@article{FreyGassenmaierHofmannetal.2020, author = {Frey, Anna and Gassenmaier, Tobias and Hofmann, Ulrich and Schmitt, Dominik and Fette, Georg and Marx, Almuth and Heterich, Sabine and Boivin-Jahns, Val{\´e}rie and Ertl, Georg and Bley, Thorsten and Frantz, Stefan and Jahns, Roland and St{\"o}rk, Stefan}, title = {Coagulation factor XIII activity predicts left ventricular remodelling after acute myocardial infarction}, series = {ESC Heart Failure}, volume = {7}, journal = {ESC Heart Failure}, number = {5}, doi = {10.1002/ehf2.12774}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236013}, pages = {2354-2364}, year = {2020}, abstract = {Aims Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing. Methods and results This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13\% women). Median FXIIIa was 118 \% (quartiles, 102-132\%) and dropped to a trough on the second day after MI: 109\%(98-109\%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124 \% (110-142\%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman's ρ = -0.31; P = 0.01) and Scan 3 (ρ = -0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively. Conclusions FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial.}, language = {en} } @article{MorbachBeyersdorfKerkauetal.2021, author = {Morbach, Caroline and Beyersdorf, Niklas and Kerkau, Thomas and Ramos, Gustavo and Sahiti, Floran and Albert, Judith and Jahns, Roland and Ertl, Georg and Angermann, Christiane E. and Frantz, Stefan and Hofmann, Ulrich and St{\"o}rk, Stefan}, title = {Adaptive anti-myocardial immune response following hospitalization for acute heart failure}, series = {ESC Heart Failure}, volume = {8}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258907}, pages = {3348-3353}, year = {2021}, abstract = {Aims It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. Methods and results AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49\%) female, and 24 (51\%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45\%) to F6 (n = 36, 77\%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88\%) compared with patients with reduced ejection fraction (n = 14, 61\%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95\% confidence interval 1.13-20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. Conclusions Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.}, 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{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @phdthesis{Hofmann2017, author = {Hofmann, Stefan}, title = {Hybridisierungsbasierte Multiplex-Detektion von microRNA mit CMOS-Technologie f{\"u}r die Anwendung in der Point-of-Care-Diagnostik}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-150949}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2017}, abstract = {MicroRNAs sind kurze, nicht-kodierende Ribonukleins{\"a}uren, die eine wichtige Rolle bei der Genregulation spielen. Sie sind an vielen physiologischen Prozessen beteiligt und werden als vielversprechende Kandidaten f{\"u}r eine neue Generation von Biomarkern gehandelt. Die Quantifizierung von miRNAs aus Blut oder anderen K{\"o}rperfl{\"u}ssigkeiten verspricht eine fr{\"u}he Diagnose verschiedener Krankheitsbilder. Dazu z{\"a}hlen neben zahlreichen Krebsformen unter anderem auch Autoimmun- oder Herz-Kreislauferkrankungen. Um diese Biomarker schnell, sensitiv und spezifisch detektieren zu k{\"o}nnen, werden geeignete Detektionssysteme ben{\"o}tigt. Dabei liegt ein besonderer Fokus auf der Entwicklung von Point-of-Care-Systemen, die eine automatisierte Durchf{\"u}hrung mit einfacher Handhabung verlangen. Mikrochips k{\"o}nnen als leistungsf{\"a}hige technische Hilfsmittel f{\"u}r eine robuste und miniaturisierte Signalerfassung an biochemischen Grenzfl{\"a}chen dienen. Auf der Grundlage eines CMOS-Chips mit einem Sensorarray aus interdigitalen Gold-Elektroden sollte in dieser Arbeit eine quantitative und multiplexf{\"a}hige miRNA-Detektionsmethode mit elektrochemischer Signaltransduktion entworfen und untersucht werden. Weitere wichtige Zielfaktoren waren eine einfache und schnelle Durchf{\"u}hrbarkeit, eine hohe Spezifit{\"a}t und eine gute Sensitivit{\"a}t bei gleichzeitigem Verzicht auf Amplifikation und Vormarkierung des Ausgangsmaterials. Es wurden verschiedene Methoden entworfen, {\"u}berpr{\"u}ft, untersucht, optimiert und weiterentwickelt. Das beste Ergebnis wurde letztlich mit einem als Sandwich-Ligations-Methode bezeichneten Verfahren erzielt. Dabei wird zun{\"a}chst ein aus zwei doppelstr{\"a}ngigen Assay-Komponenten und der Ziel-miRNA bestehender dreiteiliger Hybridisierungskomplex gebildet, der eine beidseitige spezifische Ligation der miRNA mit einem auf der Sensoroberfl{\"a}che immobilisierten F{\"a}ngerstrang und einem enzymmarkierten Reporterstrang vermittelt. Durch einen anschließenden Waschschritt werden alle {\"u}bersch{\"u}ssigen Markierungen vom Detektionsbereich entfernt, so dass bei der Detektion nur Reporterenzyme ausgelesen werden, die {\"u}ber die Ziel-miRNA kovalent mit dem immobilisierten Strang verbunden sind. Dieses Signal ist daher proportional zur Ausgangskonzentration der gesuchten miRNA. Die Methode wurde mit Hilfe von synthetischen miRNAs etabliert und optimiert. Sie erreichte eine analytische Sensitivit{\"a}t von unter 1 pM Ziel-Nukleins{\"a}ure bei einer Gesamt-Versuchsdauer von nur 30 Minuten. Konzentrationsreihen demonstrierten einen linearen dynamischen Messbereich zwischen 1 pM und 1 nM, der eine verl{\"a}ssliche Quantifizierung der detektierten miRNAs in diesem Bereich erm{\"o}glicht. Die sehr gute Spezfifit{\"a}t des Assays zeigte sich bei der Untersuchung des Einflusses verschiedener IsomiRs auf das Messergebnis sowie im Rahmen von Experimenten mit miRNAs der let-7-Familie. Dabei konnten Ziel-Nukleins{\"a}uren mit Einzelbasenunterschieden klar differenziert werden. Die Multiplexf{\"a}higkeit der vorgestellten Methode wurde durch die gleichzeitige Quantifizierung von bis zu acht miRNAs auf einem CMOS-Chip demonstriert, zuz{\"u}glich Kontrollen. Die Validierung der Detektionsmethode erfolgte mit Gesamt-RNA-Extrakten aus Vollblutproben. Dazu wurde ein kardiales Panel aus acht miRNAs, die auf Basis von Studien zu zirkulierenden miRNAs bei Herzerkrankungen ausgew{\"a}hlt wurden, festgelegt. Mit Hilfe der entsprechenden optimierten Detektionskomponenten wurden aus Spenderblut gewonnene endogene miRNAs analysiert. Dabei zeigte sich f{\"u}r f{\"u}nf der acht Kandidaten sowohl eine solide Korrelation zwischen eingesetzter Gesamt-RNA-Menge und Messsignal, als auch eine gute Reproduzierbarkeit der Ergebnisse. Die Konzentrationen der {\"u}brigen drei miRNAs lagen nah am unteren Detektionslimit und lieferten daher keine verl{\"a}sslichen Daten. Mit Hilfe sogenannter branched DNA zur Signalamplifikation k{\"o}nnte bei Bedarf die Sensitivit{\"a}t des Assays noch verbessert werden, was durch weitere Experimente dieser Arbeit demonstriert wurde. Ein Vergleichsexperiment zwischen der Sandwich-Ligations-Methode und qRT-PCR zeigte nur eine schwache Korrelation der Messergebnisse. Dies ist jedoch konsistent mit anderen Studien zur Vergleichbarkeit unterschiedlicher Detektionsmethoden. Abschließend wurden die miRNAs des kardialen Panels in Gesamt-RNA-Extrakten aus Vollblut von Herzinfarktpatienten und Kontrollen mit der entwickelten Detektionsmethode analysiert und die Ergebnisse verglichen. Dabei konnten Abweichungen in den Konzentrationen von miR-15a und miR-425 aufgedeckt werden. Eine entsprechende diagnostische Untersuchung mit der hier vorgelegten und validierten Detektionsmethode k{\"o}nnte eine Alternative oder Erg{\"a}nzung zu aktuell eingesetzten proteinbasierten Tests bieten.}, subject = {miRNS}, language = {de} } @book{FalkMarohnMicheletal.2012, author = {Falk, Michael and Marohn, Frank and Michel, Ren{\´e} and Hofmann, Daniel and Macke, Maria and Spachmann, Christoph and Englert, Stefan}, title = {A First Course on Time Series Analysis : Examples with SAS [Version 2012.August.01]}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-72617}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2012}, abstract = {The analysis of real data by means of statistical methods with the aid of a software package common in industry and administration usually is not an integral part of mathematics studies, but it will certainly be part of a future professional work. The present book links up elements from time series analysis with a selection of statistical procedures used in general practice including the statistical software package SAS. Consequently this book addresses students of statistics as well as students of other branches such as economics, demography and engineering, where lectures on statistics belong to their academic training. But it is also intended for the practician who, beyond the use of statistical tools, is interested in their mathematical background. Numerous problems illustrate the applicability of the presented statistical procedures, where SAS gives the solutions. The programs used are explicitly listed and explained. No previous experience is expected neither in SAS nor in a special computer system so that a short training period is guaranteed. This book is meant for a two semester course (lecture, seminar or practical training) where the first three chapters can be dealt within the first semester. They provide the principal components of the analysis of a time series in the time domain. Chapters 4, 5 and 6 deal with its analysis in the frequency domain and can be worked through in the second term. In order to understand the mathematical background some terms are useful such as convergence in distribution, stochastic convergence, maximum likelihood estimator as well as a basic knowledge of the test theory, so that work on the book can start after an introductory lecture on stochastics. Each chapter includes exercises. An exhaustive treatment is recommended. Chapter 7 (case study) deals with a practical case and demonstrates the presented methods. It is possible to use this chapter independent in a seminar or practical training course, if the concepts of time series analysis are already well understood. This book is consecutively subdivided in a statistical part and an SAS-specific part. For better clearness the SAS-specific parts are highlighted. This book is an open source project under the GNU Free Documentation License.}, subject = {Zeitreihenanalyse}, language = {en} } @article{BeckMorbachBeeretal.2010, author = {Beck, Christine and Morbach, Henner and Beer, Meinrad and Stenzel, Martin and Tappe, Dennis and Gattenl{\"o}hner, Stefan and Hofmann, Ulrich and Raab, Peter and Girschick, Hermann J.}, title = {Chronic nonbacterial osteomyelitis in childhood: prospective follow-up during the first year of anti-inflammatory treatment}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-67792}, year = {2010}, abstract = {Introduction: Chronic nonbacterial osteomyelitis (CNO) is an inflammatory disorder of unknown etiology. In children and adolescents CNO predominantly affects the metaphyses of the long bones, but lesions can occur at any site of the skeleton. Prospectively followed cohorts using a standardized protocol in diagnosis and treatment have rarely been reported. Methods: Thirty-seven children diagnosed with CNO were treated with naproxen continuously for the first 6 months. If assessment at that time revealed progressive disease or no further improvement, sulfasalazine and short-term corticosteroids were added. The aims of our short-term follow-up study were to describe treatment response in detail and to identify potential risk factors for an unfavorable outcome. Results: Naproxen treatment was highly effective in general, inducing a symptom-free status in 43\% of our patients after 6 months. However, four nonsteroidal anti-inflammatory drug (NSAID) partial-responders were additionally treated with sulfasalazine and short-term corticosteroids. The total number of clinical detectable lesions was significantly reduced. Mean disease activity estimated by the patient/physician and the physical aspect of health-related quality of life including functional ability (global assessment/childhood health assessment questionnaire and childhood health assessment questionnaire) and pain improved significantly. Forty-one percent of our patients showed radiological relapses, but 67\% of them were clinically silent. Conclusions: Most children show a favorable clinical course in the first year of anti-inflammatory treatment with NSAIDs. Relapses and new radiological lesions can occur at any time and at any site in the skeleton but may not be clinically symptomatic. Whole-body magnetic resonance imaging proved to be very sensitive for initial and follow-up diagnostics.}, subject = {Mikrobiologie}, language = {en} } @book{FalkMarohnMicheletal.2011, author = {Falk, Michael and Marohn, Frank and Michel, Ren{\´e} and Hofmann, Daniel and Macke, Maria and Tewes, Bernward and Dinges, Peter and Spachmann, Christoph and Englert, Stefan}, title = {A First Course on Time Series Analysis : Examples with SAS}, organization = {Universit{\"a}t W{\"u}rzburg / Lehrstuhl f{\"u}r Statistik}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-56489}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2011}, abstract = {The analysis of real data by means of statistical methods with the aid of a software package common in industry and administration usually is not an integral part of mathematics studies, but it will certainly be part of a future professional work. The present book links up elements from time series analysis with a selection of statistical procedures used in general practice including the statistical software package SAS. Consequently this book addresses students of statistics as well as students of other branches such as economics, demography and engineering, where lectures on statistics belong to their academic training. But it is also intended for the practician who, beyond the use of statistical tools, is interested in their mathematical background. Numerous problems illustrate the applicability of the presented statistical procedures, where SAS gives the solutions. The programs used are explicitly listed and explained. No previous experience is expected neither in SAS nor in a special computer system so that a short training period is guaranteed. This book is meant for a two semester course (lecture, seminar or practical training) where the first three chapters can be dealt within the first semester. They provide the principal components of the analysis of a time series in the time domain. Chapters 4, 5 and 6 deal with its analysis in the frequency domain and can be worked through in the second term. In order to understand the mathematical background some terms are useful such as convergence in distribution, stochastic convergence, maximum likelihood estimator as well as a basic knowledge of the test theory, so that work on the book can start after an introductory lecture on stochastics. Each chapter includes exercises. An exhaustive treatment is recommended. Chapter 7 (case study) deals with a practical case and demonstrates the presented methods. It is possible to use this chapter independent in a seminar or practical training course, if the concepts of time series analysis are already well understood. This book is consecutively subdivided in a statistical part and an SAS-specific part. For better clearness the SAS-specific parts are highlighted. This book is an open source project under the GNU Free Documentation License.}, subject = {Zeitreihenanalyse}, 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{FreyPoppPostetal.2014, author = {Frey, Anna and Popp, Sandy and Post, Antonia and Langer, Simon and Lehmann, Marc and Hofmann, Ulrich and Siren, Anna-Leena and Hommers, Leif and Schmitt, Angelika and Strekalova, Tatyana and Ertl, Georg and Lesch, Klaus-Peter and Frantz, Stefan}, title = {Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain}, series = {Frontiers in Behavioral Neuroscience}, volume = {8}, journal = {Frontiers in Behavioral Neuroscience}, issn = {1662-5153}, doi = {10.3389/fnbeh.2014.00376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118234}, pages = {376}, year = {2014}, abstract = {Background: Depression and anxiety are common and independent outcome predictors in patients with chronic heart failure (CHF). However, it is unclear whether CHF causes depression. Thus, we investigated whether mice develop anxiety- and depression-like behavior after induction of ischemic CHF by myocardial infarction (MI). Methods and Results: In order to assess depression-like behavior, anhedonia was investigated by repeatedly testing sucrose preference for 8 weeks after coronary artery ligation or sham operation. Mice with large MI and increased left ventricular dimensions on echocardiography (termed CHF mice) showed reduced preference for sucrose, indicating depression-like behavior. 6 weeks after MI, mice were tested for exploratory activity, anxiety-like behavior and cognitive function using the elevated plus maze (EPM), light-dark box (LDB), open field (OF), and object recognition (OR) tests. In the EPM and OF, CHF mice exhibited diminished exploratory behavior and motivation despite similar movement capability. In the OR, CHF mice had reduced preference for novelty and impaired short-term memory. On histology, CHF mice had unaltered overall cerebral morphology. However, analysis of gene expression by RNA-sequencing in prefrontal cortical, hippocampal, and left ventricular tissue revealed changes in genes related to inflammation and cofactors of neuronal signal transduction in CHF mice, with Nr4a1 being dysregulated both in prefrontal cortex and myocardium after MI. Conclusions: After induction of ischemic CHF, mice exhibited anhedonic behavior, decreased exploratory activity and interest in novelty, and cognitive impairment. Thus, ischemic CHF leads to distinct behavioral changes in mice analogous to symptoms observed in humans with CHF and comorbid depression.}, language = {en} } @article{DechHolzwarthAsametal.2021, author = {Dech, Stefan and Holzwarth, Stefanie and Asam, Sarah and Andresen, Thorsten and Bachmann, Martin and Boettcher, Martin and Dietz, Andreas and Eisfelder, Christina and Frey, Corinne and Gesell, Gerhard and Gessner, Ursula and Hirner, Andreas and Hofmann, Matthias and Kirches, Grit and Klein, Doris and Klein, Igor and Kraus, Tanja and Krause, Detmar and Plank, Simon and Popp, Thomas and Reinermann, Sophie and Reiners, Philipp and Roessler, Sebastian and Ruppert, Thomas and Scherbachenko, Alexander and Vignesh, Ranjitha and Wolfmueller, Meinhard and Zwenzner, Hendrik and Kuenzer, Claudia}, title = {Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience}, series = {Remote Sensing}, volume = {13}, journal = {Remote Sensing}, number = {18}, issn = {2072-4292}, doi = {10.3390/rs13183618}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246134}, year = {2021}, abstract = {Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper.}, language = {en} } @article{FrantzKlaiberBabaetal.2013, author = {Frantz, Stefan and Klaiber, Michael and Baba, Hideo A. and Oberwinkler, Heinz and V{\"o}lker, Katharina and Gaßner, Birgit and Bayer, Barbara and Abeßer, Marco and Schuh, Kai and Feil, Robert and Hofmann, Franz and Kuhn, Michaela}, title = {Stress-dependent dilated cardiomyopathy in mice with cardiomyocyte-restricted inactivation of cyclic GMP-dependent protein kinase I}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134693}, pages = {1233-1244}, year = {2013}, abstract = {Aims: Cardiac hypertrophy is a common and often lethal complication of arterial hypertension. Elevation of myocyte cyclic GMP levels by local actions of endogenous atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) or by pharmacological inhibition of phosphodiesterase-5 was shown to counter-regulate pathological hypertrophy. It was suggested that cGMP-dependent protein kinase I (cGKI) mediates this protective effect, although the role in vivo is under debate. Here, we investigated whether cGKI modulates myocyte growth and/or function in the intact organism. Methods and results: To circumvent the systemic phenotype associated with germline ablation of cGKI, we inactivated the murine cGKI gene selectively in cardiomyocytes by Cre/loxP-mediated recombination. Mice with cardiomyocyte-restricted cGKI deletion exhibited unaltered cardiac morphology and function under resting conditions. Also, cardiac hypertrophic and contractile responses to β-adrenoreceptor stimulation by isoprenaline (at 40 mg/kg/day during 1 week) were unaltered. However, angiotensin II (Ang II, at 1000 ng/kg/min for 2 weeks) or transverse aortic constriction (for 3 weeks) provoked dilated cardiomyopathy with marked deterioration of cardiac function. This was accompanied by diminished expression of the \([Ca^{2+}]_i\)-regulating proteins SERCA2a and phospholamban (PLB) and a reduction in PLB phosphorylation at Ser16, the specific target site for cGKI, resulting in altered myocyte \(Ca^{2+}_i\) homeostasis. In isolated adult myocytes, CNP, but not ANP, stimulated PLB phosphorylation, \(Ca^{2+}_i\)-handling, and contractility via cGKI. Conclusion: These results indicate that the loss of cGKI in cardiac myocytes compromises the hypertrophic program to pathological stimulation, rendering the heart more susceptible to dysfunction. In particular, cGKI mediates stimulatory effects of CNP on myocyte \(Ca^{2+}_i\) handling and contractility.}, language = {en} } @article{HofmannFrantz2013, author = {Hofmann, Ulrich and Frantz, Stefan}, title = {How can we cure a heart "in flame"? A translational view on inflammation in heart failure}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {356}, doi = {10.1007/s00395-013-0356-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134497}, year = {2013}, abstract = {The prevalence of chronic heart failure is still increasing making it a major health issue in the 21st century. Tremendous evidence has emerged over the past decades that heart failure is associated with a wide array of mechanisms subsumed under the term "inflammation". Based on the great success of immuno-suppressive treatments in auto-immunity and transplantation, clinical trials were launched targeting inflammatory mediators in patients with chronic heart failure. However, they widely lacked positive outcomes. The failure of the initial study program directed against tumor necrosis factor-a led to the search for alternative therapeutic targets involving a broader spectrum of mechanisms besides cytokines. We here provide an overview of the current knowledge on immune activation in chronic heart failure of different etiologies, summarize clinical studies in the field, address unresolved key questions, and highlight some promising novel therapeutic targets for clinical trials from a translational basic science and clinical perspective.}, 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{KollingBackhausHofmannetal.2022, author = {Kolling, Markus and Backhaus, Joy and Hofmann, Norbert and Keß, Stefan and Krastl, Gabriel and Soliman, Sebastian and K{\"o}nig, Sarah}, title = {Students' perception of three-dimensionally printed teeth in endodontic training}, series = {European Journal of Dental Education}, volume = {26}, journal = {European Journal of Dental Education}, number = {4}, doi = {10.1111/eje.12743}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318676}, pages = {653 -- 661}, year = {2022}, abstract = {Introduction In endodontic education, there is a need for thorough training prior to students embarking on clinical treatment. The aim of this study was to use three-dimensional printing technology to create a new model and to compare its suitability for training purposes with resin blocks and extracted teeth. Materials and Methods Multi-jet-modelling (MJM) produced the 3D model replicating a common difficulty in root-canal morphology. An evaluation study comprising 88 students was run in the sixth semester (summer 2018 and winter 2018/2019). A new questionnaire assessed students' perception of training models and educational environment. Welch's t-test analysed significant differences. Results The most pronounced differences between models were noted when rating material hardness, radiopacity, root-canal configuration and suitability for practising. Students estimated their learning outcome as greater with 3D-printed teeth compared to resin blocks. Three-dimensionally printed teeth received significantly lower ratings with regard to enthusiasm, the learning of fine motor skills and spatial awareness, when compared to human teeth (p ≤ .001). However, 3D-printed teeth were appreciated for additional benefits, such as their cleanliness, availability and standardisation of training opportunities with complex root-canal configurations. Conclusion Students preferred extracted human teeth to 3D-printed teeth with respect to their physical characteristics and training experience. However, educational advantages may compensate for the shortcomings. The new questionnaire proved both adequate and accurate to assess the models and educational environment in endodontic training. The new 3D-printed teeth enhanced the learning opportunities.}, language = {en} } @article{PoppSchmittBoehrerLangeretal.2021, author = {Popp, Sandy and Schmitt-B{\"o}hrer, Angelika and Langer, Simon and Hofmann, Ulrich and Hommers, Leif and Schuh, Kai and Frantz, Stefan and Lesch, Klaus-Peter and Frey, Anna}, title = {5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction}, series = {Journal of Clinical Medicine}, volume = {10}, journal = {Journal of Clinical Medicine}, number = {14}, issn = {2077-0383}, doi = {10.3390/jcm10143104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242739}, year = {2021}, abstract = {Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally na{\"i}ve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (-/-) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT-/- mice with infarct sizes >30\% experienced 100\% mortality, while 50\% of 5-HTT+/- and 37\% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30\%) 5-HTT-/- mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT-/- mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.}, 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{SchmidtWernerArrowsmithetal.2020, author = {Schmidt, Uwe and Werner, Luis and Arrowsmith, Merle and Deissenberger, Andrea and Hermann, Alexander and Hofmann, Alexander and Ullrich, Stefan and Mattock, James D. and Vargas, Alfredo and Braunschweig, Holger}, title = {Trans-selektive Dihydroborierung eines cis-Diborens durch Insertion: Synthese eines linearen sp\(^3\)-sp\(^2\)-sp\(^3\)-Triborans und anschließende Kationisierung}, series = {Angewandte Chemie}, volume = {132}, journal = {Angewandte Chemie}, number = {1}, doi = {10.1002/ange.201911645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219713}, pages = {333-337}, year = {2020}, abstract = {Die Reaktion zwischen Aryl- und Amino(dihydro)boranen und Dibora[2]ferrocenophan 1 f{\"u}hrt zur Bildung von 1,3-trans-Dihydrotriboranen durch formale Hydrierung und Insertion eines Borylens in die B=B Doppelbindung. Die Aryltriboran-Derivate unterliegen einer reversiblen Photoisomerisierung zugunsten eines cis-1,2-μ-H-3-Hydrotriborans, w{\"a}hrend eine Hydridabstraktion zu kationischen Triboranen f{\"u}hrt, welche die ersten doppelt basenstabilisierten B\(_3\)H\(_4\)\(^+\)-Analoga darstellen.}, language = {de} } @article{SchmidtWernerArrowsmithetal.2020, author = {Schmidt, Uwe and Werner, Luis and Arrowsmith, Merle and Deissenberger, Andrea and Hermann, Alexander and Hofmann, Alexander and Ullrich, Stefan and Mattock, James D. and Vargas, Alfredo and Braunschweig, Holger}, title = {trans-Selective Insertional Dihydroboration of a cis-Diborene: Synthesis of Linear sp\(^3\)-sp\(^2\)-sp\(^3\)-Triboranes and Subsequent Cationization}, series = {Angewandte Chemie International Edition}, volume = {59}, journal = {Angewandte Chemie International Edition}, number = {1}, doi = {10.1002/anie.201911645}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-208090}, pages = {325-329}, year = {2020}, abstract = {The reaction of aryl- and amino(dihydro)boranes with dibora[2]ferrocenophane 1 leads to the formation 1,3-trans -dihydrotriboranes by formal hydrogenation and insertion of a borylene unit into the B=B bond. The aryltriborane derivatives undergo reversible photoisomerization to the cis -1,2-μ-H-3-hydrotriboranes, while hydride abstraction affords cationic triboranes, which represent the first doubly base-stabilized B3H4\(^+\) analogues.}, language = {en} }