@article{MontellanoKluterRueckeretal.2022, author = {Montellano, Felipe A. and Kluter, Elisabeth J. and R{\"u}cker, Viktoria and Ungeth{\"u}m, Kathrin and Mackenrodt, Daniel and Wiedmann, Silke and Dege, Tassilo and Quilitzsch, Anika and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph and Heuschmann, Peter U.}, title = {Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study}, series = {BMC Neurology}, volume = {22}, journal = {BMC Neurology}, number = {1}, doi = {10.1186/s12883-022-03017-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300119}, year = {2022}, abstract = {Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, W{\"u}rzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95\% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014-02/2017. Of those, 203 (37\%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95\% CI 1.02-1.08), male sex (OR 2.65; 95\% CI 1.54-4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95\% CI 0.61-0.84), systolic dysfunction (OR 2.79; 95\% CI 1.22-6.37), diastolic dysfunction (OR 2.29; 95\% CI 1.29-4.02), atrial fibrillation (OR 2.30; 95\% CI 1.25-4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95\% CI 1.22-1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors.}, language = {en} } @article{LippertFassnachtRonchi2022, author = {Lippert, Juliane and Fassnacht, Martin and Ronchi, Cristina L.}, title = {The role of molecular profiling in adrenocortical carcinoma}, series = {Clinical Endocrinology}, volume = {97}, journal = {Clinical Endocrinology}, number = {4}, doi = {10.1111/cen.14629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258382}, pages = {460-472}, year = {2022}, abstract = {Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.}, language = {en} } @article{ReelReelErlicetal.2022, author = {Reel, Smarti and Reel, Parminder S. and Erlic, Zoran and Amar, Laurence and Pecori, Alessio and Larsen, Casper K. and Tetti, Martina and Pamporaki, Christina and Prehn, Cornelia and Adamski, Jerzy and Prejbisz, Aleksander and Ceccato, Filippo and Scaroni, Carla and Kroiss, Matthias and Dennedy, Michael C. and Deinum, Jaap and Eisenhofer, Graeme and Langton, Katharina and Mulatero, Paolo and Reincke, Martin and Rossi, Gian Paolo and Lenzini, Livia and Davies, Eleanor and Gimenez-Roqueplo, Anne-Paule and Assi{\´e}, Guillaume and Blanchard, Anne and Zennaro, Maria-Christina and Beuschlein, Felix and Jefferson, Emily R.}, title = {Predicting hypertension subtypes with machine learning using targeted metabolites and their ratios}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {8}, issn = {2218-1989}, doi = {10.3390/metabo12080755}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286161}, year = {2022}, abstract = {Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20\% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing's syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92\% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification.}, language = {en} } @article{NoseNogamiKoshinoetal.2021, author = {Nose, Naoko and Nogami, Suguru and Koshino, Kazuhiro and Chen, Xinyu and Werner, Rudolf A. and Kashima, Soki and Rowe, Steven P. and Lapa, Constantin and Fukuchi, Kazuki and Higuchi, Takahiro}, title = {[18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-90383-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-260590}, year = {2021}, abstract = {Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.}, language = {en} } @article{AertsEberleinHolmetal.2021, author = {Aerts, An and Eberlein, Uta and Holm, S{\"o}ren and Hustinx, Roland and Konijnenberg, Mark and Strigari, Lidia and van Leeuwen, Fijs W. B. and Glatting, Gerhard and Lassmann, Michael}, title = {EANM position paper on the role of radiobiology in nuclear medicine}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {48}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {11}, doi = {10.1007/s00259-021-05345-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265595}, pages = {3365-3377}, year = {2021}, abstract = {With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.}, language = {en} } @article{CapetianRoessnerKorteetal.2021, author = {Capetian, Philipp and Roessner, Veit and Korte, Caroline and Walitza, Susanne and Riederer, Franz and Taurines, Regina and Gerlach, Manfred and Moser, Andreas}, title = {Altered urinary tetrahydroisoquinoline derivatives in patients with Tourette syndrome: reflection of dopaminergic hyperactivity?}, series = {Journal of Neural Transmission}, volume = {128}, journal = {Journal of Neural Transmission}, issn = {0300-9564}, doi = {10.1007/s00702-020-02289-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235771}, pages = {115-121}, year = {2021}, abstract = {Tetrahydroisoquinolines (TIQs) such as salsolinol (SAL), norsalsolinol (NSAL) and their methylated derivatives N-methyl-norsalsolinol (NMNSAL) and N-methyl-salsolinol (NMSAL), modulate dopaminergic neurotransmission and metabolism in the central nervous system. Dopaminergic neurotransmission is thought to play an important role in the pathophysiology of chronic tic disorders, such as Tourette syndrome (TS). Therefore, the urinary concentrations of these TIQ derivatives were measured in patients with TS and patients with comorbid attention-deficit/hyperactivity disorder (TS + ADHD) compared with controls. Seventeen patients with TS, 12 with TS and ADHD, and 19 age-matched healthy controls with no medication took part in this study. Free levels of NSAL, NMNSAL, SAL, and NMSAL in urine were measured by a two-phase chromatographic approach. Furthermore, individual TIQ concentrations in TS patients were used in receiver-operating characteristics (ROC) curve analysis to examine the diagnostic value. NSAL concentrations were elevated significantly in TS [434.67 ± 55.4 nmol/l (standard error of mean = S.E.M.), two-way ANOVA, p < 0.0001] and TS + ADHD patients [605.18 ± 170.21 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] compared with controls [107.02 ± 33.18 nmol/l (S.E.M.), two-way ANOVA, p < 0.0001] and NSAL levels in TS + ADHD patients were elevated significantly in comparison with TS patients (two-way ANOVA, p = 0.017). NSAL demonstrated an AUC of 0.93 ± 0.046 (S.E.M) the highest diagnostic value of all metabolites for the diagnosis of TS. Our results suggest a dopaminergic hyperactivity underlying the pathophysiology of TS and ADHD. In addition, NSAL concentrations in urine may be a potential diagnostic biomarker of TS.}, language = {en} } @article{SperlichAchtzehndeMareesetal.2016, author = {Sperlich, Billy and Achtzehn, Silvia and de Mar{\´e}es, Markus and von Papen, Henning and Mester, Joachim}, title = {Load management in elite German distance runners during 3-weeks of high-altitude training}, series = {Physiological Reports}, volume = {4}, journal = {Physiological Reports}, number = {12}, doi = {10.14814/phy2.12845}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171294}, pages = {e12845}, year = {2016}, abstract = {There is a debate on the optimal way of monitoring training loads in elite endurance athletes especially during altitude training camps. In this case report, including nine members of the German national middle distance running team, we describe a practical approach to monitor the psychobiological stress markers during 21 days of altitude training (~2100 m above sea-level) to estimate the training load and to control muscle damage, fatigue, and/or chronic overreaching. Daily examination included: oxygen saturation of hemoglobin, resting heart rate, body mass, body and sleep perception, capillary blood concentration of creatine kinase. Every other day, venous serum concentration of blood urea nitrogen, venous blood concentration of hemoglobin, hematocrit, red and white blood cell were measured. If two or more of the above-mentioned stress markers were beyond or beneath the athlete's normal individual range, the training load of the subsequent training session was reduced. Running speed at 3 mmol L\(^{-1}\) blood lactate (V\(_{3}\)) improved and no athlete showed any signs of underperformance, chronic muscle damage, decrease body and sleep perception as well as activated inflammatory process during the 21 days. The dense screening of biomarkers in the present case study may stimulate further research to identify candidate markers for load monitoring in elite middle- and long-distance runners during a training camp at altitude.}, language = {en} } @article{SchuppStopperHeidland2016, author = {Schupp, Nicole and Stopper, Helga and Heidland, August}, title = {DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers}, series = {Oxidative Medicine and Cellular Longevity}, volume = {2016}, journal = {Oxidative Medicine and Cellular Longevity}, number = {3592042}, doi = {10.1155/2016/3592042}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166569}, year = {2016}, abstract = {Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients' burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker's potential to predict clinical outcomes.}, language = {en} } @article{LitovkinVanEyndeJoniauetal.2015, author = {Litovkin, Kirill and Van Eynde, Aleyde and Joniau, Steven and Lerut, Evelyne and Laenen, Annouschka and Gevaert, Thomas and Gevaert, Olivier and Spahn, Martin and Kneitz, Burkhard and Gramme, Pierre and Helleputte, Thibault and Isebaert, Sofie and Haustermans, Karin and Bollen, Mathieu}, title = {DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0130651}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151705}, pages = {e0130651}, year = {2015}, abstract = {Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95\% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95\% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95\% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.}, language = {en} } @article{TsonevaStritzkerBedenketal.2015, author = {Tsoneva, Desislava and Stritzker, Jochen and Bedenk, Kristina and Zhang, Qian and Cappello, Joseph and Fischer, Utz and Szalay, Aladar A.}, title = {Drug-encoded Biomarkers for Monitoring Biological Therapies}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {9}, doi = {10.1371/journal.pone.0137573}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125265}, pages = {e0137573}, year = {2015}, abstract = {Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.}, language = {en} } @article{PaholcsekFidlerKonyaetal.2015, author = {Paholcsek, Melinda and Fidler, Gabor and Konya, Jozsef and Rejto, Laszlo and Mehes, Gabor and Bukta, Evelin and Loeffler, Juergen and Biro, Sandor}, title = {Combining standard clinical methods with PCR showed improved diagnosis of invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia}, series = {BMC Infectious Diseases}, volume = {15}, journal = {BMC Infectious Diseases}, number = {251}, doi = {10.1186/s12879-015-0995-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151607}, year = {2015}, abstract = {Background: We assessed the diagnostic value of standard clinical methods and combined biomarker testing (galactomannan assay and polymerase chain reaction screening) in a prospective case-control study to detect invasive pulmonary aspergillosis in patients with hematological malignancies and prolonged neutropenia. Methods: In this observational study 162 biomarker analyses were performed on samples from 27 febrile neutropenic episodes. Sera were successively screened for galactomannan antigen and for Aspergillus fumigatus specific nucleic acid targets. Furthermore thoracic computed tomography scanning was performed along with bronchoscopy with lavage when clinically indicated. Patients were retrospectively stratified to define a case-group with "proven" or "probable" invasive pulmonary aspergillosis (25.93 \%) and a control-group of patients with no evidence for of invasive pulmonary aspergillosis (74.07 \%). In 44.44 \% of episodes fever ceased in response to antibiotic treatment (group II). Empirical antifungal therapy was administered for episodes with persistent or relapsing fever (group I). 48.15 \% of patients died during the study period. Postmortem histology was pursued in 53.85 \% of fatalities. Results: Concordant negative galactomannan and computed tomography supported by a polymerase chain reaction assay were shown to have the highest discriminatory power to exclude invasive pulmonary aspergillosis. Bronchoalveolar lavage was performed in 6 cases of invasive pulmonary aspergillosis and in 15 controls. Although bronchoalveolar lavage proved negative in 93 \% of controls it did not detect IPA in 86 \% of the cases. Remarkably post mortem histology convincingly supported the presence of Aspergillus hyphae in lung tissue from a single case which had consecutive positive polymerase chain reaction assay results but was misdiagnosed by both computed tomography and consistently negative galactomannan assay results. For the galactomannan enzyme-immunoassay the diagnostic odds ratio was 15.33 and for the polymerase chain reaction assay it was 28.67. According to Cohen's kappa our in-house polymerase chain reaction method showed a fair agreement with the galactomannan immunoassay. Combined analysis of the results from the Aspergillus galactomannan enzyme immunoassay together with those generated by our polymerase chain reaction assay led to no misdiagnoses in the control group. Conclusion: The data from this pilot-study demonstrate that the consideration of standard clinical methods combined with biomarker testing improves the capacity to make early and more accurate diagnostic decisions.}, language = {en} } @article{KraftDrechslerGunrebenetal.2014, author = {Kraft, Peter and Drechsler, Christiane and Gunreben, Ignaz and Nieswandt, Bernhard and Stoll, Guido and Heuschmann, Peter Ulrich and Kleinschnitz, Christoph}, title = {Von Willebrand Factor Regulation in Patients with Acute and Chronic Cerebrovascular Disease: A Pilot, Case-Control Study}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {6}, issn = {1932-6203}, doi = {10.1371/journal.pone.0099851}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119588}, pages = {e99851}, year = {2014}, abstract = {Background and Purpose In animal models, von Willebrand factor (VWF) is involved in thrombus formation and propagation of ischemic stroke. However, the pathophysiological relevance of this molecule in humans, and its potential use as a biomarker for the risk and severity of ischemic stroke remains unclear. This study had two aims: to identify predictors of altered VWF levels and to examine whether VWF levels differ between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods A case-control study was undertaken between 2010 and 2013 at our University clinic. In total, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HV) were included. Blood was taken at days 0, 1, and 3 in patients with AIS or TIA, and once in CCD patients and HV. VWF serum levels were measured and correlated with demographic and clinical parameters by multivariate linear regression and ANOVA. Results Patients with CCD (158±46\%) had significantly higher VWF levels than HV (113±36\%, P<0.001), but lower levels than AIS/TIA patients (200±95\%, P<0.001). Age, sex, and stroke severity influenced VWF levels (P<0.05). Conclusions VWF levels differed across disease subtypes and patient characteristics. Our study confirms increased VWF levels as a risk factor for cerebrovascular disease and, moreover, suggests that it may represent a potential biomarker for stroke severity, warranting further investigation.}, language = {en} } @article{BorgesO'ConnorPhillipsetal.2014, author = {Borges, Alvaro H. and O'Connor, Jemma L. and Phillips, Andrew N. and Baker, Jason V. and Vjecha, Michael J. and Losso, Marcelo H. and Klinker, Hartwig and Lopardo, Gustavo and Williams, Ian and Lundgren, Jens D.}, title = {Factors Associated with D-Dimer Levels in HIV-Infected Individuals}, series = {PLOS ONE}, volume = {9}, journal = {PLOS ONE}, number = {3}, doi = {10.1371/journal.pone.0090978}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117094}, pages = {e90978}, year = {2014}, abstract = {Background: Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood. Methods: In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4(+) count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol. Results: Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels. Conclusions: D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels.}, language = {en} } @article{SchubertSpahnKneitzetal.2013, author = {Schubert, Maria and Spahn, Martin and Kneitz, Susanne and Scholz, Claus J{\"u}rgen and Joniau, Steven and Stroebel, Philipp and Riedmiller, Hubertus and Kneitz, Burkhard}, title = {Distinct microRNA Expression Profile in Prostate Cancer Patients with Early Clinical Failure and the Impact of let-7 as Prognostic Marker in High-Risk Prostate Cancer}, series = {PLoS ONE}, journal = {PLoS ONE}, doi = {10.1371/journal.pone.0065064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96825}, year = {2013}, abstract = {Background The identification of additional prognostic markers to improve risk stratification and to avoid overtreatment is one of the most urgent clinical needs in prostate cancer (PCa). MicroRNAs, being important regulators of gene expression, are promising biomarkers in various cancer entities, though the impact as prognostic predictors in PCa is poorly understood. The aim of this study was to identify specific miRNAs as potential prognostic markers in high-risk PCa and to validate their clinical impact. Methodology and Principal Findings We performed miRNA-microarray analysis in a high-risk PCa study group selected by their clinical outcome (clinical progression free survival (CPFS) vs. clinical failure (CF)). We identified seven candidate miRNAs (let-7a/b/c, miR-515-3p/5p, -181b, -146b, and -361) that showed differential expression between both groups. Further qRT-PCR analysis revealed down-regulation of members of the let-7 family in the majority of a large, well-characterized high-risk PCa cohort (n = 98). Expression of let-7a/b/and -c was correlated to clinical outcome parameters of this group. While let-7a showed no association or correlation with clinical relevant data, let-7b and let-7c were associated with CF in PCa patients and functioned partially as independent prognostic marker. Validation of the data using an independent high-risk study cohort revealed that let-7b, but not let-7c, has impact as an independent prognostic marker for BCR and CF. Furthermore, we identified HMGA1, a non-histone protein, as a new target of let-7b and found correlation of let-7b down-regulation with HMGA1 over-expression in primary PCa samples. Conclusion Our findings define a distinct miRNA expression profile in PCa cases with early CF and identified let-7b as prognostic biomarker in high-risk PCa. This study highlights the importance of let-7b as tumor suppressor miRNA in high-risk PCa and presents a basis to improve individual therapy for high-risk PCa patients.}, language = {en} } @article{GerlachMaetzlerBroichetal.2012, author = {Gerlach, Manfred and Maetzler, Walter and Broich, Karl and Hampel, Harald and Rems, Lucas and Reum, Torsten and Riederer, Peter and St{\"a}ffler, Albrecht and Streffer, Johannes and Berg, Daniela}, title = {Biomarker candidates of neurodegeneration in Parkinson's disease for the evaluation of disease-modifying therapeutics}, series = {Journal of Neural Transmission}, volume = {119}, journal = {Journal of Neural Transmission}, number = {1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125375}, pages = {39-52}, year = {2012}, abstract = {Reliable biomarkers that can be used for early diagnosis and tracking disease progression are the cornerstone of the development of disease-modifying treatments for Parkinson's disease (PD). The German Society of Experimental and Clinical Neurotherapeutics (GESENT) has convened a Working Group to review the current status of proposed biomarkers of neurodegeneration according to the following criteria and to develop a consensus statement on biomarker candidates for evaluation of disease-modifying therapeutics in PD. The criteria proposed are that the biomarker should be linked to fundamental features of PD neuropathology and mechanisms underlying neurodegeneration in PD, should be correlated to disease progression assessed by clinical rating scales, should monitor the actual disease status, should be pre-clinically validated, and confirmed by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. To date, available data have not yet revealed one reliable biomarker to detect early neurodegeneration in PD and to detect and monitor effects of drug candidates on the disease process, but some promising biomarker candidates, such as antibodies against neuromelanin, pathological forms of α-synuclein, DJ-1, and patterns of gene expression, metabolomic and protein profiling exist. Almost all of the biomarker candidates were not investigated in relation to effects of treatment, validated in experimental models of PD and confirmed in independent studies.}, language = {en} } @article{MolochnikovRabeyDobronevskyetal.2012, author = {Molochnikov, Leonid and Rabey, Jose M. and Dobronevsky, Evgenya and Bonuccelli, Ubaldo and Ceravolo, Roberto and Frosini, Daniela and Gr{\"u}nblatt, Edna and Riederer, Peter and Jacob, Christian and Aharon-Peretz, Judith and Bashenko, Yulia and Youdim, Moussa B. H. and Mandel, Silvia A.}, title = {A molecular signature in blood identifies early Parkinson's disease}, series = {Molecular Neurodegeneration}, volume = {7}, journal = {Molecular Neurodegeneration}, number = {26}, doi = {10.1186/1750-1326-7-26}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134508}, year = {2012}, abstract = {Background: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. Results: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95\% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95\% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95\% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95\% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100\% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). Conclusions: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.}, language = {en} }