@article{VigoritoKuchenbaeckerBeesleyetal.2016, author = {Vigorito, Elena and Kuchenbaecker, Karoline B. and Beesley, Jonathan and Adlard, Julian and Agnarsson, Bjarni A. and Andrulis, Irene L. and Arun, Banu K. and Barjhoux, Laure and Belotti, Muriel and Benitez, Javier and Berger, Andreas and Bojesen, Anders and Bonanni, Bernardo and Brewer, Carole and Caldes, Trinidad and Caligo, Maria A. and Campbell, Ian and Chan, Salina B. and Claes, Kathleen B. M. and Cohn, David E. and Cook, Jackie and Daly, Mary B. and Damiola, Francesca and Davidson, Rosemarie and de Pauw, Antoine and Delnatte, Capucine and Diez, Orland and Domchek, Susan M. and Dumont, Martine and Durda, Katarzyna and Dworniczak, Bernd and Easton, Douglas F. and Eccles, Diana and Ardnor, Christina Edwinsdotter and Eeles, Ros and Ejlertsen, Bent and Ellis, Steve and Evans, D. Gareth and Feliubadalo, Lidia and Fostira, Florentia and Foulkes, William D. and Friedman, Eitan and Frost, Debra and Gaddam, Pragna and Ganz, Patricia A. and Garber, Judy and Garcia-Barberan, Vanesa and Gauthier-Villars, Marion and Gehrig, Andrea and Gerdes, Anne-Marie and Giraud, Sophie and Godwin, Andrew K. and Goldgar, David E. and Hake, Christopher R. and Hansen, Thomas V. O. and Healey, Sue and Hodgson, Shirley and Hogervorst, Frans B. L. and Houdayer, Claude and Hulick, Peter J. and Imyanitov, Evgeny N. and Isaacs, Claudine and Izatt, Louise and Izquierdo, Angel and Jacobs, Lauren and Jakubowska, Anna and Janavicius, Ramunas and Jaworska-Bieniek, Katarzyna and Jensen, Uffe Birk and John, Esther M. and Vijai, Joseph and Karlan, Beth Y. and Kast, Karin and Khan, Sofia and Kwong, Ava and Laitman, Yael and Lester, Jenny and Lesueur, Fabienne and Liljegren, Annelie and Lubinski, Jan and Mai, Phuong L. and Manoukian, Siranoush and Mazoyer, Sylvie and Meindl, Alfons and Mensenkamp, Arjen R. and Montagna, Marco and Nathanson, Katherine L. and Neuhausen, Susan L. and Nevanlinna, Heli and Niederacher, Dieter and Olah, Edith and Olopade, Olufunmilayo I. and Ong, Kai-ren and Osorio, Ana and Park, Sue Kyung and Paulsson-Karlsson, Ylva and Pedersen, Inge Sokilde and Peissel, Bernard and Peterlongo, Paolo and Pfeiler, Georg and Phelan, Catherine M. and Piedmonte, Marion and Poppe, Bruce and Pujana, Miquel Angel and Radice, Paolo and Rennert, Gad and Rodriguez, Gustavo C. and Rookus, Matti A. and Ross, Eric A. and Schmutzler, Rita Katharina and Simard, Jacques and Singer, Christian F. and Slavin, Thomas P. and Soucy, Penny and Southey, Melissa and Steinemann, Doris and Stoppa-Lyonnet, Dominique and Sukiennicki, Grzegorz and Sutter, Christian and Szabo, Csilla I. and Tea, Muy-Kheng and Teixeira, Manuel R. and Teo, Soo-Hwang and Terry, Mary Beth and Thomassen, Mads and Tibiletti, Maria Grazia and Tihomirova, Laima and Tognazzo, Silvia and van Rensburg, Elizabeth J. and Varesco, Liliana and Varon-Mateeva, Raymonda and Vratimos, Athanassios and Weitzel, Jeffrey N. and McGuffog, Lesley and Kirk, Judy and Toland, Amanda Ewart and Hamann, Ute and Lindor, Noralane and Ramus, Susan J. and Greene, Mark H. and Couch, Fergus J. and Offit, Kenneth and Pharoah, Paul D. P. and Chenevix-Trench, Georgia and Antoniou, Antonis C.}, title = {Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {7}, doi = {10.1371/journal.pone.0158801}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166869}, pages = {e0158801}, year = {2016}, abstract = {Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95\%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95\%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.}, language = {en} } @article{HegerlWittenburgArensmanetal.2009, author = {Hegerl, Ulrich and Wittenburg, Lisa and Arensman, Ella and Van Audenhove, Chantal and Coyne, James C. and McDaid, David and van der Feltz-Cornelis, Christina M. and Gusm{\~a}o, Ricardo and Kopp, M{\´a}ria and Maxwell, Margaret and Meise, Ullrich and Roskar, Saska and Sarchiapone, Marco and Schmidtke, Armin and V{\"a}rnik, Airi and Bramesfeld, Anke}, title = {Optimizing Suicide Prevention Programs and Their Implementation in Europe (OSPI Europe): an evidence-based multi-level approach}, series = {BMC Public Health}, volume = {9}, journal = {BMC Public Health}, number = {428}, doi = {10.1186/1471-2458-9-428}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154695}, year = {2009}, abstract = {Background Suicide and non-fatal suicidal behaviour are significant public health issues in Europe requiring effective preventive interventions. However, the evidence for effective preventive strategies is scarce. The protocol of a European research project to develop an optimized evidence based program for suicide prevention is presented. Method The groundwork for this research has been established by a regional community based intervention for suicide prevention that focuses on improving awareness and care for depression performed within the European Alliance Against Depression (EAAD). The EAAD intervention consists of (1) training sessions and practice support for primary care physicians,(2) public relations activities and mass media campaigns, (3) training sessions for community facilitators who serve as gatekeepers for depressed and suicidal persons in the community and treatment and (4) outreach and support for high risk and self-help groups (e.g. helplines). The intervention has been shown to be effective in reducing suicidal behaviour in an earlier study, the Nuremberg Alliance Against Depression. In the context of the current research project described in this paper (OSPI-Europe) the EAAD model is enhanced by other evidence based interventions and implemented simultaneously and in standardised way in four regions in Ireland, Portugal, Hungary and Germany. The enhanced intervention will be evaluated using a prospective controlled design with the primary outcomes being composite suicidal acts (fatal and non-fatal), and with intermediate outcomes being the effect of training programs, changes in public attitudes, guideline-consistent media reporting. In addition an analysis of the economic costs and consequences will be undertaken, while a process evaluation will monitor implementation of the interventions within the different regions with varying organisational and healthcare contexts. Discussion This multi-centre research seeks to overcome major challenges of field research in suicide prevention. It pools data from four European regions, considerably increasing the study sample, which will be close to one million. In addition, the study will gather important information concerning the potential to transfer this multilevel program to other health care systems. The results of this research will provide a basis for developing an evidence-based, efficient concept for suicide prevention for EU-member states.}, language = {en} } @article{WongWinterHartigetal.2014, author = {Wong, David and Winter, Oliver and Hartig, Christina and Siebels, Svenja and Szyska, Martin and Tiburzy, Benjamin and Meng, Lingzhang and Kulkarni, Upasana and F{\"a}hnrich, Anke and Bommert, Kurt and Bargou, Ralf and Berek, Claudia and Van, Trung Chu and Bogen, Bjarne and Jundt, Franziska and Manz, Rudolf Armin}, title = {Eosinophils and Megakaryocytes Support the Early Growth of Murine MOPC315 Myeloma Cells in Their Bone Marrow Niches}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {10}, doi = {10.1371/journal.pone.0109018}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115269}, pages = {e109018}, year = {2014}, abstract = {Multiple myeloma is a bone marrow plasma cell tumor which is supported by the external growth factors APRIL and IL-6, among others. Recently, we identified eosinophils and megakaryocytes to be functional components of the micro-environmental niches of benign bone marrow plasma cells and to be important local sources of these cytokines. Here, we investigated whether eosinophils and megakaryocytes also support the growth of tumor plasma cells in the MOPC315. BM model for multiple myeloma. As it was shown for benign plasma cells and multiple myeloma cells, IL-6 and APRIL also supported MOPC315. BM cell growth in vitro, IL-5 had no effect. Depletion of eosinophils in vivo by IL-5 blockade led to a reduction of the early myeloma load. Consistent with this, myeloma growth in early stages was retarded in eosinophil-deficient Delta dblGATA-1 mice. Late myeloma stages were unaffected, possibly due to megakaryocytes compensating for the loss of eosinophils, since megakaryocytes were found to be in contact with myeloma cells in vivo and supported myeloma growth in vitro. We conclude that eosinophils and megakaryocytes in the niches for benign bone marrow plasma cells support the growth of malignant plasma cells. Further investigations are required to test whether perturbation of these niches represents a potential strategy for the treatment of multiple myeloma.}, language = {en} } @article{PetersHempAppelhansetal.2016, author = {Peters, Marcell K. and Hemp, Andreas and Appelhans, Tim and Behler, Christina and Classen, Alice and Detsch, Florian and Ensslin, Andreas and Ferger, Stefan W. and Frederiksen, Sara B. and Gebert, Frederike and Haas, Michael and Helbig-Bonitz, Maria and Hemp, Claudia and Kindeketa, William J. and Mwangomo, Ephraim and Ngereza, Christine and Otte, Insa and R{\"o}der, Juliane and Rutten, Gemma and Costa, David Schellenberger and Tardanico, Joseph and Zancolli, Giulia and Deckert, J{\"u}rgen and Eardley, Connal D. and Peters, Ralph S. and R{\"o}del, Mark-Oliver and Schleuning, Matthias and Ssymank, Axel and Kakengi, Victor and Zhang, Jie and B{\"o}hning-Gaese, Katrin and Brandl, Roland and Kalko, Elisabeth K.V. and Kleyer, Michael and Nauss, Thomas and Tschapka, Marco and Fischer, Markus and Steffan-Dewenter, Ingolf}, title = {Predictors of elevational biodiversity gradients change from single taxa to the multi-taxa community level}, series = {Nature Communications}, volume = {7}, journal = {Nature Communications}, doi = {10.1038/ncomms13736}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169374}, year = {2016}, abstract = {The factors determining gradients of biodiversity are a fundamental yet unresolved topic in ecology. While diversity gradients have been analysed for numerous single taxa, progress towards general explanatory models has been hampered by limitations in the phylogenetic coverage of past studies. By parallel sampling of 25 major plant and animal taxa along a 3.7 km elevational gradient on Mt. Kilimanjaro, we quantify cross-taxon consensus in diversity gradients and evaluate predictors of diversity from single taxa to a multi-taxa community level. While single taxa show complex distribution patterns and respond to different environmental factors, scaling up diversity to the community level leads to an unambiguous support for temperature as the main predictor of species richness in both plants and animals. Our findings illuminate the influence of taxonomic coverage for models of diversity gradients and point to the importance of temperature for diversification and species coexistence in plant and animal communities.}, language = {en} } @article{GomezFernandezLopezdeLapuentePortillaAstobizaetal.2020, author = {G{\´o}mez-Fern{\´a}ndez, Paloma and Lopez de Lapuente Portilla, Aitzkoa and Astobiza, Ianire and Mena, Jorge and Urtasun, Andoni and Altmann, Vivian and Matesanz, Fuencisla and Otaegui, David and Urcelay, Elena and Antig{\"u}edad, Alfredo and Malhotra, Sunny and Montalban, Xavier and Castillo-Trivi{\~n}o, Tamara and Espino-Pais{\´a}n, Laura and Aktas, Orhan and Buttmann, Mathias and Chan, Andrew and Fontaine, Bertrand and Gourraud, Pierre-Antoine and Hecker, Michael and Hoffjan, Sabine and Kubisch, Christian and K{\"u}mpfel, Tania and Luessi, Felix and Zettl, Uwe K. and Zipp, Frauke and Alloza, Iraide and Comabella, Manuel and Lill, Christina M. and Vandenbroeck, Koen}, title = {The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis}, series = {Cells}, volume = {9}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells9010175}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200769}, year = {2020}, abstract = {The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50\%-60\% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS.}, language = {en} } @article{ZieglerMeyerOtteetal.2022, author = {Ziegler, Alice and Meyer, Hanna and Otte, Insa and Peters, Marcell K. and Appelhans, Tim and Behler, Christina and B{\"o}hning-Gaese, Katrin and Classen, Alice and Detsch, Florian and Deckert, J{\"u}rgen and Eardley, Connal D. and Ferger, Stefan W. and Fischer, Markus and Gebert, Friederike and Haas, Michael and Helbig-Bonitz, Maria and Hemp, Andreas and Hemp, Claudia and Kakengi, Victor and Mayr, Antonia V. and Ngereza, Christine and Reudenbach, Christoph and R{\"o}der, Juliane and Rutten, Gemma and Schellenberger Costa, David and Schleuning, Matthias and Ssymank, Axel and Steffan-Dewenter, Ingolf and Tardanico, Joseph and Tschapka, Marco and Vollst{\"a}dt, Maximilian G. R. and W{\"o}llauer, Stephan and Zhang, Jie and Brandl, Roland and Nauss, Thomas}, title = {Potential of airborne LiDAR derived vegetation structure for the prediction of animal species richness at Mount Kilimanjaro}, series = {Remote Sensing}, volume = {14}, journal = {Remote Sensing}, number = {3}, issn = {2072-4292}, doi = {10.3390/rs14030786}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262251}, year = {2022}, abstract = {The monitoring of species and functional diversity is of increasing relevance for the development of strategies for the conservation and management of biodiversity. Therefore, reliable estimates of the performance of monitoring techniques across taxa become important. Using a unique dataset, this study investigates the potential of airborne LiDAR-derived variables characterizing vegetation structure as predictors for animal species richness at the southern slopes of Mount Kilimanjaro. To disentangle the structural LiDAR information from co-factors related to elevational vegetation zones, LiDAR-based models were compared to the predictive power of elevation models. 17 taxa and 4 feeding guilds were modeled and the standardized study design allowed for a comparison across the assemblages. Results show that most taxa (14) and feeding guilds (3) can be predicted best by elevation with normalized RMSE values but only for three of those taxa and two of those feeding guilds the difference to other models is significant. Generally, modeling performances between different models vary only slightly for each assemblage. For the remaining, structural information at most showed little additional contribution to the performance. In summary, LiDAR observations can be used for animal species prediction. However, the effort and cost of aerial surveys are not always in proportion with the prediction quality, especially when the species distribution follows zonal patterns, and elevation information yields similar results.}, language = {en} } @article{ChagtaiZillDaineseetal.2016, author = {Chagtai, Tasnim and Zill, Christina and Dainese, Linda and Wegert, Jenny and Savola, Suvi and Popov, Sergey and Mifsud, William and Vujanic, Gordan and Sebire, Neil and Le Bouc, Yves and Ambros, Peter F. and Kager, Leo and O`Sullivan, Maureen J. and Blaise, Annick and Bergeron, Christophe and Holmquist Mengelbier, Linda and Gisselsson, David and Kool, Marcel and Tytgat, Godelieve A.M. and van den Heuvel-Eibrink, Marry M. and Graf, Norbert and van Tinteren, Harm and Coulomb, Aurore and Gessler, Manfred and Williams, Richard Dafydd and Pritchard-Jones, Kathy}, title = {Gain of 1q As a Prognostic Biomarker in Wilms Tumors (WTs) Treated With Preoperative Chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 Trial: a SIOP Renal Tumours Biology Consortium Study}, series = {Journal of Clinical Oncology}, volume = {34}, journal = {Journal of Clinical Oncology}, number = {26}, doi = {10.1200/JCO.2015.66.0001}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-187478}, pages = {3195-3205}, year = {2016}, abstract = {Purpose Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results One hundred sixty-seven (28\%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0\% in patients with 1q gain (95\% CI, 68.5\% to 82.0\%) and 88.2\% in patients without gain (95\% CI, 85.0\% to 91.4\%). OS was 88.4\% with gain (95\% CI, 83.5\% to 93.6\%) and 94.4\% without gain (95\% CI, 92.1\% to 96.7\%). In univariable analysis, 1q gain was associated with poorer EFS (P<.001; hazard ratio, 2.33) and OS (P=.01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.}, language = {en} } @article{WeisschuhMayerStrometal.2016, author = {Weisschuh, Nicole and Mayer, Anja K. and Strom, Tim M. and Kohl, Susanne and Gl{\"o}ckle, Nicola and Schubach, Max and Andreasson, Sten and Bernd, Antje and Birch, David G. and Hamel, Christian P. and Heckenlively, John R. and Jacobson, Samuel G. and Kamme, Christina and Kellner, Ulrich and Kunstmann, Erdmute and Maffei, Pietro and Reiff, Charlotte M. and Rohrschneider, Klaus and Rosenberg, Thomas and Rudolph, G{\"u}nther and V{\´a}mos, Rita and Vars{\´a}nyi, Bal{\´a}zs and Weleber, Richard G. and Wissinger, Bernd}, title = {Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0145951}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167398}, pages = {e0145951}, year = {2016}, abstract = {Retinal dystrophies (RD) constitute a group of blinding diseases that are characterized by clinical variability and pronounced genetic heterogeneity. The different nonsyndromic and syndromic forms of RD can be attributed to mutations in more than 200 genes. Consequently, next generation sequencing (NGS) technologies are among the most promising approaches to identify mutations in RD. We screened a large cohort of patients comprising 89 independent cases and families with various subforms of RD applying different NGS platforms. While mutation screening in 50 cases was performed using a RD gene capture panel, 47 cases were analyzed using whole exome sequencing. One family was analyzed using whole genome sequencing. A detection rate of 61\% was achieved including mutations in 34 known and two novel RD genes. A total of 69 distinct mutations were identified, including 39 novel mutations. Notably, genetic findings in several families were not consistent with the initial clinical diagnosis. Clinical reassessment resulted in refinement of the clinical diagnosis in some of these families and confirmed the broad clinical spectrum associated with mutations in RD genes.}, language = {en} } @article{HeinzeSchirbelNannenetal.2021, author = {Heinze, Britta and Schirbel, Andreas and Nannen, Lukas and Michelmann, David and Hartrampf, Philipp E. and Bluemel, Christina and Schneider, Magdalena and Herrmann, Ken and Haenscheid, Heribert and Fassnacht, Martin and Buck, Andreas K. and Hahner, Stefanie}, title = {Novel CYP11B-ligand [\(^{123/131}\)I]IMAZA as promising theranostic tool for adrenocortical tumors: comprehensive preclinical characterization and first clinical experience}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {1}, issn = {1619-7089}, doi = {10.1007/s00259-021-05477-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265606}, pages = {301-310}, year = {2021}, abstract = {Purpose Adrenal tumors represent a diagnostic and therapeutic challenge. Promising results have been obtained through targeting the cytochrome P450 enzymes CYP11B1 and CYP11B2 for molecular imaging, and [\(^{123/131}\)I]iodometomidate ([\(^{123/131}\)I]IMTO) has even been successfully introduced as a theranostic agent. As this radiopharmaceutical shows rapid metabolic inactivation, we aimed at developing new improved tracers. Methods Several IMTO derivatives were newly designed by replacing the unstable methyl ester by different carboxylic esters or amides. The inhibition of aldosterone and cortisol synthesis was tested in different adrenocortical cell lines. The corresponding radiolabeled compounds were assessed regarding their stability, in vitro cell uptake, in vivo biodistribution in mice, and their binding specificity to cryosections of human adrenocortical and non-adrenocortical tissue. Furthermore, a first investigation was performed in patients with known metastatic adrenal cancer using both [\(^{123}\)I]IMTO and the most promising compound (R)-1-[1-(4-[\(^{123/}\)I]iodophenyl)ethyl]-1H-imidazole-5-carboxylic acid azetidinylamide ([\(^{123}\)I]IMAZA) for scintigraphy. Subsequently, a first endoradiotherapy with [\(^{131}\)I]IMAZA in one of these patients was performed. Results We identified three analogues to IMTO with high-affinity binding to the target enzymes and comparable or higher metabolic stability and very high and specific accumulation in adrenocortical cells in vitro and in vivo. Labeled IMAZA exhibited superior pharmacokinetic and imaging properties compared to IMTO in mice and 3 patients, too. An endoradiotherapy with [\(^{131}\)I]IMAZA induced a 21-month progression-free interval in a patient with rapidly progressing ACC prior this therapy. Conclusion We developed the new radiopharmaceutical [\(^{123/131}\)I]IMAZA with superior properties compared to the reference compound IMTO and promising first experiences in humans.}, language = {en} } @article{StolteHechtXieetal.2020, author = {Stolte, Matthias and Hecht, Reinhard and Xie, Zengqi and Liu, Linlin and Kaufmann, Christina and Kudzus, Astrid and Schmidt, David and W{\"u}rthner, Frank}, title = {Crystal Engineering of 1D Exciton Systems Composed of Single- and Double-Stranded Perylene Bisimide J-Aggregates}, series = {Advanced Optical Materials}, volume = {8}, journal = {Advanced Optical Materials}, number = {18}, doi = {10.1002/adom.202000926}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218221}, year = {2020}, abstract = {Single crystals of three at bay area tetraphenoxy-substituted perylene bisimide dyes are grown by vacuum sublimation. X-ray analysis reveals the self-assembly of these highly twisted perylene bisimides (PBIs) in the solid state via imide-imide hydrogen bonding into hydrogen-bonded PBI chains. The crystallographic insights disclose that the conformation and sterical congestion imparted by the phenoxy substituents can be controlled by ortho-substituents. Accordingly, whilst sterically less demanding methyl and isopropyl substituents afford double-stranded PBI chains of complementary P and M atropo-enantiomers, single hydrogen-bonded chains of homochiral PBIs are observed for the sterically more demanding ortho-phenyl substituents. Investigation of the absorption and fluorescence properties of microcrystals and thin films of these PBIs allow for an unambiguous interpretation of these exciton systems. Thus, the J-aggregates of the double-stranded crystals exhibit a much larger (negative) exciton coupling than the single-stranded one, which in contrast has the higher solid-state fluorescence quantum yield.}, language = {en} } @article{RolfesRuckDavidetal.2022, author = {Rolfes, Leoni and Ruck, Tobias and David, Christina and Mencl, Stine and Bock, Stefanie and Schmidt, Mariella and Strecker, Jan-Kolja and Pfeuffer, Steffen and Mecklenbeck, Andreas-Schulte and Gross, Catharina and Gliem, Michael and Minnerup, Jens and Schuhmann, Michael K. and Kleinschnitz, Christoph and Meuth, Sven G.}, title = {Natural Killer Cells Are Present in Rag1\(^{-/-}\) Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke}, series = {Translational Stroke Research}, volume = {13}, journal = {Translational Stroke Research}, number = {1}, issn = {1868-4483}, doi = {10.1007/s12975-021-00923-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308924}, pages = {197-211}, year = {2022}, abstract = {Rag1\(^{-/-}\) mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1\(^{-/-}\) mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1\(^{null}\)IL2rg\(^{null}\) (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1\(^{-/-}\) and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1\(^{-/-}\) NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1\(^{-/-}\) were comparable in number and function to those in WT mice. Rag1\(^{-/-}\) mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1-/- controls. Our results indicate that NK cells from Rag1-/- mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.}, language = {en} }