@article{GesslerLehmannBoeseletal.2021, author = {Gessler, Florian and Lehmann, Felix and B{\"o}sel, Julian and Fuhrer, Hannah and Neugebauer, Hermann and Wartenberg, Katja E. and Wolf, Stefan and Bernstock, Joshua D. and Niesen, Wolf-Dirk and Schuss, Patrick}, title = {Triage and Allocation of Neurocritical Care Resources During the COVID 19 Pandemic - A National Survey}, series = {Frontiers in Neurology}, volume = {11}, journal = {Frontiers in Neurology}, issn = {1664-2295}, doi = {10.3389/fneur.2020.609227}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221593}, year = {2021}, abstract = {Objective: In light of the ongoing COVID-19 pandemic and the associated hospitalization of an overwhelming number of ventilator-dependent patients, medical and/or ethical patient triage paradigms have become essential. While guidelines on the allocation of scarce resources do exist, such work within the subdisciplines of intensive care (e.g., neurocritical care) remains limited. Methods: A 16-item questionnaire was developed that sought to explore/quantify the expert opinions of German neurointensivists with regard to triage decisions. The anonymous survey was conducted via a web-based platform and in total, 96 members of the Initiative of German Neurointensive Trial Engagement (IGNITE)-study group were contacted via e-mail. The IGNITE consortium consists of an interdisciplinary panel of specialists with expertise in neuro-critical care (i.e., anesthetists, neurologists and neurosurgeons). Results: Fifty members of the IGNITE consortium responded to the questionnaire; in total the respondents were in charge of more than 500 Neuro ICU beds throughout Germany. Common determinants reported which affected triage decisions included known patient wishes (98\%), the state of health before admission (96\%), SOFA-score (85\%) and patient age (69\%). Interestingly, other principles of allocation, such as a treatment of "youngest first" (61\%) and members of the healthcare sector (50\%) were also noted. While these were the most accepted parameters affecting the triage of patients, a "first-come, first-served" principle appeared to be more accepted than a lottery for the allocation of ICU beds which contradicts much of what has been reported within the literature. The respondents also felt that at least one neurointensivist should serve on any interdisciplinary triage team. Conclusions: The data gathered in the context of this survey reveal the estimation/perception of triage algorithms among neurointensive care specialists facing COVID-19. Further, it is apparent that German neurointensivists strongly feel that they should be involved in any triage decisions at an institutional level given the unique resources needed to treat patients within the Neuro ICU.}, language = {en} } @article{BochSpiessHeinzetal.2019, author = {Boch, Tobias and Spiess, Birgit and Heinz, Werner and Cornely, Oliver A. and Schwerdtfeger, Rainer and Hahn, Joachim and Krause, Stefan W. and Duerken, Matthias and Bertz, Hartmut and Reuter, Stefan and Kiehl, Michael and Claus, Bernd and Deckert, Peter Markus and Hofmann, Wolf-Karsten and Buchheidt, Dieter and Reinwald, Mark}, title = {Aspergillus specific nested PCR from the site of infection is superior to testing concurrent blood samples in immunocompromised patients with suspected invasive aspergillosis}, series = {Mycoses}, volume = {62}, journal = {Mycoses}, number = {11}, doi = {10.1111/myc.12983}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214065}, pages = {1035 -- 1042}, year = {2019}, abstract = {Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time-consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus-specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high-risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85\%, sensitivity varied markedly in BAL (64\%), CSF (100\%), tissue samples (67\%) as opposed to concurrent blood samples (8\%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.}, language = {en} } @article{MeierjohannHufnagelWendeetal.2010, author = {Meierjohann, Svenja and Hufnagel, Anita and Wende, Elisabeth and Kleinschmidt, Markus A. and Wolf, Katarina and Friedl, Peter and Gaubatz, Stefan and Schartl, Manfred}, title = {MMP13 mediates cell cycle progression in melanocytes and melanoma cells: in vitro studies of migration and proliferation}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68335}, year = {2010}, abstract = {Background: Melanoma cells are usually characterized by a strong proliferative potential and efficient invasive migration. Among the multiple molecular changes that are recorded during progression of this disease, aberrant activation of receptor tyrosine kinases (RTK) is often observed. Activation of matrix metalloproteases goes along with RTK activation and usually enhances RTK-driven migration. The purpose of this study was to examine RTKdriven three-dimensional migration of melanocytes and the pro-tumorigenic role of matrix metalloproteases for melanocytes and melanoma cells. Results: Using experimental melanocyte dedifferentiation as a model for early melanomagenesis we show that an activated EGF receptor variant potentiates migration through three-dimensional fibrillar collagen. EGFR stimulation also resulted in a strong induction of matrix metalloproteases in a MAPK-dependent manner. However, neither MAPK nor MMP activity were required for migration, as the cells migrated in an entirely amoeboid mode. Instead, MMPs fulfilled a function in cell cycle regulation, as their inhibition resulted in strong growth inhibition of melanocytes. The same effect was observed in the human melanoma cell line A375 after stimulation with FCS. Using sh- and siRNA techniques, we could show that MMP13 is the protease responsible for this effect. Along with decreased proliferation, knockdown of MMP13 strongly enhanced pigmentation of melanocytes. Conclusions: Our data show for the first time that growth stimuli are mediated via MMP13 in melanocytes and melanoma, suggesting an autocrine MMP13-driven loop. Given that MMP13-specific inhibitors are already developed, these results support the evaluation of these inhibitors in the treatment of melanoma.}, subject = {Medizin}, language = {en} } @article{ProetelPletschLausekeretal.2014, author = {Proetel, Ulrike and Pletsch, Nadine and Lauseker, Michael and M{\"u}ller, Martin C. and Hanfstein, Benjamin and Krause, Stefan W. and Kalmanti, Lida and Schreiber, Annette and Heim, Dominik and Baerlocher, Gabriela M. and Hofmann, Wolf-Karsten and Lange, Elisabeth and Einsele, Hermann and Wernli, Martin and Kremers, Stephan and Schlag, Rudolf and M{\"u}ller, Lothar and H{\"a}nel, Mathias and Link, Hartmut and Hertenstein, Bernd and Pfirrmann, Markus and Hochhaus, Andreas and Hasford, Joerg and Hehlmann, R{\"u}diger and Saußele, Susanne}, title = {Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV}, series = {Annals of Hematology}, volume = {93}, journal = {Annals of Hematology}, number = {7}, issn = {0939-5555}, doi = {10.1007/s00277-014-2041-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121574}, pages = {1167-76}, year = {2014}, abstract = {The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 \%) on IM400 and 83 (21 \%) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874}, language = {en} } @article{OttoRubenwolfBurgeretal.2012, author = {Otto, Wolfgang and Rubenwolf, Peter C. and Burger, Maximilian and Fritsche, Hans-Martin and R{\"o}ßler, Wolfgang and May, Matthias and Hartmann, Arndt and Hofst{\"a}dter, Ferdinand and Wieland, Wolf F. and Denzinger, Stefan}, title = {Loss of aquaporin 3 protein expression constitutes an independent prognostic factor for progression-free survival: an immunohistochemical study on stage pT1 urothelial bladder cancer}, series = {BMC Cancer}, volume = {12}, journal = {BMC Cancer}, number = {459}, doi = {10.1186/1471-2407-12-459}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135679}, year = {2012}, abstract = {Background: Treatment of patients with stage pT1 urothelial bladder cancer (UBC) continues to be a challenge due to its unpredictable clinical course. Reliable molecular markers that help to determine appropriate individual treatment are still lacking. Loss of aquaporin (AQP) 3 protein expression has previously been shown in muscle-invasive UBC. The aim of the present study was to investigate the prognostic value of AQP3 protein expression with regard to the prognosis of stage pT1 UBC. Method: AQP 3 protein expression was investigated by immunohistochemistry in specimens of 87 stage T1 UBC patients, who were diagnosed by transurethral resection of the bladder (TURB) and subsequent second resection at a high-volume urological centre between 2002 and 2009. Patients underwent adjuvant instillation therapy with Bacillus Calmette-Guerin (BCG). Loss of AQP3 protein expression was defined as complete absence of the protein within the whole tumour. Expression status was correlated retrospectively with clinicopathological and follow-up data (median: 31 months). Multivariate Cox regression analysis was used to assess the value of AQP3 tumour expression with regard to recurrence-free (RFS), progression-free (PFS) and cancer-specific survival (CSS). RFS, PFS and CSS were calculated by Kaplan-Meier analysis and Log rank test. Results: 59\% of patients were shown to exhibit AQP3-positive tumours, whereas 41\% of tumours did not express the marker. Loss of AQP3 protein expression was associated with a statistically significantly worse PFS (20\% vs. 72\%, p=0.020). This finding was confirmed by multivariate Cox regression analysis (HR 7.58, CI 1.29 - 44.68; p=0.025). Conclusions: Loss of AQP3 protein expression in pT1 UBC appears to play a key role in disease progression and is associated with worse PFS. Considering its potential prognostic value, assessment of AQP3 protein expression could be used to help stratify the behavior of patients with pT1 UBC.}, language = {en} } @article{GroteNoeldekeBlauthetal.2013, author = {Grote, Stefan and Noeldeke, Tatjana and Blauth, Michael and Mutschler, Wolf and B{\"u}rklein, Dominik}, title = {Mechanical torque measurement in the proximal femur correlates to failure load and bone mineral density ex vivo}, series = {Orthopedic Reviews (Pavia)}, volume = {5}, journal = {Orthopedic Reviews (Pavia)}, number = {e16}, doi = {10.4081/or.2013.e16}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132358}, year = {2013}, abstract = {Knowledge of local bone quality is essential for surgeons to determine operation techniques. A device for intraoperative measurement of local bone quality has been developed by the AO-Research Foundation (DensiProbe®). We used this device to experimentally measure peak breakaway torque of trabecular bone in the proximal femur and correlated this with local bone mineral density (BMD) and failure load. Bone mineral density of 160 cadaver femurs was measured by ex situ dual-energy X-ray absorptiometry. The failure load of all femurs was analyzed by side-impact analysis. Femur fractures were fixed and mechanical peak torque was measured with the DensiProbe® device. Correlation was calculated whereas correlation coefficient and significance was calculated by Fisher's Z-transformation. Moreover, linear regression analysis was carried out. The unpaired Student's t-test was used to assess the significance of differences. The Ward triangle region had the lowest BMD with 0.511 g/cm2 (±0.17 g/cm2), followed by the upper neck region with 0.546 g/cm2 (±0.16 g/cm2), trochanteric region with 0.685 g/cm2 (±0.19 g/cm2) and the femoral neck with 0.813 g/cm2 (±0.2 g/cm2). Peak torque of DensiProbe® in the femoral head was 3.48 Nm (±2.34 Nm). Load to failure was 4050.2 N (±1586.7 N). The highest correlation of peak torque measured by Densi Probe® and load to failure was found in the femoral neck (r=0.64, P<0.001). The overall correlation of mechanical peak torque with T-score was r=0.60 (P<0.001). A correlation was found between mechanical peak torque, load to failure of bone and BMD in vitro. Trabecular strength of bone and bone mineral density are different aspects of bone strength, but a correlation was found between them. Mechanical peak torque as measured may contribute additional information about bone strength, especially in the perioperative testing.}, language = {en} } @article{HanfsteinLausekerHehlmannetal.2014, author = {Hanfstein, Benjamin and Lauseker, Michael and Hehlmann, R{\"u}diger and Saussele, Susanne and Erben, Philipp and Dietz, Christian and Fabarius, Alice and Proetel, Ulrike and Schnittger, Susanne and Haferlach, Claudia and Krause, Stefan W. and Schubert, J{\"o}rg and Einsele, Hermann and H{\"a}nel, Mathias and Dengler, Jolanta and Falge, Christiane and Kanz, Lothar and Neubauer, Andreas and Kneba, Michael and Stengelmann, Frank and Pfreundschuh, Michael and Waller, Cornelius F. and Spiekerman, Karsten and Baerlocher, Gabriela M. and Pfirrmann, Markus and Hasford, Joerg and Hofmann, Wolf-Karsten and Hochhaus, Andreas and M{\"u}ller, Martin C.}, title = {Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib}, series = {Haematologica}, volume = {99}, journal = {Haematologica}, number = {9}, issn = {1592-8721}, doi = {10.3324/haematol.2013.096537}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115476}, pages = {1441-1447}, year = {2014}, abstract = {The vast majority of chronic myeloid leukemia patients express a BCR-ABL1 fusion gene mRNA encoding a 210 kDa tyrosine kinase which promotes leukemic transformation. A possible differential impact of the corresponding BCR-ABL1 transcript variants e13a2 ("b2a2") and e14a2 ("b3a2") on disease phenotype and outcome is still a subject of debate. A total of 1105 newly diagnosed imatinib-treated patients were analyzed according to transcript type at diagnosis (e13a2, n=451; e14a2, n=496; e13a2+e14a2, n=158). No differences regarding age, sex, or Euro risk score were observed. A significant difference was found between e13a2 and e14a2 when comparing white blood cells (88 vs. 65 x 10(9)/L, respectively; P<0.001) and platelets (296 vs. 430 x 109/L, respectively; P<0.001) at diagnosis, indicating a distinct disease phenotype. No significant difference was observed regarding other hematologic features, including spleen size and hematologic adverse events, during imatinib-based therapies. Cumulative molecular response was inferior in e13a2 patients (P=0.002 for major molecular response; P<0.001 for MR4). No difference was observed with regard to cytogenetic response and overall survival. In conclusion, e13a2 and e14a2 chronic myeloid leukemia seem to represent distinct biological entities. However, clinical outcome under imatinib treatment was comparable and no risk prediction can be made according to e13a2 versus e14a2 BCR-ABL1 transcript type at diagnosis. (clinicaltrials.gov identifier: 00055874)}, language = {en} } @article{HudsonNewboldContuetal.2014, author = {Hudson, Lawrence N. and Newbold, Tim and Contu, Sara and Hill, Samantha L. L. and Lysenko, Igor and De Palma, Adriana and Phillips, Helen R. P. and Senior, Rebecca A. and Bennett, Dominic J. and Booth, Hollie and Choimes, Argyrios and Correia, David L. P. and Day, Julie and Echeverria-Londono, Susy and Garon, Morgan and Harrison, Michelle L. K. and Ingram, Daniel J. and Jung, Martin and Kemp, Victoria and Kirkpatrick, Lucinda and Martin, Callum D. and Pan, Yuan and White, Hannah J. and Aben, Job and Abrahamczyk, Stefan and Adum, Gilbert B. and Aguilar-Barquero, Virginia and Aizen, Marcelo and Ancrenaz, Marc and Arbelaez-Cortes, Enrique and Armbrecht, Inge and Azhar, Badrul and Azpiroz, Adrian B. and Baeten, Lander and B{\´a}ldi, Andr{\´a}s and Banks, John E. and Barlow, Jos and Bat{\´a}ry, P{\´e}ter and Bates, Adam J. and Bayne, Erin M. and Beja, Pedro and Berg, Ake and Berry, Nicholas J. and Bicknell, Jake E. and Bihn, Jochen H. and B{\"o}hning-Gaese, Katrin and Boekhout, Teun and Boutin, Celine and Bouyer, Jeremy and Brearley, Francis Q. and Brito, Isabel and Brunet, J{\"o}rg and Buczkowski, Grzegorz and Buscardo, Erika and Cabra-Garcia, Jimmy and Calvino-Cancela, Maria and Cameron, Sydney A. and Cancello, Eliana M. and Carrijo, Tiago F. and Carvalho, Anelena L. and Castro, Helena and Castro-Luna, Alejandro A. and Cerda, Rolando and Cerezo, Alexis and Chauvat, Matthieu and Clarke, Frank M. and Cleary, Daniel F. R. and Connop, Stuart P. and D'Aniello, Biagio and da Silva, Pedro Giovani and Darvill, Ben and Dauber, Jens and Dejean, Alain and Diek{\"o}tter, Tim and Dominguez-Haydar, Yamileth and Dormann, Carsten F. and Dumont, Bertrand and Dures, Simon G. and Dynesius, Mats and Edenius, Lars and Elek, Zolt{\´a}n and Entling, Martin H. and Farwig, Nina and Fayle, Tom M. and Felicioli, Antonio and Felton, Annika M. and Ficetola, Gentile F. and Filgueiras, Bruno K. C. and Fonte, Steve J. and Fraser, Lauchlan H. and Fukuda, Daisuke and Furlani, Dario and Ganzhorn, J{\"o}rg U. and Garden, Jenni G. and Gheler-Costa, Carla and Giordani, Paolo and Giordano, Simonetta and Gottschalk, Marco S. and Goulson, Dave and Gove, Aaron D. and Grogan, James and Hanley, Mick E. and Hanson, Thor and Hashim, Nor R. and Hawes, Joseph E. and H{\´e}bert, Christian and Helden, Alvin J. and Henden, John-Andr{\´e} and Hern{\´a}ndez, Lionel and Herzog, Felix and Higuera-Diaz, Diego and Hilje, Branko and Horgan, Finbarr G. and Horv{\´a}th, Roland and Hylander, Kristoffer and Horv{\´a}th, Roland and Isaacs-Cubides, Paola and Ishitani, Mashiro and Jacobs, Carmen T. and Jaramillo, Victor J. and Jauker, Birgit and Jonsell, Matts and Jung, Thomas S. and Kapoor, Vena and Kati, Vassiliki and Katovai, Eric and Kessler, Michael and Knop, Eva and Kolb, Annette and K{\"o}r{\"o}si, {\`A}d{\´a}m and Lachat, Thibault and Lantschner, Victoria and Le F{\´e}on, Violette and LeBuhn, Gretchen and L{\´e}gar{\´e}, Jean-Philippe and Letcher, Susan G. and Littlewood, Nick A. and L{\´o}pez-Quintero, Carlos A. and Louhaichi, Mounir and L{\"o}vei, Gabor L. and Lucas-Borja, Manuel Esteban and Luja, Victor H. and Maeto, Kaoru and Magura, Tibor and Mallari, Neil Aldrin and Marin-Spiotta, Erika and Marhall, E. J. P. and Mart{\´i}nez, Eliana and Mayfield, Margaret M. and Mikusinski, Gregorz and Milder, Jeffery C. and Miller, James R. and Morales, Carolina L. and Muchane, Mary N. and Muchane, Muchai and Naidoo, Robin and Nakamura, Akihiro and Naoe, Shoji and Nates-Parra, Guiomar and Navarerete Gutierrez, Dario A. and Neuschulz, Eike L. and Noreika, Norbertas and Norfolk, Olivia and Noriega, Jorge Ari and N{\"o}ske, Nicole M. and O'Dea, Niall and Oduro, William and Ofori-Boateng, Caleb and Oke, Chris O. and Osgathorpe, Lynne M. and Paritsis, Juan and Parrah, Alejandro and Pelegrin, Nicol{\´a}s and Peres, Carlos A. and Persson, Anna S. and Petanidou, Theodora and Phalan, Ben and Philips, T. Keith and Poveda, Katja and Power, Eileen F. and Presley, Steven J. and Proen{\c{c}}a, V{\^a}nia and Quaranta, Marino and Quintero, Carolina and Redpath-Downing, Nicola A. and Reid, J. Leighton and Reis, Yana T. and Ribeiro, Danilo B. and Richardson, Barbara A. and Richardson, Michael J. and Robles, Carolina A. and R{\"o}mbke, J{\"o}rg and Romero-Duque, Luz Piedad and Rosselli, Loreta and Rossiter, Stephen J. and Roulston, T'ai H. and Rousseau, Laurent and Sadler, Jonathan P. and S{\´a}fi{\´a}n, Szbolcs and Salda{\~n}a-V{\´a}squez, Romeo A. and Samneg{\aa}rd, Ulrika and Sch{\"u}epp, Christof and Schweiger, Oliver and Sedlock, Jodi L. and Shahabuddin, Ghazala and Sheil, Douglas and Silva, Fernando A. B. and Slade, Eleanor and Smith-Pardo, Allan H. and Sodhi, Navjot S. and Somarriba, Eduardo J. and Sosa, Ram{\´o}n A. and Stout, Jane C. and Struebig, Matthew J. and Sung, Yik-Hei and Threlfall, Caragh G. and Tonietto, Rebecca and T{\´o}thm{\´e}r{\´e}sz, B{\´e}la and Tscharntke, Teja and Turner, Edgar C. and Tylianakis, Jason M. and Vanbergen, Adam J. and Vassilev, Kiril and Verboven, Hans A. F. and Vergara, Carlos H. and Vergara, Pablo M. and Verhulst, Jort and Walker, Tony R. and Wang, Yanping and Watling, James I. and Wells, Konstans and Williams, Christopher D. and Willig, Michael R. and Woinarski, John C. Z. and Wolf, Jan H. D. and Woodcock, Ben A. and Yu, Douglas W. and Zailsev, Andreys and Collen, Ben and Ewers, Rob M. and Mace, Georgina M. and Purves, Drew W. and Scharlemann, J{\"o}rn P. W. and Pervis, Andy}, title = {The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts}, series = {Ecology and Evolution}, volume = {4}, journal = {Ecology and Evolution}, number = {24}, doi = {10.1002/ece3.1303}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114425}, pages = {4701 - 4735}, year = {2014}, abstract = {Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1\% of the total number of all species described, and more than 1\% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.}, language = {en} } @article{SimonRauskolbGunnersenetal.2015, author = {Simon, Christian M. and Rauskolb, Stefanie and Gunnersen, Jennifer M. and Holtmann, Bettina and Drepper, Carsten and Dombert, Benjamin and Braga, Massimiliano and Wiese, Stefan and Jablonka, Sibylle and P{\"u}hringer, Dirk and Zielasek, J{\"u}rgen and Hoeflich, Andreas and Silani, Vincenzo and Wolf, Eckhard and Kneitz, Susanne and Sommer, Claudia and Toyka, Klaus V. and Sendtner, Michael}, title = {Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy}, series = {Acta Neuropathologica}, volume = {130}, journal = {Acta Neuropathologica}, doi = {10.1007/s00401-015-1446-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154569}, pages = {373 -- 387}, year = {2015}, abstract = {Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.}, language = {en} } @article{MurakawaHinzMothesetal.2015, author = {Murakawa, Yasuhiro and Hinz, Michael and Mothes, Janina and Schuetz, Anja and Uhl, Michael and Wyler, Emanuel and Yasuda, Tomoharu and Mastrobuoni, Guido and Friedel, Caroline C. and D{\"o}lken, Lars and Kempa, Stefan and Schmidt-Supprian, Marc and Bl{\"u}thgen, Nils and Backofen, Rolf and Heinemann, Udo and Wolf, Jana and Scheidereit, Claus and Landthaler, Markus}, title = {RC3H1 post-transcriptionally regulates A20 mRNA and modulates the activity of the IKK/NF-\(\kappa\)B pathway}, series = {Nature Communications}, volume = {6}, journal = {Nature Communications}, number = {7367}, doi = {10.1038/ncomms8367}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151596}, year = {2015}, abstract = {The RNA-binding protein RC3H1 (also known as ROQUIN) promotes TNF\(\alpha\) mRNA decay via a 3'UTR constitutive decay element (CDE). Here we applied PAR-CLIP to human RC3H1 to identify ~3,800 mRNA targets with >16,000 binding sites. A large number of sites are distinct from the consensus CDE and revealed a structure-sequence motif with U-rich sequences embedded in hairpins. RC3H1 binds preferentially short-lived and DNA damage-induced mRNAs, indicating a role of this RNA-binding protein in the post-transcriptional regulation of the DNA damage response. Intriguingly, RC3H1 affects expression of the NF-\(\kappa\)B pathway regulators such as I\(\kappa\)B\(\alpha\) and A20. RC3H1 uses ROQ and Zn-finger domains to contact a binding site in the A20 3'UTR, demonstrating a not yet recognized mode of RC3H1 binding. Knockdown of RC3H1 resulted in increased A20 protein expression, thereby interfering with I\(\kappa\)B kinase and NF-\(\kappa\)B activities, demonstrating that RC3H1 can modulate the activity of the IKK/NF-\(\kappa\)B pathway.}, language = {en} } @article{SausseleHehlmannFabariusetal.2018, author = {Saussele, Susanne and Hehlmann, Ruediger and Fabarius, Alice and Jeromin, Sabine and Proetel, Ulrike and Rinaldetti, Sebastien and Kohlbrenner, Katharina and Einsele, Hermann and Falge, Christine and Kanz, Lothar and Neubauer, Andreas and Kneba, Michael and Stegelmann, Frank and Pfreundschuh, Michael and Waller, Cornelius F. and Oppliger Leibundgut, Elisabeth and Heim, Dominik and Krause, Stefan W. and Hofmann, Wolf-Karsten and Hasford, Joerg and Pfirrmann, Markus and M{\"u}ller, Martin C. and Hochhaus, Andreas and Lauseker, Michael}, title = {Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV}, series = {Leukemia}, volume = {32}, journal = {Leukemia}, number = {5}, doi = {10.1038/s41375-018-0055-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227528}, pages = {1222-1228}, year = {2018}, abstract = {Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1\% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.}, language = {en} } @article{RinaldettiPfirrmannManzetal.2018, author = {Rinaldetti, S{\´e}bastien and Pfirrmann, Markus and Manz, Kirsi and Guilhot, Joelle and Dietz, Christian and Panagiotidis, Panayiotidis and Spiess, Birgit and Seifarth, Wolfgang and Fabarius, Alice and M{\"u}ller, Martin and Pagoni, Maria and Dimou, Maria and Dengler, Jolanta and Waller, Cornelius F. and Br{\"u}mmendorf, Tim H. and Herbst, Regina and Burchert, Andreas and Janßen, Carsten and Goebeler, Maria Elisabeth and Jost, Philipp J. and Hanzel, Stefan and Schafhausen, Philippe and Prange-Krex, Gabriele and Illmer, Thomas and Janzen, Viktor and Klausmann, Martine and Eckert, Robert and B{\"u}schel, Gerd and Kiani, Alexander and Hofmann, Wolf-Karsten and Mahon, Fran{\c{c}}ois-Xavier and Saussele, Susanne}, title = {Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial}, series = {Clinical Lymphoma, Myeloma \& Leukemia}, volume = {18}, journal = {Clinical Lymphoma, Myeloma \& Leukemia}, number = {4}, doi = {10.1016/j.clml.2018.02.004}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226281}, pages = {266-271}, year = {2018}, abstract = {Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54\% (95\% confidence interval [CI], 46\%-62\%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95\% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47\% (95\% CI, 37\%-57\%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72\% (95\% CI, 55\%-82\%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.}, language = {en} } @article{SchulzRuppertHermsetal.2017, author = {Schulz, Herbert and Ruppert, Ann-Kathrin and Herms, Stefan and Wolf, Christiane and Mirza-Schreiber, Nazanin and Stegle, Oliver and Czamara, Darina and Forstner, Andreas J. and Sivalingam, Sugirthan and Schoch, Susanne and Moebus, Susanne and P{\"u}tz, Benno and Hillmer, Axel and Fricker, Nadine and Vatter, Hartmut and M{\"u}ller-Myhsok, Bertram and N{\"o}then, Markus M. and Becker, Albert J. and Hoffmann, Per and Sander, Thomas and Cichon, Sven}, title = {Genome-wide mapping of genetic determinants influencing DNA methylation and gene expression in human hippocampus}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, doi = {10.1038/s41467-017-01818-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173168}, year = {2017}, abstract = {Emerging evidence emphasizes the strong impact of regulatory genomic elements in neurodevelopmental processes and the complex pathways of brain disorders. The present genome-wide quantitative trait loci analyses explore the \(cis\)-regulatory effects of single-nucleotide polymorphisms (SNPs) on DNA methylation (meQTL) and gene expression (eQTL) in 110 human hippocampal biopsies. We identify \(cis\)-meQTLs at 14,118 CpG methylation sites and \(cis\)-eQTLs for 302 3′-mRNA transcripts of 288 genes. Hippocampal \(cis\)-meQTL-CpGs are enriched in flanking regions of active promoters, CpG island shores, binding sites of the transcription factor CTCF and brain eQTLs. \(Cis\)-acting SNPs of hippocampal meQTLs and eQTLs significantly overlap schizophrenia-associated SNPs. Correlations of CpG methylation and RNA expression are found for 34 genes. Our comprehensive maps of \(cis\)-acting hippocampal meQTLs and eQTLs provide a link between disease-associated SNPs and the regulatory genome that will improve the functional interpretation of non-coding genetic variants in the molecular genetic dissection of brain disorders.}, language = {en} } @article{WallaschekReuterSilkenatetal.2021, author = {Wallaschek, Nina and Reuter, Saskia and Silkenat, Sabrina and Wolf, Katharina and Niklas, Carolin and {\"O}zge, Kayisoglu and Aguilar, Carmen and Wiegering, Armin and Germer, Christoph-Thomas and Kircher, Stefan and Rosenwald, Andreas and Shannon-Lowe, Claire and Bartfeld, Sina}, title = {Ephrin receptor A2, the epithelial receptor for Epstein-Barr virus entry, is not available for efficient infection in human gastric organoids}, series = {PLoS Pathogens}, volume = {17}, journal = {PLoS Pathogens}, number = {2}, doi = {10.1371/journal.ppat.1009210}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259206}, pages = {e1009210}, year = {2021}, abstract = {Epstein-Barr virus (EBV) is best known for infection of B cells, in which it usually establishes an asymptomatic lifelong infection, but is also associated with the development of multiple B cell lymphomas. EBV also infects epithelial cells and is associated with all cases of undifferentiated nasopharyngeal carcinoma (NPC). EBV is etiologically linked with at least 8\% of gastric cancer (EBVaGC) that comprises a genetically and epigenetically distinct subset of GC. Although we have a very good understanding of B cell entry and lymphomagenesis, the sequence of events leading to EBVaGC remains poorly understood. Recently, ephrin receptor A2 (EPHA2) was proposed as the epithelial cell receptor on human cancer cell lines. Although we confirm some of these results, we demonstrate that EBV does not infect healthy adult stem cell-derived gastric organoids. In matched pairs of normal and cancer-derived organoids from the same patient, EBV only reproducibly infected the cancer organoids. While there was no clear pattern of differential expression between normal and cancer organoids for EPHA2 at the RNA and protein level, the subcellular location of the protein differed markedly. Confocal microscopy showed EPHA2 localization at the cell-cell junctions in primary cells, but not in cancer cell lines. Furthermore, histologic analysis of patient tissue revealed the absence of EBV in healthy epithelium and presence of EBV in epithelial cells from inflamed tissue. These data suggest that the EPHA2 receptor is not accessible to EBV on healthy gastric epithelial cells with intact cell-cell contacts, but either this or another, yet to be identified receptor may become accessible following cellular changes induced by inflammation or transformation, rendering changes in the cellular architecture an essential prerequisite to EBV infection.}, language = {en} } @article{PattschullWalzGruendletal.2019, author = {Pattschull, Grit and Walz, Susanne and Gr{\"u}ndl, Marco and Schwab, Melissa and R{\"u}hl, Eva and Baluapuri, Apoorva and Cindric-Vranesic, Anita and Kneitz, Susanne and Wolf, Elmar and Ade, Carsten P. and Rosenwald, Andreas and von Eyss, Bj{\"o}rn and Gaubatz, Stefan}, title = {The Myb-MuvB complex is required for YAP-dependent transcription of mitotic genes}, series = {Cell Reports}, volume = {27}, journal = {Cell Reports}, number = {12}, doi = {10.1016/j.celrep.2019.05.071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202039}, pages = {3533-3546}, year = {2019}, abstract = {YAP and TAZ, downstream effectors of the Hippo pathway, are important regulators of proliferation. Here, we show that the ability of YAP to activate mitotic gene expression is dependent on the Myb-MuvB (MMB) complex, a master regulator of genes expressed in the G2/M phase of the cell cycle. By carrying out genome-wide expression and binding analyses, we found that YAP promotes binding of the MMB subunit B-MYB to the promoters of mitotic target genes. YAP binds to B-MYB and stimulates B-MYB chromatin association through distal enhancer elements that interact with MMB-regulated promoters through chromatin looping. The cooperation between YAP and B-MYB is critical for YAP-mediated entry into mitosis. Furthermore, the expression of genes coactivated by YAP and B-MYB is associated with poor survival of cancer patients. Our findings provide a molecular mechanism by which YAP and MMB regulate mitotic gene expression and suggest a link between two cancer-relevant signaling pathways.}, language = {en} } @article{TopsakalAgrawalAtlasetal.2022, author = {Topsakal, Vedat and Agrawal, Sumit and Atlas, Marcus and Baumgartner, Wolf-Dieter and Brown, Kevin and Bruce, Iain A. and Dazert, Stefan and Hagen, Rudolf and Lassaletta, Luis and Mlynski, Robert and Raine, Christopher H. and Rajan, Gunesh P. and Schmutzhard, Joachim and Sprinzl, Georg Mathias and Staecker, Hinrich and Usami, Shin-ichi and Van Rompaey, Vincent and Zernotti, Mario and Heyning, Paul van de}, title = {Minimally traumatic cochlear implant surgery: expert opinion in 2010 and 2020}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {10}, issn = {2075-4426}, doi = {10.3390/jpm12101551}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288196}, year = {2022}, abstract = {This study aimed to discover expert opinion on the surgical techniques and materials most likely to achieve maximum postoperative residual hearing preservation in cochlear implant (CI) surgery and to determine how these opinions have changed since 2010. A previously published questionnaire used in a study published in 2010 was adapted and expanded. The questionnaire was distributed to an international group of experienced CI surgeons. Present results were compared, via descriptive statistics, to those from the 2010 survey. Eighteen surgeons completed the questionnaire. Respondents clearly favored the following: round window insertion, slow array insertion, and the peri- and postoperative use of systematic antibiotics. Insertion depth was regarded as important, and electrode arrays less likely to induce trauma were preferred. The usefulness of dedicated soft-surgery training was also recognized. A lack of agreement was found on whether the middle ear cavity should be flushed with a non-aminoglycoside antibiotic solution or whether a sheath or insertion tube should be used to avoid contaminating the array with blood or bone dust. In conclusion, this paper demonstrates how beliefs about CI soft surgery have changed since 2010 and shows areas of current consensus and disagreement.}, language = {en} } @article{PinkawaAebersoldBoehmeretal.2021, author = {Pinkawa, Michael and Aebersold, Daniel M. and B{\"o}hmer, Dirk and Flentje, Michael and Ghadjar, Pirus and Schmidt-Hegemann, Nina-Sophie and H{\"o}cht, Stefan and H{\"o}lscher, Tobias and M{\"u}ller, Arndt-Christian and Niehoff, Peter and Sedlmayer, Felix and Wolf, Frank and Zamboglou, Constantinos and Zips, Daniel and Wiegel, Thomas}, title = {Radiotherapy in nodal oligorecurrent prostate cancer}, series = {Strahlentherapie und Onkologie}, volume = {197}, journal = {Strahlentherapie und Onkologie}, number = {7}, issn = {0179-7158}, doi = {10.1007/s00066-021-01778-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307763}, pages = {575-580}, year = {2021}, abstract = {Objective The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer. Materials and methods A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations. Results Metastasis-directed radiotherapy results in high local control (often > 90\% within a follow-up of 1-2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels. Conclusion ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.}, language = {en} }