@article{HersterBittnerCodreaetal.2019, author = {Herster, Franziska and Bittner, Zsofia and Codrea, Marius Cosmin and Archer, Nathan K. and Heister, Martin and L{\"o}ffler, Markus W. and Heumos, Simon and Wegner, Joanna and Businger, Ramona and Schindler, Michael and Stegner, David and Sch{\"a}kel, Knut and Grabbe, Stephan and Ghoreschi, Kamran and Miller, Lloyd S. and Weber, Alexander N. R.}, title = {Platelets Aggregate With Neutrophils and Promote Skin Pathology in Psoriasis}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2019.01867}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320175}, year = {2019}, abstract = {Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes, but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well-defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo mouse model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease incidence directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in mice in vivo ameliorated disease severity significantly, indicating that both PMNs and platelets may be relevant for psoriasis pathology and disease severity.}, language = {en} } @article{SchneiderWiewelhoveRaederetal.2019, author = {Schneider, Christoph and Wiewelhove, Thimo and Raeder, Christian and Flatt, Andrew A. and Hoos, Olaf and Hottenrott, Laura and Schumbera, Oliver and Kellmann, Michael and Meyer, Tim and Pfeiffer, Mark and Ferrauti, Alexander}, title = {Heart Rate Variability Monitoring During Strength and High-Intensity Interval Training Overload Microcycles}, series = {Frontiers in Physiology}, volume = {10}, journal = {Frontiers in Physiology}, doi = {10.3389/fphys.2019.00582}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231515}, year = {2019}, abstract = {Objective: In two independent study arms, we determine the effects of strength training (ST) and high-intensity interval training (HIIT) overload on cardiac autonomic modulation by measuring heart rate (HR) and vagal heart rate variability (HRV). Methods: In the study, 37 well-trained athletes (ST: 7 female, 12 male; HIIT: 9 female, 9 male) were subjected to orthostatic tests (HR and HRV recordings) each day during a 4-day baseline period, a 6-day overload microcycle, and a 4-day recovery period. Discipline-specific performance was assessed before and 1 and 4 days after training. Results: Following ST overload, supine HR, and vagal HRV (Ln RMSSD) were clearly increased and decreased (small effects), respectively, and the standing recordings remained unchanged. In contrast, HIIT overload resulted in decreased HR and increased Ln RMSSD in the standing position (small effects), whereas supine recordings remained unaltered. During the recovery period, these responses were reversed (ST: small effects, HIIT: trivial to small effects). The correlations between changes in HR, vagal HRV measures, and performance were weak or inconsistent. At the group and individual levels, moderate to strong negative correlations were found between HR and Ln RMSSD when analyzing changes between testing days (ST: supine and standing position, HIIT: standing position) and individual time series, respectively. Use of rolling 2-4-day averages enabled more precise estimation of mean changes with smaller confidence intervals compared to single-day values of HR or Ln RMSSD. However, the use of averaged values displayed unclear effects for evaluating associations between HR, vagal HRV measures, and performance changes, and have the potential to be detrimental for classification of individual short-term responses. Conclusion: Measures of HR and Ln RMSSD during an orthostatic test could reveal different autonomic responses following ST or HIIT which may not be discovered by supine or standing measures alone. However, these autonomic changes were not consistently related to short-term changes in performance and the use of rolling averages may alter these relationships differently on group and individual level.}, language = {en} } @article{KervarrecSamimiGuyetantetal.2019, author = {Kervarrec, Thibault and Samimi, Mahtab and Guy{\´e}tant, Serge and Sarma, Bhavishya and Ch{\´e}ret, J{\´e}r{\´e}my and Blanchard, Emmanuelle and Berthon, Patricia and Schrama, David and Houben, Roland and Touz{\´e}, Antoine}, title = {Histogenesis of Merkel Cell Carcinoma: A Comprehensive Review}, series = {Frontiers in Oncology}, volume = {9}, journal = {Frontiers in Oncology}, doi = {10.3389/fonc.2019.00451}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325733}, year = {2019}, abstract = {Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin. This neoplasia features aggressive behavior, resulting in a 5-year overall survival rate of 40\%. In 2008, Feng et al. identified Merkel cell polyomavirus (MCPyV) integration into the host genome as the main event leading to MCC oncogenesis. However, despite identification of this crucial viral oncogenic trigger, the nature of the cell in which MCC oncogenesis occurs is actually unknown. In fact, several hypotheses have been proposed. Despite the large similarity in phenotype features between MCC tumor cells and physiological Merkel cells (MCs), a specialized subpopulation of the epidermis acting as mechanoreceptor of the skin, several points argue against the hypothesis that MCC derives directly from MCs. Alternatively, MCPyV integration could occur in another cell type and induce acquisition of an MC-like phenotype. Accordingly, an epithelial as well as a fibroblastic or B-cell origin of MCC has been proposed mainly based on phenotype similarities shared by MCC and these potential ancestries. The aim of this present review is to provide a comprehensive review of the current knowledge of the histogenesis of MCC.}, language = {en} } @article{NagyvanGeffenStegneretal.2019, author = {Nagy, Magdolna and van Geffen, Johanna P. and Stegner, David and Adams, David J. and Braun, Attila and de Witt, Susanne M. and Elvers, Margitta and Geer, Mitchell J. and Kuijpers, Marijke J. E. and Kunzelmann, Karl and Mori, Jun and Oury, C{\´e}cile and Pircher, Joachim and Pleines, Irina and Poole, Alastair W. and Senis, Yotis A. and Verdoold, Remco and Weber, Christian and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Baaten, Constance C. F. M. J.}, title = {Comparative Analysis of Microfluidics Thrombus Formation in Multiple Genetically Modified Mice: Link to Thrombosis and Hemostasis}, series = {Frontiers in Cardiovascular Medicine}, volume = {6}, journal = {Frontiers in Cardiovascular Medicine}, doi = {10.3389/fcvm.2019.00099}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232194}, year = {2019}, abstract = {Genetically modified mice are indispensable for establishing the roles of platelets in arterial thrombosis and hemostasis. Microfluidics assays using anticoagulated whole blood are commonly used as integrative proxy tests for platelet function in mice. In the present study, we quantified the changes in collagen-dependent thrombus formation for 38 different strains of (genetically) modified mice, all measured with the same microfluidics chamber. The mice included were deficient in platelet receptors, protein kinases or phosphatases, small GTPases or other signaling or scaffold proteins. By standardized re-analysis of high-resolution microscopic images, detailed information was obtained on altered platelet adhesion, aggregation and/or activation. For a subset of 11 mouse strains, these platelet functions were further evaluated in rhodocytin- and laminin-dependent thrombus formation, thus allowing a comparison of glycoprotein VI (GPVI), C-type lectin-like receptor 2 (CLEC2) and integrin α6β1 pathways. High homogeneity was found between wild-type mice datasets concerning adhesion and aggregation parameters. Quantitative comparison for the 38 modified mouse strains resulted in a matrix visualizing the impact of the respective (genetic) deficiency on thrombus formation with detailed insight into the type and extent of altered thrombus signatures. Network analysis revealed strong clusters of genes involved in GPVI signaling and Ca2+ homeostasis. The majority of mice demonstrating an antithrombotic phenotype in vivo displayed with a larger or smaller reduction in multi-parameter analysis of collagen-dependent thrombus formation in vitro. Remarkably, in only approximately half of the mouse strains that displayed reduced arterial thrombosis in vivo, this was accompanied by impaired hemostasis. This was also reflected by comparing in vitro thrombus formation (by microfluidics) with alterations in in vivo bleeding time. In conclusion, the presently developed multi-parameter analysis of thrombus formation using microfluidics can be used to: (i) determine the severity of platelet abnormalities; (ii) distinguish between altered platelet adhesion, aggregation and activation; and (iii) elucidate both collagen and non-collagen dependent alterations of thrombus formation. This approach may thereby aid in the better understanding and better assessment of genetic variation that affect in vivo arterial thrombosis and hemostasis.}, language = {en} } @article{HauerPoppTaheretal.2019, author = {Hauer, Nadine N. and Popp, Bernt and Taher, Leila and Vogl, Carina and Dhandapany, Perundurai S. and B{\"u}ttner, Christian and Uebe, Steffen and Sticht, Heinrich and Ferrazzi, Fulvia and Ekici, Arif B. and De Luca, Alessandro and Klinger, Patrizia and Kraus, Cornelia and Zweier, Christiane and Wiesener, Antje and Abou Jamra, Rami and Kunstmann, Erdmute and Rauch, Anita and Wieczorek, Dagmar and Jung, Anna-Marie and Rohrer, Tilman R. and Zenker, Martin and Doerr, Helmuth-Guenther and Reis, Andr{\´e} and Thiel, Christian T.}, title = {Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature}, series = {European Journal of Human Genetics}, volume = {27}, journal = {European Journal of Human Genetics}, doi = {10.1038/s41431-019-0362-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227899}, pages = {1061-1071}, year = {2019}, abstract = {Height is a heritable and highly heterogeneous trait. Short stature affects 3\% of the population and in most cases is genetic in origin. After excluding known causes, 67\% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36\%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.}, language = {en} } @article{GotruvanGeffenNagyetal.2019, author = {Gotru, Sanjeev Kiran and van Geffen, Johanna P. and Nagy, Magdolna and Mammadova-Bach, Elmina and Eilenberger, Julia and Volz, Julia and Manukjan, Georgi and Schulze, Harald and Wagner, Leonard and Eber, Stefan and Schambeck, Christian and Deppermann, Carsten and Brouns, Sanne and Nurden, Paquita and Greinacher, Andreas and Sachs, Ulrich and Nieswandt, Bernhard and Hermanns, Heike M. and Heemskerk, Johan W. M. and Braun, Attila}, title = {Defective Zn2+ homeostasis in mouse and human platelets with α- and δ-storage pool diseases}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-44751-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227455}, year = {2019}, abstract = {Zinc (Zn2+) can modulate platelet and coagulation activation pathways, including fibrin formation. Here, we studied the (patho)physiological consequences of abnormal platelet Zn2+ storage and release. To visualize Zn2+ storage in human and mouse platelets, the Zn2+ specific fluorescent dye FluoZin3 was used. In resting platelets, the dye transiently accumulated into distinct cytosolic puncta, which were lost upon platelet activation. Platelets isolated from Unc13d-/- mice, characterized by combined defects of α/δ granular release, showed a markedly impaired Zn2+ release upon activation. Platelets from Nbeal2-/- mice mimicking Gray platelet syndrome (GPS), characterized by primarily loss of the α-granule content, had strongly reduced Zn2+ levels, which was also confirmed in primary megakaryocytes. In human platelets isolated from patients with GPS, Hermansky-Pudlak Syndrome (HPS) and Storage Pool Disease (SPD) altered Zn2+ homeostasis was detected. In turbidity and flow based assays, platelet-dependent fibrin formation was impaired in both Nbeal2-/- and Unc13d-/- mice, and the impairment could be partially restored by extracellular Zn2+. Altogether, we conclude that the release of ionic Zn2+ store from secretory granules upon platelet activation contributes to the procoagulant role of Zn2+ in platelet-dependent fibrin formation.}, language = {en} } @article{Gohla2019, author = {Gohla, Antje}, title = {Do metabolic HAD phosphatases moonlight as protein phosphatases?}, series = {BBA - Molecular Cell Research}, volume = {1866}, journal = {BBA - Molecular Cell Research}, doi = {10.1016/j.bbamcr.2018.07.007}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233168}, pages = {153-166}, year = {2019}, abstract = {Mammalian haloacid dehalogenase (HAD)-type phosphatases have evolved to dephosphorylate a wide range of small metabolites, but can also target macromolecules such as serine/threonine, tyrosine-, and histidine-phosphorylated proteins. To accomplish these tasks, HAD phosphatases are equipped with cap domains that control access to the active site and provide substrate specificity determinants. A number of capped HAD phosphatases impact protein phosphorylation, although structural data are consistent with small metabolite substrates rather than protein substrates. This review discusses the structures, functions and disease implications of the three closely related, capped HAD phosphatases pyridoxal phosphatase (PDXP or chronophin), phosphoglycolate phosphatase (PGP, also termed AUM or glycerol phosphatase) and phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP or HDHD2B). Evidence in support of small metabolite and protein phosphatase activity is discussed in the context of the diversity of their biological functions.}, language = {en} } @article{CasarottoTurcoComanduccietal.2019, author = {Casarotto, Silvia and Turco, Francesco and Comanducci, Angela and Perretti, Alessio and Marotta, Giorgio and Pezzoli, Gianni and Rosanova, Mario and Isaias, Ioannis U.}, title = {Excitability of the supplementary motor area in Parkinson's disease depends on subcortical damage}, series = {Brain Stimulation}, volume = {12}, journal = {Brain Stimulation}, doi = {10.1016/j.brs.2018.10.011}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222261}, pages = {152-160}, year = {2019}, abstract = {Background Cortical dysfunctioning significantly contributes to the pathogenesis of motor symptoms in Parkinson's disease (PD). Objective We aimed at testing whether an acute levodopa administration has measurable and specific cortical effects possibly related to striatal dopaminergic deficit. Methods In thirteen PD patients, we measured the electroencephalographic responses to transcranial magnetic stimulation (TMS/EEG) of the supplementary motor area and superior parietal lobule (n = 8) before and after an acute intake of levodopa. We also performed a single-photon emission computed tomography and [123I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane to identify the more affected and the less affected brain side in each patient, according to the dopaminergic innervation loss of the putamen. Cortical excitability changes before and after an acute intake of levodopa were computed and compared between the more and the less affected brain side at the single-patient as well as at the group level. Results We found that levodopa intake induces a significant increase (P < 0.01) of cortical excitability nearby the supplementary motor area in the more affected brain side, greater (P < 0.025) than in the less affected brain side. Notably, cortical excitability changes nearby the superior parietal lobule were not statistically significant. Conclusions These results strengthen the idea that dysfunction of specific cortico-subcortical circuits may contribute to pathophysiology of PD symptoms. Most important, they support the use of navigated TMS/EEG as a non-invasive tool to better understand the pathophysiology of PD.}, language = {en} } @article{EisenhoferPeitzschKadenetal.2019, author = {Eisenhofer, Graeme and Peitzsch, Mirko and Kaden, Denise and Langton, Katharina and Mangelis, Anastasios and Pamporaki, Christina and Masjkur, Jimmy and Geroula, Aikaterini and Kurlbaum, Max and Deutschbein, Timo and Beuschlein, Felix and Prejbisz, Aleksander and Bornstein, Stefan R. and Lenders, Jacques W. M.}, title = {Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine}, series = {Clinica Chimica Acta}, volume = {490}, journal = {Clinica Chimica Acta}, doi = {10.1016/j.cca.2018.12.019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226598}, pages = {46-54}, year = {2019}, abstract = {Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites.}, language = {en} } @article{LieseSchoenvanderLindenetal.2019, author = {Liese, J. G. and Schoen, C. and van der Linden, M. and Lehmann, L. and Goettler, D. and Keller, S. and Maier, A. and Segerer, F. and Rose, M. A. and Streng, A.}, title = {Changes in the incidence and bacterial aetiology of paediatric parapneumonic pleural effusions/empyema in Germany, 2010-2017: a nationwide surveillance study}, series = {Clinical Microbiology and Infection}, volume = {25}, journal = {Clinical Microbiology and Infection}, doi = {10.1016/j.cmi.2018.10.020}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236866}, pages = {857-864}, year = {2019}, abstract = {Objectives Parapneumonic pleural effusions/empyema (PPE/PE) are severe complications of community-acquired pneumonia. We investigated the bacterial aetiology and incidence of paediatric PPE/PE in Germany after the introduction of universal pneumococcal conjugate vaccine (PCV) immunization for infants. Methods Children <18 years of age hospitalized with pneumonia-associated PPE/PE necessitating pleural drainage or persisting >7 days were reported to the German Surveillance Unit for Rare Diseases in Childhood between October 2010 and June 2017. All bacteria detected in blood or pleural fluid (by culture/PCR) were included, with serotyping for Streptococcus pneumoniae. Results The median age of all 1447 PPE/PE patients was 5 years (interquartile range 3-10). In 488 of the 1447 children with PPE/PE (34\%), 541 bacteria (>40 species) were detected. Aerobic gram-positive cocci accounted for 469 of 541 bacteria detected (87\%); these were most frequently Streptococcus pneumoniae (41\%), Streptococcus pyogenes (19\%) and Staphylococcus aureus (6\%). Serotype 3 accounted for 45\% of 78 serotyped S. pneumoniae strains. Annual PPE/PE incidence varied between 14 (95\%CI 12-16) and 18 (95\%CI 16-21) PPE/PE per million children. Incidence of S. pneumoniae PPE/PE decreased from 3.5 (95\%CI 2.5-4.6) per million children in 2010/11 to 1.5 (95\%CI 0.9-2.4) in 2013/14 (p 0.002), followed by a re-increase to 2.2 (95\%CI 1.5-3.2) by 2016/17 (p 0.205). Conclusions In the era of widespread PCV immunization, cases of paediatric PPE/PE were still caused mainly by S. pneumoniae and, increasingly, by S. pyogenes. The re-increase in the incidence of PPE/PE overall and in S. pneumoniae-associated PPE/PE indicates ongoing changes in the bacterial aetiology and requires further surveillance.}, language = {en} } @article{SteinKantarjianGoekbugetetal.2019, author = {Stein, Anthony S. and Kantarjian, Hagop and G{\"o}kbuget, Nicola and Bargou, Ralf and Litzow, Mark R. and Rambaldi, Alessandro and Ribera, Josep-Maria and Zhang, Alicia and Zimmerman, Zachary and Zugmaier, Gerhard and Topp, Max S.}, title = {Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation}, series = {Biology of Blood and Marrow Transplantation}, volume = {25}, journal = {Biology of Blood and Marrow Transplantation}, doi = {10.1016/j.bbmt.2019.04.010}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239510}, pages = {1498-1504}, year = {2019}, abstract = {Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43\% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36\% at 1 year and 18\% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31\%) and 28 patients (44\%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.}, language = {en} } @article{TesfamariamJakobWoeckeletal.2019, author = {Tesfamariam, Y. and Jakob, T. and W{\"o}ckel, A. and Adams, A. and Weigl, A. and Monsef, I. and Kuhr, K. and Skoetz, N.}, title = {Adjuvant bisphosphonates or RANK-ligand inhibitors for patients with breast cancer and bone metastases: A systematic review and network meta-analysis}, series = {Critical Reviews in Oncology / Hematology}, volume = {137}, journal = {Critical Reviews in Oncology / Hematology}, doi = {10.1016/j.critrevonc.2019.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-240827}, pages = {1-8}, year = {2019}, abstract = {Bone-modifying agents like bisphosphonates and receptor activator of nuclear factor kappaβ ligand (RANK-L) inhibitors are used as supportive treatments in breast cancer patients with bone metastases to prevent skeletal-related events (SREs). Due to missing head-to-head comparisons, a network meta-analysis was performed to provide a hierarchy of these therapeutic options. Through a systematic literature search, 21 randomized controlled trials (RCTs) that fulfilled the inclusion criteria were identified. To prevent SREs, the ranking through P-scores showed denosumab (RR: 0.62; 95\%CI: 0.50-0.76), zoledronic acid (RR: 0.72; 95\%CI: 0.61-0.84) and pamidronate (RR: 0.76; 95\%CI: 0.67-0.85) to be significantly superior to placebo. Due to insufficient or heterogeneous data, overall survival, quality of life, pain response and adverse events were not able to be analyzed within the network. Although data were sparse on adverse events, the risk of significant adverse events appeared low. The results of this review can therefore be used to formulate clinical studies more precisely in order to standardise and focus on patient-relevant outcomes.}, language = {en} } @article{BrinkerHeklerHauschildetal.2019, author = {Brinker, Titus J. and Hekler, Achim and Hauschild, Axel and Berking, Carola and Schilling, Bastian and Enk, Alexander H. and Haferkamp, Sebastian and Karoglan, Ante and von Kalle, Christof and Weichenthal, Michael and Sattler, Elke and Schadendorf, Dirk and Gaiser, Maria R. and Klode, Joachim and Utikal, Jochen S.}, title = {Comparing artificial intelligence algorithms to 157 German dermatologists: the melanoma classification benchmark}, series = {European Journal of Cancer}, volume = {111}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2018.12.016}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220569}, pages = {30-37}, year = {2019}, abstract = {Background Several recent publications have demonstrated the use of convolutional neural networks to classify images of melanoma at par with board-certified dermatologists. However, the non-availability of a public human benchmark restricts the comparability of the performance of these algorithms and thereby the technical progress in this field. Methods An electronic questionnaire was sent to dermatologists at 12 German university hospitals. Each questionnaire comprised 100 dermoscopic and 100 clinical images (80 nevi images and 20 biopsy-verified melanoma images, each), all open-source. The questionnaire recorded factors such as the years of experience in dermatology, performed skin checks, age, sex and the rank within the university hospital or the status as resident physician. For each image, the dermatologists were asked to provide a management decision (treat/biopsy lesion or reassure the patient). Main outcome measures were sensitivity, specificity and the receiver operating characteristics (ROC). Results Total 157 dermatologists assessed all 100 dermoscopic images with an overall sensitivity of 74.1\%, specificity of 60.0\% and an ROC of 0.67 (range = 0.538-0.769); 145 dermatologists assessed all 100 clinical images with an overall sensitivity of 89.4\%, specificity of 64.4\% and an ROC of 0.769 (range = 0.613-0.9). Results between test-sets were significantly different (P < 0.05) confirming the need for a standardised benchmark. Conclusions We present the first public melanoma classification benchmark for both non-dermoscopic and dermoscopic images for comparing artificial intelligence algorithms with diagnostic performance of 145 or 157 dermatologists. Melanoma Classification Benchmark should be considered as a reference standard for white-skinned Western populations in the field of binary algorithmic melanoma classification.}, language = {en} } @article{BrinkerHeklerEnketal.2019, author = {Brinker, Titus J. and Hekler, Achim and Enk, Alexander H. and Berking, Carola and Haferkamp, Sebastian and Hauschild, Axel and Weichenthal, Michael and Klode, Joachim and Schadendorf, Dirk and Holland-Letz, Tim and von Kalle, Christof and Fr{\"o}hling, Stefan and Schilling, Bastian and Utikal, Jochen S.}, title = {Deep neural networks are superior to dermatologists in melanoma image classification}, series = {European Journal of Cancer}, volume = {119}, journal = {European Journal of Cancer}, doi = {10.1016/j.ejca.2019.05.023}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220539}, pages = {11-17}, year = {2019}, abstract = {Background Melanoma is the most dangerous type of skin cancer but is curable if detected early. Recent publications demonstrated that artificial intelligence is capable in classifying images of benign nevi and melanoma with dermatologist-level precision. However, a statistically significant improvement compared with dermatologist classification has not been reported to date. Methods For this comparative study, 4204 biopsy-proven images of melanoma and nevi (1:1) were used for the training of a convolutional neural network (CNN). New techniques of deep learning were integrated. For the experiment, an additional 804 biopsy-proven dermoscopic images of melanoma and nevi (1:1) were randomly presented to dermatologists of nine German university hospitals, who evaluated the quality of each image and stated their recommended treatment (19,296 recommendations in total). Three McNemar's tests comparing the results of the CNN's test runs in terms of sensitivity, specificity and overall correctness were predefined as the main outcomes. Findings The respective sensitivity and specificity of lesion classification by the dermatologists were 67.2\% (95\% confidence interval [CI]: 62.6\%-71.7\%) and 62.2\% (95\% CI: 57.6\%-66.9\%). In comparison, the trained CNN achieved a higher sensitivity of 82.3\% (95\% CI: 78.3\%-85.7\%) and a higher specificity of 77.9\% (95\% CI: 73.8\%-81.8\%). The three McNemar's tests in 2 × 2 tables all reached a significance level of p < 0.001. This significance level was sustained for both subgroups. Interpretation For the first time, automated dermoscopic melanoma image classification was shown to be significantly superior to both junior and board-certified dermatologists (p < 0.001).}, language = {en} } @article{JeanclosAlbersenRamosetal.2019, author = {Jeanclos, Elisabeth and Albersen, Monique and Ramos, R{\´u}ben J. J. and Raab, Annette and Wilhelm, Christian and Hommers, Leif and Lesch, Klaus-Peter and Verhoeven-Duif, Nanda M. and Gohla, Antje}, title = {Improved cognition, mild anxiety-like behavior and decreased motor performance in pyridoxal phosphatase-deficient mice}, series = {BBA - Molecular Basis of Disease}, volume = {1865}, journal = {BBA - Molecular Basis of Disease}, doi = {10.1016/j.bbadis.2018.08.018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323396}, pages = {193-205}, year = {2019}, abstract = {Pyridoxal 5′-phosphate (PLP) is an essential cofactor in the catalysis of ~140 different enzymatic reactions. A pharmacological elevation of cellular PLP concentrations is of interest in neuropsychiatric diseases, but whole-body consequences of higher intracellular PLP levels are unknown. To address this question, we have generated mice allowing a conditional ablation of the PLP phosphatase PDXP. Ubiquitous PDXP deletion increased PLP levels in brain, skeletal muscle and red blood cells up to 3-fold compared to control mice, demonstrating that PDXP acts as a major regulator of cellular PLP concentrations in vivo. Neurotransmitter analysis revealed that the concentrations of dopamine, serotonin, epinephrine and glutamate were unchanged in the brains of PDXP knockout mice. However, the levels of γ-aminobutyric acid (GABA) increased by ~20\%, demonstrating that elevated PLP levels can drive additional GABA production. Behavioral phenotyping of PDXP knockout mice revealed improved spatial learning and memory, and a mild anxiety-like behavior. Consistent with elevated GABA levels in the brain, PDXP loss in neural cells decreased performance in motor tests, whereas PDXP-deficiency in skeletal muscle increased grip strength. Our findings suggest that PDXP is involved in the fine-tuning of GABA biosynthesis. Pharmacological inhibition of PDXP might correct the excitatory/inhibitory imbalance in some neuropsychiatric diseases.}, language = {en} } @article{KreinbergPorteSchickeetal.2019, author = {Kreinberg, S{\"o}ren and Porte, Xavier and Schicke, David and Lingnau, Benjamin and Schneider, Christian and H{\"o}fling, Sven and Kanter, Ido and L{\"u}dge, Kathy and Reitzenstein, Stephan}, title = {Mutual coupling and synchronization of optically coupled quantum-dot micropillar lasers at ultra-low light levels}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-09559-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229811}, year = {2019}, abstract = {Synchronization of coupled oscillators at the transition between classical physics and quantum physics has become an emerging research topic at the crossroads of nonlinear dynamics and nanophotonics. We study this unexplored field by using quantum dot microlasers as optical oscillators. Operating in the regime of cavity quantum electrodynamics (cQED) with an intracavity photon number on the order of 10 and output powers in the 100 nW range, these devices have high β-factors associated with enhanced spontaneous emission noise. We identify synchronization of mutually coupled microlasers via frequency locking associated with a sub-gigahertz locking range. A theoretical analysis of the coupling behavior reveals striking differences from optical synchronization in the classical domain with negligible spontaneous emission noise. Beyond that, additional self-feedback leads to zero-lag synchronization of coupled microlasers at ultra-low light levels. Our work has high potential to pave the way for future experiments in the quantum regime of synchronization.}, language = {en} } @article{KremerBiesenthalMaczewskyetal.2019, author = {Kremer, Mark and Biesenthal, Tobias and Maczewsky, Lukas J. and Heinrich, Matthias and Thomale, Ronny and Szameit, Alexander}, title = {Demonstration of a two-dimensional PT-symmetric crystal}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-018-08104-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230132}, year = {2019}, abstract = {With the discovery of PT-symmetric quantum mechanics, it was shown that even non-Hermitian systems may exhibit entirely real eigenvalue spectra. This finding did not only change the perception of quantum mechanics itself, it also significantly influenced the field of photonics. By appropriately designing one-dimensional distributions of gain and loss, it was possible to experimentally verify some of the hallmark features of PT-symmetry using electromagnetic waves. Nevertheless, an experimental platform to study the impact of PT-symmetry in two spatial dimensions has so far remained elusive. We break new grounds by devising a two-dimensional PT-symmetric system based on photonic waveguide lattices with judiciously designed refractive index landscape and alternating loss. With this system at hand, we demonstrate a non-Hermitian two-dimensional topological phase transition that is closely linked to the emergence of topological mid-gap edge states.}, language = {en} } @article{NerreterLetschertGoetzetal.2019, author = {Nerreter, Thomas and Letschert, Sebastian and G{\"o}tz, Ralph and Doose, S{\"o}ren and Danhof, Sophia and Einsele, Hermann and Sauer, Markus and Hudecek, Michael}, title = {Super-resolution microscopy reveals ultra-low CD19 expression on myeloma cells that triggers elimination by CD19 CAR-T}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10948-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232258}, year = {2019}, abstract = {Immunotherapy with chimeric antigen receptor-engineered T-cells (CAR-T) is under investigation in multiple myeloma. There are reports of myeloma remission after CD19 CAR-T therapy, although CD19 is hardly detectable on myeloma cells by flow cytometry (FC). We apply single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM), and demonstrate CD19 expression on a fraction of myeloma cells (10.3-80\%) in 10 out of 14 patients (density: 13-5,000 molecules per cell). In contrast, FC detects CD19 in only 2 of these 10 patients, on a smaller fraction of cells. Treatment with CD19 CAR-T in vitro results in elimination of CD19-positive myeloma cells, including those with <100 CD19 molecules per cell. Similar data are obtained by dSTORM analyses of CD20 expression on myeloma cells and CD20 CAR-T. These data establish a sensitivity threshold for CAR-T and illustrate how super-resolution microscopy can guide patient selection in immunotherapy to exploit ultra-low density antigens.}, language = {en} } @article{MusselHewig2019, author = {Mussel, Patrick and Hewig, Johannes}, title = {A neural perspective on when and why trait greed comes at the expense of others}, series = {Scientific Reports}, volume = {9}, journal = {Scientific Reports}, doi = {10.1038/s41598-019-47372-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231652}, year = {2019}, abstract = {Depending on the point of view, conceptions of greed range from being a desirable and inevitable feature of a well-regulated, well-balanced economy to the root of all evil - radix omnium malorum avaritia (Tim 6.10). Regarding the latter, it has been proposed that greedy individuals strive for obtaining desired goods at all costs. Here, we show that trait greed predicts selfish economic decisions that come at the expense of others in a resource dilemma. This effect was amplified when individuals strived for obtaining real money, as compared to points, and when their revenue was at the expense of another person, as compared to a computer. On the neural level, we show that individuals high, compared to low in trait greed showed a characteristic signature in the EEG, a reduced P3 effect to positive, compared to negative feedback, indicating that they may have a lack of sensitivity to adjust behavior according to positive and negative stimuli from the environment. Brain-behavior relations further confirmed this lack of sensitivity to behavior adjustment as a potential underlying neuro-cognitive mechanism which explains selfish and reckless behavior that may come at the expense of others.}, language = {en} } @article{SchmittMorasBihlmayeretal.2019, author = {Schmitt, Martin and Moras, Paolo and Bihlmayer, Gustav and Cotsakis, Ryan and Vogt, Matthias and Kemmer, Jeannette and Belabbes, Abderrezak and Sheverdyaeva, Polina M. and Kundu, Asish K. and Carbone, Carlo and Bl{\"u}gel, Stefan and Bode, Matthias}, title = {Indirect chiral magnetic exchange through Dzyaloshinskii-Moriya-enhanced RKKY interactions in manganese oxide chains on Ir(100)}, series = {Nature Communications}, volume = {10}, journal = {Nature Communications}, doi = {10.1038/s41467-019-10515-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230986}, year = {2019}, abstract = {Localized electron spins can couple magnetically via the Ruderman-Kittel-Kasuya-Yosida interaction even if their wave functions lack direct overlap. Theory predicts that spin-orbit scattering leads to a Dzyaloshinskii-Moriya type enhancement of this indirect exchange interaction, giving rise to chiral exchange terms. Here we present a combined spin-polarized scanning tunneling microscopy, angle-resolved photoemission, and density functional theory study of MnO2 chains on Ir(100). Whereas we find antiferromagnetic Mn-Mn coupling along the chain, the inter-chain coupling across the non-magnetic Ir substrate turns out to be chiral with a 120° rotation between adjacent MnO2 chains. Calculations reveal that the Dzyaloshinskii-Moriya interaction results in spin spirals with a periodicity in agreement with experiment. Our findings confirm the existence of indirect chiral magnetic exchange, potentially giving rise to exotic phenomena, such as chiral spin-liquid states in spin ice systems or the emergence of new quasiparticles.}, language = {en} }