@article{KotlyarKrebsSolimandoetal.2023,
  author    = {Kotlyar, Mischa J. and Krebs, Markus and Solimando, Antonio Giovanni and Marquardt, Andr{\´e} and Burger, Maximilian and K{\"u}bler, Hubert and Bargou, Ralf and Kneitz, Susanne and Otto, Wolfgang and Breyer, Johannes and Vergho, Daniel C. and Kneitz, Burkhard and Kalogirou, Charis},
  title     = {Critical evaluation of a microRNA-based risk classifier predicting cancer-specific survival in renal cell carcinoma with tumor thrombus of the inferior vena cava},
  series = {Cancers},
  volume    = {15},
  journal   = {Cancers},
  number    = {7},
  issn      = {2072-6694},
  doi       = {10.3390/cancers15071981},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311040},
  year      = {2023},
  abstract  = {(1) Background: Clear cell renal cell carcinoma extending into the inferior vena cava (ccRCC\(^{IVC}\)) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier — containing miR-21-5p, miR-126-3p and miR-221-3p expression — which significantly predicted the cancer-specific survival (CSS) of ccRCC\(^{IVC}\) patients. (2) Methods: Examining a single-center cohort of tumor tissue from n = 56 patients with ccRCC\(^{IVC}\), we measured the expression levels of miR-21, miR-126, and miR-221 using qRT-PCR. The prognostic impact of clinicopathological parameters and miR expression were investigated via single-variable and multivariable Cox regression. Referring to the previously established risk classifier, we performed Kaplan-Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study. (3) Results: miR-21 and miR-126 expression were significantly associated with lymphonodal status at the time of surgery, the development of metastasis during follow-up, and cancer-related death. In Kaplan-Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCC\(^{IVC}\) according to CSS. (4) Conclusions: In our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCC\(^{IVC}\) cohort.},
  language  = {en}
}
@article{HaarmannVollmuthKollikowskietal.2023,
  author    = {Haarmann, Axel and Vollmuth, Christoph and Kollikowski, Alexander M. and Heuschmann, Peter U. and Pham, Mirko and Stoll, Guido and Neugebauer, Hermann and Schuhmann, Michael K.},
  title     = {Vasoactive soluble endoglin: a novel biomarker indicative of reperfusion after cerebral large-vessel occlusion},
  series = {Cells},
  volume    = {12},
  journal   = {Cells},
  number    = {2},
  issn      = {2073-4409},
  doi       = {10.3390/cells12020288},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304995},
  year      = {2023},
  abstract  = {Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-β co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.},
  language  = {en}
}
@phdthesis{Hauser2022,
  author    = {Hauser, Tobias Gregor},
  title     = {Mineralocorticoid-receptor antagonism and its metabolic consequences in haemodialysis patients},
  doi       = {10.25972/OPUS-25938},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259382},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2022},
  abstract  = {Patients on haemodialysis are highly susceptible to different forms of heart failure. To date, the benefit of Mineralocorticoid-receptor antagonist (MRA) administration in haemodialysis patients remains subject to discussion. Biomarkers play an important role in therapy guidance and pose a promising tool to detect pathological processes of heart failure in an earlier stage. The randomised-controlled Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease (MiREnDa) trial was set up to investigate the effect of 50 mg of spironolactone once daily on left ventricular mass index in haemodialysis patients and several secondary endpoints. This dissertation reports findings from the MiREnDa trial on (a) the efficacy of spironolactone to influence serum levels of biomarkers of heart failure, fibrosis and inflammation and electrolytes and (b) the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Galectin-3 and soluble source of tumorigenicity 2 (sST2) to reflect left ventricular hypertrophy and diastolic dysfunction assessed by imaging characteristics. Treatment of spironolactone over a 40-week period did not alter serum levels of biomarkers of heart failure, fibrosis and inflammation including NT-proBNP, Galectin-3 and sST2. A small but significant effect on serum sodium but not potassium was observed. NT-proBNP was significantly different in the presence or absence of left ventricular hypertrophy (LVH) (normal vs. LVH (median [IQR]): 2,120 [810; 5,040] vs. 6,340 [2,410; 15,360] pg/ml, p<0.01) or moderate and severe diastolic dysfunction (DD) (normal diastolic function and DD grade I vs. DD grade II and DD grade III: 2,300 [850; 6,050] vs. 12,260 [3,340; 34,830] pg/ml, p=0.02). NT-proBNP further showed a significant correlation at baseline with LVMi (Spearman's rho=0.41, p<0.001), LAVi (Spearman's rho=0.55, p<0.001) and septal E/e' (Spearman's rho=0.45, p<0.001). No correlation was observed between Galectin-3 and the investigated functional and morphological parameters. sST2 was mildly correlated to LVMi at baseline (Spearman's rho=0.21, p=0.05) and NT-proBNP at baseline (Spearman's rho=0.37, p<0.001). In conclusion, spironolactone did not affect the investigated parameters but NT-proBNP proved to be significantly correlated to cardiac imaging measurements.},
  subject      = {Dialyse},
  language  = {en}
}
@article{JohnFranckAlAouaetal.2022,
  author    = {John, Katharina and Franck, Martin and Al Aoua, Sherin and Rau, Monika and Huber, Yvonne and Schattenberg, Joern M. and Geier, Andreas and Bahr, Matthias J. and Wedemeyer, Heiner and Schulze-Osthoff, Klaus and Bantel, Heike},
  title     = {Non-invasive detection of fibrotic NASH in NAFLD patients with low or intermediate FIB-4},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {15},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11154394},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281824},
  year      = {2022},
  abstract  = {Background: Non-alcoholic steatohepatitis (NASH) and fibrosis are the main prognostic factors in non-alcoholic fatty liver disease (NAFLD). The FIB-4 score has been suggested as an initial test for the exclusion of progressed fibrosis. However, increasing evidence suggests that also NASH patients with earlier fibrosis stages are at risk of disease progression, emphasizing the need for improved non-invasive risk stratification. Methods: We evaluated whether the apoptosis biomarker M30 can identify patients with fibrotic NASH despite low or intermediate FIB-4 values. Serum M30 levels were assessed by ELISA, and FIB-4 was calculated in an exploration (n = 103) and validation (n = 100) cohort of patients with histologically confirmed NAFLD. Results: The majority of patients with low FIB-4 (cut-off value < 1.3) in the exploration cohort revealed increased M30 levels (>200 U/L) and more than 80\% of them had NASH, mostly with fibrosis. NASH was also detected in all patients with intermediate FIB-4 (1.3 to 2.67) and elevated M30, from which ~80\% showed fibrosis. Importantly, in the absence of elevated M30, most patients with FIB-4 < 1.3 and NASH showed also no fibrosis. Similar results were obtained in the validation cohort. Conclusions: The combination of FIB-4 with M30 enables a more reliable identification of patients at risk for progressed NAFLD and might, therefore, improve patient stratification.},
  language  = {en}
}
@article{WendlingerWohlfarthKreftetal.2022,
  author    = {Wendlinger, Simone and Wohlfarth, Jonas and Kreft, Sophia and Siedel, Claudia and Kilian, Teresa and Dischinger, Ulrich and Heppt, Markus V. and Wistuba-Hamprecht, Kilian and Meier, Friedegund and Goebeler, Matthias and Schadendorf, Dirk and Gesierich, Anja and Kosnopfel, Corinna and Schilling, Bastian},
  title     = {Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {9},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14092294},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275137},
  year      = {2022},
  abstract  = {Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.},
  language  = {en}
}
@article{HussAbdelhakMayeretal.2022,
  author    = {Huss, Andr{\´e} and Abdelhak, Ahmed and Mayer, Benjamin and Tumani, Hayrettin and M{\"u}ller, Hans-Peter and Althaus, Katharina and Kassubek, Jan and Otto, Markus and Ludolph, Albert C. and Yilmazer-Hanke, Deniz and Neugebauer, Hermann},
  title     = {Association of serum GFAP with functional and neurocognitive outcome in sporadic small vessel disease},
  series = {Biomedicines},
  volume    = {10},
  journal   = {Biomedicines},
  number    = {8},
  issn      = {2227-9059},
  doi       = {10.3390/biomedicines10081869},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285973},
  year      = {2022},
  abstract  = {Cerebrospinal fluid (CSF) and serum biomarkers are critical for clinical decision making in neurological diseases. In cerebral small vessel disease (CSVD), white matter hyperintensities (WMH) are an important neuroimaging biomarker, but more blood-based biomarkers capturing different aspects of CSVD pathology are needed. In 42 sporadic CSVD patients, we prospectively analysed WMH on magnetic resonance imaging (MRI) and the biomarkers neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), chitinase3-like protein 1 (CHI3L1), Tau and Aβ1-42 in CSF and NfL and GFAP in serum. GFAP and CHI3L1 expression was studied in post-mortem brain tissue in additional cases. CSVD cases with higher serum NfL and GFAP levels had a higher modified Rankin Scale (mRS) and NIHSS score and lower CSF Aβ1-42 levels, whereas the CSF NfL and CHI3L1 levels were positively correlated with the WMH load. Moreover, the serum GFAP levels significantly correlated with the neurocognitive functions. Pathological analyses in CSVD revealed a high density of GFAP-immunoreactive fibrillary astrocytic processes in the periventricular white matter and clusters of CHI3L1-immunoreactive astrocytes in the basal ganglia and thalamus. Thus, besides NfL, serum GFAP is a highly promising fluid biomarker of sporadic CSVD, because it does not only correlate with the clinical severity but also correlates with the cognitive function in patients.},
  language  = {en}
}
@article{BohnertTrellaPreissetal.2022,
  author    = {Bohnert, Simone and Trella, Stefanie and Preiß, Ulrich and Heinsen, Helmut and Bohnert, Michael and Zwirner, Johann and Tremblay, Marie-{\`E}ve and Monoranu, Camelia-Maria and Ondruschka, Benjamin},
  title     = {Density of TMEM119-positive microglial cells in postmortem cerebrospinal fluid as a surrogate marker for assessing complex neuropathological processes in the CNS},
  series = {International Journal of Legal Medicine},
  volume    = {136},
  journal   = {International Journal of Legal Medicine},
  number    = {6},
  doi       = {10.1007/s00414-022-02863-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325009},
  pages     = {1841-1850},
  year      = {2022},
  abstract  = {Routine coronal paraffin-sections through the dorsal frontal and parieto-occipital cortex of a total of sixty cases with divergent causes of death were immunohistochemically (IHC) stained with an antibody against TMEM119. Samples of cerebrospinal fluid (CSF) of the same cases were collected by suboccipital needle-puncture, subjected to centrifugation and processed as cytospin preparations stained with TMEM119. Both, cytospin preparations and sections were subjected to computer-assisted density measurements. The density of microglial TMEM119-positive cortical profiles correlated with that of cytospin results and with the density of TMEM119-positive microglial profiles in the medullary layer. There was no statistically significant correlation between the density of medullary TMEM119-positive profiles and the cytospin data. Cortical microglial cells were primarily encountered in supragranular layers I, II, and IIIa and in infragranular layers V and VI, the region of U-fibers and in circumscribed foci or spread in a diffuse manner and high density over the white matter. We have evidence that cortical microglia directly migrate into CSF without using the glympathic pathway. Microglia in the medullary layer shows a strong affinity to the adventitia of deep vessels in the myelin layer. Selected rapidly fatal cases including myocardial infarcts and drowning let us conclude that microglia in cortex and myelin layer can react rapidly and its reaction and migration is subject to pre-existing external and internal factors. Cytospin preparations proved to be a simple tool to analyze and assess complex changes in the CNS after rapid fatal damage. There is no statistically significant correlation between cytospin and postmortem interval. Therefore, the quantitative analyses of postmortem cytospins obviously reflect the neuropathology of the complete central nervous system. Cytospins provide forensic pathologists a rather simple and easy to perform method for the global assessment of CNS affliction.},
  language  = {en}
}
@article{LauruschkatEtterSchnacketal.2021,
  author    = {Lauruschkat, Chris D. and Etter, Sonja and Schnack, Elisabeth and Ebel, Frank and Sch{\"a}uble, Sascha and Page, Lukas and R{\"u}mens, Dana and Dragan, Mariola and Schlegel, Nicolas and Panagiotou, Gianni and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Wurster, Sebastian and Loeffler, Juergen},
  title     = {Chronic occupational mold exposure drives expansion of Aspergillus-reactive type 1 and type 2 T-helper cell responses},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {9},
  issn      = {2309-608X},
  doi       = {10.3390/jof7090698},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245202},
  year      = {2021},
  abstract  = {Occupational mold exposure can lead to Aspergillus-associated allergic diseases including asthma and hypersensitivity pneumonitis. Elevated IL-17 levels or disbalanced T-helper (Th) cell expansion were previously linked to Aspergillus-associated allergic diseases, whereas alterations to the Th cell repertoire in healthy occupationally exposed subjects are scarcely studied. Therefore, we employed functional immunoassays to compare Th cell responses to A. fumigatus antigens in organic farmers, a cohort frequently exposed to environmental molds, and non-occupationally exposed controls. Organic farmers harbored significantly higher A. fumigatus-specific Th-cell frequencies than controls, with comparable expansion of Th1- and Th2-cell frequencies but only slightly elevated Th17-cell frequencies. Accordingly, Aspergillus antigen-induced Th1 and Th2 cytokine levels were strongly elevated, whereas induction of IL-17A was minimal. Additionally, increased levels of some innate immune cell-derived cytokines were found in samples from organic farmers. Antigen-induced cytokine release combined with Aspergillus-specific Th-cell frequencies resulted in high classification accuracy between organic farmers and controls. Aspf22, CatB, and CipC elicited the strongest differences in Th1 and Th2 responses between the two cohorts, suggesting these antigens as potential candidates for future bio-effect monitoring approaches. Overall, we found that occupationally exposed agricultural workers display a largely balanced co-expansion of Th1 and Th2 immunity with only minor changes in Th17 responses.},
  language  = {en}
}
@article{LauruschkatPageWhiteetal.2021,
  author    = {Lauruschkat, Chris D. and Page, Lukas and White, P. Lewis and Etter, Sonja and Davies, Helen E. and Duckers, Jamie and Ebel, Frank and Schnack, Elisabeth and Backx, Matthijs and Dragan, Mariola and Schlegel, Nicolas and Kniemeyer, Olaf and Brakhage, Axel A. and Einsele, Hermann and Loeffler, Juergen and Wurster, Sebastian},
  title     = {Development of a simple and robust whole blood assay with dual co-stimulation to quantify the release of T-cellular signature cytokines in response to Aspergillus fumigatus antigens},
  series = {Journal of Fungi},
  volume    = {7},
  journal   = {Journal of Fungi},
  number    = {6},
  issn      = {2309-608X},
  doi       = {10.3390/jof7060462},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-241025},
  year      = {2021},
  abstract  = {Deeper understanding of mold-induced cytokine signatures could promote advances in the diagnosis and treatment of invasive mycoses and mold-associated hypersensitivity syndromes. Currently, most T-cellular immunoassays in medical mycology require the isolation of mononuclear cells and have limited robustness and practicability, hampering their broader applicability in clinical practice. Therefore, we developed a simple, cost-efficient whole blood (WB) assay with dual α-CD28 and α-CD49d co-stimulation to quantify cytokine secretion in response to Aspergillus fumigatus antigens. Dual co-stimulation strongly enhanced A. fumigatus-induced release of T-cellular signature cytokines detectable by enzyme-linked immunosorbent assay (ELISA) or a multiplex cytokine assay. Furthermore, T-cell-dependent activation and cytokine response of innate immune cells was captured by the assay. The protocol consistently showed little technical variation and high robustness to pre-analytic delays of up to 8 h. Stimulation with an A. fumigatus lysate elicited at least 7-fold greater median concentrations of key T-helper cell signature cytokines, including IL-17 and the type 2 T-helper cell cytokines IL-4 and IL-5 in WB samples from patients with Aspergillus-associated lung pathologies versus patients with non-mold-related lung diseases, suggesting high discriminatory power of the assay. These results position WB-ELISA with dual co-stimulation as a simple, accurate, and robust immunoassay for translational applications, encouraging further evaluation as a platform to monitor host immunity to opportunistic pathogens.},
  language  = {en}
}
@article{HeilingKnuttiScherretal.2021,
  author    = {Heiling, Sven and Knutti, Nadine and Scherr, Franziska and Geiger, J{\"o}rg and Weikert, Juliane and Rose, Michael and Jahns, Roland and Ceglarek, Uta and Scherag, Andr{\´e} and Kiehntopf, Michael},
  title     = {Metabolite ratios as quality indicators for pre-analytical variation in serum and EDTA plasma},
  series = {Metabolites},
  volume    = {11},
  journal   = {Metabolites},
  number    = {9},
  issn      = {2218-1989},
  doi       = {10.3390/metabo11090638},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246261},
  year      = {2021},
  abstract  = {In clinical diagnostics and research, blood samples are one of the most frequently used materials. Nevertheless, exploring the chemical composition of human plasma and serum is challenging due to the highly dynamic influence of pre-analytical variation. A prominent example is the variability in pre-centrifugation delay (time-to-centrifugation; TTC). Quality indicators (QI) reflecting sample TTC are of utmost importance in assessing sample history and resulting sample quality, which is essential for accurate diagnostics and conclusive, reproducible research. In the present study, we subjected human blood to varying TTCs at room temperature prior to processing for plasma or serum preparation. Potential sample QIs were identified by Ultra high pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) based metabolite profiling in samples from healthy volunteers (n = 10). Selected QIs were validated by a targeted MS/MS approach in two independent sets of samples from patients (n = 40 and n = 70). In serum, the hypoxanthine/guanosine (HG) and hypoxanthine/inosine (HI) ratios demonstrated high diagnostic performance (Sensitivity/Specificity > 80\%) for the discrimination of samples with a TTC > 1 h. We identified several eicosanoids, such as 12-HETE, 15-(S)-HETE, 8-(S)-HETE, 12-oxo-HETE, (±)13-HODE and 12-(S)-HEPE as QIs for a pre-centrifugation delay > 2 h. 12-HETE, 12-oxo-HETE, 8-(S)-HETE, and 12-(S)-HEPE, and the HI- and HG-ratios could be validated in patient samples.},
  language  = {en}
}
@article{VetrivelZhangEngeletal.2021,
  author    = {Vetrivel, Sharmilee and Zhang, Ru and Engel, Mareen and Altieri, Barbara and Braun, Leah and Osswald, Andrea and Bidlingmaier, Martin and Fassnacht, Martin and Beuschlein, Felix and Reincke, Martin and Chen, Alon and Sbiera, Silviu and Riester, Anna},
  title     = {Circulating microRNA Expression in Cushing's Syndrome},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.620012},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229761},
  year      = {2021},
  abstract  = {Context Cushing's syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging. Objective Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes. Methods We included three groups of patients from the German Cushing's registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing's Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls. Results NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression. Outcome In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.},
  language  = {en}
}
@article{BohnertReinertTrellaetal.2021,
  author    = {Bohnert, Simone and Reinert, Christoph and Trella, Stefanie and Schmitz, Werner and Ondruschka, Benjamin and Bohnert, Michael},
  title     = {Metabolomics in postmortem cerebrospinal fluid diagnostics: a state-of-the-art method to interpret central nervous system-related pathological processes},
  series = {International Journal of Legal Medicine},
  volume    = {135},
  journal   = {International Journal of Legal Medicine},
  issn      = {0937-9827},
  doi       = {10.1007/s00414-020-02462-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235724},
  pages     = {183-191},
  year      = {2021},
  abstract  = {In the last few years, quantitative analysis of metabolites in body fluids using LC/MS has become an established method in laboratory medicine and toxicology. By preparing metabolite profiles in biological specimens, we are able to understand pathophysiological mechanisms at the biochemical and thus the functional level. An innovative investigative method, which has not yet been used widely in the forensic context, is to use the clinical application of metabolomics. In a metabolomic analysis of 41 samples of postmortem cerebrospinal fluid (CSF) samples divided into cohorts of four different causes of death, namely, cardiovascular fatalities, isoIated torso trauma, traumatic brain injury, and multi-organ failure, we were able to identify relevant differences in the metabolite profile between these individual groups. According to this preliminary assessment, we assume that information on biochemical processes is not gained by differences in the concentration of individual metabolites in CSF, but by a combination of differently distributed metabolites forming the perspective of a new generation of biomarkers for diagnosing (fatal) TBI and associated neuropathological changes in the CNS using CSF samples.},
  language  = {en}
}
@article{BohnertWirthSchmitzetal.2021,
  author    = {Bohnert, Simone and Wirth, Christoph and Schmitz, Werner and Trella, Stefanie and Monoranu, Camelia-Maria and Ondruschka, Benjamin and Bohnert, Michael},
  title     = {Myelin basic protein and neurofilament H in postmortem cerebrospinal fluid as surrogate markers of fatal traumatic brain injury},
  series = {International Journal of Legal Medicine},
  volume    = {135},
  journal   = {International Journal of Legal Medicine},
  number    = {4},
  issn      = {1437-1596},
  doi       = {10.1007/s00414-021-02606-y},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266929},
  pages     = {1525-1535},
  year      = {2021},
  abstract  = {The aim of this study was to investigate if the biomarkers myelin basic protein (MBP) and neurofilament-H (NF-H) yielded informative value in forensic diagnostics when examining cadaveric cerebrospinal fluid (CSF) biochemically via an enzyme-linked immunosorbent assay (ELISA) and comparing the corresponding brain tissue in fatal traumatic brain injury (TBI) autopsy cases by immunocytochemistry versus immunohistochemistry. In 21 trauma and 19 control cases, CSF was collected semi-sterile after suboccipital puncture and brain specimens after preparation. The CSF MBP (p = 0.006) and NF-H (p = 0.0002) levels after TBI were significantly higher than those in cardiovascular controls. Immunohistochemical staining against MBP and against NF-H was performed on cortical and subcortical samples from also biochemically investigated cases (5 TBI cases/5 controls). Compared to the controls, the TBI cases showed a visually reduced staining reaction against MBP or repeatedly ruptured neurofilaments against NF-H. Immunocytochemical tests showed MBP-positive phagocytizing macrophages in CSF with a survival time of > 24 h. In addition, numerous TMEM119-positive microglia could be detected with different degrees of staining intensity in the CSF of trauma cases. As a result, we were able to document that elevated levels of MBP and NF-H in the CSF should be considered as useful neuroinjury biomarkers of traumatic brain injury.},
  language  = {en}
}
@article{HartrampfHeinrichSeitzetal.2020,
  author    = {Hartrampf, Philipp E. and Heinrich, Marieke and Seitz, Anna Katharina and Brumberg, Joachim and Sokolakis, Ioannis and Kalogirou, Charis and Schirbel, Andreas and K{\"u}bler, Hubert and Buck, Andreas K. and Lapa, Constantin and Krebs, Markus},
  title     = {Metabolic Tumour Volume from PSMA PET/CT Scans of Prostate Cancer Patients during Chemotherapy — Do Different Software Solutions Deliver Comparable Results?},
  series = {Journal of Clinical Medicine},
  volume    = {9},
  journal   = {Journal of Clinical Medicine},
  number    = {5},
  issn      = {2077-0383},
  doi       = {10.3390/jcm9051390},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-205893},
  year      = {2020},
  abstract  = {(1) Background: Prostate-specific membrane antigen (PSMA)-derived tumour volume (PSMA-TV) and total lesion PSMA (TL-PSMA) from PSMA PET/CT scans are promising biomarkers for assessing treatment response in prostate cancer (PCa). Currently, it is unclear whether different software tools for assessing PSMA-TV and TL-PSMA produce comparable results. (2) Methods: \(^{68}\)Ga-PSMA PET/CT scans from n = 21 patients with castration-resistant PCa (CRPC) receiving chemotherapy were identified from our single-centre database. PSMA-TV and TL-PSMA were calculated with Syngo.via (Siemens) as well as the freely available Beth Israel plugin for FIJI (Fiji Is Just ImageJ) before and after chemotherapy. While statistical comparability was illustrated and quantified via Bland-Altman diagrams, the clinical agreement was estimated by matching PSMA-TV, TL-PSMA and relative changes of both variables during chemotherapy with changes in serum PSA (ΔPSA) and PERCIST (Positron Emission Response Criteria in Solid Tumors). (3) Results: Comparing absolute PSMA-TV and TL-PSMA as well as Bland-Altman plotting revealed a good statistical comparability of both software algorithms. For clinical agreement, classifying therapy response did not differ between PSMA-TV and TL-PSMA for both software solutions and showed highly positive correlations with BR. (4) Conclusions: due to the high levels of statistical and clinical agreement in our CRPC patient cohort undergoing taxane chemotherapy, comparing PSMA-TV and TL-PSMA determined by Syngo.via and FIJI appears feasible.},
  language  = {en}
}
@article{OregliaSbieraFassnachtetal.2020,
  author    = {Oreglia, Maurine and Sbiera, Silviu and Fassnacht, Martin and Guyon, Laurent and Denis, Josiane and Cristante, Justine and Chabre, Olivier and Cherradi, Nadia},
  title     = {Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {3},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12030724},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203227},
  year      = {2020},
  abstract  = {We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5\% sensitivity (CI 31.6-86.1) and 100\% specificity (CI 71.5-100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.},
  language  = {en}
}
@article{DichtlForsterOrmannsetal.2020,
  author    = {Dichtl, Karl and Forster, Johannes and Ormanns, Steffen and Horns, Heidi and Suerbaum, Sebastian and Seybold, Ulrich and Wagener, Johannes},
  title     = {Comparison of β-D-Glucan and galactomannan in serum for detection of invasive aspergillosis: retrospective analysis with focus on early diagnosis},
  series = {Journal of Fungi},
  volume    = {6},
  journal   = {Journal of Fungi},
  number    = {4},
  issn      = {2309-608X},
  doi       = {10.3390/jof6040253},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216298},
  year      = {2020},
  abstract  = {The early diagnosis of invasive aspergillosis (IA) relies mainly on computed tomography imaging and testing for fungal biomarkers such as galactomannan (GM). We compared an established ELISA for the detection of GM with a turbidimetric assay for detection of the panfungal biomarker β-D-glucan (BDG) for early diagnosis of IA. A total of 226 serum specimens from 47 proven and seven probable IA cases were analysed. Sensitivity was calculated for samples obtained closest to the day of IA-diagnosis (d0). Additional analyses were performed by including samples obtained during the presumed course of disease. Most IA cases involved the respiratory system (63\%), and Aspergillus fumigatus was the most frequently isolated species (59\%). For proven cases, sensitivity of BDG/GM analysis was 57\%/40\%. Including all samples dating from -6 to +1 weeks from d0 increased sensitivities to 74\%/51\%. Sensitivity of BDG testing was as high as or higher than GM testing for all subgroups and time intervals analysed. BDG testing was less specific (90-93\%) than GM testing (99-100\%). Combining BDG and GM testing resulted in sensitivity/specificity of 70\%/91\%. Often, BDG testing was positive before GM testing. Our study backs the use of BDG for diagnosis of suspected IA. We suggest combining BDG and GM to improve the overall sensitivity.},
  language  = {en}
}
@phdthesis{Kuzkina2020,
  author    = {Kuzkina, Anastasia},
  title     = {Dermal α-synuclein oligomers and aggregates in Parkinson's disease},
  doi       = {10.25972/OPUS-20436},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204369},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease (PD). These depositions in the brain mostly consist of aggregated α-synuclein (α-syn) phosphorylated at Ser129. A number of studies reported detection of phosphorylated α-syn (p-α-syn) in the dermal nerve fibers in Parkinson's disease. The objective of this study was to investigate whether pathological α-syn accumulations detected in the skin represent aggregated protein. A number of methods aimed at detecting α-syn oligomers and aggregates were first tested and optimized on the brain samples in PD and normal control. These methods included proximity ligation assay (PLA), PET-blot, immunohistochemical (IHC) stains with α-syn aggregate (5G4) or oligomer specific (ASyO5) antibodies and a stain against native α-syn (syn211) after proteinase K (PK) digestion. Subsequently, the most specific methods (stains with 5G4, ASyO5 and syn211 after PK digestion) were studied in two separate patient and control cohorts. Anti-p-α-syn stain was performed in parallel. Single sections from at least 2 biopsy sites from 44 patients and 22 controls (cohort 1) as well as serial sections of 4 biopsy sites from 27 patients and 5 controls (cohort 2) were systematically studied for presence of aggregated and oligomeric α-syn. In total, 5G4 positive deposits were found in 24\% (cohort 1) and 37\% (cohort 2), ASyO5 positive lesions in 17,7\% (cohort 1) and 33\% (cohort 2), syn211 positive lesions after PK digestion in 38,7\% (cohort 1) and 48\% (cohort 2) of cases. There was a major overlap among positivity for a particular staining on the patient level and in most cases, the same nerve fiber was found to be positive for all 4 markers in neighboring sections. Among the skin biopsies which contained p-α-syn accumulation, 59\% were also PK resistant, 41\% were 5G4 positive and 45\% were ASyO5 positive. The samples belonging to normal controls did not show any positive signal in either of the newly established stainings or in the anti-p-α-syn staining. Using 3 distinct IHC methods, α-syn oligomers and aggregates were detectable in the majority of p-α-syn positive skin biopsies. This finding supports the hypothesis that α-syn aggregation occurs in the peripheral (i.e. dermal) nerves and can be specifically detected using skin biopsy.},
  subject      = {Parkinson-Krankheit},
  language  = {en}
}
@article{AltieriSbieraHerterichetal.2020,
  author    = {Altieri, Barbara and Sbiera, Silviu and Herterich, Sabine and De Francia, Silvia and Della Casa, Silvia and Calabrese, Anna and Pontecorvi, Alfredo and Quinkler, Marcus and Kienitz, Tina and Mannelli, Massimo and Canu, Letizia and Angelousi, Anna and Chortis, Vasileios and Kroiss, Matthias and Terzolo, Massimo and Fassnacht, Martin and Ronchi, Cristina L.},
  title     = {Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {2},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12020359},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200565},
  pages     = {359},
  year      = {2020},
  abstract  = {Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2\% vs 51.7\%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55\% of patients with CYP2B6*6 vs. 28.2\% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6\%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.},
  language  = {en}
}
@article{BohnertSeiffertTrellaetal.2020,
  author    = {Bohnert, Simone and Seiffert, Anja and Trella, Stefanie and Bohnert, Michael and Distel, Luitpold and Ondruschka, Benjamin and Monoranu, Camelia-Marie},
  title     = {TMEM119 as a specific marker of microglia reaction in traumatic brain injury in postmortem examination},
  series = {International Journal of Legal Medicine},
  volume    = {134},
  journal   = {International Journal of Legal Medicine},
  issn      = {0937-9827},
  doi       = {10.1007/s00414-020-02384-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235346},
  pages     = {2167-2176},
  year      = {2020},
  abstract  = {The aim of the present study was a refined analysis of neuroinflammation including TMEM119 as a useful microglia-specific marker in forensic assessments of traumatic causes of death, e.g., traumatic brain injury (TBI). Human brain tissue samples were obtained from autopsies and divided into cases with lethal TBI (n = 25) and subdivided into three groups according to their trauma survival time and compared with an age-, gender-, and postmortem interval-matched cohort of sudden cardiovascular fatalities as controls (n = 23). Brain tissue samples next to cortex contusions and surrounding white matter as well as samples of the ipsilateral uninjured brain stem and cerebellum were collected and stained immunohistochemically with antibodies against TMEM119, CD206, and CCR2. We could document the highest number of TMEM119-positive cells in acute TBI death with highly significant differences to the control numbers. CCR2-positive monocytes showed a significantly higher cell count in the cortex samples of TBI cases than in the controls with an increasing number of immunopositive cells over time. The number of CD206-positive M2 microglial cells increased survival time-dependent. After 3 days of survival, the cell number increased significantly in all four regions investigated compared with controls. In sum, we validate a specific and robustly expressed as well as fast reacting microglia marker, TMEM119, which distinguishes microglia from resident and infiltrating macrophages and thus offers a great potential for the estimation of the minimum survival time after TBI.},
  language  = {en}
}
@article{Menke2019,
  author    = {Menke, Andreas},
  title     = {Is the HPA axis as target for depression outdated, or is there a new hope?},
  series = {Frontiers in Psychiatry},
  volume    = {10},
  journal   = {Frontiers in Psychiatry},
  number    = {101},
  issn      = {1664-0640},
  doi       = {10.3389/fpsyt.2019.00101},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-195780},
  year      = {2019},
  abstract  = {Major depressive disorder (MDD) is a very common stress-related mental disorder that carries a huge burden for affected patients and the society. It is associated with a high mortality that derives from suicidality and the development of serious medical conditions such as heart diseases, diabetes, and stroke. Although a range of effective antidepressants are available, more than 50\% of the patients do not respond to the first treatment they are prescribed and around 30\% fail to respond even after several treatment attempts. The heterogeneous condition of MDD, the lack of biomarkers matching patients with the right treatments and the situation that almost all available drugs are only targeting the serotonin, norepinephrine, or dopamine signaling, without regulating other potentially dysregulated systems may explain the insufficient treatment status. The hypothalamic-pituitary-adrenal (HPA) axis is one of these other systems, there is numerous and robust evidence that it is implicated in MDD and other stress-related conditions, but up to date there is no specific drug targeting HPA axis components that is approved and no test that is routinely used in the clinical setting identifying patients for such a specific treatment. Is there still hope after these many years for a breakthrough of agents targeting the HPA axis? This review will cover tests detecting altered HPA axis function and the specific treatment options such as glucocorticoid receptor (GR) antagonists, corticotropin-releasing hormone 1 (CRH1) receptor antagonists, tryptophan 2,3-dioxygenase (TDO) inhibitors and FK506 binding protein 5 (FKBP5) receptor antagonists.},
  language  = {en}
}
@article{AkhrifRomanosDomschkeetal.2018,
  author    = {Akhrif, Atae and Romanos, Marcel and Domschke, Katharina and Schmitt-Boehrer, Angelika and Neufang, Susanne},
  title     = {Fractal Analysis of BOLD Time Series in a Network Associated With Waiting Impulsivity},
  series = {Frontiers in Physiology},
  volume    = {9},
  journal   = {Frontiers in Physiology},
  issn      = {1664-042X},
  doi       = {10.3389/fphys.2018.01378},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189191},
  pages     = {1378},
  year      = {2018},
  abstract  = {Fractal phenomena can be found in numerous scientific areas including neuroscience. Fractals are structures, in which the whole has the same shape as its parts. A specific structure known as pink noise (also called fractal or 1/f noise) is one key fractal manifestation, exhibits both stability and adaptability, and can be addressed via the Hurst exponent (H). FMRI studies using H on regional fMRI time courses used fractality as an important characteristic to unravel neural networks from artificial noise. In this fMRI-study, we examined 103 healthy male students at rest and while performing the 5-choice serial reaction time task. We addressed fractality in a network associated with waiting impulsivity using the adaptive fractal analysis (AFA) approach to determine H. We revealed the fractal nature of the impulsivity network. Furthermore, fractality was influenced by individual impulsivity in terms of decreasing fractality with higher impulsivity in regions of top-down control (left middle frontal gyrus) as well as reward processing (nucleus accumbens and anterior cingulate cortex). We conclude that fractality as determined via H is a promising marker to quantify deviations in network functions at an early stage and, thus, to be able to inform preventive interventions before the manifestation of a disorder.},
  language  = {en}
}
@article{HofmannBoettgerRangeetal.2017,
  author    = {Hofmann, Sigrun Ruth and B{\"o}ttger, Fanny and Range, Ursula and L{\"u}ck, Christian and Morbach, Henner and Girschick, Hermann Joseph and Suttorp, Meinolf and Hedrich, Christian Michael},
  title     = {Serum interleukin-6 and CCL11/eotaxin may be suitable biomarkers for the diagnosis of chronic nonbacterial osteomyelitis},
  series = {Frontiers in Pediatrics},
  volume    = {5},
  journal   = {Frontiers in Pediatrics},
  doi       = {10.3389/fped.2017.00256},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172744},
  year      = {2017},
  abstract  = {Objectives: Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis (CNO), is an autoinflammatory bone disorder. In the absence of diagnostic criteria or biomarkers, CNO/CRMO remains a diagnosis of exclusion. The aim of this study was to identify biomarkers for diagnosing multifocal disease (CRMO). Study design: Sera from 71 pediatric CRMO patients, 11 patients with osteoarticular infections, 62 patients with juvenile idiopathic arthritis (JIA), 7 patients with para-infectious or reactive arthritis, and 43 patients with acute leukemia or lymphoma, as well as 59 healthy individuals were collected. Multiplex analysis of 18 inflammation- and/or bone remodeling-associated serum proteins was performed. Statistical analysis included univariate ANOVA, discriminant analysis, univariate receiver operating characteristic (ROC) analysis, and logistic regression analyses. Results: For 14 of 18 blood serum proteins, significant differences were determined between CRMO patients, at least one alternative diagnosis, or healthy controls. Multi-component discriminant analysis delivered five biomarkers (IL-6, CCL11/eotaxin, CCL5/RANTES, collagen Iα, sIL-2R) for the diagnosis of CRMO. ROC analysis allowed further reduction to a core set of 2 biomarkers (CCL11/eotaxin, IL-6) that are sufficient to discern between CRMO, healthy controls, and alternative diagnoses. Conclusion: Serum biomarkers CCL11/eotaxin and IL-6 differentiate between patients with CRMO, healthy controls, and alternative diagnoses (leukemia and lymphoma, osteoarticular infections, para-infectious arthritis, and JIA). Easily accessible biomarkers may aid in diagnosing CRMO. Further studies testing biomarkers in larger unrelated cohorts are warranted.},
  language  = {en}
}
@article{KunzGoettlichWallesetal.2017,
  author    = {Kunz, Meik and G{\"o}ttlich, Claudia and Walles, Thorsten and Nietzer, Sarah and Dandekar, Gudrun and Dandekar, Thomas},
  title     = {MicroRNA-21 versus microRNA-34: Lung cancer promoting and inhibitory microRNAs analysed in silico and in vitro and their clinical impact},
  series = {Tumor Biology},
  volume    = {39},
  journal   = {Tumor Biology},
  number    = {7},
  doi       = {10.1177/1010428317706430},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158399},
  year      = {2017},
  abstract  = {MicroRNAs are well-known strong RNA regulators modulating whole functional units in complex signaling networks. Regarding clinical application, they have potential as biomarkers for prognosis, diagnosis, and therapy. In this review, we focus on two microRNAs centrally involved in lung cancer progression. MicroRNA-21 promotes and microRNA-34 inhibits cancer progression. We elucidate here involved pathways and imbed these antagonistic microRNAs in a network of interactions, stressing their cancer microRNA biology, followed by experimental and bioinformatics analysis of such microRNAs and their targets. This background is then illuminated from a clinical perspective on microRNA-21 and microRNA-34 as general examples for the complex microRNA biology in lung cancer and its diagnostic value. Moreover, we discuss the immense potential that microRNAs such as microRNA-21 and microRNA-34 imply by their broad regulatory effects. These should be explored for novel therapeutic strategies in the clinic.},
  language  = {en}
}
@article{SeydelmannLiuKraemeretal.2016,
  author    = {Seydelmann, Nora and Liu, Dan and Kr{\"a}mer, Johannes and Drechsler, Christiane and Hu, Kai and Nordbeck, Peter and Schneider, Andreas and St{\"o}rk, Stefan and Bijnens, Bart and Ertl, Georg and Wanner, Christoph and Weidemann, Frank},
  title     = {High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease},
  series = {Journal of the American Heart Association},
  volume    = {5},
  journal   = {Journal of the American Heart Association},
  number    = {e002839},
  doi       = {10.1161/JAHA.115.002839},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165682},
  year      = {2016},
  abstract  = {Background High-sensitivity troponin (hs-TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs-TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow-up study to assess longitudinal hs-TNT changes relative to fibrosis and cardiomyopathy progression. Methods and Results For the prospective analysis, hs-TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry-associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs-TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs-TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95\% CI, 3.56-302.59]; P=0.002); patients with elevated baseline hs-TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1-3.3] \%; follow-up, 3.2 [2.3-4.9] \%; P<0.001) and slightly elevated hs-TNT (baseline, 44.7 [30.1-65.3] ng/L; follow-up, 49.1 [27.6-69.5] ng/L; P=0.116) during follow-up. Left ventricular wall thickness and EF of patients with elevated hs-TNT were decreased during follow-up, indicating potential cardiomyopathy progression. Conclusions hs-TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs-TNT could be helpful for staging and follow-up of Fabry patients.},
  language  = {en}
}
@article{HackerEscalonaEspinosaConsalvoetal.2016,
  author    = {Hacker, Ulrich T. and Escalona-Espinosa, Laura and Consalvo, Nicola and Goede, Valentin and Schiffmann, Lars and Scherer, Stefan J. and Hedge, Priti and Van Cutsem, Eric and Coutelle, Oliver and B{\"u}ning, Hildegard},
  title     = {Evaluation of Angiopoietin-2 as a biomarker in gastric cancer: results from the randomised phase III AVAGAST trial},
  series = {British Journal of Cancer},
  volume    = {114},
  journal   = {British Journal of Cancer},
  number    = {8},
  doi       = {10.1038/bjc.2016.30},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-189578},
  pages     = {855-862},
  year      = {2016},
  abstract  = {Background: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker. Methods: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Results: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml\(^-\)\(^1\)) vs non-Asian patients (3193 pg ml\(^-\)\(^1\)), P<0.0001. Baseline plasma Ang-2 was identified as an independent prognostic marker for OS but did not predict bevacizumab efficacy alone or in combination with baseline VEGF. Baseline plasma Ang-2 correlated with the frequency of liver metastasis (LM) at any time: Odds ratio per 1000 pg ml\(^-\)\(^1\) increase: 1.19; 95\% CI 1.10-1.29; P<0.0001 (non-Asians) and 1.37; 95\% CI 1.13-1.64; P = 0.0010 (Asians). Conclusions: Baseline plasma Ang-2 is a novel prognostic biomarker for OS in advanced gastric cancer strongly associated with LM. Differences in Ang-2 mediated vascular response may, in part, account for outcome differences between Asian and non-Asian patients; however, data have to be further validated. Ang-2 is a promising drug target in gastric cancer.},
  language  = {en}
}
@article{HussHalbgebauerOeckletal.2016,
  author    = {Huss, Andr{\´e} M. and Halbgebauer, Steffen and {\"O}ckl, Patrick and Trebst, Corinna and Spreer, Annette and Borisow, Nadja and Harrer, Andrea and Brecht, Isabel and Balint, Bettina and Stich, Oliver and Schlegel, Sabine and Retzlaff, Nele and Winkelmann, Alexander and Roesler, Romy and Lauda, Florian and Yildiz, {\"O}zlem and Voß, Elke and Muche, Rainer and Rauer, Sebastian and Bergh, Florian Then and Otto, Markus and Paul, Friedemann and Wildemann, Brigitte and Kraus, J{\"o}rg and Ruprecht, Klemens and Stangel, Martin and Buttmann, Mathias and Zettl, Uwe K. and Tumani, Hayrettin},
  title     = {Importance of cerebrospinal fluid analysis in the era of McDonald 2010 criteria: a German-Austrian retrospective multicenter study in patients with a clinically isolated syndrome},
  series = {Journal of Neurology},
  volume    = {263},
  journal   = {Journal of Neurology},
  number    = {12},
  doi       = {10.1007/s00415-016-8302-1},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186619},
  pages     = {2499-2504},
  year      = {2016},
  abstract  = {The majority of patients presenting with a first clinical symptom suggestive of multiple sclerosis (MS) do not fulfill the MRI criteria for dissemination in space and time according to the 2010 revision of the McDonald diagnostic criteria for MS and are thus classified as clinically isolated syndrome (CIS). To re-evaluate the utility of cerebrospinal fluid (CSF) analysis in the context of the revised McDonald criteria from 2010, we conducted a retrospective multicenter study aimed at determining the prevalence and predictive value of oligoclonal IgG bands (OCBs) in patients with CIS. Patients were recruited from ten specialized MS centers in Germany and Austria. We collected data from 406 patients; at disease onset, 44/406 (11 \%) fulfilled the McDonald 2010 criteria for MS. Intrathecal IgG OCBs were detected in 310/362 (86 \%) of CIS patients. Those patients were twice as likely to convert to MS according to McDonald 2010 criteria as OCB-negative individuals (hazard ratio = 2.1, p = 0.0014) and in a shorter time period of 25 months (95 \% CI 21-34) compared to 47 months in OCB-negative individuals (95 \% CI 36-85). In patients without brain lesions at first attack and presence of intrathecal OCBs (30/44), conversion rate to MS was 60 \% (18/30), whereas it was only 21 \% (3/14) in those without OCBs. Our data confirm that in patients with CIS the risk of conversion to MS substantially increases if OCBs are present at onset. CSF analysis definitely helps to evaluate the prognosis in patients who do not have MS according to the revised McDonald criteria.},
  language  = {en}
}
@article{OrthCazesButtetal.2015,
  author    = {Orth, Martin F. and Cazes, Alex and Butt, Elke and Grunewald, Thomas G. P.},
  title     = {An update on the LIM and SH3 domain protein 1 (LASP1): a versatile structural, signaling, and biomarker protein},
  series = {Oncotarget},
  volume    = {6},
  journal   = {Oncotarget},
  number    = {1},
  doi       = {10.18632/oncotarget.3083},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144546},
  pages     = {26-42},
  year      = {2015},
  abstract  = {The gene encoding the LIM and SH3 domain protein (LASP1) was cloned two decades ago from a cDNA library of breast cancer metastases. As the first protein of a class comprising one N-terminal LIM and one C-terminal SH3 domain, LASP1 founded a new LIM-protein subfamily of the nebulin group. Since its discovery LASP1 proved to be an extremely versatile protein because of its exceptional structure allowing interaction with various binding partners, its ubiquitous expression in normal tissues, albeit with distinct expression patterns, and its ability to transmit signals from the cytoplasm into the nucleus. As a result, LASP1 plays key roles in cell structure, physiological processes, and cell signaling. Furthermore, LASP1 overexpression contributes to cancer aggressiveness hinting to a potential value of LASP1 as a cancer biomarker. In this review we summarize published data on structure, regulation, function, and expression pattern of LASP1, with a focus on its role in human cancer and as a biomarker protein. In addition, we provide a comprehensive transcriptome analysis of published microarrays (n=2,780) that illustrates the expression profile of LASP1 in normal tissues and its overexpression in a broad range of human cancer entities.},
  language  = {en}
}
@article{KraftDrechslerSchuhmannetal.2015,
  author    = {Kraft, Peter and Drechsler, Christiane and Schuhmann, Michael K. and Gunreben, Ignaz and Kleinschnitz, Christoph},
  title     = {Characterization of Peripheral Immune Cell Subsets in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {International Journal of Molecular Science},
  volume    = {16},
  journal   = {International Journal of Molecular Science},
  number    = {10},
  doi       = {10.3390/ijms161025433},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126319},
  pages     = {25433-25449},
  year      = {2015},
  abstract  = {Immune cells (IC) play a crucial role in murine stroke pathophysiology. However, data are limited on the role of these cells in ischemic stroke in humans. We therefore aimed to characterize and compare peripheral IC subsets in patients with acute ischemic stroke/transient ischemic attack (AIS/TIA), chronic cerebrovascular disease (CCD) and healthy volunteers (HV). We conducted a case-control study of patients with AIS/TIA (n = 116) or CCD (n = 117), and HV (n = 104) who were enrolled at the University Hospital W{\"u}rzburg from 2010 to 2013. We determined the expression and quantity of IC subsets in the three study groups and performed correlation analyses with demographic and clinical parameters. The quantity of several IC subsets differed between the AIS/TIA, CCD, and HV groups. Several clinical and demographic variables independently predicted the quantity of IC subsets in patients with AIS/TIA. No significant changes in the quantity of IC subsets occurred within the first three days after AIS/TIA. Overall, these findings strengthen the evidence for a pathophysiologic role of IC in human ischemic stroke and the potential use of IC-based biomarkers for the prediction of stroke risk. A comprehensive description of IC kinetics is crucial to enable the design of targeted treatment strategies.},
  language  = {en}
}
@article{KraftDrechslerGunrebenetal.2014,
  author    = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph},
  title     = {Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study},
  series = {Cerebrovascular Diseases},
  volume    = {38},
  journal   = {Cerebrovascular Diseases},
  number    = {5},
  issn      = {1015-9770},
  doi       = {10.1159/000368434},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-199076},
  pages     = {337-343},
  year      = {2014},
  abstract  = {Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58\%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26\% vs. 97 ± 24\%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.},
  language  = {en}
}
@article{KellerLeidingerVogeletal.2014,
  author    = {Keller, Andreas and Leidinger, Petra and Vogel, Britta and Backes, Christina and ElSharawy, Abdou and Galata, Valentina and Mueller, Sabine C. and Marquart, Sabine and Schrauder, Michael G. and Strick, Reiner and Bauer, Andrea and Wischhusen, J{\"o}rg and Beier, Markus and Kohlhaas, Jochen and Katus, Hugo A. and Hoheisel, J{\"o}rg and Franke, Andre and Meder, Benjamin and Meese, Eckart},
  title     = {miRNAs can be generally associated with human pathologies as exemplified for miR-144*},
  series = {BMC MEDICINE},
  volume    = {12},
  journal   = {BMC MEDICINE},
  issn      = {1741-7015},
  doi       = {10.1186/s12916-014-0224-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114349},
  pages     = {224},
  year      = {2014},
  abstract  = {Background: miRNA profiles are promising biomarker candidates for a manifold of human pathologies, opening new avenues for diagnosis and prognosis. Beyond studies that describe miRNAs frequently as markers for specific traits, we asked whether a general pattern for miRNAs across many diseases exists. Methods: We evaluated genome-wide circulating profiles of 1,049 patients suffering from 19 different cancer and non-cancer diseases as well as unaffected controls. The results were validated on 319 individuals using qRT-PCR. Results: We discovered 34 miRNAs with strong disease association. Among those, we found substantially decreased levels of hsa-miR-144* and hsa-miR-20b with AUC of 0.751 ( 95\% CI: 0.703-0.799), respectively. We also discovered a set of miRNAs, including hsa-miR-155*, as rather stable markers, offering reasonable control miRNAs for future studies. The strong downregulation of hsa-miR-144* and the less variable pattern of hsa-miR-155* has been validated in a cohort of 319 samples in three different centers. Here, breast cancer as an additional disease phenotype not included in the screening phase has been included as the 20th trait. Conclusions: Our study on 1,368 patients including 1,049 genome-wide miRNA profiles and 319 qRT-PCR validations further underscores the high potential of specific blood-borne miRNA patterns as molecular biomarkers. Importantly, we highlight 34 miRNAs that are generally dysregulated in human pathologies. Although these markers are not specific to certain diseases they may add to the diagnosis in combination with other markers, building a specific signature. Besides these dysregulated miRNAs, we propose a set of constant miRNAs that may be used as control markers.},
  language  = {en}
}
@article{KressHuettenhoferLandryetal.2013,
  author    = {Kress, Michaela and H{\"u}ttenhofer, Alexander and Landry, Marc and Kuner, Rohini and Favereaux, Alexandre and Greenberg, David and Bednarik, Josef and Heppenstall, Paul and Kronenberg, Florian and Malcangio, Marzia and Rittner, Heike and {\"U}{\c{c}}eyler, Nurcan and Trajanoski, Zlatko and Mouritzen, Peter and Birklein, Frank and Sommer, Claudia and Soreq, Hermona},
  title     = {microRNAs in nociceptive circuits as predictors of future clinical applications},
  series = {Frontiers in Molecular Neuroscience},
  volume    = {6},
  journal   = {Frontiers in Molecular Neuroscience},
  number    = {33},
  doi       = {10.3389/fnmol.2013.00033},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-154597},
  year      = {2013},
  abstract  = {Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain, and non-coding RNAs - and microRNAs (miRNAs) in particular - regulate both immune and neuronal processes. Specifically, miRNAs control macromolecular complexes in neurons, glia and immune cells and regulate signals used for neuro-immune communication in the pain pathway. Therefore, miRNAs may be hypothesized as critically important master switches modulating chronic pain. In particular, understanding the concerted function of miRNA in the regulation of nociception and endogenous analgesia and defining the importance of miRNAs in the circuitries and cognitive, emotional and behavioral components involved in pain is expected to shed new light on the enigmatic pathophysiology of neuropathic pain, migraine and complex regional pain syndrome. Specific miRNAs may evolve as new druggable molecular targets for pain prevention and relief. Furthermore, predisposing miRNA expression patterns and inter-individual variations and polymorphisms in miRNAs and/or their binding sites may serve as biomarkers for pain and help to predict individual risks for certain types of pain and responsiveness to analgesic drugs. miRNA-based diagnostics are expected to develop into hands-on tools that allow better patient stratification, improved mechanism-based treatment, and targeted prevention strategies for high risk individuals.},
  language  = {en}
}
@article{KneitzKalogirouSpahnetal.2013,
  author    = {Kneitz, Burkhard and Kalogirou, Charis and Spahn, Martin and Krebs, Markus and Joniau, Steven and Lerut, Evelyne and Burger, Maximilian and Scholz, Claus-J{\"u}rgen and Kneitz, Susanne and Riedmiller, Hubertus},
  title     = {MiR-205 Is Progressively Down-Regulated in Lymph Node Metastasis but Fails as a Prognostic Biomarker in High-Risk Prostate Cancer},
  series = {International Journal of Molecular Sciences},
  journal   = {International Journal of Molecular Sciences},
  doi       = {10.3390/ijms141121414},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97321},
  year      = {2013},
  abstract  = {The treatment of high-risk prostate cancer (HRPCa) is a tremendous challenge for uro-oncologists. The identification of predictive moleculobiological markers allowing risk assessment of lymph node metastasis and systemic progression is essential in establishing effective treatment. In the current study, we investigate the prognostic potential of miR-205 in HRPCa study and validation cohorts, setting defined clinical endpoints for both. We demonstrate miR-205 to be significantly down-regulated in over 70\% of the HRPCa samples analysed and that reconstitution of miR-205 causes inhibition of proliferation and invasiveness in prostate cancer (PCa) cell lines. Additionally, miR-205 is increasingly down-regulated in lymph node metastases compared to the primary tumour indicating that miR-205 plays a role in migration of PCa cells from the original location into extraprostatic tissue. Nevertheless, down-regulation of miR-205 in primary PCa was not correlated to the synchronous presence of metastasis and failed to predict the outcome for HRPCa patients. Moreover, we found a tendency for miR-205 up-regulation to correlate with an adverse outcome of PCa patients suggesting a pivotal role of miR-205 in tumourigenesis. Overall, we showed that miR-205 is involved in the development and metastasis of PCa, but failed to work as a useful clinical biomarker in HRPCa. These findings might have implications for the use of miR-205 as a prognostic or therapeutic target in HRPCa.},
  language  = {en}
}
@phdthesis{Hess2013,
  author    = {Heß, Michael},
  title     = {Vaccinia virus-encoded bacterial beta-glucuronidase as a diagnostic biomarker for oncolytic virotherapy},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86789},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2013},
  abstract  = {Oncolytic virotherapy represents a promising approach to revolutionize cancer therapy. Several preclinical and clinical trials display the safety of oncolytic viruses as wells as their efficiency against solid tumors. The development of complementary diagnosis and monitoring concepts as well as the optimization of anti-tumor activity are key points of current virotherapy research. Within the framework of this thesis, the diagnostic and therapeutic prospects of beta-glucuronidase expressed by the oncolytic vaccinia virus strain GLV-1h68 were evaluated. In this regard, a beta-glucuronidase-based, therapy-accompanying biomarker test was established which is currently under clinical validation. By using fluorescent substrates, the activity of virally expressed beta-glucuronidase could be detected and quantified. Thereby conclusions about the replication kinetics of oncolytic viruses in animal models and virus-induced cancer cell lysis could be drawn. These findings finally led to the elaboration and establishment of a versatile biomarker assay which allows statements regarding the replication of oncolytic viruses in mice based on serum samples. Besides the analysis of retrospective conditions, this test is able to serve as therapy-accompanying monitoring tool for virotherapy approaches with beta-glucuronidase-expressing viruses. The newly developed assay also served as complement to routinely used plaque assays as well as reference for virally expressed anti-angiogenic antibodies in additional preclinical studies. Further validation of this biomarker test is currently taking place in the context of clinical trials with GL-ONC1 (clinical grade GLV-1h68) and has already shown promising preliminary results. It was furthermore demonstrated that fluorogenic substrates in combination with beta-glucuronidase expressed by oncolytic viruses facilitated the optical detection of solid tumors in preclinical models. In addition to diagnostic purposes, virus-encoded enzymes could also be combined with prodrugs resulting in an improved therapeutic outcome of oncolytic virotherapy. In further studies, the visualization of virus-induced immune reactions as well as the establishment of innovative concepts to improve the therapeutic outcome of oncolytic virotherapy could be accomplished. In conclusion, the results of this thesis provide crucial findings about the influence of virally expressed beta-glucuronidase on various diagnostic concepts in the context of oncolytic virotherapy. In addition, innovative monitoring and therapeutic strategies could be established. Our preclinical findings have important clinical influence, particularly by the development of a therapy-associated biomarker assay which is currently used in different clinical trials.},
  subject      = {Vaccinia-Virus},
  language  = {en}
}
@phdthesis{Adler2012,
  author    = {Adler, Melanie},
  title     = {New approaches to improve prediction of drug-induced liver injury},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-69512},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2012},
  abstract  = {Das h{\"a}ufige Scheitern neuer Arzneistoffkandidaten aufgrund von Lebertoxizit{\"a}t in pr{\"a}klinischen und klinischen Studien stellt ein erhebliches Problem in der Entwicklung von neuen Arzneimitteln dar. Deshalb ist es wichtig, neue Ans{\"a}tze zu entwickeln, mit deren Hilfe unerw{\"u}nschte Wirkungen von Arzneimitteln fr{\"u}her und zuverl{\"a}ssiger erkannt werden k{\"o}nnen. Um die Vorhersage von Lebertoxizit{\"a}t in pr{\"a}klinischen Studien zu verbessern, wurden im Rahmen dieser Arbeit zwei wesentliche Ans{\"a}tze gew{\"a}hlt: 1) die Evaluierung neuer Biomarker, durch die Lebertoxizit{\"a}t zuverl{\"a}ssiger und empfindlicher detektiert werden k{\"o}nnte und 2.) wirkmechanistische Untersuchungen mittels Toxcicogenomics f{\"u}r ein besseres Verst{\"a}ndnis der zugrunde liegenden Mechanismen der Arzneimittel-induzierten Toxizit{\"a}t. Ein Ziel dieser Arbeit war, die F{\"a}higkeit einiger neuer potenzieller Biomarker (NGAL, Thiostatin, Clusterin und PON1) zu bewerten, Arzmeimittel-induzierte Lebertoxizit{\"a}t in Ratten fr{\"u}hzeitig zu erkennen. Die Ergebnisse zeigen, dass PON1 und Clusterin infolge eines durch die verabreichten Arzneistoffkandidaten verursachten Leberschadens nicht konsistent ver{\"a}ndert waren. Diese beiden Marker sind daher, verglichen mit bestehenden klinisch-chemischen Markern, nicht f{\"u}r eine sichere Vorhersage von Arzneistoff-induzierten Lebersch{\"a}den geeignet. Bei Thiostatin und NGAL zeigte sich hingegen ein zeit- und dosisabh{\"a}ngiger Anstieg im Serum und Urin behandelter Tiere. Diese Ver{\"a}nderungen, die gut mit der mRNA Expression im Zielorgan {\"u}bereinstimmten, korrelierten mit dem Schweregrad der Arzneistoff-induzierten Lebersch{\"a}den. Die Analyse mittels ROC zeigte, Thiostatin im Serum, nicht aber NGAL, ein besserer Indikator f{\"u}r Arzneimittel-induzierte hepatobili{\"a}re Sch{\"a}den ist als die routinem{\"a}ßig verwendeten klinische-chemischen Marker, wie z.B. die Leberenzyme ALP, ALT und AST. Thiostatin wird jedoch als Akute-Phase-Protein in einer Vielzahl von Geweben exprimiert und kann somit nicht spezifisch als Lebermarker betrachtet werden. Dennoch zeigen unsere Ergebnisse, dass Thiostatin als sensitiver, minimal-invasiver diagnostischer Marker f{\"u}r Entz{\"u}ndungsprozesse und Gewebesch{\"a}den eine sinnvolle Erg{\"a}nzung in der pr{\"a}klinischen Testung auf Lebertoxizit{\"a}t darstellt. Im zweiten Teil dieser Arbeit wurde mittels RNA-Interferenz das pharmakologische Target des Arzneistoffkandidaten BAY16, der Glukagonrezeptor, auf mRNA-Ebene gehemmt und anhand von Genexpressionsanalysen untersucht, ob die pharmakologisch-bedingte Modulation des Glukagonrezeptors eine Rolle in der Toxizit{\"a}t von BAY16 spielt. Desweiteren sollten diese Arbeiten Aufschluss geben, welche molekularen Ver{\"a}nderungen auf die pharmakologische Wirkung des Arzneistoffs zur{\"u}ckzuf{\"u}hren sind, und daher f{\"u}r den Mechanismus der Toxizit{\"a}t m{\"o}glicherweise wenig relevant sind. W{\"a}hrend BAY16 in Konzentrationen von 75 µM starke zytotoxische Wirkungen aufwies, hatte die siRNA vermittelte Depletion des Glukagonrezeptors keinen Einfluss auf die Vitalit{\"a}t prim{\"a}rer Rattenhepatozyten. Daraus l{\"a}sst sich ableiten, dass die Hepatotoxizi{\"a}t von BAY16 in vitro und in vivo nicht mit der pharmakologischen Modulation des Glukagonrezeptors assoziiert ist. Diese Ergebnisse wurden durch die Tatsache gest{\"u}tzt, dass die meisten der durch BAY16 induzierten Genexpressionsver{\"a}nderungen unabh{\"a}ngig von der pharmakologischen Modulation des Glucagonrezeptors auftraten. Diese beobachteten off-target-Effekte beinhalteten Ver{\"a}nderungen im Fremdstoffmetabolismus, oxidativer Stress, erh{\"o}hte Fetts{\"a}uresynthese und Ver{\"a}nderungen im Cholesterol- und Gallens{\"a}uremetabolismus. Obwohl Ver{\"a}nderungen in diesen molekularen Mechanismen zum Fortschreiten eines Leberschadens beitragen k{\"o}nnen, ist es anhand dieser Daten nicht m{\"o}glich einen eindeutigen Mechanismus f{\"u}r die Toxizit{\"a}t von BAY16 abzuleiten. In dieser Arbeit konnte jedoch gezeigt werden, dass die Anwendung der siRNA-Technologie einen neuen methodischen Ansatz darstellt, um Mechanismen arzneimittelbedingter Toxizit{\"a}t besser verstehen zu k{\"o}nnen.},
  subject      = {Biomarker},
  language  = {en}
}
@phdthesis{Simon2006,
  author    = {Simon, Karoline},
  title     = {Development and Evaluation of a Generic HPLC-Tandem MS Screening Method for the Detection of Potential Biomarkers for Reactive Intermediates},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-21916},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2006},
  abstract  = {Conjugation of reactive intermediates of drugs with proteins or DNA may result in toxic effects such as hepatotoxicity, agranulocytosis, allergies, tumors, etc. From 1975 to 1999, 2.9\% of drugs were withdrawn from the market due to such severe adverse drug reactions. Thus, formation of chemically reactive intermediates is a widely discussed problem in drug development processes. Early detection of potentially toxic compounds is required for drug discovery and drug development. Conjugation of such electrophilic compounds with glutathione (GSH) is one of the most important detoxifying reactions in vivo. Processing of these GSH-conjugates ultimately leads to the formation of renally cleared mercapturic acids, which may also be oxidized to sulfoxides. Thus, mercapturic acids may be generated and detected in vitro and non-invasively in vivo in urine to assess the reactivity of a compound in early stages of drug development processes. Therefore, the aim of this work was to develop and evaluate a HPLC-MS/MS screening method for simple and rapid detection and characterization of known and unknown mercapturic acids and application of the method to several different matrices. Based on the common constant neutral loss (CNL) of 129 Da of all mercapturic acids tested (in negative ion mode), a CNL survey scan was performed using a linear ion trap instrument and was combined with two enhanced product ion (EPI) scans with different collision energies to characterize the detected signals. The CNL resulted from the cleavage between the sulfur and the carbon atom in the N-acetyl-L-cysteine moiety. After optimization of the experimental parameters, the detection limits of the reference substances in rat urine ranged from 0.3 to 15.5 pmol on column (i.e. 20 ng/ml to 800 ng/ml). For in vitro evaluation of the method, the model compounds acetaminophen, diclofenac, bifonazole, clozapine, troglitazone, carbamazepine, and bisphenol A were screened for formation of reactive intermediates and, hence, detection of the corresponding mercapturic acids. To determine possible species- and tissue-specific toxicities, the model compounds were incubated with stimulated neutrophils and with liver microsomes from rats and humans. Species-specific differences were observed in incubations of acetaminophen and diclofenac with rat and human hepatic microsomes. Tissue-specific differences in biotransformation of the model compounds in incubations with human neutrophils and human liver microsomes were observed for diclofenac, carbamazepine, clozapine, and bifonazole. The developed HPLC-MS/MS method was also evaluated in vivo by analysis of rat and human urine. Drug-related mercapturic acids were detected in urine of rats orally treated with acetaminophen (20 mg/kg and 640 mg/kg b.w.) or diclofenac (10 mg/kg and 20 mg/kg b.w.). Human urine samples were analyzed before and after oral administration of a clinically used dose of 500 mg and 50 mg of acetaminophen. Besides detection of the mercapturic acid of N-acetylbenzoquinoneimine (AAP-MA), a second mercapturic acid with m/z 327 occurred dose-dependently in rat and human urine samples after administration of acetaminophen. Further investigations on identification of this metabolite using authentic compounds and comparing their MS/MS mass spectra demonstrated oxidation of AAP-MA to stereoisomeric sulfoxides in vivo. For diclofenac, a novel mercapturic acid with m/z 441 was detected in rat urine samples that was identical to a metabolite obtained in incubations with human neutrophils before. The in vivo formation of this diclofenac metabolite is described here for the first time. In addition, three endogenously formed mercapturic acids were detected and identified. In conclusion, the results of the in vitro and in vivo evaluation demonstrate the advantages of the rapid and generic HPLC-MS/MS screening method for the detection of mercapturic acids, that can be obtained with a minimum of sample preparation and a high throughput in diverse matrices.},
  subject      = {Acetylcysteinderivate},
  language  = {en}
}