TY - JOUR A1 - Thomann, Anna Sophie A1 - Schneider, Theresa A1 - Cyran, Laura A1 - Eckert, Ina Nathalie A1 - Kerstan, Andreas A1 - Lutz, Manfred B. T1 - Conversion of Anergic T Cells Into Foxp3\(^-\) IL-10\(^+\) Regulatory T Cells by a Second Antigen Stimulus In Vivo JF - Frontiers in Immunology N2 - T cell anergy is a common mechanism of T cell tolerance. However, although anergic T cells are retained for longer time periods in their hosts, they remain functionally passive. Here, we describe the induction of anergic CD4\(^+\) T cells in vivo by intravenous application of high doses of antigen and their subsequent conversion into suppressive Foxp3\(^-\) IL-10\(^+\) Tr1 cells but not Foxp3\(^+\) Tregs. We describe the kinetics of up-regulation of several memory-, anergy- and suppression-related markers such as CD44, CD73, FR4, CD25, CD28, PD-1, Egr-2, Foxp3 and CTLA-4 in this process. The conversion into suppressive Tr1 cells correlates with the transient intracellular CTLA-4 expression and required the restimulation of anergic cells in a short-term time window. Restimulation after longer time periods, when CTLA-4 is down-regulated again retains the anergic state but does not lead to the induction of suppressor function. Our data require further functional investigations but at this stage may suggest a role for anergic T cells as a circulating pool of passive cells that may be re-activated into Tr1 cells upon short-term restimulation with high and systemic doses of antigen. It is tentative to speculate that such a scenario may represent cases of allergen responses in non-allergic individuals. KW - T cells KW - anergy KW - Tr1 KW - conversion KW - in vivo Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241429 SN - 1664-3224 VL - 12 ER - TY - JOUR A1 - Briese, Michael A1 - Sendtner, Michael T1 - Keeping the balance: the noncoding RNA 7SK as a master regulator for neuron development and function JF - BioEssays N2 - The noncoding RNA 7SK is a critical regulator of transcription by adjusting the activity of the kinase complex P-TEFb. Release of P-TEFb from 7SK stimulates transcription at many genes by promoting productive elongation. Conversely, P-TEFb sequestration by 7SK inhibits transcription. Recent studies have shown that 7SK functions are particularly important for neuron development and maintenance and it can thus be hypothesized that 7SK is at the center of many signaling pathways contributing to neuron function. 7SK activates neuronal gene expression programs that are key for terminal differentiation of neurons. Proteomics studies revealed a complex protein interactome of 7SK that includes several RNA-binding proteins. Some of these novel 7SK subcomplexes exert non-canonical cytosolic functions in neurons by regulating axonal mRNA transport and fine-tuning spliceosome production in response to transcription alterations. Thus, a picture emerges according to which 7SK acts as a multi-functional RNA scaffold that is integral for neuron homeostasis. KW - medicine Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256613 VL - 43 IS - 8 ER - TY - JOUR A1 - Barrea, Luigi A1 - Vetrani, Claudia A1 - Altieri, Barbara A1 - Verde, Ludovica A1 - Savastano, Silvia A1 - Colao, Annamaria A1 - Muscogiuri, Giovanna T1 - The importance of being a ‘lark’ in post-menopausal women with obesity: a ploy to prevent type 2 diabetes mellitus? JF - Nutrients N2 - Chronotype is defined as the behavioral manifestation of circadian rhythms related to the external light–dark cycle. Evening chronotype has been associated with an increased risk of developing cardiometabolic diseases in obesity. Menopause is a lifestage associated with an increased risk of developing cardiometabolic diseases and a change in circadian rhythmicity compared to pre-menopause. However, the prevalence of chronotype categories in menopause and their role in determining menopause-related cardiometabolic risk, mostly in obesity, have not been investigated. Thus, we aimed to investigate the prevalence of chronotype categories in post-menopausal women with obesity and their role in menopause-related cardiometabolic risk. In this cross-sectional study we enrolled 49 pre-menopausal and 74 post-menopausal women with obesity. Anthropometric parameters, lifestyle habits, adherence to the Mediterranean Diet (MD), sleep quality, chronotype and the presence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) were studied. No significance differences were detected in terms of lifestyle and adherence to the MD between pre- and post-menopausal women. Chronotype was classified as morning in 66 (53.6%), evening in 20 (16.3%) and intermediate in 37 (30.1%) women. In addition, pre-menopausal women with obesity showed a significantly higher chance to have an intermediate chronotype (OR = 2.21, 95% CI 1.28–3.83; p = 0.004), whereas post-menopausal women with obesity showed a trend to have a higher morning chronotype (OR = 1.42, 95% CI 0.98–2.06; p = 0.051), although this did not reach statistical significance. No significant differences were detected in terms of prevalence of evening chronotype between the two groups. However, the evening chronotype had a significantly higher risk to have T2DM compared to the morning (OR = 17.29, 95% CI 2.40–124.27; p = 0.005) and intermediate chronotypes (OR = 30.86, 95% CI 2.05–464.32; p = 0.013) in both pre- and post-menopausal women with obesity. In conclusion, the intermediate chronotype was significantly more prevalent in pre-menopausal women with obesity compared to post-menopausal women. Evening chronotype was associated to T2DM in both pre- and post-menopause. These results support the importance of including the assessment of chronotype in the management of women with obesity in post-menopause. KW - chronotype KW - circadian rhythms KW - menopause KW - obesity KW - type 2 diabetes KW - cardiovascular diseases Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248572 SN - 2072-6643 VL - 13 IS - 11 ER - TY - JOUR A1 - Blum, Carina A1 - Taskin, Mehmet Berat A1 - Shan, Junwen A1 - Schilling, Tatjana A1 - Schlegelmilch, Katrin A1 - Teßmar, Jörg A1 - Groll, Jürgen T1 - Appreciating the First Line of the Human Innate Immune Defense: A Strategy to Model and Alleviate the Neutrophil Elastase-Mediated Attack toward Bioactivated Biomaterials JF - Small N2 - Biointerface engineering is a wide-spread strategy to improve the healing process and subsequent tissue integration of biomaterials. Especially the integration of specific peptides is one promising strategy to promote the regenerative capacity of implants and 3D scaffolds. In vivo, these tailored interfaces are, however, first confronted with the innate immune response. Neutrophils are cells with pronounced proteolytic potential and the first recruited immune cells at the implant site; nonetheless, they have so far been underappreciated in the design of biomaterial interfaces. Herein, an in vitro approach is introduced to model and analyze the neutrophil interaction with bioactivated materials at the example of nano-bioinspired electrospun surfaces that reveals the vulnerability of a given biointerface design to the contact with neutrophils. A sacrificial, transient hydrogel coating that demonstrates optimal protection for peptide-modified surfaces and thus alleviates the immediate cleavage by neutrophil elastase is further introduced. KW - solution electrospinning KW - human neutrophil elastase (HNE) KW - peptide immobilization KW - polymeric matrix Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257691 VL - 17 IS - 13 ER - TY - JOUR A1 - Rajendran, Ranjithkumar A1 - Böttiger, Gregor A1 - Stadelmann, Christine A1 - Karnati, Srikanth A1 - Berghoff, Martin T1 - FGF/FGFR pathways in multiple sclerosis and in its disease models JF - Cells N2 - Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS) affecting more than two million people worldwide. In MS, oligodendrocytes and myelin sheaths are destroyed by autoimmune-mediated inflammation, while remyelination is impaired. Recent investigations of post-mortem tissue suggest that Fibroblast growth factor (FGF) signaling may regulate inflammation and myelination in MS. FGF2 expression seems to correlate positively with macrophages/microglia and negatively with myelination; FGF1 was suggested to promote remyelination. In myelin oligodendrocyte glycoprotein (MOG)\(_{35–55}\)-induced experimental autoimmune encephalomyelitis (EAE), systemic deletion of FGF2 suggested that FGF2 may promote remyelination. Specific deletion of FGF receptors (FGFRs) in oligodendrocytes in this EAE model resulted in a decrease of lymphocyte and macrophage/microglia infiltration as well as myelin and axon degeneration. These effects were mediated by ERK/Akt phosphorylation, a brain-derived neurotrophic factor, and downregulation of inhibitors of remyelination. In the first part of this review, the most important pharmacotherapeutic principles for MS will be illustrated, and then we will review recent advances made on FGF signaling in MS. Thus, we will suggest application of FGFR inhibitors, which are currently used in Phase II and III cancer trials, as a therapeutic option to reduce inflammation and induce remyelination in EAE and eventually MS. KW - FGF KW - FGFR KW - multiple sclerosis KW - EAE KW - ERK KW - Akt KW - BDNF KW - LINGO-1 KW - SEMA3A Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236594 SN - 2073-4409 VL - 10 IS - 4 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Higuchi, Takahiro A1 - Pomper, Martin G. A1 - Rowe, Steven P. T1 - Theranostics in oncology — thriving, now more than ever JF - Diagnostics N2 - Tracing its roots back to the 1940s, theranostics in nuclear oncology has proved successful mainly due to the beneficial effects of image-guided therapeutic concepts for patients afflicted with a variety of different cancers. The majority of these treatments are not only characterized by substantial prolongation of progression-free and overall survival, but are also generally safe, rendering theranostic agents as an attractive treatment option in various clinical scenarios in oncology. In this Special Issue Novel Theranostic Agents, nine original articles from around the globe provide further evidence on the use of the theranostic concept for neuroendocrine neoplasm (NEN), prostate cancer (PC), meningioma, and neuroblastoma. The investigated diagnostic and therapeutic radiotracers target not only established structures, such as somatostatin receptor, prostate-specific membrane antigen or norepinephrine transporter, but also recently emerging targets such as the C-X-C motif chemokine receptor 4. Moreover, the presented original articles also combine the concept of theranostics with in-depth read-out techniques such as radiomics or novel reconstruction algorithms on pretherapeutic scans, e.g., for outcome prediction. Even 80 years after its initial clinical introduction, theranostics in oncology continues to thrive, now more than ever. KW - theranostics KW - somatostatin receptor (SSTR) KW - prostate-specific membrane antigen (PSMA) KW - prostate cancer KW - neuroendocrine neoplasms (NEN) KW - neuroendocrine tumors (NET) KW - meningioma KW - norepinephrine transporter KW - neuroblastoma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236662 SN - 2075-4418 VL - 11 IS - 5 ER - TY - JOUR A1 - Ziegler, Georg C. A1 - Radtke, Franziska A1 - Vitale, Maria Rosaria A1 - Preuße, André A1 - Klopocki, Eva A1 - Herms, Stefan A1 - Lesch, Klaus-Peter T1 - Generation of multiple human iPSC lines from peripheral blood mononuclear cells of two SLC2A3 deletion and two SLC2A3 duplication carriers JF - Stem Cell Research N2 - Copy number variants of SLC2A3, which encodes the glucose transporter GLUT3, are associated with several neuropsychiatric and cardiac diseases. Here, we report the successful reprogramming of peripheral blood mononuclear cells from two SLC2A3 duplication and two SLC2A3 deletion carriers and subsequent generation of two transgene-free iPSC clones per donor by Sendai viral transduction. All eight clones represent bona fide hiPSCs with high expression of pluripotency genes, ability to differentiate into cells of all three germ layers and normal karyotype. The generated cell lines will be helpful to enlighten the role of glucometabolic alterations in pathophysiological processes shared across organ boundaries. KW - congenital heart-deffects KW - transporter gene SLC2A3 KW - copy-number variation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264696 VL - 56 ER - TY - JOUR A1 - Rauschenberger, Lisa A1 - Knorr, Susanne A1 - Pisani, Antonio A1 - Hallett, Mark A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment? JF - Neurobiology of Disease N2 - One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology. KW - dystonia KW - second hit KW - pathophysiology KW - gene-environment interaction Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265028 VL - 159 ER - TY - JOUR A1 - Hose, Dorothea A1 - Schreder, Martin A1 - Hefner, Jochen A1 - Bittrich, Max A1 - Danhof, Sophia A1 - Strifler, Susanne A1 - Krauth, Maria-Theresa A1 - Schoder, Renate A1 - Gisslinger, Bettina A1 - Einsele, Hermann A1 - Gisslinger, Heinz A1 - Knop, Stefan T1 - Elotuzumab, pomalidomide, and dexamethasone is a very well tolerated regimen associated with durable remission even in very advanced myeloma: a retrospective study from two academic centers JF - Journal of Cancer Research and Clinical Oncology N2 - Background The anti-SLAMF7 monoclonal antibody, elotuzumab (elo), plus lenalidomide (len) and dexamethasone (dex) is approved for relapsed/refractory MM in the U.S. and Europe. Recently, a small phase 2 study demonstrated an advantage in progression-free survival (PFS) for elo plus pomalidomide (pom)/dex compared to pom/dex alone and resulted in licensing of this novel triplet combination, but clinical experience is still limited. Purpose To analyze the efficacy and safety of elo/pom/dex in a “real world” cohort of patients with advanced MM, we queried the databases of the university hospitals of Würzburg and Vienna. Findings We identified 22 patients with a median number of five prior lines of therapy who received elo/pom/dex prior to licensing within an early access program. Patients received a median number of 5 four-week treatment cycles. Median PFS was 6.4 months with 12-month and 18-month PFS rates of 35% and 28%, respectively. The overall response rate was 50% and 64% of responding patients who achieved a longer PFS with elo/pom/dex compared to their most recent line of therapy. Objective responses were also seen in five patients who had been pretreated with pomalidomide. Low tumor burden was associated with improved PFS (13.5 months for patients with ISS stage I/II at study entry v 6.4 months for ISS III), although this difference did not reach statistical significance. No infusion-related reactions were reported. The most frequent grade 3/4 adverse events were neutropenia and pneumonia. Conclusion Elo/pom/dex is an active and well-tolerated regimen in highly advanced MM even after pretreatment with pomalidomide. KW - multiple myeloma KW - elotuzumab KW - SLAMF7 KW - pomalidomide KW - lenalidomide Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235762 SN - 0171-5216 VL - 147 ER - TY - JOUR A1 - Terekhov, Maxim A1 - Elabyad, Ibrahim A. A1 - Schreiber, Laura M. T1 - Global optimization of default phases for parallel transmit coils for ultra-high-field cardiac MRI JF - PLoS One N2 - The development of novel multiple-element transmit-receive arrays is an essential factor for improving B\(_1\)\(^+\) field homogeneity in cardiac MRI at ultra-high magnetic field strength (B\(_0\) > = 7.0T). One of the key steps in the design and fine-tuning of such arrays during the development process is finding the default driving phases for individual coil elements providing the best possible homogeneity of the combined B\(_1\)\(^+\)-field that is achievable without (or before) subject-specific B\(_1\)\(^+\)-adjustment in the scanner. This task is often solved by time-consuming (brute-force) or by limited efficiency optimization methods. In this work, we propose a robust technique to find phase vectors providing optimization of the B-1-homogeneity in the default setup of multiple-element transceiver arrays. The key point of the described method is the pre-selection of starting vectors for the iterative solver-based search to maximize the probability of finding a global extremum for a cost function optimizing the homogeneity of a shaped B\(_1\)\(^+\)-field. This strategy allows for (i) drastic reduction of the computation time in comparison to a brute-force method and (ii) finding phase vectors providing a combined B\(_1\)\(^+\)-field with homogeneity characteristics superior to the one provided by the random-multi-start optimization approach. The method was efficiently used for optimizing the default phase settings in the in-house-built 8Tx/16Rx arrays designed for cMRI in pigs at 7T. KW - optimization KW - magnetic resonance imaging KW - power grids KW - swine KW - electromagnetics KW - linear regression analysis KW - thorax KW - wave interference Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265737 VL - 16 IS - 8 ER - TY - JOUR A1 - Koelmel, Wolfgang A1 - Kuper, Jochen A1 - Kisker, Caroline T1 - Cesium based phasing of macromolecules: a general easy to use approach for solving the phase problem JF - Scientific Reports N2 - Over the last decades the phase problem in macromolecular x-ray crystallography has become more controllable as methods and approaches have diversified and improved. However, solving the phase problem is still one of the biggest obstacles on the way of successfully determining a crystal structure. To overcome this caveat, we have utilized the anomalous scattering properties of the heavy alkali metal cesium. We investigated the introduction of cesium in form of cesium chloride during the three major steps of protein treatment in crystallography: purification, crystallization, and cryo-protection. We derived a step-wise procedure encompassing a "quick-soak"-only approach and a combined approach of CsCl supplement during purification and cryo-protection. This procedure was successfully applied on two different proteins: (i) Lysozyme and (ii) as a proof of principle, a construct consisting of the PH domain of the TFIIH subunit p62 from Chaetomium thermophilum for de novo structure determination. Usage of CsCl thus provides a versatile, general, easy to use, and low cost phasing strategy. KW - structural biology KW - X-ray crystallography Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261644 VL - 11 IS - 1 ER - TY - JOUR A1 - Krieter, Detlef H. A1 - Jeyaseelan, Jarline A1 - Rüth, Marieke A1 - Lemke, Horst-Dieter A1 - Wanner, Christoph A1 - Drechsler, Christiane T1 - Clinical hemocompatibility of double-filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes JF - Artificial Organs N2 - Activation of the complement system and leukocytes by blood–membrane interactions may further promote arteriosclerosis typically present in patients on lipoprotein apheresis. As clinical data on the hemocompatibility of lipoprotein apheresis are scarce, a controlled clinical study comparing two different types of plasma separation and fractionation membranes used in double-filtration lipoprotein apheresis was urgently needed, as its outcome may influence clinical decision-making. In a prospective, randomized, crossover controlled trial, eight patients on double-filtration lipoprotein apheresis were subjected to one treatment with recent polyethersulfone (PES) plasma separation and fractionation membranes and one control treatment using a set of ethylene-vinyl alcohol copolymer (EVAL) membranes. White blood cell (WBC) and platelet (PC) counts, complement factor C5a and thrombin–antithrombin III (TAT) concentrations were determined in samples drawn at defined times from different sites of the extracorporeal blood and plasma circuit. With a nadir at 25 minutes, WBCs in EVAL decreased to 33.5 ± 10.7% of baseline compared with 63.8 ± 22.0% at 20 minutes in PES (P < .001). The maximum C5a levels in venous blood reentering the patients were measured at 30 minutes, being 30.0 ± 11.2 µg/L with EVAL and 12.3 ± 9.0 µg/L with PES (P < .05). The highest C5a concentrations were found in plasma after the plasma filters (EVAL 56.1 ± 22.0 µg/L at 15 minutes vs PES 23.3 ± 15.2 µg/L at 10 minutes; P < .001). PC did not significantly decrease over time with both membrane types, whereas TAT levels did not rise until the end of the treatment without differences between membranes. Regarding lipoprotein(a) and low-density lipoprotein (LDL) cholesterol removal, both membrane sets performed equally. Compared with EVAL, PES membranes cause less leukocyte and complement system activation, the classical parameters of hemocompatibility of extracorporeal treatment procedures, at identical treatment efficacy. Better hemocompatibility may avoid inflammation-promoting effects through blood–material interactions in patients requiring double-filtration lipoprotein apheresis. KW - lipoprotein(a) KW - biocompatibility KW - fractionation membranev KW - hypercholesterolemia KW - LDL cholesterol KW - lipoprotein apheresis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258307 VL - 45 IS - 9 ER - TY - JOUR A1 - Schlee, Winfried A1 - Simoes, Jorge A1 - Pryss, Rüdiger T1 - Auricular acupressure combined with self-help intervention for treating chronic tinnitus: a longitudinal observational study JF - Journal of Clinical Medicine N2 - Tinnitus is a phantom sound perception in the ears or head and can arise from many different medical disorders. Currently, there is no standard treatment for tinnitus that reliably reduces tinnitus. Individual patients reported that acupressure at various points around the ear can help to reduce tinnitus, which was investigated here. With this longitudinal observational study, we report a systematic evaluation of auricular acupressure on 39 tinnitus sufferers, combined with a self-help smartphone app. The participants were asked to report on tinnitus, stress, mood, neck, and jaw muscle tensions twice a day using an ecological momentary assessment study design for six weeks. On average, 123.6 questionnaires per person were provided and used for statistical analysis. The treatment responses of the participants were heterogeneous. On average, we observed significant negative trends for tinnitus loudness (Cohen's d effect size: −0.861), tinnitus distress (d = −0.478), stress (d = −0.675), and tensions in the neck muscles (d = −0.356). Comparison with a matched control group revealed significant improvements for tinnitus loudness (p = 0.027) and self-reported stress level (p = 0.003). The positive results of the observational study motivate further research including a randomized clinical trial and long-term assessment of the clinical improvement. KW - tinnitus KW - acupressure KW - self-help KW - ecological momentary assessment KW - stress Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246209 SN - 2077-0383 VL - 10 IS - 18 ER - TY - JOUR A1 - Heimberg, Linda A1 - Knop, Stefan T1 - Updated Perspectives on the Management of Relapsed and Refractory Multiple Myeloma JF - Oncology Research and Treatment N2 - Background: With the availability of T-cell-directed therapy and next-generation compounds of established classes of drugs, the treatment of relapsed/refractory (r/r) myeloma is getting more complex. However, treatment options in practice are limited by availability, approval, and patient comorbidity. The aim of this article is to provide a practical approach toward the choice of treatment for r/r myeloma patients. Summary: Regarding market authorization and current guidelines, at least in Germany, most patients nowadays will have received a doublet or triplet combination as first-line therapy containing a proteasome inhibitor and an immunomodulatory drug, mostly lenalidomide. We focus on the treatment options for patients that are ineligible for (another) stem cell transplantation. We will review treatment options for relapse after first- or second-line therapy and beyond third-line. Key Messages: There is promising data supporting the efficacy and safety of triplet combinations containing anti-CD38-monoclonal antibodies (anti-CD38 mAbs) at first or second relapse in combination with next-generation compounds. For the treatment beyond third-line, comparative studies are scarce but some promising compounds are available via conditional authorization, and there is more to come in the future. We will present some early phase trials featuring promising results. KW - lenalidomide-refractory patients KW - myeloma Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-249773 SN - 2296-5270 SN - 2296-5262 VL - 44 IS - 12 ER - TY - JOUR A1 - Stratos, Ioannis A1 - Scarlat, Marius M. A1 - Rudert, Maximilian T1 - Bibliometrics of orthopaedic articles published by authors of Germanophone countries JF - International Orthopaedics N2 - No abstract available. KW - scientific publications KW - orthopaedics KW - germanophone Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266343 VL - 45 IS - 5 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Skorb, Ekaterina V. A1 - Förster, Carola Y. A1 - Dandekar, Thomas T1 - Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease JF - Frontiers in Chemistry N2 - Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial. KW - scaffold search KW - approved drugs KW - drug repurposing KW - alzheimer's disease KW - chemical similarity KW - molecular modeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248703 SN - 2296-2646 VL - 9 ER - TY - JOUR A1 - Cadar, Dániel A1 - Jellinger, Kurt A. A1 - Riederer, Peter A1 - Strobel, Sabrina A1 - Monoranu, Camelia-Maria A1 - Tappe, Dennis T1 - No metagenomic evidence of causative viral pathogens in postencephalitic parkinsonism following encephalitis lethargica JF - Microorganisms N2 - Postencephalitic parkinsonism (PEP) is a disease of unknown etiology and pathophysiology following encephalitis lethargica (EL), an acute-onset polioencephalitis of cryptic cause in the 1920s. PEP is a tauopathy with multisystem neuronal loss and gliosis, clinically characterized by bradykinesia, rigidity, rest tremor, and oculogyric crises. Though a viral cause of EL is likely, past polymerase chain reaction-based investigations in the etiology of both PEP and EL were negative. PEP might be caused directly by an unknown viral pathogen or the consequence of a post-infectious immunopathology. The development of metagenomic next-generation sequencing in conjunction with bioinformatic techniques has generated a broad-range tool for the detection of unknown pathogens in the recent past. Retrospective identification and characterization of pathogens responsible for past infectious diseases can be successfully performed with formalin-fixed paraffin-embedded (FFPE) tissue samples. In this study, we analyzed 24 FFPE brain samples from six patients with PEP by unbiased metagenomic next-generation sequencing. Our results show that no evidence for the presence of a specific or putative (novel) viral pathogen was found, suggesting a likely post-infectious immune-mediated etiology of PEP. KW - postencephalitic parkinsonism KW - encephalitis lethargica KW - von Economo KW - metagenomics KW - neuropathology KW - tauopathy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245074 SN - 2076-2607 VL - 9 IS - 8 ER - TY - JOUR A1 - Chen, Jeremy Tsung-Chieh A1 - Schmidt, Lea A1 - Schürger, Christina A1 - Hankir, Mohammed K. A1 - Krug, Susanne M. A1 - Rittner, Heike L. T1 - Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury JF - International Journal of Molecular Sciences N2 - The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain. KW - neuropathic pain KW - netrin-1 KW - blood-nerve barrier KW - tight junction proteins Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261695 SN - 1422-0067 VL - 22 IS - 18 ER - TY - JOUR A1 - Allgaier, Johannes A1 - Schlee, Winfried A1 - Langguth, Berthold A1 - Probst, Thomas A1 - Pryss, Rüdiger T1 - Predicting the Gender of Individuals with Tinnitus based on Daily Life Data of the TrackYourTinnitus mHealth Platform JF - Scientific Reports N2 - Tinnitus is an auditory phantom perception in the absence of an external sound stimulation. People with tinnitus often report severe constraints in their daily life. Interestingly, indications exist on gender differences between women and men both in the symptom profile as well as in the response to specific tinnitus treatments. In this paper, data of the TrackYourTinnitus platform (TYT) were analyzed to investigate whether the gender of users can be predicted. In general, the TYT mobile Health crowdsensing platform was developed to demystify the daily and momentary variations of tinnitus symptoms over time. The goal of the presented investigation is a better understanding of gender-related differences in the symptom profiles of users from TYT. Based on two questionnaires of TYT, four machine learning based classifiers were trained and analyzed. With respect to the provided daily answers, the gender of TYT users can be predicted with an accuracy of 81.7%. In this context, worries, difficulties in concentration, and irritability towards the family are the three most important characteristics for predicting the gender. Note that in contrast to existing studies on TYT, daily answers to the worst symptom question were firstly investigated in more detail. It was found that results of this question significantly contribute to the prediction of the gender of TYT users. Overall, our findings indicate gender-related differences in tinnitus and tinnitus-related symptoms. Based on evidence that gender impacts the development of tinnitus, the gathered insights can be considered relevant and justify further investigations in this direction. KW - computer science KW - machine learning KW - psychology KW - signs and symptoms Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261753 VL - 11 IS - 1 ER - TY - JOUR A1 - Ye, Mingyu A1 - Keicher, Markus A1 - Gentschev, Ivaylo A1 - Szalay, Aladar A. T1 - Efficient selection of recombinant fluorescent vaccinia virus strains and rapid virus titer determination by using a multi-well plate imaging system JF - Biomedicines N2 - Engineered vaccinia virus (VACV) strains are used extensively as vectors for the development of novel cancer vaccines and cancer therapeutics. In this study, we describe for the first time a high-throughput approach for both fluorescent rVACV generation and rapid viral titer measurement with the multi-well plate imaging system, IncuCyte\(^®\)S3. The isolation of a single, well-defined plaque is critical for the generation of novel recombinant vaccinia virus (rVACV) strains. Unfortunately, current methods of rVACV engineering via plaque isolation are time-consuming and laborious. Here, we present a modified fluorescent viral plaque screening and selection strategy that allows one to generally obtain novel fluorescent rVACV strains in six days, with a minimum of just four days. The standard plaque assay requires chemicals for fixing and staining cells. Manual plaque counting based on visual inspection of the cell culture plates is time-consuming. Here, we developed a fluorescence-based plaque assay for quantifying the vaccinia virus that does not require a cell staining step. This approach is less toxic to researchers and is reproducible; it is thus an improvement over the traditional assay. Lastly, plaque counting by virtue of a fluorescence-based image is very convenient, as it can be performed directly on the computer. KW - fluorescent recombinant vaccinia virus KW - plaque isolation KW - IncuCyte\(^®\)S3 KW - plaque assay Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245104 SN - 2227-9059 VL - 9 IS - 8 ER -