 - Obinutuzumab and venetoclax induced complete remission in a patient with ibrutinib‐resistant non‐nodal leukemic mantle cell lymphoma JF - European Journal of Haematology N2 - 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. KW - mantle cell lymphoma KW - obinutuzumab KW - venetoclax Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215513 VL - 104 IS - 4 SP - 352 EP - 355 ER - TY - JOUR A1 - Weißbach, Susann A1 - Heredia-Guerrero, Sofia Catalina A1 - Barnsteiner, Stefanie A1 - Großhans, Lukas A1 - Bodem, Jochen A1 - Starz, Hanna A1 - Langer, Christian A1 - Appenzeller, Silke A1 - Knop, Stefan A1 - Steinbrunn, Torsten A1 - Rost, Simone A1 - Einsele, Hermann A1 - Bargou, Ralf Christian A1 - Rosenwald, Andreas A1 - Stühmer, Thorsten A1 - Leich, Ellen T1 - Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines JF - Cancers N2 - 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. KW - multiple myeloma KW - KRAS KW - MEK/ERK-signaling KW - AKT-signaling KW - amplicon sequencing Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200617 SN - 2072-6694 VL - 12 IS - 2 ER - TY - JOUR A1 - Lapa, Constantin A1 - Garcia-Velloso, Maria J. A1 - Lückerath, Katharina A1 - Samnick, Samuel A1 - Schreder, Martin A1 - Otero, Paula Rodriguez A1 - Schmid, Jan-Stefan A1 - Herrmann, Ken A1 - Knop, Stefan A1 - Buck, Andreas K. A1 - Einsele, Hermann A1 - San-Miguel, Jesus A1 - Kortüm, Klaus Martin T1 - \(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions JF - Theranostics N2 - \(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG). 78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available. MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases. MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72). This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM. KW - medicine KW - PET/CT KW - \(^{11}\)C-methionine KW - multiple myeloma KW - FDG Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172038 VL - 7 IS - 11 ER - TY - JOUR A1 - Hartel, Andreas J.W. A1 - Glogger, Marius A1 - Jones, Nicola G. A1 - Abuillan, Wasim A1 - Batram, Christopher A1 - Hermann, Anne A1 - Fenz, Susanne F. A1 - Tanaka, Motomu A1 - Engstler, Markus T1 - N-glycosylation enables high lateral mobility of GPI-anchored proteins at a molecular crowding threshold JF - Nature Communications N2 - The protein density in biological membranes can be extraordinarily high, but the impact of molecular crowding on the diffusion of membrane proteins has not been studied systematically in a natural system. The diversity of the membrane proteome of most cells may preclude systematic studies. African trypanosomes, however, feature a uniform surface coat that is dominated by a single type of variant surface glycoprotein (VSG). Here we study the density-dependence of the diffusion of different glycosylphosphatidylinositol-anchored VSG-types on living cells and in artificial membranes. Our results suggest that a specific molecular crowding threshold (MCT) limits diffusion and hence affects protein function. Obstacles in the form of heterologous proteins compromise the diffusion coefficient and the MCT. The trypanosome VSG-coat operates very close to its MCT. Importantly, our experiments show that N-linked glycans act as molecular insulators that reduce retarding intermolecular interactions allowing membrane proteins to function correctly even when densely packed. KW - parasitology KW - cellular imaging KW - membrane biophysics KW - single-molecule biophysics Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171368 VL - 7 ER - TY - JOUR A1 - Tanoey, Justine A1 - Baechle, Christina A1 - Brenner, Hermann A1 - Deckert, Andreas A1 - Fricke, Julia A1 - Günther, Kathrin A1 - Karch, André A1 - Keil, Thomas A1 - Kluttig, Alexander A1 - Leitzmann, Michael A1 - Mikolajczyk, Rafael A1 - Obi, Nadia A1 - Pischon, Tobias A1 - Schikowski, Tamara A1 - Schipf, Sabine M. A1 - Schulze, Matthias B. A1 - Sedlmeier, Anja A1 - Moreno Velásquez, Ilais A1 - Weber, Katharina S. A1 - Völzke, Henry A1 - Ahrens, Wolfgang A1 - Gastell, Sylvia A1 - Holleczek, Bernd A1 - Jöckel, Karl-Heinz A1 - Katzke, Verena A1 - Lieb, Wolfgang A1 - Michels, Karin B. A1 - Schmidt, Börge A1 - Teismann, Henning A1 - Becher, Heiko T1 - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort JF - International Journal of Environmental Research and Public Health N2 - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection. KW - perinatal KW - adult-onset KW - late-onset KW - autoimmune KW - delivery mode KW - sex KW - offspring KW - NAKO Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216 SN - 1660-4601 VL - 19 IS - 17 ER - TY - JOUR A1 - Weselek, Grit A1 - Keiner, Silke A1 - Fauser, Mareike A1 - Wagenführ, Lisa A1 - Müller, Julia A1 - Kaltschmidt, Barbara A1 - Brandt, Moritz D. A1 - Gerlach, Manfred A1 - Redecker, Christoph A1 - Hermann, Andreas A1 - Storch, Alexander T1 - Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche JF - Stem Cells N2 - The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease. KW - adult neurogenesis KW - hippocampus KW - noradrenaline KW - norepinephrine KW - olfactory bulb neurogenesis KW - subventricular zone Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218250 VL - 38 IS - 9 SP - 1188 EP - 1201 ER - TY - JOUR A1 - Fauser, Mareike A1 - Weselek, Grit A1 - Hauptmann, Christine A1 - Markert, Franz A1 - Gerlach, Manfred A1 - Hermann, Andreas A1 - Storch, Alexander T1 - Catecholaminergic Innervation of Periventricular Neurogenic Regions of the Developing Mouse Brain JF - Frontiers in Neuroanatomy N2 - The major catecholamines—dopamine (DA) and norepinephrine (NE)—are not only involved in synaptic communication but also act as important trophic factors and might ultimately be involved in mammalian brain development. The catecholaminergic innervation of neurogenic regions of the developing brain and its putative relationship to neurogenesis is thus of pivotal interest. We here determined DA and NE innervation around the ventricular/subventricular zone (VZ/SVZ) bordering the whole ventricular system of the developing mouse brain from embryonic day 14.5 (E14.5), E16.5, and E19.5 until postnatal day zero (P0) by histological evaluation and HPLC with electrochemical detection. We correlated these data with the proliferation capacity of the respective regions by quantification of MCM\(^{2+}\) cells. During development, VZ/SVZ catecholamine levels dramatically increased between E16.5 and P0 with DA levels increasing in forebrain VZ/SVZ bordering the lateral ventricles and NE levels raising in midbrain/hindbrain VZ/SVZ bordering the third ventricle, the aqueduct, and the fourth ventricle. Conversely, proliferating MCM\(^{2+}\) cell counts dropped between E16.5 and E19.5 with a special focus on all VZ/SVZs outside the lateral ventricles. We detected an inverse strong negative correlation of the proliferation capacity in the periventricular neurogenic regions (log-transformed MCM\(^{2+}\) cell counts) with their NE levels (r = −0.932; p < 0.001), but not their DA levels (r = 0.440; p = 0.051) suggesting putative inhibitory effects of NE on cell proliferation within the periventricular regions during mouse brain development. Our data provide the first framework for further demandable studies on the functional importance of catecholamines, particularly NE, in regulating neural stem/progenitor cell proliferation and differentiation during mammalian brain development. KW - brain development KW - ventricular zone KW - catecholamines KW - norepinephrine KW - dopamine KW - neurogenesis Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212485 VL - 14 ER - TY - JOUR A1 - Garitano-Trojaola, Andoni A1 - Sancho, Ana A1 - Götz, Ralph A1 - Eiring, Patrick A1 - Walz, Susanne A1 - Jetani, Hardikkumar A1 - Gil-Pulido, Jesus A1 - Da Via, Matteo Claudio A1 - Teufel, Eva A1 - Rhodes, Nadine A1 - Haertle, Larissa A1 - Arellano-Viera, Estibaliz A1 - Tibes, Raoul A1 - Rosenwald, Andreas A1 - Rasche, Leo A1 - Hudecek, Michael A1 - Sauer, Markus A1 - Groll, Jürgen A1 - Einsele, Hermann A1 - Kraus, Sabrina A1 - Kortüm, Martin K. T1 - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia JF - Communications Biology N2 - 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. KW - actin KW - acute myeloid leukaemia Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709 VL - 4 IS - 1 ER - TY - JOUR A1 - Czakai, Kristin A1 - Leonhardt, Ines A1 - Dix, Andreas A1 - Bonin, Michael A1 - Linde, Joerg A1 - Einsele, Hermann A1 - Kurzai, Oliver A1 - Loeffler, Jürgen T1 - Krüppel-like Factor 4 modulates interleukin-6 release in human dendritic cells after in vitro stimulation with Aspergillus fumigatus and Candida albicans JF - Scientific Reports N2 - Invasive fungal infections are associated with high mortality rates and are mostly caused by the opportunistic fungi Aspergillus fumigatus and Candida albicans. Immune responses against these fungi are still not fully understood. Dendritic cells (DCs) are crucial players in initiating innate and adaptive immune responses against fungal infections. The immunomodulatory effects of fungi were compared to the bacterial stimulus LPS to determine key players in the immune response to fungal infections. A genome wide study of the gene regulation of human monocyte-derived dendritic cells (DCs) confronted with A. fumigatus, C. albicans or LPS was performed and Krüppel-like factor 4 (KLF4) was identified as the only transcription factor that was down-regulated in DCs by both fungi but induced by stimulation with LPS. Downstream analysis demonstrated the influence of KLF4 on the interleukine-6 expression in human DCs. Furthermore, KLF4 regulation was shown to be dependent on pattern recognition receptor ligation. Therefore KLF4 was identified as a controlling element in the IL-6 immune response with a unique expression pattern comparing fungal and LPS stimulation. KW - gene regulation in immune cells KW - fungal host response KW - Aspergillus fumigatus KW - Candida albicans Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-181185 VL - 6 ER -