TY - JOUR A1 - Hrudka, Jan A1 - Eis, Václav A1 - Heřman, Josef A1 - Prouzová, Zuzana A1 - Rosenwald, Andreas A1 - František, Duška T1 - Panniculitis-like T-cell-lymphoma in the mesentery associated with hemophagocytic syndrome: autopsy case report JF - Diagnostic Pathology N2 - Background Panniculitis-like T-cell lymphoma is an uncommon type of non-Hodgkin lymphoma, occurring usually in the form of nodules within the subcutaneous fat tissue of the extremities or trunk. In the literature, subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is described as a distinct type of T-cell lymphoma with a variable clinical behavior, depending on molecular phenotype of T-cell receptor (TCR) and on the presence or absence of hemophagocytic syndrome. Case presentation We present a bioptic and autoptic case of a 65-years old Caucasian man with panniculitic T-cell lymphoma with morphological and immunohistochemical features of SPTCL, limited to the retroperitoneal and mesenteric mass, i.e. without any cutaneous involvement, and associated with severe hemophagocytic lymphohistiocytosis. Conclusion A panniculitic T-cell lymphoma with morphological and molecular features of SPTCL, which is limited to mesentery, i.e. does not involve subcutaneous fat, seems to be exceedingly rare. KW - panniculitis KW - T-cell lymphoma KW - mesentery KW - hemophagocytosis KW - lymphohistiocytosis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-322665 VL - 14 ER - TY - JOUR A1 - Nentwich, Julia A1 - Ruf, Katharina A1 - Girschick, Hermann A1 - Holl-Wieden, Annette A1 - Morbach, Henner A1 - Hebestreit, Helge A1 - Hofmann, Christine T1 - Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis JF - Pediatric Rheumatology N2 - Background Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC). Methods 15 patients with CNO and 15 age and gender matched HC aged 13–18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior. Results At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL. Conclusion Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity. KW - chronic non-bacterial osteomyelitis KW - CRMO KW - HRQOL KW - physical activity Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323710 VL - 17 ER - TY - JOUR A1 - Hörterer, Hubert A1 - Baumbach, Sebastian Felix A1 - Lemperle, Stefan A1 - Altenberger, Sebastian A1 - Gottschalk, Oliver A1 - Mehlhorn, Alexander Tobias A1 - Röser, Anke A1 - Walther, Markus T1 - Clinical outcome and concomitant injuries in operatively treated fractures of the lateral process of the talus JF - BMC Musculoskeletal Disorders N2 - Background The aim of this study was to review the patient rated outcome (PROM) of surgically treated fractures to the lateral process of the talus (LPTF) and identify factors influencing the outcome. Methods Retrospective study with a current follow-up. Eligible were all patients treated surgically for a LPTF (n = 23) with a minimum follow-up of one year. Demographics, medical history, trauma mechanism, fracture characteristics, concomitant injuries, treatment details, complications, return to work and sports were assessed retrospectively. The current follow-up included the VAS FA, Karlsson Score, and SF-12. The primary outcome was the VAS FA. Secondary aim was the identification of parameters influencing the PROMs. Results 22 patients (96% follow-up) with a mean age of 32 ± 9 (18 to 49) years were included. 73% suffered a Hawkins Type 1, 23% a Type 2, and one patient a Type 3 fracture. 82% suffered concomitant injuries. 9% suffered minor surgical side infections, 50% developed symptomatic subtalar osteoarthritis. At final follow-up (44 ± 2 (12 to 97) months), the mean VAS FA Overall was 77 ± 21 (20 to 100), the Karlsson Score 72 ± 21 (34 to 97), and for the SF 12 the PCS 53 ± 8 (36 to 64) and the MCS 53 ± 7 (32 to 63). 50% of patients returned to their previous level of sports. Hawkins Type 1 fractures resulted in better VAS FA Overall score than Type 2 fractures. Posttraumatic subtalar osteoarthritis was the independent factor associated to a poor patient rated outcome (VAS FA, Karlsson Score). Conclusion After a follow-up of over 3.5 years, surgically treated LPTF resulted in only moderate results. 50% suffered posttraumatic symptomatic subtalar osteoarthritis, which was the primary independent parameter for a poor outcome following LPTF. Level of evidence Level III. KW - fracture KW - snowboarder's ankle KW - snowboarder's fracture KW - lateral process of the talus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321207 VL - 20 ER - TY - JOUR A1 - Kiener, Mirjam A1 - Chen, Lanpeng A1 - Krebs, Markus A1 - Grosjean, Joȅl A1 - Klima, Irena A1 - Kalogirou, Charis A1 - Riedmiller, Hubertus A1 - Kneitz, Burkhard A1 - Thalmann, George N. A1 - Snaar-Jagalska, Ewa A1 - Spahn, Martin A1 - Kruithof-de Julio, Marianna A1 - Zoni, Eugenio T1 - miR-221-5p regulates proliferation and migration in human prostate cancer cells and reduces tumor growth in vivo JF - BMC Cancer N2 - Background Despite latest advances in prostate cancer (PCa) therapy, PCa remains the third-leading cause of cancer-related death in European men. Dysregulation of microRNAs (miRNAs), small non-coding RNA molecules with gene expression regulatory function, has been reported in all types of epithelial and haematological cancers. In particular, miR-221-5p alterations have been reported in PCa. Methods miRNA expression data was retrieved from a comprehensive publicly available dataset of 218 PCa patients (GSE21036) and miR-221-5p expression levels were analysed. The functional role of miR-221-5p was characterised in androgen- dependent and androgen- independent PCa cell line models (C4–2 and PC-3M-Pro4 cells) by miR-221-5p overexpression and knock-down experiments. The metastatic potential of highly aggressive PC-3M-Pro4 cells overexpressing miR-221-5p was determined by studying extravasation in a zebrafish model. Finally, the effect of miR-221-5p overexpression on the growth of PC-3M-Pro4luc2 cells in vivo was studied by orthotopic implantation in male Balb/cByJ nude mice and assessment of tumor growth. Results Analysis of microRNA expression dataset for human primary and metastatic PCa samples and control normal adjacent benign prostate revealed miR-221-5p to be significantly downregulated in PCa compared to normal prostate tissue and in metastasis compared to primary PCa. Our in vitro data suggest that miR-221-5p overexpression reduced PCa cell proliferation and colony formation. Furthermore, miR-221-5p overexpression dramatically reduced migration of PCa cells, which was associated with differential expression of selected EMT markers. The functional changes of miR-221-5p overexpression were reversible by the loss of miR-221-5p levels, indicating that the tumor suppressive effects were specific to miR-221-5p. Additionally, miR-221-5p overexpression significantly reduced PC-3M-Pro4 cell extravasation and metastasis formation in a zebrafish model and decreased tumor burden in an orthotopic mouse model of PCa. Conclusions Together these data strongly support a tumor suppressive role of miR-221-5p in the context of PCa and its potential as therapeutic target. KW - prostate cancer KW - miR-221-5p KW - proliferation KW - migration KW - tumor suppressor miRNA Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325762 VL - 19 ER - TY - JOUR A1 - Klement, Rainer J. A1 - Abbasi-Senger, N. A1 - Adebahr, S. A1 - Alheid, H. A1 - Allgaeuer, M. A1 - Becker, G. A1 - Blanck, O. A1 - Boda-Heggemann, J. A1 - Brunner, T. A1 - Duma, M. A1 - Eble, M. J. A1 - Ernst, I. A1 - Gerum, S. A1 - Habermehl, D. A1 - Hass, P. A1 - Henkenberens, C. A1 - Hildebrandt, G. A1 - Imhoff, D. A1 - Kahl, H. A1 - Klass, N. D. A1 - Krempien, R. A1 - Lewitzki, V. A1 - Lohaus, F. A1 - Ostheimer, C. A1 - Papachristofilou, A. A1 - Petersen, C. A1 - Rieber, J. A1 - Schneider, T. A1 - Schrade, E. A1 - Semrau, R. A1 - Wachter, S. A1 - Wittig, A. A1 - Guckenberger, M. A1 - Andratschke, N. T1 - The impact of local control on overall survival after stereotactic body radiotherapy for liver and lung metastases from colorectal cancer: a combined analysis of 388 patients with 500 metastases JF - BMC Cancer N2 - Background The aim of this analysis was to model the effect of local control (LC) on overall survival (OS) in patients treated with stereotactic body radiotherapy (SBRT) for liver or lung metastases from colorectal cancer. Methods The analysis is based on pooled data from two retrospective SBRT databases for pulmonary and hepatic metastases from 27 centers from Germany and Switzerland. Only patients with metastases from colorectal cancer were considered to avoid histology as a confounding factor. An illness-death model was employed to model the relationship between LC and OS. Results Three hundred eighty-eight patients with 500 metastatic lesions (lung n = 209, liver n = 291) were included and analyzed. Median follow-up time for local recurrence assessment was 12.1 months. Ninety-nine patients with 112 lesions experienced local failure. Seventy-one of these patients died after local failure. Median survival time was 27.9 months in all patients and 25.4 months versus 30.6 months in patients with and without local failure after SBRT. The baseline risk of death after local failure exceeds the baseline risk of death without local failure at 10 months indicating better survival with LC. Conclusion In CRC patients with lung or liver metastases, our findings suggest improved long-term OS by achieving metastatic disease control using SBRT in patients with a projected OS estimate of > 12 months. KW - colorectal cancer KW - illness-death model KW - liver metastases KW - lung metastases KW - tumor control probability KW - stereotactic body radiation therapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325877 VL - 19 ER - TY - JOUR A1 - Hinkelbein, Jochen A1 - Iovino, Ivan A1 - De Robertis, Edoardo A1 - Kranke, Peter T1 - Outcomes in video laryngoscopy studies from 2007 to 2017: systematic review and analysis of primary and secondary endpoints for a core set of outcomes in video laryngoscopy research JF - BMC Anesthesiology N2 - Background Airway management is crucial and, probably, even the most important key competence in anaesthesiology, which directly influences patient safety and outcome. However, high-quality research is rarely published and studies usually have different primary or secondary endpoints which impedes clear unbiased comparisons between studies. The aim of the present study was to gather and analyse primary and secondary endpoints in video laryngoscopy studies being published over the last ten years and to create a core set of uniform or homogeneous outcomes (COS). Methods Retrospective analysis. Data were identified by using MEDLINE® database and the terms “video laryngoscopy” and “video laryngoscope” limited to the years 2007 to 2017. A total of 3351 studies were identified by the applied search strategy in PubMed. Papers were screened by two anaesthesiologists independently to identify study endpoints. The DELPHI method was used for consensus finding. Results In the 372 studies analysed and included, 49 different outcome categories/columns were reported. The items “time to intubation” (65.86%), “laryngeal view grade” (44.89%), “successful intubation rate” (36.56%), “number of intubation attempts” (23.39%), “complications” (21.24%), and “successful first-pass intubation rate” (19.09%) were reported most frequently. A total of 19 specific parameters is recommended. Conclusions In recent video laryngoscopy studies, many different and inhomogeneous parameters were used as outcome descriptors/endpoints. Based on these findings, we recommend that 19 specific parameters (e.g., “time to intubation” (inserting the laryngoscope to first ventilation), “laryngeal view grade” (C&L and POGO), “successful intubation rate”, etc.) should be used in coming research to facilitate future comparisons of video laryngoscopy studies. KW - airway management KW - video laryngoscopy KW - primary outcome KW - primary endpoint Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320747 VL - 19 ER - TY - JOUR A1 - Brumberg, Joachim A1 - Blazhenets, Ganna A1 - Schröter, Nils A1 - Frings, Lars A1 - Jost, Wolfgang H. A1 - Lapa, Constantin A1 - Meyer, Philipp T. T1 - Imaging cardiac sympathetic innervation with MIBG: linear conversion of the heart-to-mediastinum ratio between different collimators JF - EJNMMI Physics N2 - Background The heart-to-mediastinum (H/M) ratio is a commonly used parameter to measure cardiac I-123 metaiodobenzylguanidine (MIBG) uptake. Since the H/M ratio is substantially influenced by the collimator type, we investigated whether an empirical linear conversion of H/M ratios between camera systems with low-energy (LE) and medium-energy (ME) collimator is possible. Methods We included 18 patients with parkinsonism who were referred to one of the two participating molecular imaging facilities for the evaluation of cardiac sympathetic innervation by MIBG scintigraphy. Two consecutive planar image datasets were acquired with LE and ME collimators at 4 h after MIBG administration. Linear regression analyses were performed to describe the association between the H/M ratios gained with both collimator settings, and the accuracy of a linear transfer of the H/M ratio between collimators and across centers was assessed using a leave-one-out procedure. Results H/M ratios acquired with LE and ME collimators showed a strong linear relationship both within each imaging facility (R\(^2\) = 0.99, p < 0.001 and R\(^2\) = 0.90, p < 0.001) and across centers (H/M-LE = 0.41 × H/M-ME + 0.63, R\(^2\) = 0.97, p < 0.001). A linear conversion of H/M ratios between collimators and across centers was estimated to be very accurate (mean absolute error 0.05 ± 0.04; mean relative absolute error 3.2 ± 2.6%). Conclusions The present study demonstrates that a simple linear conversion of H/M ratios acquired with different collimators is possible with high accuracy. This should greatly facilitate the exchange of normative data between settings and pooling of data from different institutions. KW - MIBG KW - collimator KW - heart-to-mediastinum ratio KW - linear conversion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221675 VL - 6 ER - TY - JOUR A1 - Hetzer, Benjamin A1 - Orth-Höller, Dorothea A1 - Würzner, Reinhard A1 - Kreidl, Peter A1 - Lackner, Michaela A1 - Müller, Thomas A1 - Knabl, Ludwig A1 - Geisler-Moroder, Daniel Rudolf A1 - Mellmann, Alexander A1 - Sesli, Özcan A1 - Holzknecht, Jeanett A1 - Noce, Damia A1 - Akarathum, Noppadon A1 - Chotinaruemol, Somporn A1 - Prelog, Martina A1 - Oberdorfer, Peninnah T1 - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” JF - Antimicrobial Resistance & Infection Control N2 - Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance. KW - Escherichia coli KW - antibiotic resistance KW - multiresistance KW - transmission KW - persistence KW - children KW - neonates Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284 VL - 8 ER - TY - JOUR A1 - Moremi, Nyambura A1 - Claus, Heike A1 - Vogel, Ulrich A1 - Mshana, Stephen E. T1 - The role of patients and healthcare workers Staphylococcus aureus nasal colonization in occurrence of surgical site infection among patients admitted in two centers in Tanzania JF - Antimicrobial Resistance & Infection Control N2 - Background Colonization with Staphylococcus aureus has been identified as a risk for subsequent occurrence of infection. This study investigated the relationship between S. aureus colonization of patients and healthcare workers (HCWs), and subsequent surgical site infections (SSI). Methods Between December 2014 and September 2015, a total of 930 patients and 143 HCWs were enrolled from the Bugando Medical Centre and Sekou Toure hospital in Mwanza, Tanzania. On admission and discharge nasal swabs, with an additional of wound swab for those who developed SSI were collected from patients whereas HCWs were swabbed once. Identification and antimicrobial susceptibility testing were done by VITEK-MS and VITEK-2, respectively. Detection of Panton Valentine leukocidin (PVL) and mecA genes was done by PCR. S. aureus isolates were further characterized by spa typing and Multi-Locus Sequence Typing (MLST). Results Among 930 patients screened for S. aureus on admission, 129 (13.9%) were positive of which 5.4% (7/129) were methicillin-resistant S. aureus (MRSA). Amongst 363 patients rescreened on discharge, 301 patients had been tested negative on admission of whom 29 (9.6%) turned positive after their hospital stay. Three (10.3%) of the 29 acquired S. aureus were MRSA. Inducible Clindamycin resistance occurred more often among acquired S. aureus isolates than among isolates from admission [34.5% (10/29) vs. 17.1% (22/129), P = 0.018]. S. aureus contributed to 21.1% (n = 12) of the 57 cases of investigated SSIs among 536 patients followed. Seven out of eight S. aureus carriage/infection pairs had the same spa and sequence types. The previously reported dominant PVL-positive ST88 MRSA strain with spa type t690 was detected in patients and HCW. Conclusion A significant proportion of patients acquired S. aureus during hospitalization. The finding of more than 90% of S. aureus SSI to be of endogenous source underscores the need of improving infection prevention and control measures including screening and decolonization of high risk patients. KW - S. aureus KW - colonization KW - surgical site infection KW - Tanzania Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224185 VL - 8 ER - TY - JOUR T1 - FCC-ee: The Lepton Collider: Future Circular Collider Conceptual Design Report Volume 2 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) study was launched, as an international collaboration hosted by CERN. This study covers a highest-luminosity high-energy lepton collider (FCC-ee) and an energy-frontier hadron collider (FCC-hh), which could, successively, be installed in the same 100 km tunnel. The scientific capabilities of the integrated FCC programme would serve the worldwide community throughout the 21st century. The FCC study also investigates an LHC energy upgrade, using FCC-hh technology. This document constitutes the second volume of the FCC Conceptual Design Report, devoted to the electron-positron collider FCC-ee. After summarizing the physics discovery opportunities, it presents the accelerator design, performance reach, a staged operation scenario, the underlying technologies, civil engineering, technical infrastructure, and an implementation plan. FCC-ee can be built with today's technology. Most of the FCC-ee infrastructure could be reused for FCC-hh. Combining concepts from past and present lepton colliders and adding a few novel elements, the FCC-ee design promises outstandingly high luminosity. This will make the FCC-ee a unique precision instrument to study the heaviest known particles (Z, W and H bosons and the top quark), offering great direct and indirect sensitivity to new physics. KW - Large Hadron Collider KW - Double-Beta Decay KW - e(+)e(-) Collisions KW - Flavor Violation KW - Electroweak Measurements KW - Bhabha Scattering KW - Missing Energy KW - Single-Photon KW - Neutrino Mass KW - Higgy-Boson Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226947 VL - 228 IS - 2 ER - TY - JOUR T1 - FCC Physics Opportunities: Future Circular Collider Conceptual Design Report Volume 1 JF - European Physical Journal C N2 - We review the physics opportunities of the Future Circular Collider, covering its e(+)e(-), pp, ep and heavy ion programmes. We describe the measurement capabilities of each FCC component, addressing the study of electroweak, Higgs and strong interactions, the top quark and flavour, as well as phenomena beyond the Standard Model. We highlight the synergy and complementarity of the different colliders, which will contribute to a uniquely coherent and ambitious research programme, providing an unmatchable combination of precision and sensitivity to new physics. KW - Electroweak Phase-Transition KW - By-Light Scattering KW - Deep Inelastic-scattering KW - Strange Baryon Production KW - Dark-Matter KW - Radiative-corrections KW - E(+)E(-) collicions KW - Transverse-Momentum KW - Top-Quark KW - Branching fractions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226938 VL - 79 IS - 474 ER - TY - JOUR T1 - HE-LHC: The High-Energy Large Hadron Collider : Future Circular Collider Conceptual Design Report Volume 4 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100 km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100 TeV. Its unprecedented centre-of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries. KW - Event builder KW - Impact Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226928 VL - 228 IS - 5 ER - TY - JOUR T1 - FCC-hh: The Hadron Collider: Future Circular Collider Conceptual Design Report Volume 3 JF - European Physical Journal - Special Topics N2 - In response to the 2013 Update of the European Strategy for Particle Physics (EPPSU), the Future Circular Collider (FCC) study was launched as a world-wide international collaboration hosted by CERN. The FCC study covered an energy-frontier hadron collider (FCC-hh), a highest-luminosity high-energy lepton collider (FCC-ee), the corresponding 100km tunnel infrastructure, as well as the physics opportunities of these two colliders, and a high-energy LHC, based on FCC-hh technology. This document constitutes the third volume of the FCC Conceptual Design Report, devoted to the hadron collider FCC-hh. It summarizes the FCC-hh physics discovery opportunities, presents the FCC-hh accelerator design, performance reach, and staged operation plan, discusses the underlying technologies, the civil engineering and technical infrastructure, and also sketches a possible implementation. Combining ingredients from the Large Hadron Collider (LHC), the high-luminosity LHC upgrade and adding novel technologies and approaches, the FCC-hh design aims at significantly extending the energy frontier to 100TeV. Its unprecedented centre of-mass collision energy will make the FCC-hh a unique instrument to explore physics beyond the Standard Model, offering great direct sensitivity to new physics and discoveries. KW - Multiple-Scattering KW - Top-Quark KW - CERN KW - Energy KW - Reduction KW - Impact Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226917 VL - 228 ER - TY - JOUR T1 - Search for diboson resonances in hadronic final states in 139 fb\(^{-1}\) of \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Journal of High Energy Physics N2 - Narrow resonances decaying into WW, WZ or ZZ boson pairs are searched for in 139 fb(-1) of proton-proton collision data at a centre-of-mass energy of root s = 13TeV recorded with the ATLAS detector at the Large Hadron Collider from 2015 to 2018. The diboson system is reconstructed using pairs of high transverse momentum, large-radius jets. These jets are built from a combination of calorimeter- and tracker-inputs compatible with the hadronic decay of a boosted W or Z boson, using jet mass and substructure properties. The search is performed for diboson resonances with masses greater than 1.3TeV. No significant deviations from the background expectations are observed. Exclusion limits at the 95% confidence level are set on the production cross-section times branching ratio into dibosons for resonances in a range of theories beyond the Standard Model, with the highest excluded mass of a new gauge boson at 3.8TeV in the context of mass-degenerate resonances that couple predominantly to gauge bosons. KW - Hadron-Hadron scattering (experiments) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226905 VL - 09 IS - 91 ER - TY - JOUR T1 - Identification of boosted Higgs bosons decaying into \(b\)-quark pairs with the ATLAS detector at 13 TeV JF - European Physical Journal C N2 - This paper describes a study of techniques for identifying Higgs bosons at high transverse momenta decaying into bottom-quark pairs, H -> b (b) over bar, for proton-proton collision data collected by the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy root s = 13 TeV. These decays are reconstructed from calorimeter jets found with the anti-k(t) R = 1.0 jet algorithm. To tag Higgs bosons, a combination of requirements is used: b-tagging of R = 0.2 track-jets matched to the large-R calorimeter jet, and requirements on the jet mass and other jet substructure variables. The Higgs boson tagging efficiency and corresponding multijet and hadronic top-quark background rejections are evaluated using Monte Carlo simulation. Several benchmark tagging selections are defined for different signal efficiency targets. The modelling of the relevant input distributions used to tag Higgs bosons is studied in 36 fb(-1) of data collected in 2015 and 2016 using g -> b (b) over bar and Z(-> b (b) over bar)gamma event selections in data. Both processes are found to be well modelled within the statistical and systematic uncertainties. KW - Parton distributions KW - PP collisions KW - search KW - MASS Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226812 VL - 79 IS - 836 ER - TY - JOUR T1 - Measurement of the inclusive cross-section for the production of jets in association with a \(Z\) boson in proton-proton collisions at 8 TeV using the ATLAS detector JF - European Physical Journal C N2 - The inclusive cross-section for jet production in association with a Z boson decaying into an electronpositron pair is measured as a function of the transverse momentum and the absolute rapidity of jets using 19.9 fb(-1) of root s = 8 TeV proton-proton collision data collected with the ATLAS detector at the Large Hadron Collider. The measured Z + jets cross-section is unfolded to the particle level. The cross-section is compared with state-of-the-art Standard Model calculations, including the next-to-leading-order and next-to-next-to-leading-order perturbative QCD calculations, corrected for non-perturbative and QED radiation effects. The results of the measurements cover final-state jets with transverse momenta up to 1 TeV, and show good agreement with fixed-order calculations. KW - P(P) over-bar collisions KW - + KW - distributions KW - decay Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226821 VL - 79 IS - 847 ER - TY - JOUR T1 - Measurement of the cross-section and charge asymmetry of W bosons produced in proton-proton collisions at √\(s\)=8 TeV with the ATLAS detector JF - European Physical Journal C N2 - This paper presents measurements of the W+->mu+nu and W-->mu-nu cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton-proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2fb(-1). The precision of the cross-section measurements varies between 0.8 and 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them. KW - Pair Production KW - Monte-Carlo Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226850 VL - 79 IS - 760 ER - TY - JOUR T1 - Measurement of distributions sensitive to the underlying event in inclusive Z boson production in \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - European Physical Journal C N2 - This paper presents measurements of charged-particle distributions sensitive to the properties of the underlying event in events containing a Z boson decaying into a muon pair. The data were obtained using the ATLAS detector at the LHC in proton-proton collisions at a centre-of-mass energy of 13 TeV with an integrated luminosity of 3.2 fb(-1). Distributions of the charged-particle multiplicity and of the charged-particle transverse momentum are measured in regions of the azimuth defined relative to the Z boson direction. The measured distributions are compared with the predictions of various Monte Carlo generators which implement different underyling event models. The Monte Carlo model predictions qualitatively describe the data well, but with some significant discrepancies. KW - Cross-Section Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226883 VL - 79 IS - 666 ER - TY - JOUR T1 - Observation of Light-by-Light Scattering in Ultraperipheral Pb + Pb Collisions with the ATLAS Detector JF - Physical Review Letters N2 - This Letter describes the observation of the light-by-light scattering process, gamma gamma -> gamma gamma, in Pb + Pb collisions at root S-NN = 5.02 TeV. The analysis is conducted using a data sample corresponding to an integrated luminosity of 1.73 nb(-1), collected in November 2018 by the ATLAS experiment at the LHC. Light-by-light scattering candidates are selected in events with two photons produced exclusively, each with transverse energy E-T(gamma) > 3 GeV and pseudorapidity vertical bar eta(gamma)vertical bar < 2.4, diphoton invariant mass above 6 GeV, and small diphoton transverse momentum and acoplanarity. After applying all selection criteria, 59 candidate events are observed for a background expectation of 12 +/- 3 events. The observed excess of events over the expected background has a significance of 8.2 standard deviations. The measured fiducial cross section is 78 +/- 13(stat) +/- 7(syst) +/- 3(lumi) nb. KW - Ultrarelativistic Heavy-Ion KW - Delbruck Scattering KW - Physics KW - Relativistic heavy-ion collisions Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226892 VL - 123 ER - TY - JOUR T1 - Search for a heavy charged boson in events with a charged lepton and missing transverse momentum from \(pp\) collisions at √\(s\)=13 TeV with the ATLAS detector JF - Physical Review D N2 - A search for a heavy charged-boson resonance decaying into a charged lepton (electron or muon) and a neutrino is reported. A data sample of 139 fb(-1) of proton-proton collisions at root s = 13 TeV collected with the ATLAS detector at the LHC during 2015-2018 is used in the search. The observed transverse mass distribution computed from the lepton and missing transverse momenta is consistent with the distribution expected from the Standard Model, and upper limits on the cross section for pp -> W'-> lv are extracted (l = e or mu). These vary between 1.3 pb and 0.05 tb depending on the resonance mass in the range between 0.15 and 7.0 TeV at 95% confidence level for the electron and muon channels combined. Gauge bosons with a mass below 6.0 and 5.1 TeV are excluded in the electron and muon channels, respectively, in a model with a resonance that has couplings to fermions identical to those of the Standard Model W boson. Cross-section limits are also provided for resonances with several fixed Gamma/m values in the range between 1% and 15%. Model-independent limits are derived in single-bin signal regions defined by a varying minimum transverse mass threshold. The resulting visible cross-section upper limits range between 4.6 (15) ph and 22 (22) ab as the threshold increases from 130 (110) GeV to 5.1 (5.1) TeV in the electron (muon) channel. KW - Pair Production KW - Symmetry KW - Decay KW - Monte-Carlo KW - semileptonic & radiative decays KW - Leptonic KW - Hadron-hadron interactions KW - Extensions of gauge sector Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226835 VL - 100 ER - TY - JOUR T1 - Search for electroweak diboson production in association with a high-mass dijet system in semileptonic final states in \(pp\) collisions at √\(s\) =13 TeV with the ATLAS detector JF - Physical Review D N2 - This paper reports on a search for electroweak diboson (WW/WZ/ZZ) production in association with a high-mass dijet system, using data from proton-proton collisions at a center-of-mass energy of N root s = 13 TeV. The data, corresponding to an integrated luminosity of 35.5 fb(-1), were recorded with the ATLAS detector in 2015 and 2016 at the Large Hadron Collider. The search is performed in final states in which one boson decays leptonically, and the other boson decays hadronically. The hadronically decaying W/Z boson is reconstructed as either two small-radius jets or one large-radius jet using jet substructure techniques. The electroweak production of WW/WZ/ZZ in association with two jets is measured with an observed (expected) significance of 2.7 (2.5) standard deviations, and the fiducial cross section is measured to be 45.1 +/- 8.6(stat.)(-14.6)(+15.9)(syst.) fb. KW - Proton-Proton Collisions KW - 2 Jets KW - Parton Distributions KW - Weak-Interactions KW - Cross-Section KW - High-Energies KW - Boson KW - Constraints KW - Scattering KW - Couplings KW - Particle accelerators KW - Hadron colliders KW - W & Z bosons KW - Gauge bosons KW - Quantum electrodynamics KW - Electroweak interaction Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226877 VL - 100 ER - TY - JOUR T1 - Resolution of the ATLAS muon spectrometer monitored drift tubes in LHC Run 2 JF - Journal of Instrumentation N2 - The momentum measurement capability of the ATLAS muon spectrometer relies fundamentally on the intrinsic single-hit spatial resolution of the monitored drift tube precision tracking chambers. Optimal resolution is achieved with a dedicated calibration program that addresses the specific operating conditions of the 354 000 high-pressure drift tubes in the spectrometer. The calibrations consist of a set of timing offsets and drift time to drift distance transfer relations, and result in chamber resolution functions. This paper describes novel algorithms to obtain precision calibrations from data collected by ATLAS in LHC Run 2 and from a gas monitoring chamber, deployed in a dedicated gas facility. The algorithm output consists of a pair of correction constants per chamber which are applied to baseline calibrations, and determined to be valid for the entire ATLAS Run 2. The final single-hit spatial resolution, averaged over 1172 monitored drift tube chambers, is 81.7 +/- 2.2 mu m. KW - Gaseous detectors KW - Chambers KW - Muon spectrometers KW - Particle tracking detectors (Gaseous detectors) KW - Wire chambers (MWPC, Thin-gap chambers, drift chambers, drift tubes, proportional chambers etc) Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226869 VL - 14 ER - TY - JOUR T1 - Search for high-mass dilepton resonances using 139 fb\(^{-1}\) of \(pp\) collision data collected at root \(s\)=13 TeV with the ATLAS detector JF - Physics Letters B N2 - A search for high-mass dielectron and dimuon resonances in the mass range of 250 GeV to 6TeV is presented. The data were recorded by the ATLAS experiment in proton-proton collisions at a centre-ofmass energy of root s = 13 TeV during Run 2 of the Large Hadron Collider and correspond to an integrated luminosity of 139 fb(-1). A functional form is fitted to the dilepton invariant-mass distribution to model the contribution from background processes, and a generic signal shape is used to determine the significance of observed deviations from this background estimate. No significant deviation is observed and upper limits are placed at the 95% confidence level on the fiducial cross-section times branching ratio for various resonance width hypotheses. The derived limits are shown to be applicable to spin-0, spin-1 and spin-2 signal hypotheses. For a set of benchmark models, the limits are converted into lower limits on the resonance mass and reach 4.5 TeV for the E-6-motivated Z(psi)' boson. Also presented are limits on Heavy Vector Triplet model couplings. (C) 2019 The Author. Published by Elsevier B.V. KW - Monte-Carlo KW - Bosons KW - Decay Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226844 VL - 796 ER - TY - JOUR T1 - Search for heavy particles decaying into a top-quark pair in the fully hadronic final state in \({pp}\) collisions at root s=13 TeV with the ATLAS detector JF - Physical Review D N2 - A search for new particles decaying into a pair of top quarks is performed using proton-proton collision data recorded with the ATLAS detector at the Large Hadron Collider at a center-of-mass energy of root s = 13 TeV corresponding to an integrated luminosity of 36.1 fb(-1). Events consistent with top-quark pair production and the fully hadronic decay mode of the top quarks are selected by requiring multiple high transverse momentum jets including those containing b-hadrons. Two analysis techniques, exploiting dedicated top-quark pair reconstruction in different kinematic regimes, are used to optimize the search sensitivity to new hypothetical particles over a wide mass range. The invariant mass distribution of the two reconstructed top-quark candidates is examined for resonant production of new particles with various spins and decay widths. No significant deviation from the Standard Model prediction is observed and limits are set on the production cross-section times branching fraction for new hypothetical Z' bosons, dark-matter mediators, Kaluza-Klein gravitons and Kaluza-Klein gluons. By comparing with the predicted production cross sections, the Z' boson in the topcolor-assisted-technicolor model is excluded for masses up to 3.1-3.6 TeV, the dark-matter mediators in a simplified framework are excluded in the mass ranges from 0.8 to 0.9 TeV and from 2.0 to 2.2 TeV, and the Kaluza-Klein gluon is excluded for masses up to 3.4 TeV, depending on the decay widths of the particles. KW - Parton distributions KW - ++ KW - Algorithm KW - Cross-section KW - Physics KW - LHC KW - Gravitons KW - Hypothetical gauge bosons KW - Top quark KW - Hadron colliders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317362 VL - 99 IS - 9 ER - TY - JOUR T1 - Search for light resonances decaying to boosted quark pairs and produced in association with a photon or a jet in proton-proton collisions at root s=13 TeV with the ATLAS detector JF - Physics Letters B N2 - This Letter presents a search for new light resonances decaying to pairs of quarks and produced in association with a high-p(T) photon or jet. The dataset consists of proton-proton collisions with an integrated luminosity of 36.1 fb(-1) at a centre-of-mass energy of root s = 13 TeV recorded by the ATLAS detector at the Large Hadron Collider. Resonance candidates are identified as massive large-radius jets with substructure consistent with a particle decaying into a quark pair. The mass spectrum of the candidates is examined for local excesses above background. No evidence of a new resonance is observed in the data, which are used to exclude the production of a lepto-phobic axial-vector Z' boson. (C) 2018 The Author(s). Published by Elsevier B.V. KW - Parton Distributions KW - Dark-matter KW - Constraints Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319552 VL - 788 ER - TY - JOUR A1 - Rager, Sabrina A1 - Jakowetz, Andreas C. A1 - Gole, Bappaditya A1 - Beuerle, Florian A1 - Medina, Dana D. A1 - Bein, Thomas T1 - Scaffold-Induced Diketopyrrolopyrrole Molecular Stacks in a Covalent Organic Framework JF - Chemistry of Materials N2 - In recent years, covalent organic frameworks (COFs) have attracted considerable attention due to their crystalline and porous nature, which positions them as intriguing candidates for diverse applications such as catalysis, sensing, or optoelectronics. The incorporation of dyes or semiconducting moieties into a rigid two-dimensional COF can offer emergent features such as enhanced light harvesting or charge transport. However, this approach can be challenging when dealing with dye molecules that exhibit a large aromatic backbone, since the steric demand of solubilizing side chains also needs to be integrated into the framework. Here, we report the successful synthesis of DPP2-HHTP-COF consisting of diketopyrrolopyrrole (DPP) diboronic acid and hexahydroxytriphenylene (HHTP) building blocks. The well-known boronate ester coupling motif guides the formation of a planar and rigid backbone and long-range molecular DPP stacks, resulting in a highly crystalline and porous material. DPP2-HHTP-COF exhibits excellent optical properties including strong absorption over the visible spectral range, broad emission into the NIR and a singlet lifetime of over 5 ns attributed to the formation of molecular stacks with J-type interactions between the DPP subcomponents in the COF. Electrical measurements of crystalline DPP2-HHTP-COF pellets revealed conductivity values of up to 10(-6) S cm(-1). KW - Polymers KW - Electron KW - Design Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224927 VL - 31 IS - 8 ER - TY - JOUR A1 - Lux, Thomas J. A1 - Hu, Xiawei A1 - Ben-Kraiem, Adel A1 - Blum, Robert A1 - Chen, Jeremy Tsung-Chieh A1 - Rittner, Heike L. T1 - Regional differences in tight junction protein expression in the blood−DRG barrier and their alterations after nerve traumatic injury in rats JF - International Journal of Molecular Sciences N2 - The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy. KW - tight junction KW - claudin-5 KW - neuropathic pain KW - nerve injury KW - dorsal root ganglion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285029 SN - 1422-0067 VL - 21 IS - 1 ER - TY - JOUR A1 - Gablonski, Thorsten-Christian A1 - Pryss, Rüdiger A1 - Probst, Thomas A1 - Vogel, Carsten A1 - Andreas, Sylke T1 - Intersession-Online: A smartphone application for systematic recording and controlling of intersession experiences in psychotherapy JF - J — Multidisciplinary Scientific Journal N2 - Mobile health technologies have become more and more important in psychotherapy research and practice. The market is being flooded by several psychotherapeutic online services for different purposes. However, mobile health technologies are particularly suitable for data collection and monitoring, as data can be recorded economically in real time. Currently, there is no appropriate method to assess intersession experiences systematically in psychotherapeutic practice. The aim of our project was the development of a smartphone application framework for systematic recording and controlling of intersession experiences. Intersession-Online, an iOS- and Android-App, offers the possibility to collect data on intersession experiences easily, to provide the results to therapists in an evaluated form and, if necessary, to induce or interrupt intersession experiences with the primary aim to improve outcome of psychotherapy. In general, the smartphone application could be a helpful, evidence-based tool for research and practice. Overall speaking, further research to investigate the efficacy of Intersession-Online is necessary. KW - intersession experiences KW - intersession processes KW - psychotherapy KW - mobile app KW - smartphone app Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285597 SN - 2571-8800 VL - 2 IS - 4 SP - 480 EP - 495 ER - TY - JOUR A1 - Mammadova-Bach, Elmina A1 - Braun, Attila T1 - Zinc homeostasis in platelet-related diseases JF - International Journal of Molecular Sciences N2 - Zn\(^{2+}\) deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn\(^{2+}\)-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn\(^{2+}\) deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn\(^{2+}\) status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn\(^{2+}\) uptake in the gut using different nutritional supplementation of Zn\(^{2+}\) could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn\(^{2+}\) diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn\(^{2+}\) in hemostasis. Storage protein metallothionein maintains or releases Zn\(^{2+}\) in the cytoplasm, and the dynamic change of this cytoplasmic Zn\(^{2+}\) pool is regulated by the redox status of the cell. An increase of labile Zn\(^{2+}\) pool can be toxic for the cells, and therefore cytoplasmic Zn\(^{2+}\) levels are tightly regulated by several Zn\(^{2+}\) transporters located on the cell surface and also on the intracellular membrane of Zn\(^{2+}\) storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn\(^{2+}\) is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn\(^{2+}\) transport and the physiological role of Zn\(^{2+}\) store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn\(^{2+}\) to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn\(^{2+}\) homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases. KW - Zinc KW - platelets KW - hemostasis KW - thrombosis KW - ischemic stroke KW - storage-pool diseases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285554 SN - 1422-0067 VL - 20 IS - 21 ER - TY - JOUR A1 - Breitenbach, Tim A1 - Lorenz, Kristina A1 - Dandekar, Thomas T1 - How to steer and control ERK and the ERK signaling cascade exemplified by looking at cardiac insufficiency JF - International Journal of Molecular Sciences N2 - Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK\(^{Thr188}\) phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations. KW - optimal pharmacological modulation KW - efficient intervention points KW - ERK signaling KW - optimal treatment strategies KW - optimal drug targeting KW - optimal drug combination Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285164 SN - 1422-0067 VL - 20 IS - 9 ER - TY - JOUR A1 - Herrmann, Marietta A1 - Hildebrand, Maria A1 - Menzel, Ursula A1 - Fahy, Niamh A1 - Alini, Mauro A1 - Lang, Siegmund A1 - Benneker, Lorin A1 - Verrier, Sophie A1 - Stoddart, Martin J. A1 - Bara, Jennifer J. T1 - Phenotypic characterization of bone marrow mononuclear cells and derived stromal cell populations from human iliac crest, vertebral body and femoral head JF - International Journal of Molecular Sciences N2 - (1) In vitro, bone marrow-derived stromal cells (BMSCs) demonstrate inter-donor phenotypic variability, which presents challenges for the development of regenerative therapies. Here, we investigated whether the frequency of putative BMSC sub-populations within the freshly isolated mononuclear cell fraction of bone marrow is phenotypically predictive for the in vitro derived stromal cell culture. (2) Vertebral body, iliac crest, and femoral head bone marrow were acquired from 33 patients (10 female and 23 male, age range 14–91). BMSC sub-populations were identified within freshly isolated mononuclear cell fractions based on cell-surface marker profiles. Stromal cells were expanded in monolayer on tissue culture plastic. Phenotypic assessment of in vitro derived cell cultures was performed by examining growth kinetics, chondrogenic, osteogenic, and adipogenic differentiation. (3) Gender, donor age, and anatomical site were neither predictive for the total yield nor the population doubling time of in vitro derived BMSC cultures. The abundance of freshly isolated progenitor sub-populations (CD45−CD34−CD73+, CD45−CD34−CD146+, NG2+CD146+) was not phenotypically predictive of derived stromal cell cultures in terms of growth kinetics nor plasticity. BMSCs derived from iliac crest and vertebral body bone marrow were more responsive to chondrogenic induction, forming superior cartilaginous tissue in vitro, compared to those isolated from femoral head. (4) The identification of discrete progenitor populations in bone marrow by current cell-surface marker profiling is not predictive for subsequently derived in vitro BMSC cultures. Overall, the iliac crest and the vertebral body offer a more reliable tissue source of stromal progenitor cells for cartilage repair strategies compared to femoral head. KW - bone marrow stromal cells KW - MSC KW - pericytes KW - femoral head KW - vertebral body KW - iliac crest KW - chondrogenesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285054 SN - 1422-0067 VL - 20 IS - 14 ER - TY - JOUR A1 - Rapa, Shara Francesca A1 - Di Iorio, Biagio Raffaele A1 - Campiglia, Pietro A1 - Heidland, August A1 - Marzocco, Stefania T1 - Inflammation and oxidative stress in chronic kidney disease — Potential therapeutic role of minerals, vitamins and plant-derived metabolites JF - International Journal of Molecular Sciences N2 - Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary. KW - chronic kidney disease (CKD) KW - inflammation KW - oxidative stress KW - uremic toxins KW - minerals KW - vitamins KW - plant-derived metabolites Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284998 SN - 1422-0067 VL - 21 IS - 1 ER - TY - JOUR A1 - Rasche, Leo A1 - Kumar, Manoj A1 - Gershner, Grant A1 - Samant, Rohan A1 - Van Hemert, Rudy A1 - Heidemeier, Anke A1 - Lapa, Constantin A1 - Bley, Thorsten A1 - Buck, Andreas A1 - McDonald, James A1 - Hillengass, Jens A1 - Epstein, Joshua A1 - Thanendrarajan, Sharmilan A1 - Schinke, Carolina A1 - van Rhee, Frits A1 - Zangari, Maurizio A1 - Barlogie, Bart A1 - Davies, Faith E. A1 - Morgan, Gareth J. A1 - Weinhold, Niels T1 - Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis? JF - Theranostics N2 - Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM. KW - multiple myeloma KW - diffusion weighted mri KW - spleen KW - tumor burden KW - high risk KW - extramedullary hematopoiesis Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224982 VL - 9 IS - 16 ER - TY - JOUR A1 - Schmalzl, J. A1 - Plumhoff, P. A1 - Gilbert, F. A1 - Gohlke, F. A1 - Konrads, C. A1 - Brunner, U. A1 - Jakob, F. A1 - Ebert, R. A1 - Steinert, AF T1 - The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis JF - Journal of Orthopaedic Surgery N2 - Introduction: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. Materials and methods: Twenty-two resected LHB tendons were classified into inflamed (n = 11) and noninflamed (n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. Results: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression Conclusion: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches. KW - biceps tendinitis KW - biomolecular processes KW - inflammatory gene KW - interleukin KW - long head of biceps tendon KW - pain generator KW - shoulder pain Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228611 VL - 27 IS - 1 ER - TY - JOUR A1 - Bothe, Friederike A1 - Deubel, Anne-Kathrin A1 - Hesse, Eliane A1 - Lotz, Benedict A1 - Groll, Jürgen A1 - Werner, Carsten A1 - Richter, Wiltrud A1 - Hagmann, Sebastien T1 - Treatment of focal cartilage defects in minipigs with zonal chondrocyte/mesenchymal progenitor cell constructs JF - International Journal of Molecular Sciences N2 - Despite advances in cartilage repair strategies, treatment of focal chondral lesions remains an important challenge to prevent osteoarthritis. Articular cartilage is organized into several layers and lack of zonal organization of current grafts is held responsible for insufficient biomechanical and biochemical quality of repair-tissue. The aim was to develop a zonal approach for cartilage regeneration to determine whether the outcome can be improved compared to a non-zonal strategy. Hydrogel-filled polycaprolactone (PCL)-constructs with a chondrocyte-seeded upper-layer deemed to induce hyaline cartilage and a mesenchymal stromal cell (MSC)-containing bottom-layer deemed to induce calcified cartilage were compared to chondrocyte-based non-zonal grafts in a minipig model. Grafts showed comparable hardness at implantation and did not cause visible signs of inflammation. After 6 months, X-ray microtomography (µCT)-analysis revealed significant bone-loss in both treatment groups compared to empty controls. PCL-enforcement and some hydrogel-remnants were retained in all defects, but most implants were pressed into the subchondral bone. Despite important heterogeneities, both treatments reached a significantly lower modified O’Driscoll-score compared to empty controls. Thus, PCL may have induced bone-erosion during joint loading and misplacement of grafts in vivo precluding adequate permanent orientation of zones compared to surrounding native cartilage. KW - cartilage repair KW - osteochondral defect KW - tissue engineering KW - starPEG hydrogel KW - chondrocyte KW - MSC KW - zonal construct KW - minipig Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285118 SN - 1422-0067 VL - 20 IS - 3 ER - TY - JOUR A1 - Rice, Carmel A1 - Eikema, Dirk-Jan A1 - Marsh, Judith C. W. A1 - Knol, Cora A1 - Hebert, Kyle A1 - Putter, Hein A1 - Peterson, Eefke A1 - Deeg, H. Joachim A1 - Halkes, Stijn A1 - Pidala, Joseph A1 - Anderlini, Paolo A1 - Tischer, Johanna A1 - Kroger, Nicolaus A1 - McDonald, Andrew A1 - Antin, Joseph H. A1 - Schaap, Nicolaas P. A1 - Hallek, Michael A1 - Einsele, Herman A1 - Mathews, Vikram A1 - Kapoor, Neena A1 - Boelens, Jaap-Jan A1 - Mufti, Ghulam J. A1 - Potter, Victoria A1 - de la Tour, Régis Pefault A1 - Eapen, Mary A1 - Dufour, Carlo T1 - Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50 Years or Older with Severe Aplastic Anemia JF - Biology of Blood and Marrow Transplantation N2 - We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55%) or HLA-matched (8/8) unrelated donors (n =187, 37%) between 2005 and 2016. The median age at HCT was 57.8 years; 16% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90% (hazard ratio HR], 1.41; 95% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66% (range, 57% to 75%) and 57% (range, 47% to 76%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57% (range, 48% to 67%) and 48% (range, 36% to 59%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved. KW - Aplastic anemia KW - Hematopoietic cell transplant KW - Survival Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225229 VL - 25 IS - 3 ER - TY - JOUR A1 - Wiechmann, Tobias A1 - Röh, Simone A1 - Sauer, Susann A1 - Czamara, Darina A1 - Arloth, Janine A1 - Ködel, Maik A1 - Beintner, Madita A1 - Knop, Lisanne A1 - Menke, Andreas A1 - Binder, Elisabeth B. A1 - Provençal, Nadine T1 - Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus JF - Clinical Epigenetics N2 - Background Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. Results We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. Conclusion Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure. KW - DNA methylation KW - FKBP5 KW - glucocorticoid receptor KW - early-life stress KW - targeted bisulfite sequencing KW - dexamethasone Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233673 VL - 11 ER - TY - JOUR A1 - Loeffler-Wirth, Henry A1 - Kreuz, Markus A1 - Hopp, Lydia A1 - Arakelyan, Arsen A1 - Haake, Andrea A1 - Cogliatti, Sergio B. A1 - Feller, Alfred C. A1 - Hansmann, Martin-Leo A1 - Lenze, Dido A1 - Möller, Peter A1 - Müller-Hermelink, Hans Konrad A1 - Fortenbacher, Erik A1 - Willscher, Edith A1 - Ott, German A1 - Rosenwald, Andreas A1 - Pott, Christiane A1 - Schwaenen, Carsten A1 - Trautmann, Heiko A1 - Wessendorf, Swen A1 - Stein, Harald A1 - Szczepanowski, Monika A1 - Trümper, Lorenz A1 - Hummel, Michael A1 - Klapper, Wolfram A1 - Siebert, Reiner A1 - Loeffler, Markus A1 - Binder, Hans T1 - A modular transcriptome map of mature B cell lymphomas JF - Genome Medicine N2 - Background Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. Methods We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. Results We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on ‘double-hit’ MYC and BCL2 transformed lymphomas. Conclusions The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities. KW - tumor heterogeneity KW - B cell malignancies KW - gene regulation KW - molecular subtypes KW - machine learning Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237262 VL - 11 ER - TY - JOUR A1 - Neugebauer, Hermann A1 - Schneider, Hauke A1 - Kollmar, Rainer T1 - Letter by Neugebauer et al. regarding article “Hypothermia after decompressive hemicraniectomy in treatment of malignant middle cerebral artery stroke: comment on the randomized clinical trial” JF - Critical Care N2 - No abstract available. KW - stroke KW - hypothermia KW - hemicraniectomy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232268 VL - 23 ER - TY - JOUR A1 - König, Kirsten A1 - Pechmann, Astrid A1 - Thiele, Simone A1 - Walter, Maggie C. A1 - Schorling, David A1 - Tassoni, Adrian A1 - Lochmüller, Hanns A1 - Müller-Reible, Clemens A1 - Kirschner, Janbernd T1 - De-duplicating patient records from three independent data sources reveals the incidence of rare neuromuscular disorders in Germany JF - Orphanet Journal of Rare Diseases N2 - Background Estimation of incidence in rare diseases is often challenging due to unspecific and incomplete coding and recording systems. Patient- and health care provider-driven data collections are held with different organizations behind firewalls to protect the privacy of patients. They tend to be fragmented, incomplete and their aggregation leads to further inaccuracies, as the duplicated records cannot easily be identified. We here report about a novel approach to evaluate the incidences of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) in Germany. Methods We performed a retrospective epidemiological study collecting data from patients with dystrophinopathies (DMD and Becker muscular dystrophy) and SMA born between 1995 and 2018. We invited all neuromuscular centers, genetic institutes and the patient registries for DMD and SMA in Germany to participate in the data collection. A novel web-based application for data entry was developed converting patient identifying information into a hash code. Duplicate entries were reliably allocated to the distinct patient. Results We collected 5409 data entries in our web-based database representing 1955 distinct patients with dystrophinopathies and 1287 patients with SMA. 55.0% of distinct patients were found in one of the 3 data sources only, while 32.0% were found in 2, and 13.0% in all 3 data sources. The highest number of SMA patients was reported by genetic testing laboratories, while for DMD the highest number was reported by the clinical specialist centers. After the removal of duplicate records, the highest yearly incidence for DMD was calculated as 2.57:10,000 in 2001 and the highest incidence for SMA as 1.36:10,000 in 2014. Conclusion With our novel approach (compliant with data protection regulations), we were able to identify unique patient records and estimate the incidence of DMD and SMA in Germany combining and de-duplicating data from patient registries, genetic institutes, and clinical care centers. Although we combined three different data sources, an unknown number of patients might not have been reported by any of these sources. Therefore, our results reflect the minimal incidence of these diseases. KW - incidence KW - neuromuscular disease KW - spinal muscular atrophy KW - duchenne muscular dystrophy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222807 VL - 14 ER - TY - JOUR A1 - Leistner, Marcus A1 - Sommer, Stefanie A1 - Kanofsky, Peer A1 - Leyh, Rainer A1 - Sommer, Sebastian-Patrick T1 - Ischemia time impacts on respiratory chain functions and Ca\(^{2+}\)-handling of cardiac subsarcolemmal mitochondria subjected to ischemia reperfusion injury JF - Journal of Cardiothoracic Surgery N2 - Background Mitochondrial impairment can result from myocardial ischemia reperfusion injury (IR). Despite cardioplegic arrest, IR-associated cardiodepression is a major problem in heart surgery. We determined the effect of increasing ischemia time on the respiratory chain (RC) function, the inner membrane polarization and Ca\(^{2+}\) homeostasis of rat cardiac subsarcolemmal mitochondria (SSM). Methods Wistar rat hearts were divided into 4 groups of stop-flow induced warm global IR using a pressure-controlled Langendorff system: 0, 15, 30 and 40 min of ischemia with 30 min of reperfusion, respectively. Myocardial contractility was determined from left ventricular pressure records (dP/dt, dPmax) with an intraventricular balloon. Following reperfusion, SSM were isolated and analyzed regarding electron transport chain (ETC) coupling by polarography (Clark-Type electrode), membrane polarization (JC1 fluorescence) and Ca2+-handling in terms of Ca\(^{2+}\)-induced swelling and Ca\(^{2+}\)-uptake/release (Calcium Green-5 N® fluorescence). Results LV contractility and systolic pressure during reperfusion were impaired by increasing ischemic times. Ischemia reduced ETC oxygen consumption in IR40/30 compared to IR0/30 at complex I-V (8.1 ± 1.2 vs. 18.2 ± 2.0 nmol/min) and II-IV/V (16.4 ± 2.6/14.8 ± 2.3 vs. 2.3 ± 0.6 nmol/min) in state 3 respiration (p < 0.01). Relative membrane potential revealed a distinct hyperpolarization in IR30/30 and IR40/30 (171.5 ± 17.4% and 170.9 ± 13.5%) compared to IR0/30 (p < 0.01), wearing off swiftly after CCCP-induced uncoupling. Excess mitochondrial permeability transition pore (mPTP)-gated Ca\(^{2+}\)-induced swelling was recorded in all groups and was most pronounced in IR40/30. Pyruvate addition for mPTP blocking strongly reduced SSM swelling in IR40/30 (relative AUC, ± pyruvate; IR0/30: 1.00 vs. 0.61, IR15/30: 1.68 vs. 1.00, IR30/30: 1.42 vs. 0.75, IR40/30: 1.97 vs. 0.85; p < 0.01). Ca2+-uptake remained unaffected by previous IR. Though Ca\(^{2+}\)-release was delayed for ≥30 min of ischemia (p < 0.01), Ca\(^{2+}\) retention was highest in IR15/30 (RFU; IR0/30: 6.3 ± 3.6, IR 15/30 42.9 ± 5.0, IR30/30 15.9 ± 3.8, IR40/30 11.5 ± 6.6; p ≤ 0.01 for IR15/30 against all other groups). Conclusions Ischemia prolongation in IR injury gradually impaired SSM in terms of respiratory chain function and Ca\(^{2+}\)-homeostasis. Membrane hyperpolarization appears to be responsible for impaired Ca2+-cycling and ETC function. Ischemia time should be considered an important factor influencing IR experimental data on subsarcolemmal mitochondria. Periods of warm global ischemia should be minimized during cardiac surgery to avoid excessive damage to SSMs. KW - subsarcolemmal mitochondria KW - ischemia reperfusion injury KW - ischemia time Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236455 VL - 14 ER - TY - JOUR A1 - Rubo, Marius A1 - Gamer, Matthias T1 - Visuo-tactile congruency influences the body schema during full body ownership illusion JF - Consciousness and Cognition N2 - Previous research showed that full body ownership illusions in virtual reality (VR) can be robustly induced by providing congruent visual stimulation, and that congruent tactile experiences provide a dispensable extension to an already established phenomenon. Here we show that visuo-tactile congruency indeed does not add to already high measures for body ownership on explicit measures, but does modulate movement behavior when walking in the laboratory. Specifically, participants who took ownership over a more corpulent virtual body with intact visuo-tactile congruency increased safety distances towards the laboratory's walls compared to participants who experienced the same illusion with deteriorated visuo-tactile congruency. This effect is in line with the body schema more readily adapting to a more corpulent body after receiving congruent tactile information. We conclude that the action-oriented, unconscious body schema relies more heavily on tactile information compared to more explicit aspects of body ownership. KW - Full body ownership illusion KW - Visuo-tactile congruency KW - Body schema KW - Movement behavior Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227095 VL - 73 ER - TY - JOUR A1 - Minev, Boris R. A1 - Lander, Elliot A1 - Feller, John F. A1 - Berman, Mark A1 - Greenwood, Bernadette M. A1 - Minev, Ivelina A1 - Santidrian, Antonio F. A1 - Nguyen, Duong A1 - Draganov, Dobrin A1 - Killinc, Mehmet O. A1 - Vyalkova, Anna A1 - Kesari, Santosh A1 - McClay, Edward A1 - Carabulea, Gabriel A1 - Marincola, Francesco M. A1 - Butterfield, Lisa H. A1 - Szalay, Aladar A. T1 - First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells JF - Journal of Translational Medicine N2 - Background ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). Methods Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. Results No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days—an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients’ blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. Conclusions Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018. KW - clinical trial KW - oncolytic vaccinia virus KW - stromal vascular fraction KW - immunotherapy of cancer Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224105 VL - 17 ER - TY - JOUR A1 - Draganov, Dobrin D. A1 - Santidrian, Antonio F. A1 - Minev, Ivelina A1 - Duong, Nguyen A1 - Kilinc, Mehmet Okyay A1 - Petrov, Ivan A1 - Vyalkova, Anna A1 - Lander, Elliot A1 - Berman, Mark A1 - Minev, Boris A1 - Szalay, Aladar A. T1 - Delivery of oncolytic vaccinia virus by matched allogeneic stem cells overcomes critical innate and adaptive immune barriers JF - Journal of Translational Medicine N2 - Background Previous studies have identified IFNγ as an important early barrier to oncolytic viruses including vaccinia. The existing innate and adaptive immune barriers restricting oncolytic virotherapy, however, can be overcome using autologous or allogeneic mesenchymal stem cells as carrier cells with unique immunosuppressive properties. Methods To test the ability of mesenchymal stem cells to overcome innate and adaptive immune barriers and to successfully deliver oncolytic vaccinia virus to tumor cells, we performed flow cytometry and virus plaque assay analysis of ex vivo co-cultures of stem cells infected with vaccinia virus in the presence of peripheral blood mononuclear cells from healthy donors. Comparative analysis was performed to establish statistically significant correlations and to evaluate the effect of stem cells on the activity of key immune cell populations. Results Here, we demonstrate that adipose-derived stem cells (ADSCs) have the potential to eradicate resistant tumor cells through a combination of potent virus amplification and sensitization of the tumor cells to virus infection. Moreover, the ADSCs demonstrate ability to function as a virus-amplifying Trojan horse in the presence of both autologous and allogeneic human PBMCs, which can be linked to the intrinsic immunosuppressive properties of stem cells and their unique potential to overcome innate and adaptive immune barriers. The clinical application of ready-to-use ex vivo expanded allogeneic stem cell lines, however, appears significantly restricted by patient-specific allogeneic differences associated with the induction of potent anti-stem cell cytotoxic and IFNγ responses. These allogeneic responses originate from both innate (NK)- and adaptive (T)- immune cells and might compromise therapeutic efficacy through direct elimination of the stem cells or the induction of an anti-viral state, which can block the potential of the Trojan horse to amplify and deliver vaccinia virus to the tumor. Conclusions Overall, our findings and data indicate the feasibility to establish simple and informative assays that capture critically important patient-specific differences in the immune responses to the virus and stem cells, which allows for proper patient-stem cell matching and enables the effective use of off-the-shelf allogeneic cell-based delivery platforms, thus providing a more practical and commercially viable alternative to the autologous stem cell approach. KW - vaccinia KW - cancer KW - stem Cells KW - oncolysis KW - oncolytic virus KW - virotherapy KW - immunity KW - immunotherapy Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226312 SN - 100 VL - 17 ER - TY - JOUR A1 - Bartel, Karin A1 - Pein, Helmut A1 - Popper, Bastian A1 - Schmitt, Sabine A1 - Janaki-Raman, Sudha A1 - Schulze, Almut A1 - Lengauer, Florian A1 - Koeberle, Andreas A1 - Werz, Oliver A1 - Zischka, Hans A1 - Müller, Rolf A1 - Vollmar, Angelika M. A1 - Schwarzenberg, Karin von T1 - Connecting lysosomes and mitochondria – a novel role for lipid metabolism in cancer cell death JF - Cell Communication and Signaling N2 - Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors. KW - lysosome KW - V-ATPase KW - mitochondria KW - fission KW - apoptosis KW - lipid metabolism KW - cardiolipin Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221524 VL - 17 ER - TY - JOUR A1 - Rödel, Michaela A1 - Teßmar, Jörg A1 - Groll, Jürgen A1 - Gbureck, Uwe T1 - Tough and Elastic alpha-Tricalcium Phosphate Cement Composites with Degradable PEG-Based Cross-Linker JF - Materials N2 - Dual setting cements composed of an in situ forming hydrogel and a reactive mineral phase combine high compressive strength of the cement with sufficient ductility and bending strength of the polymeric network. Previous studies were focused on the modification with non-degradable hydrogels based on 2-hydroxyethyl methacrylate (HEMA). Here, we describe the synthesis of suitable triblock degradable poly(ethylene glycol)-poly(lactide) (PEG-PLLA) cross-linker to improve the resorption capacity of such composites. A study with four different formulations was established. As reference, pure hydroxyapatite (HA) cements and composites with 40 wt% HEMA in the liquid cement phase were produced. Furthermore, HEMA was modified with 10 wt% of PEG-PLLA cross-linker or a test series containing only 25% cross-linker was chosen for composites with a fully degradable polymeric phase. Hence, we developed suitable systems with increased elasticity and 5-6 times higher toughn ess values in comparison to pure inorganic cement matrix. Furthermore, conversion rate from alpha-tricalcium phosphate (alpha-TCP) to HA was still about 90% for all composite formulations, whereas crystal size decreased. Based on this material development and advancement for a dual setting system, we managed to overcome the drawback of brittleness for pure calcium phosphate cements. KW - dual setting system KW - bending strength KW - calcium phosphate cement KW - composite material KW - HEMA KW - hydroxyapatite KW - free radical polymerization Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226437 VL - 12 IS - 53 ER - TY - JOUR A1 - Sepahi, Ilnaz A1 - Faust, Ulrike A1 - Sturm, Marc A1 - Bosse, Kristin A1 - Kehrer, Martin A1 - Heinrich, Tilman A1 - Grundman-Hauser, Kathrin A1 - Bauer, Peter A1 - Ossowski, Stephan A1 - Susak, Hana A1 - Varon, Raymonda A1 - Schröck, Evelin A1 - Niederacher, Dieter A1 - Auber, Bernd A1 - Sutter, Christian A1 - Arnold, Norbert A1 - Hahnen, Eric A1 - Dworniczak, Bernd A1 - Wang-Gorke, Shan A1 - Gehrig, Andrea A1 - Weber, Bernhard H. F. A1 - Engel, Christoph A1 - Lemke, Johannes R. A1 - Hartkopf, Andreas A1 - Huu Phuc, Nguyen A1 - Riess, Olaf A1 - Schroeder, Christopher T1 - Investigating the effects of additional truncating variants in DNA-repair genes on breast cancer risk in BRCA1-positive women JF - BMC Cancer N2 - Background Inherited pathogenic variants in BRCA1 and BRCA2 are the most common causes of hereditary breast and ovarian cancer (HBOC). The risk of developing breast cancer by age 80 in women carrying a BRCA1 pathogenic variant is 72%. The lifetime risk varies between families and even within affected individuals of the same family. The cause of this variability is largely unknown, but it is hypothesized that additional genetic factors contribute to differences in age at onset (AAO). Here we investigated whether truncating and rare missense variants in genes of different DNA-repair pathways contribute to this phenomenon. Methods We used extreme phenotype sampling to recruit 133 BRCA1-positive patients with either early breast cancer onset, below 35 (early AAO cohort) or cancer-free by age 60 (controls). Next Generation Sequencing (NGS) was used to screen for variants in 311 genes involved in different DNA-repair pathways. Results Patients with an early AAO (73 women) had developed breast cancer at a median age of 27 years (interquartile range (IQR); 25.00–27.00 years). A total of 3703 variants were detected in all patients and 43 of those (1.2%) were truncating variants. The truncating variants were found in 26 women of the early AAO group (35.6%; 95%-CI 24.7 - 47.7%) compared to 16 women of controls (26.7%; 95%-CI 16.1 to 39.7%). When adjusted for environmental factors and family history, the odds ratio indicated an increased breast cancer risk for those carrying an additional truncating DNA-repair variant to BRCA1 mutation (OR: 3.1; 95%-CI 0.92 to 11.5; p-value = 0.07), although it did not reach the conventionally acceptable significance level of 0.05. Conclusions To our knowledge this is the first time that the combined effect of truncating variants in DNA-repair genes on AAO in patients with hereditary breast cancer is investigated. Our results indicate that co-occurring truncating variants might be associated with an earlier onset of breast cancer in BRCA1-positive patients. Larger cohorts are needed to confirm these results. KW - breast cancer KW - age at onset KW - DNA-repair genes KW - next-generation-sequencing KW - panel sequencing KW - extreme phenotypes KW - hereditary breast and ovarian cancer KW - BRCA1 KW - DNA-repair Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-237676 VL - 19 ER - TY - JOUR A1 - Ebner, Florian A1 - Wöckel, Achim A1 - Schwentner, Lukas A1 - Blettner, Maria A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Wischnewsky, Manfred T1 - Does the number of removed axillary lymphnodes in high risk breast cancer patients influence the survival? JF - BMC Cancer N2 - Background The decision making process for axillary dissection has changed in recent years for patients with early breast cancer and positive sentinel lymph nodes (LN). The question now arises, what is the optimal surgical treatment for patients with positive axillary LN (pN+). This article tries to answer the following questions: (1) Is there a survival benefit for breast cancer patients with 3 or more positive LN (pN3+) and with more than 10 removed LN? (2) Is there a survival benefit for high risk breast cancer patients (triple negative or Her2 + breast cancer) and with 3 or more positive LN (pN3+) with more than 10 removed LN? (3) In pN + patients is the prognostic value of the lymph node ratio (LNR) of pN+/pN removed impaired if 10 or less LN are removed? Methods A retrospective database analysis of the multi center cohort database BRENDA (breast cancer under evidence based guidelines) with data from 9625 patients from 17 breast centers was carried out. Guideline adherence was defined by the 2008 German National consensus guidelines. Results 2992 out of 9625 patients had histological confirmed positive lymph nodes. The most important factors for survival were intrinsic sub types, tumor size and guideline adherent chemo- and hormonal treatment (and age at diagnosis for overall survival (OAS)). Uni-and multivariable analyses for recurrence free survival (RFS) and OAS showed no significant survival benefit when removing more than 10 lymph nodes even for high-risk patients. The mean and median of LNR were significantly higher in the pN+ patients with ≤10 excised LN compared to patients with > 10 excised LN. LNR was in both, uni-and multivariable, analysis a highly significant prognostic factor for RFS and OAS in both subgroups of pN + patients with less respective more than 10 excised LN. Multivariable COX regression analysis was adjusted by age, tumor size, intrinsic sub types and guideline adherent adjuvant systemic therapy. Conclusion The removal of more than 10 LN did not result in a significant survival benefit even in high risk pN + breast cancer patients. KW - advanced breast cancer KW - axillary dissection KW - lymph nodes KW - number of KW - sentinel KW - survival KW - guideline adherent treatment Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226445 VL - 19 ER - TY - JOUR A1 - Kolb-Mäurer, Annette A1 - Sunderkötter, Cord A1 - Kukowski, Borries A1 - Meuth, Sven G. T1 - An update on Peginterferon beta-1a Management in Multiple Sclerosis: results from an interdisciplinary Board of German and Austrian Neurologists and dermatologists JF - BMC Neurology N2 - Background: Interferon (IFN) beta drugs have been approved for the treatment of relapsing forms of multiple sclerosis (RMS) for more than 20years and are considered to offer a favourable benefit-risk profile. In July 2014, subcutaneous (SC) peginterferon beta-1a 125g dosed every 2weeks, a pegylated form of interferon beta-1a, was approved by the EMA for the treatment of adult patients with RRMS and in August 2014 by the FDA for RMS. Peginterferon beta-1a shows a prolonged half-life and increased systemic drug exposure resulting in a reduced dosing frequency compared to other available interferon-based products in MS. In the Phase 3 ADVANCE trial peginterferon beta-1a demonstrated significant positive effects on clinical and MRI outcome measures versus placebo after one year. Furthermore, in the ATTAIN extension study, sustained efficacy with long-term treatment for nearly 6years was shown. Main text In July 2016, an interdisciplinary panel of German and Austrian experts convened to discuss the management of side effects associated with peginterferon beta-1a and other interferon beta-based treatments in MS in daily practice. The panel was composed of experts from university hospitals and private clinics comprised of neurologists, dermatologists, and an MS nurse. In this paper we report recommendations regarding best practices for adverse event management, focussing on peginterferon beta-1a. Injection site reactions (ISRs) and influenza-like illness are the most common adverse effects of interferon beta therapies and can present a burden for MS patients leading to non-adherence and discontinuation of therapy. Peginterferon beta-1a shows improved pharmacological properties. In clinical trials, the adverse event (AE) profile of peginterferon beta-1a was similar to other interferon beta formulations. The most common AEs were mild to moderate ISRs, influenza-like illness, pyrexia, and headache. Current information on the underlying cause of skin reactions associated with SC interferon treatment, and the management strategies for these AEs are limited. In pivotal trials, ISRs were mainly characterized and classified by neurologists, while dermatologists were only rarely consulted. Conclusions This report addresses expert recommendations on the management of most relevant adverse effects related to peginterferon beta-1a and other interferon betas, based on literature and interdisciplinary experience. KW - multiple sclerosis KW - peginterferon bet-1a KW - interferon beta KW - flu-like symptoms KW - injection site reactions KW - management Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224646 VL - 19 ER - TY - JOUR A1 - Rasche, Leo A1 - Kortüm, K. Martin A1 - Raab, Marc S. A1 - Weinhold, Niels T1 - The impact of tumor heterogeneity on diagnostics and novel therapeutic strategies in multiple myeloma JF - International Journal of Molecular Sciences N2 - Myeloma is characterized by extensive inter-patient genomic heterogeneity due to multiple different initiating events. A recent multi-region sequencing study demonstrated spatial differences, with progression events, such as TP53 mutations, frequently being restricted to focal lesions. In this review article, we describe the clinical impact of these two types of tumor heterogeneity. Target mutations are often dominant at one site but absent at other sites, which poses a significant challenge to personalized therapy in myeloma. The same holds true for high-risk subclones, which can be locally restricted, and as such not detectable at the iliac crest, which is the usual sampling site. Imaging can improve current risk classifiers and monitoring of residual disease, but does not allow for deciphering the molecular characteristics of tumor clones. In the era of novel immunotherapies, the clinical impact of heterogeneity certainly needs to be re-defined. Yet, preliminary observations indicate an ongoing impact of spatial heterogeneity on the efficacy of monoclonal antibodies. In conclusion, we recommend combining molecular tests with imaging to improve risk prediction and monitoring of residual disease. Overcoming intra-tumor heterogeneity is the prerequisite for curing myeloma. Novel immunotherapies are promising but research addressing their impact on the spatial clonal architecture is highly warranted. KW - multiple myeloma KW - spatial heterogeneity KW - risk stratification KW - minimal residual disease KW - targeted therapy KW - clinical imaging KW - immunotherapy KW - daratumumab Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285402 SN - 1422-0067 VL - 20 IS - 5 ER -