@article{UeceylerSchroeterKafkeetal.2016, author = {{\"U}{\c{c}}eyler, Nurcan and Schr{\"o}ter, Nils and Kafke, Waldemar and Kramer, Daniela and Wanner, Christoph and Weidemann, Frank and Sommer, Claudia}, title = {Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease}, series = {PLoS ONE}, volume = {11}, journal = {PLoS ONE}, number = {11}, doi = {10.1371/journal.pone.0166484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-178856}, year = {2016}, abstract = {Background The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity. Methods At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data. Results We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy. Conclusions Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.}, language = {en} } @article{UeceylerKahnKrameretal.2013, author = {{\"U}{\c{c}}eyler, Nurcan and Kahn, Ann-Kathrin and Kramer, Daniela and Zeller, Daniel and Casanova-Molla, Jordi and Wanner, Christoph and Weidemann, Frank and Katsarava, Zaza and Sommer, Claudia}, title = {Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case-control study}, series = {BMC Neurology}, journal = {BMC Neurology}, doi = {10.1186/1471-2377-13-47}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96527}, year = {2013}, abstract = {Background Fabry disease is an inborn lysosomal storage disorder which is associated with small fiber neuropathy. We set out to investigate small fiber conduction in Fabry patients using pain-related evoked potentials (PREP). Methods In this case-control study we prospectively studied 76 consecutive Fabry patients for electrical small fiber conduction in correlation with small fiber function and morphology. Data were compared with healthy controls using non-parametric statistical tests. All patients underwent neurological examination and were investigated with pain and depression questionnaires. Small fiber function (quantitative sensory testing, QST), morphology (skin punch biopsy), and electrical conduction (PREP) were assessed and correlated. Patients were stratified for gender and disease severity as reflected by renal function. Results All Fabry patients (31 men, 45 women) had small fiber neuropathy. Men with Fabry disease showed impaired cold (p < 0.01) and warm perception (p < 0.05), while women did not differ from controls. Intraepidermal nerve fiber density (IENFD) was reduced at the lower leg (p < 0.001) and the back (p < 0.05) mainly of men with impaired renal function. When investigating A-delta fiber conduction with PREP, men but not women with Fabry disease had lower amplitudes upon stimulation at face (p < 0.01), hands (p < 0.05), and feet (p < 0.01) compared to controls. PREP amplitudes further decreased with advance in disease severity. PREP amplitudes and warm (p < 0.05) and cold detection thresholds (p < 0.01) at the feet correlated positively in male patients. Conclusion Small fiber conduction is impaired in men with Fabry disease and worsens with advanced disease severity. PREP are well-suited to measure A-delta fiber conduction.}, language = {en} } @article{ZopfFreyKienitzetal.2017, author = {Zopf, Kathrin and Frey, Kathrin R. and Kienitz, Tina and Ventz, Manfred and Bauer, Britta and Quinkler, Marcus}, title = {\(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency}, series = {Endocrine Connections}, volume = {6}, journal = {Endocrine Connections}, number = {8}, doi = {10.1530/EC-17-0269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173276}, pages = {685-691}, year = {2017}, abstract = {Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR). Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH. Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented. Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)). Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC.}, language = {en} } @article{ZinmanInzucchiLachinetal.2014, author = {Zinman, Bernard and Inzucchi, Silvio E. and Lachin, John M. and Wanner, Christoph and Ferrari, Roberto and Fitchett, David and Bluhmki, Erich and Hantel, Stefan and Kempthorne-Rawson, Joan and Newman, Jennifer and Johansen, Odd Erik and Woerle, Hans-Juergen and Broedl, Uli C.}, title = {Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME (TM))}, series = {Cardiovascular Diabetology}, volume = {13}, journal = {Cardiovascular Diabetology}, number = {102}, issn = {1475-2840}, doi = {10.1186/1475-2840-13-102}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116036}, year = {2014}, abstract = {Background: Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME (TM) trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes. Methods: Patients who were drug naive (HbA(1c) >= 7.0\% and <= 9.0\%), or on background glucose-lowering therapy (HbA(1c) >= 7.0\% and <= 10.0\%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until >= 691 confirmed primary outcome events have occurred, providing a power of 90\% to yield an upper limit of the adjusted 95\% CI for a hazard ratio of <1.3 with a one-sided a of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved. Results: Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41\% from Europe, 20\% from North America, and 19\% from Asia). At baseline, the mean age was 63 +/- 9 years, BMI 30.6 +/- 5.3 kg/m(2), HbA1c 8.1 +/- 0.8\%, and eGFR 74 +/- 21 ml/min/1.73 m(2). The study is expected to report in 2015. Discussion: EMPA REG OUTCOME (TM) will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.}, language = {en} } @article{ZhaoYuHuetal.2015, author = {Zhao, De-Wei and Yu, Mang and Hu, Kai and Wang, Wei and Yang, Lei and Wang, Ben-Jie and Gao, Xiao-Hong and Guo, Yong-Ming and Xu, Yong-Qing and Wei, Yu-Shan and Tian, Si-Miao and Yang, Fan and Wang, Nan and Huang, Shi-Bo and Xie, Hui and Wei, Xiao-Wei and Jiang, Hai-Shen and Zang, Yu-Qiang and Ai, Jun and Chen, Yuan-Liang and Lei, Guang-Hua and Li, Yu-Jin and Tian, Geng and Li, Zong-Sheng and Cao, Yong and Ma, Li}, title = {Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey}, series = {Chinese Medical Journal}, volume = {128}, journal = {Chinese Medical Journal}, number = {21}, doi = {10.4103/0366-6999.168017}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138482}, pages = {2843-2850}, year = {2015}, abstract = {Background: Nontraumatic osteonecrosis of the femoral head (NONFH) is a debilitating disease that represents a significant financial burden for both individuals and healthcare systems. Despite its significance, however, its prevalence in the Chinese general population remains unknown. This study aimed to investigate the prevalence of NONFH and its associated risk factors in the Chinese population. Methods: A nationally representative survey of 30,030 respondents was undertaken from June 2012 to August 2013. All participants underwent a questionnaire investigation, physical examination of hip, and bilateral hip joint X-ray and/or magnetic resonance imaging examination. Blood samples were taken after overnight fasting to test serum total cholesterol, triglyceride, and high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels. We then used multivariate logistic regression analysis to investigate the associations between various metabolic, demographic, and lifestyle-related variables and NONFH. Results: NONFH was diagnosed in 218 subjects (0.725\%) and the estimated NONFH cases were 8.12 million among Chinese people aged 15 years and over. The prevalence of NONFH was significantly higher in males than in females (1.02\% vs. 0.51\%, \(\chi^2\) = 24.997, P < 0.001). Among NONFH patients, North residents were subjected to higher prevalence of NONFH than that of South residents (0.85\% vs. 0.61\%, \(\chi^2\) = 5.847, P = 0.016). Our multivariate regression analysis showed that high blood levels of triglycerides, total cholesterol, LDL-cholesterol, and non-HDL-cholesterol, male, urban residence, family history of osteonecrosis of the femoral head, heavy smoking, alcohol abuse and glucocorticoid intake, overweight, and obesity were all significantly associated with an increased risk of NONFH. Conclusions: Our findings highlight that NONFH is a significant public health challenge in China and underscore the need for policy measures on the national level. Furthermore, NONFH shares a number of risk factors with atherosclerosis.}, language = {en} } @article{YurdadoganMalschKotsevaetal.2021, author = {Yurdadogan, Tino and Malsch, Carolin and Kotseva, Kornelia and Wood, David and Leyh, Rainer and Ertl, Georg and Karmann, Wolfgang and M{\"u}ller-Scholden, Lara and Morbach, Caroline and Breuning, Margret and Wagner, Martin and Gelbrich, G{\"o}tz and Bots, Michiel L. and Heuschmann, Peter U. and St{\"o}rk, Stefan}, title = {Functional versus morphological assessment of vascular age in patients with coronary heart disease}, series = {Scientific Reports}, volume = {11}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-021-96998-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265810}, year = {2021}, abstract = {Communicating cardiovascular risk based on individual vascular age (VA) is a well acknowledged concept in patient education and disease prevention. VA may be derived functionally, e.g. by measurement of pulse wave velocity (PWV), or morphologically, e.g. by assessment of carotid intima-media thickness (cIMT). The purpose of this study was to investigate whether both approaches produce similar results. Within the context of the German subset of the EUROASPIRE IV survey, 501 patients with coronary heart disease underwent (a) oscillometric PWV measurement at the aortic, carotid-femoral and brachial-ankle site (PWVao, PWVcf, PWVba) and derivation of the aortic augmentation index (AIao); (b) bilateral cIMT assessment by high-resolution ultrasound at three sites (common, bulb, internal). Respective VA was calculated using published equations. According to VA derived from PWV, most patients exhibited values below chronological age indicating a counterintuitive healthier-than-anticipated vascular status: for VA(PWVao) in 68\% of patients; for VA\(_{AIao}\) in 52\% of patients. By contrast, VA derived from cIMT delivered opposite results: e.g. according to VA\(_{total-cIMT}\) accelerated vascular aging in 75\% of patients. To strengthen the concept of VA, further efforts are needed to better standardise the current approaches to estimate VA and, thereby, to improve comparability and clinical utility.}, language = {en} } @article{WinterAndelovicKampfetal.2021, author = {Winter, Patrick M. and Andelovic, Kristina and Kampf, Thomas and Hansmann, Jan and Jakob, Peter Michael and Bauer, Wolfgang Rudolf and Zernecke, Alma and Herold, Volker}, title = {Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {23}, journal = {Journal of Cardiovascular Magnetic Resonance}, number = {1}, doi = {10.1186/s12968-021-00725-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-259152}, pages = {34}, year = {2021}, abstract = {Purpose Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement. Methods Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE\(^{-/-}\) mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification. Results 4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE\(^{-/-}\) mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m\(^2\) in wildtype mice and (1.27 ± 0.10) N/m\(^2\) in ApoE\(^{-/-}\) mice. Conclusion The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements.}, language = {en} } @article{WinterKampfHelluyetal.2013, author = {Winter, Patrick and Kampf, Thomas and Helluy, Xavier and Gutjahr, Fabian T. and Meyer, Cord B. and Rommel, Eberhard and Bauer, Wolfgang R. and Jakob, Peter M. and Herold, Volker}, title = {Fast retrospectively triggered local pulse-wave velocity measurements in mice with CMR-microscopy using a radial trajectory}, series = {Journal of Cardiovascular Magnetic Resonance}, journal = {Journal of Cardiovascular Magnetic Resonance}, doi = {10.1186/1532-429X-15-88}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96602}, year = {2013}, abstract = {Background The aortic pulse-wave velocity (PWV) is an important indicator of cardiovascular risk. In recent studies MRI methods have been developed to measure this parameter noninvasively in mice. Present techniques require additional hardware for cardiac and respiratory gating. In this work a robust self-gated measurement of the local PWV in mice without the need of triggering probes is proposed. Methods The local PWV of 6-months-old wild-type C57BL/6J mice (n=6) was measured in the abdominal aorta with a retrospectively triggered radial Phase Contrast (PC) MR sequence using the flow-area (QA) method. A navigator signal was extracted from the CMR data of highly asymmetric radial projections with short repetition time (TR=3 ms) and post-processed with high-pass and low-pass filters for retrospective cardiac and respiratory gating. The self-gating signal was used for a reconstruction of high-resolution Cine frames of the aortic motion. To assess the local PWV the volume flow Q and the cross-sectional area A of the aorta were determined. The results were compared with the values measured with a triggered Cartesian and an undersampled triggered radial PC-Cine sequence. Results In all examined animals a self-gating signal could be extracted and used for retrospective breath-gating and PC-Cine reconstruction. With the non-triggered measurement PWV values of 2.3±0.2 m/s were determined. These values are in agreement with those measured with the triggered Cartesian (2.4±0.2 m/s) and the triggered radial (2.3±0.2 m/s) measurement. Due to the strong robustness of the radial trajectory against undersampling an acceleration of more than two relative to the prospectively triggered Cartesian sampling could be achieved with the retrospective method. Conclusion With the radial flow-encoding sequence the extraction of a self-gating signal is feasible. The retrospective method enables a robust and fast measurement of the local PWV without the need of additional trigger hardware.}, language = {en} } @article{WinterAndelovicKampfetal.2019, author = {Winter, Patrick and Andelovic, Kristina and Kampf, Thomas and Gutjahr, Fabian Tobias and Heidenreich, Julius and Zernecke, Alma and Bauer, Wolfgang Rudolf and Jakob, Peter Michael and Herold, Volker}, title = {Fast self-navigated wall shear stress measurements in the murine aortic archusing radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {21}, journal = {Journal of Cardiovascular Magnetic Resonance}, doi = {10.1186/s12968-019-0566-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201120}, pages = {64}, year = {2019}, abstract = {Purpose 4D flow cardiovascular magnetic resonance (CMR) and the assessment of wall shear stress (WSS) are non-invasive tools to study cardiovascular risks in vivo. Major limitations of conventional triggered methods are the long measurement times needed for high-resolution data sets and the necessity of stable electrocardiographic (ECG) triggering. In this work an ECG-free retrospectively synchronized method is presented that enables accelerated high-resolution measurements of 4D flow and WSS in the aortic arch of mice. Methods 4D flow and WSS were measured in the aortic arch of 12-week-old wildtype C57BL/6 J mice (n = 7) with a radial 4D-phase-contrast (PC)-CMR sequence, which was validated in a flow phantom. Cardiac and respiratory motion signals were extracted from the radial CMR signal and were used for the reconstruction of 4D-flow data. Rigid motion correction and a first order B0 correction was used to improve the robustness of magnitude and velocity data. The aortic lumen was segmented semi-automatically. Temporally averaged and time-resolved WSS and oscillatory shear index (OSI) were calculated from the spatial velocity gradients at the lumen surface at 14 locations along the aortic arch. Reproducibility was tested in 3 animals and the influence of subsampling was investigated. Results Volume flow, cross-sectional areas, WSS and the OSI were determined in a measurement time of only 32 min. Longitudinal and circumferential WSS and radial stress were assessed at 14 analysis planes along the aortic arch. The average longitudinal, circumferential and radial stress values were 1.52 ± 0.29 N/m2, 0.28 ± 0.24 N/m2 and - 0.21 ± 0.19 N/m2, respectively. Good reproducibility of WSS values was observed. Conclusion This work presents a robust measurement of 4D flow and WSS in mice without the need of ECG trigger signals. The retrospective approach provides fast flow quantification within 35 min and a flexible reconstruction framework.}, language = {en} } @article{WilliamsMachannKuehleretal.2011, author = {Williams, Tatjana and Machann, Wolfram and K{\"u}hler, Leif and Hamm, Henning and M{\"u}ller-H{\"o}cker, Josef and Zimmer, Michael and Ertl, Georg and Ritter, Oliver and Beer, Meinrad and Sch{\"o}nberger, Jost}, title = {Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma}, series = {Clinical Research in Cardiology}, volume = {100}, journal = {Clinical Research in Cardiology}, number = {12}, doi = {10.1007/s00392-011-0345-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-141198}, pages = {1087-1093}, year = {2011}, abstract = {Two sons of a consanguineous marriage developed biventricular cardiomyopathy. One boy died of severe heart failure at the age of 6 years, the other was transplanted because of severe heart failure at the age of 10 years. In addition, focal palmoplantar keratoderma and woolly hair were apparent in both boys. As similar phenotypes have been described in Naxos disease and Carvajal syndrome, respectively, the genes for plakoglobin (JUP) and desmoplakin (DSP) were screened for mutations using direct genomic sequencing. A novel homozygous 2 bp deletion was identified in an alternatively spliced region of DSP. The deletion 5208_5209delAG led to a frameshift downstream of amino acid 1,736 with a premature truncation of the predominant cardiac isoform DSP-1. This novel homozygous truncating mutation in the isoform-1 specific region of the DSP C-terminus caused Carvajal syndrome comprising severe early-onset heart failure with features of non-compaction cardiomyopathy, woolly hair and an acantholytic form of palmoplantar keratoderma in our patient. Congenital hair abnormality and manifestation of the cutaneous phenotype in toddler age can help to identify children at risk for cardiac death.}, language = {en} } @article{WiegeringRiedmeierThompsonetal.2022, author = {Wiegering, Verena and Riedmeier, Maria and Thompson, Lester D. R. and Virgone, Calogero and Redlich, Antje and Kuhlen, Michaela and Gultekin, Melis and Yalcin, Bilgehan and Decarolis, Boris and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Timmermann, Beate}, title = {Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature}, series = {Clinical and Translational Radiation Oncology}, volume = {35}, journal = {Clinical and Translational Radiation Oncology}, doi = {10.1016/j.ctro.2022.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300472}, pages = {56-63}, year = {2022}, abstract = {Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70\% female); 78\% of patients presented with hormonal activity. RT was mostly performed for curative intent (78\%). 88\% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76\%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64\% of the patients died of disease, with 33\% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33\%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.}, language = {en} } @inproceedings{WernerWakabayashiJahnsetal.2017, author = {Werner, Rudolf and Wakabayashi, Hiroshi and Jahns, Roland and Erg{\"u}n, S{\"u}leyman and Jahns, Valerie and Higuchi, Takahiro}, title = {PET-Guided Histological Characterization of Myocardial Infiltrating Cells in a Rat Model of Myocarditis}, series = {European Heart Journal - Cardiovascular Imaging}, volume = {18}, booktitle = {European Heart Journal - Cardiovascular Imaging}, number = {Supplement}, publisher = {Oxford University Press}, issn = {2047-2404}, doi = {10.1093/ehjci/jex071}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161127}, pages = {i1-i3}, year = {2017}, abstract = {No abstract available.}, subject = {Myokarditis}, language = {en} } @article{WernerSchmidHiguchietal.2018, author = {Werner, Rudolf and Schmid, Jan-Stefan and Higuchi, Takahiro and Javadi, Mehrbod S. and Rowe, Steven P. and M{\"a}rkl, Bruno and Aulmann, Christoph and Fassnacht, Martin and Kroiß, Matthias and Reiners, Christoph and Buck, Andreas and Kreissl, Michael and Lapa, Constantin}, title = {Predictive value of \(^{18}\)F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib}, series = {Journal of Nuclear Medicine}, journal = {Journal of Nuclear Medicine}, issn = {0161-5505}, doi = {10.2967/jnumed.117.199778}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161256}, year = {2018}, abstract = {Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We aimed to assess the role of metabolic imaging using 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after TKI treatment initiation. During follow-up, CT scans were performed every 3 months and analyzed according to Response Evaluation Criteria In Solid Tumors (RECIST). The predictive value for estimating progression-free (PFS) and overall survival (OS) was examined by investigating \(^{18}\)F-FDG mean/maximum standardized uptake values (SUVmean/max) of the metabolically most active lesion as well as by analyzing clinical parameters (tumor marker doubling times {calcitonin, carcinoembryonic antigen (CEA)}, prior therapies, RET (rearranged during transfection) mutational status, and disease type). Results: Within a median follow-up of 5.2 years, 9 patients experienced disease progression after a median time interval of 2.1y whereas the remainder had ongoing disease control (n=5 partial response and n=4 stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5y after TKI initiation. Pre-therapeutic SUVmean >4.0 predicted a significantly shorter PFS (PFS: 1.9y vs. 5.2y; p=0.04). Furthermore, sustained high 18F-FDG uptake at 3 months with a SUVmean>2.8 tended to portend an unfavorable prognosis with a PFS of 1.9y (vs. 3.5y; p=0.3). Prolonged CEA doubling times were significantly correlated with longer PFS (r=0.7) and OS (r=0.76, p<0.01, respectively). None of the other clinical parameters had prognostic significance. Conclusions: Pre-therapeutic \(^{18}\)F-FDG PET/CT holds prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. Low tumor metabolism of SUVmean < 4.0 prior to treatment predicts longer progression-free survival.}, subject = {Medull{\"a}rer Schilddr{\"u}senkrebs}, language = {en} } @inproceedings{WernerHiguchiMueggeetal.2017, author = {Werner, Rudolf and Higuchi, Takahiro and Muegge, Dirk and Javadi, Mehrbod S. and M{\"a}rkl, Bruno and Aulmann, Christoph and Buck, Andreas K. and Fassnacht, Martin and Lapa, Constantin and Kreissl, Michael C.}, title = {Predictive value of FDG-PET in patients with advanced medullary thyroid cancer undergoing vandetanib treatment}, series = {Journal of Nuclear Medicine}, volume = {58}, booktitle = {Journal of Nuclear Medicine}, number = {no. supplement 1}, issn = {0161-5505}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-161147}, pages = {169}, year = {2017}, abstract = {Introduction: The prognosis of medullary thyroid carcinoma (MTC) is poor using common chemotherapeutic approaches. However, during the last years encouraging results of recently introduced tyrosine kinase inhibitors (TKI) such as vandetanib have been published. In this study we aimed to correlate the results of \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG) positron emission tomography (PET) imaging with treatment outcome. Methods: Eighteen patients after thyroidectomy with recurrent/advanced MTC lesions receiving vandetanib (300 mg orally/day) could be analysed. A baseline \(^{18}\)F-FDG PET prior to and a follow-up \(^{18}\)F-FDG PET 3 months after TKI initiation were performed. During follow-up, tumor progression was assessed every 3 months including computed tomography according to RECIST. Progression-free survival (PFS) was correlated with the maximum standardized uptake value of \(^{18}\)F-FDG in lymph nodes (SUV(LN)max) or visceral metastases (SUV(MTS)max) as well as with clinical parameters using ROC analysis. Results: Within median 3.6 years of follow-up, 9 patients showed disease progression at median 8.5 months after TKI initiation. An elevated glucose consumption assessed by baseline \(^{18}\)F-FDG PET (SUV(LN)max > 7.25) could predict a shorter PFS (2 y) with an accuracy of 76.5\% (SUV(LN)max <7.25, 4.3 y; p=0.03). Accordingly, preserved tumor metabolism in the follow-up PET (SUV(MTS)max >2.7) also demonstrated an unfavorable prognosis (accuracy, 85.7\%). On the other hand, none of the clinical parameters reached significance in response prediction. Conclusions: In patients with advanced and progressive MTC, tumors with higher metabolic activity at baseline are more aggressive and more prone to progression as reflected by a shorter PFS; they should be monitored more closely. Preserved glucose consumption 3 months after treatment initiation was also related to poorer prognosis.}, language = {en} } @article{WernerSayehliHaenscheidetal.2023, author = {Werner, Rudolf A. and Sayehli, Cyrus and H{\"a}nscheid, Heribert and Higuchi, Takahiro and Serfling, Sebastian E. and Fassnacht, Martin and Goebeler, Maria-Elisabeth and Buck, Andreas K. and Kroiss, Matthias}, title = {Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {50}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {6}, doi = {10.1007/s00259-022-06061-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324435}, pages = {1833-1834}, year = {2023}, abstract = {No abstract available.}, language = {en} } @article{WernerEisslerHayakawaetal.2018, author = {Werner, Rudolf A. and Eissler, Christoph and Hayakawa, Nobuyuki and Arias-Loza, Paula and Wakabayashi, Hiroshi and Javadi, Mehrbod S. and Chen, Xinyu and Shinaji, Tetsuya and Lapa, Constantin and Pelzer, Theo and Higuchi, Takahiro}, title = {Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, number = {17631}, doi = {10.1038/s41598-018-35986-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171765}, year = {2018}, abstract = {In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated \(^{18}\)F-fluorodeoxyglucose positron emission tomography (\(^{18}\)F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated \(^{18}\)F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n=6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, \(^{18}\)F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5±4.2 vs. 59.4±4.5\%; HR: 331±35 vs. 309±24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1±0.8 vs. 10.2±1 Enddiastolic Volume/sec, P<0.01). Investigating a diabetic rat model, ECG-gated \(^{18}\)F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.}, language = {en} } @article{WernerBundschuhHiguchietal.2018, author = {Werner, Rudolf A. and Bundschuh, Ralph A. and Higuchi, Takahiro and Javadi, Mehrbod S. and Rowe, Steven P. and Zs{\´o}t{\´e}r, Norbert and Kroiss, Matthias and Fassnacht, Martin and Buck, Andreas K. and Kreissl, Michael C. and Lapa, Constantin}, title = {Volumetric and Texture Analysis of Pretherapeutic \(^{18}\)F-FDG PET can Predict Overall Survival in Medullary Thyroid Cancer Patients Treated with Vandetanib}, series = {Endocrine}, journal = {Endocrine}, issn = {1355-008X}, doi = {10.1007/s12020-018-1749-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167910}, year = {2018}, abstract = {Purpose: The metabolically most active lesion in 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) PET/CT can predict progression-free survival (PFS) in patients with medullary thyroid carcinoma (MTC) starting treatment with the tyrosine kinase inhibitor (TKI) vandetanib. However, this metric failed in overall survival (OS) prediction. In the present proof of concept study, we aimed to explore the prognostic value of intratumoral textural features (TF) as well as volumetric parameters (total lesion glycolysis, TLG) derived by pre-therapeutic \(^{18}\)F-FDG PET. Methods: Eighteen patients with progressive MTC underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after vandetanib initiation. By manual segmentation of the tumor burden at baseline and follow-up PET, intratumoral TF and TLG were computed. The ability of TLG, imaging-based TF, and clinical parameters (including age, tumor marker doubling times, prior therapies and RET (rearranged during transfection) mutational status) for prediction of both PFS and OS were evaluated. Results: The TF Complexity and the volumetric parameter TLG obtained at baseline prior to TKI initiation successfully differentiated between low- and high-risk patients. Complexity allocated 10/18 patients to the high-risk group with an OS of 3.3y (vs. low-risk group, OS=5.3y, 8/18, AUC=0.78, P=0.03). Baseline TLG designated 11/18 patients to the high-risk group (OS=3.5y vs. low-risk group, OS=5y, 7/18, AUC=0.83, P=0.005). The Hazard Ratio for cancer-related death was 6.1 for Complexity (TLG, 9.5). Among investigated clinical parameters, the age at initiation of TKI treatment reached significance for PFS prediction (P=0.02, OS, n.s.). Conclusions: The TF Complexity and the volumetric parameter TLG are both independent parameters for OS prediction.}, subject = {Positronen-Emissions-Tomografie}, 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{WeissGruendahlDeckertetal.2023, author = {Weiß, Martin and Gr{\"u}ndahl, Marthe and Deckert, J{\"u}rgen and Eichner, Felizitas A. and Kohls, Mirjam and St{\"o}rk, Stefan and Heuschmann, Peter U. and Hein, Grit}, title = {Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, organization = {STAAB-COVID Study Group}, doi = {10.1038/s41598-023-38525-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357858}, year = {2023}, abstract = {Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the "Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)" cohort study, a representative age- and gender-stratified sample of the general population of W{\"u}rzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis.}, language = {en} } @article{WeissRamosDelgobo2022, author = {Weiß, Emil and Ramos, Gustavo Campos and Delgobo, Murilo}, title = {Myocardial-Treg crosstalk: How to tame a wolf}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.914033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275591}, year = {2022}, abstract = {The immune system plays a vital role in maintaining tissue integrity and organismal homeostasis. The sudden stress caused by myocardial infarction (MI) poses a significant challenge for the immune system: it must quickly substitute dead myocardial with fibrotic tissue while controlling overt inflammatory responses. In this review, we will discuss the central role of myocardial regulatory T-cells (Tregs) in orchestrating tissue repair processes and controlling local inflammation in the context of MI. We herein compile recent advances enabled by the use of transgenic mouse models with defined cardiac antigen specificity, explore whole-heart imaging techniques, outline clinical studies and summarize deep-phenotyping conducted by independent labs using single-cell transcriptomics and T-cell repertoire analysis. Furthermore, we point to multiple mechanisms and cell types targeted by Tregs in the infarcted heart, ranging from pro-fibrotic responses in mesenchymal cells to local immune modulation in myeloid and lymphoid lineages. We also discuss how both cardiac-specific and polyclonal Tregs participate in MI repair. In addition, we consider intriguing novel evidence on how the myocardial milieu takes control of potentially auto-aggressive local immune reactions by shaping myosin-specific T-cell development towards a regulatory phenotype. Finally, we examine the potential use of Treg manipulating drugs in the clinic after MI.}, language = {en} } @article{WeismannSchneiderHoeybye2016, author = {Weismann, Dirk and Schneider, Andreas and H{\"o}ybye, Charlotte}, title = {Clinical aspects of symptomatic hyponatremia}, series = {Endocrine Connections}, volume = {5}, journal = {Endocrine Connections}, number = {5}, doi = {10.1530/EC-16-0046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162936}, pages = {R35-R43}, year = {2016}, abstract = {Hyponatremia (HN) is a common condition, with a large number of etiologies and a complicated treatment. Although chronic HN has been shown to be a predictor of poor outcome, sodium-increasing treatments in chronic stable and asymptomatic HN have not proven to increase life expectancy. For symptomatic HN, in contrast, the necessity for urgent treatment has broadly been accepted to avoid the development of fatal cerebral edema. On the other hand, a too rapid increase of serum sodium in chronic HN may result in cerebral damage due to osmotic demyelinisation. Recently, administration of hypertonic saline bolus has been recommended as first-line treatment in patients with moderate-to-severe symptomatic HN. This approach is easy to memorize and holds the potential to greatly facilitate the initial treatment of symptomatic HN. First-line treatment of chronic HN is fluid restriction and if ineffective treatment with tolvaptan or in some patients other agents should be considered. A number of recommendations and guidelines have been published on HN. In the present review, the management of patients with HN in relation to everyday clinical practice is summarized with focus on the acute management.}, language = {en} } @article{WeismannMoeckelPaethetal.2023, author = {Weismann, Dirk and M{\"o}ckel, Martin and Paeth, Heiko and Slagman, Anna}, title = {Modelling variations of emergency attendances using data on community mobility, climate and air pollution}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-47857-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357578}, year = {2023}, abstract = {Air pollution is associated with morbidity and mortality worldwide. We investigated the impact of improved air quality during the economic lockdown during the SARS-Cov2 pandemic on emergency room (ER) admissions in Germany. Weekly aggregated clinical data from 33 hospitals were collected in 2019 and 2020. Hourly concentrations of nitrogen and sulfur dioxide (NO2, SO2), carbon and nitrogen monoxide (CO, NO), ozone (O3) and particulate matter (PM10, PM2.5) measured by ground stations and meteorological data (ERA5) were selected from a 30 km radius around the corresponding ED. Mobility was assessed using aggregated cell phone data. A linear stepwise multiple regression model was used to predict ER admissions. The average weekly emergency numbers vary from 200 to over 1600 cases (total n = 2,216,217). The mean maximum decrease in caseload was 5 standard deviations. With the enforcement of the shutdown in March, the mobility index dropped by almost 40\%. Of all air pollutants, NO2 has the strongest correlation with ER visits when averaged across all departments. Using a linear stepwise multiple regression model, 63\% of the variation in ER visits is explained by the mobility index, but still 6\% of the variation is explained by air quality and climate change.}, language = {en} } @article{WeigandRonchiVanselowetal.2021, author = {Weigand, Isabel and Ronchi, Cristina L. and Vanselow, Jens T. and Bathon, Kerstin and Lenz, Kerstin and Herterich, Sabine and Schlosser, Andreas and Kroiss, Matthias and Fassnacht, Martin and Calebiro, Davide and Sbiera, Silviu}, title = {PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser\(^{114}\) phosphorylation}, series = {Science Advances}, volume = {7}, journal = {Science Advances}, number = {8}, doi = {10.1126/sciadv.abd4176}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270445}, year = {2021}, abstract = {Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing's syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser\(^{114}\) phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing's syndrome.}, language = {en} } @article{WeigandRonchiRizkRabinetal.2017, author = {Weigand, Isabel and Ronchi, Cristina L. and Rizk-Rabin, Marthe and Dalmazi, Guido Di and Wild, Vanessa and Bathon, Kerstin and Rubin, Beatrice and Calebiro, Davide and Beuschlein, Felix and Bertherat, J{\´e}r{\^o}me and Fassnacht, Martin and Sbiera, Silviu}, title = {Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {49}, doi = {10.1038/s41598-017-00125-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157952}, year = {2017}, abstract = {Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40\% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion.}, language = {en} } @phdthesis{Weigand2021, author = {Weigand, Isabel}, title = {Consequences of Protein Kinase A mutations in adrenocortical cells and tumours}, doi = {10.25972/OPUS-16064}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160646}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2021}, abstract = {Adrenal Cushing's Syndrome (CS) is a rare but life-threatening disease and therefore it is of great importance to understand the pathogenesis leading to adrenal CS. It is well accepted that Protein Kinase A (PKA) signalling mediates steroid secretion in adrenocortical cells. PKA is an inactive heterotetramer, consisting of two catalytic and two regulatory subunits. Upon cAMP binding to the regulatory subunits, the catalytic subunits are released and are able to phosphorylate their target proteins. Recently, activating somatic mutations affecting the catalytic subunit a of PKA have been identified in a sub-population of cortisol-producing adenomas (CPAs) associated with overt CS. Interestingly, the PKA regulatory subunit IIb has long been known to have significantly lower protein levels in a sub-group of CPAs compared to other adrenocortical tumours. Yet, it is unknown, why these CPAs lack the regulatory subunit IIb, neither are any functional consequences nor are the underlying regulation mechanisms leading to reduced RIIb levels known. The results obtained in this thesis show a clear connection between Ca mutations and reduced RIIb protein levels in CPAs but not in other adrenocortical tumours. Furthermore, a specific pattern of PKA subunit expression in the different zones of the normal adrenal gland is demonstrated. In addition, a Ca L206R mutation-mediated degradation of RIIb was observed in adrenocortical cells in vitro. RIIb degradation was found to be mediated by caspases and by performing mutagenesis experiments of the regulatory subunits IIb and Ia, S114 phosphorylation of RIIb was identified to make RIIb susceptible for degradation. LC-MS/MS revealed RIIb interaction partners to differ in the presence of either Ca WT and Ca L206R. These newly identified interaction partners are possibly involved in targeting RIIb to subcellular compartments or bringing it into spatial proximity of degrading enzymes. Furthermore, reducing RIIb protein levels in an in vitro system were shown to correlate with increased cortisol secretion also in the absence of PRKACA mutations. The inhibiting role of RIIb in cortisol secretion demonstrates a new function of this regulatory PKA subunit, improving the understanding of the complex regulation of PKA as key regulator in many cells.}, subject = {Cushing-Syndrom}, language = {en} } @article{WeidemannSanchezNinoPoliteietal.2013, author = {Weidemann, Frank and Sanchez-Nino, Maria D. and Politei, Juan and Oliveira, Jo{\~a}o-Paulo and Wanner, Christoph and Warnock, David G. and Oritz, Alberto}, title = {Fibrosis: a key feature of Fabry disease with potential therapeutic implications}, series = {Orphanet Journal of Rare Diseases}, volume = {8}, journal = {Orphanet Journal of Rare Diseases}, number = {116}, issn = {1750-1172}, doi = {10.1186/1750-1172-8-116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124773}, year = {2013}, abstract = {Fabry disease is a rare X-linked hereditary disease caused by mutations in the AGAL gene encoding the lysosomal enzyme alpha-galactosidase A. Enzyme replacement therapy (ERT) is the current cornerstone of Fabry disease management. Involvement of kidney, heart and the central nervous system shortens life span, and fibrosis of these organs is a hallmark of the disease. Fibrosis was initially thought to result from tissue ischemia secondary to endothelial accumulation of glycosphingolipids in the microvasculature. However, despite ready clearance of endothelial deposits, ERT is less effective in patients who have already developed fibrosis. Several potential explanations of this clinical observation may impact on the future management of Fabry disease. Alternative molecular pathways linking glycosphingolipids and fibrosis may be operative; tissue injury may recruit secondary molecular mediators of fibrosis that are unresponsive to ERT, or fibrosis may represent irreversible tissue injury that limits the therapeutic response to ERT. We provide an overview of Fabry disease, with a focus on the assessment of fibrosis, the clinical consequences of fibrosis, and recent advances in understanding the cellular and molecular mechanisms of fibrosis that may suggest novel therapeutic approaches to Fabry disease.}, language = {en} } @article{WeidemannNiemannStorketal.2013, author = {Weidemann, F. and Niemann, M. and Stork, S. and Breunig, F. and Beer, M. and Sommer, C. and Herrmann, S. and Ertl, G. and Wanner, C.}, title = {Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications}, series = {Journal of Internal Medicine}, volume = {247}, journal = {Journal of Internal Medicine}, number = {4}, doi = {10.1111/joim.12077}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132075}, pages = {331-4}, year = {2013}, abstract = {The long-term effects of enzyme-replacement therapy (ERT) in Fabry disease are unknown. Thus, the aim of this study was to determine whether ERT in patients with advanced Fabry disease affects progression towards 'hard' clinical end-points in comparison with the natural course of the disease. METHODS: A total of 40 patients with genetically proven Fabry disease (mean age 40 ± 9 years; n = 9 women) were treated prospectively with ERT for 6 years. In addition, 40 subjects from the Fabry Registry, matched for age, sex, chronic kidney disease stage and previous transient ischaemic attack (TIA), served as a comparison group. The main outcome was a composite of stroke, end-stage renal disease (ESRD) and death. Secondary outcomes included changes in myocardial left ventricular (LV) wall thickness and replacement fibrosis, change in glomerular filtration rate (GFR), new TIA and change in neuropathic pain. RESULTS: During a median follow-up of 6.0 years (bottom and top quartiles: 5.1, 7.2), 15 events occurred in 13 patients (n = 7 deaths, n = 4 cases of ESRD and n = 4 strokes). Sudden death occurred (n = 6) only in patients with documented ventricular tachycardia and myocardial replacement fibrosis. The annual progression of myocardial LV fibrosis in the entire cohort was 0.6 ± 0.7\%. As a result, posterior end-diastolic wall thinning was observed (baseline, 13.2 ± 2.0 mm; follow-up, 11.4 ± 2.1 mm; P < 0.01). GFR decreased by 2.3 ± 4.6 mL min(-1) per year. Three patients experienced a TIA. The major clinical symptom was neuropathic pain (n = 37), and this symptom improved in 25 patients. The event rate was not different between the ERT group and the untreated (natural history) group of the Fabry Registry. CONCLUSION: Despite ERT, clinically meaningful events including sudden cardiac death continue to develop in patients with advanced Fabry disease.}, language = {en} } @article{WeichWernerBucketal.2021, author = {Weich, Alexander and Werner, Rudolf A. and Buck, Andreas K. and Hartrampf, Philipp E. and Serfling, Sebastian E. and Scheurlen, Michael and Wester, Hans-J{\"u}rgen and Meining, Alexander and Kircher, Stefan and Higuchi, Takahiro and Pomper, Martin G. and Rowe, Steven P. and Lapa, Constantin and Kircher, Malte}, title = {CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas}, series = {Diagnostics}, volume = {11}, journal = {Diagnostics}, number = {4}, issn = {2075-4418}, doi = {10.3390/diagnostics11040605}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234231}, year = {2021}, abstract = {We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-na{\"i}ve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.}, language = {en} } @phdthesis{Weber2024, author = {Weber, Justus C.}, title = {Development and preclinical assessment of ROR2-specific CAR-T cells for the treatment of clear cell renal cell carcinoma and multiple myeloma}, doi = {10.25972/OPUS-31039}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-310399}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells is an effective treatment for hematological malignancies that are refractory to conventional chemotherapy. To address a wider variety of cancer entities, there is a need to identify and characterize additional target antigens for CAR-T cell therapy. The two members of the receptor tyrosine kinase-like orphan receptor family, ROR1 and ROR2, have been found to be overexpressed on cancer cells and to correlate with aggressive cancer phenotypes. Recently, ROR1-specific CAR-T cells have entered testing in phase I clinical trials, encouraging us to assess the suitability of ROR2 as a novel target for CAR-T cell therapy. To study the therapeutic potential of targeting ROR2 in solid and hematological malignancies, we selected two representative cancer entities with high unmet medical need: renal cell carcinoma and multiple myeloma. Our data show that ROR2 is commonly expressed on primary samples and cell lines of clear cell renal cell carcinoma and multiple myeloma. To study the efficacy of ROR2-specific CAR T cell therapy, we designed two CAR constructs with 10-fold binding affinity differences for the same epitope of ROR2. We found both cell products to exhibit antigen-specific anti-tumor reactivity in vitro, including tumor cell lysis, secretion of the effector cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ), and T cell proliferation. In vivo studies revealed ROR2 specific CAR-T cells to confer durable responses, significant survival benefits and long-term persistence of CAR-expressing T cells. Overall, there was a trend towards more potent anti-tumor efficacy upon treatment with T cells that expressed the CAR with higher affinity for ROR2, both in vitro and in vivo. We performed a preclinical safety and toxicology assessment comprising analyses of ROR2 expression in healthy human and murine tissues, cross-reactivity, and adoptive T cell transfer in immunodeficient mice. We found ROR2 expression to be conserved in mice, and low-level expression was detectable in the male and female reproductive system as well as parts of the gastrointestinal tract. CAR-T cells targeting human ROR2 were found to elicit similarly potent reactivity upon recognition of murine ROR2. In vivo analyses showed transient tissue-specific enrichment and activation of ROR2-specific CAR-T cells in organs with high blood circulation, such as lung, liver, or spleen, without evidence for clinical toxicity or tissue damage as determined by histological analyses. Furthermore, we humanized the CAR binding domain of ROR2-specific CAR-T cells to mitigate the risk of adverse immune reactions and concomitant CAR-T cell rejection. Functional analyses confirmed that humanized CARs retained their specificity and functionality against ROR2-positive tumor cells in vitro. In summary, we show that ROR2 is a prevalent target in RCC and MM, which can be addressed effectively with ROR2-specific CAR-T cells in preclinical models. Our preliminary toxicity studies suggest a favorable safety profile for ROR2-specific CAR-T cells. These findings support the potential to develop ROR2-specific CAR-T cells clinically to obtain cell products with broad utility.}, subject = {CAR-T-Zell-Therapie}, language = {en} } @article{WarnockOrtizMaueretal.2012, author = {Warnock, David G. and Ortiz, Alberto and Mauer, Michael and Linthorst, Gabor E. and Oliveira, Jo{\~a}o P. and Serra, Andreas L. and Mar{\´o}di, L{\´a}szl{\´o} and Mignani, Renzo and Vujkovac, Bojan and Beitner-Johnson, Dana and Lemay, Roberta and Cole, J. Alexander and Svarstad, Einar and Waldek, Stephen and Germain, Dominique P. and Wanner, Christoph}, title = {Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation}, series = {Nephrology Dialysis Transplantation}, volume = {27}, journal = {Nephrology Dialysis Transplantation}, number = {3}, organization = {Fabry Registry}, doi = {10.1093/ndt/gfr420}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124697}, pages = {1042-1049}, year = {2012}, abstract = {Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta. Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression. Results. Men within the first quartile had a mean eGFR slope of -0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of -6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95\% confidence interval (95\% CI) 4-3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95\% CI 2-184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope -4.4 mL/min/1.73m2/year). Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.}, language = {en} } @article{WannerFeldtRasmussenJovanovicetal.2020, author = {Wanner, Christoph and Feldt-Rasmussen, Ulla and Jovanovic, Ana and Linhart, Aleš and Yang, Meng and Ponce, Elvira and Brand, Eva and Germain, Dominique P. and Hughes, Derralynn A. and Jefferies, John L. and Martins, Anna Maria and Nowak, Albina and Vujkovac, Bojan and Weidemann, Frank and West, Michael L. and Ortiz, Alberto}, title = {Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis}, series = {ESC Heart Failure}, volume = {7}, journal = {ESC Heart Failure}, number = {3}, doi = {10.1002/ehf2.12647}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235963}, pages = {825-834}, year = {2020}, abstract = {Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes. Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9-1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95\% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre-post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre-post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95\% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre-post difference}\) = 0.80). Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.}, language = {en} } @article{WagnerWannerSchichetal.2017, author = {Wagner, Martin and Wanner, Christoph and Schich, Martin and Kotseva, Kornelia and Wood, David and Hartmann, Katrin and Fette, Georg and R{\"u}cker, Viktoria and Oezkur, Mehmet and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {Patient's and physician's awareness of kidney disease in coronary heart disease patients - a cross-sectional analysis of the German subset of the EUROASPIRE IV survey}, series = {BMC Nephrology}, volume = {18}, journal = {BMC Nephrology}, number = {321}, doi = {10.1186/s12882-017-0730-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158387}, year = {2017}, abstract = {Background Chronic kidney disease (CKD) is a common comorbid condition in coronary heart disease (CHD). CKD predisposes the patient to acute kidney injury (AKI) during hospitalization. Data on awareness of kidney dysfunction among CHD patients and their treating physicians are lacking. In the current cross-sectional analysis of the German EUROASPIRE IV sample we aimed to investigate the physician's awareness of kidney disease of patients hospitalized for CHD and also the patient's awareness of CKD in a study visit following hospital discharge. Methods All serum creatinine (SCr) values measured during the hospital stay were used to describe impaired kidney function (eGFR\(_{CKD-EPI}\) < 60 ml/min/1.73m2) at admission, discharge and episodes of AKI (KDIGO definition). Information extracted from hospital discharge letters and correct ICD coding for kidney disease was studied as a surrogate of physician's awareness of kidney disease. All patients were interrogated 0.5 to 3 years after hospital discharge, whether they had ever been told about kidney disease by a physician. Results Of the 536 patients, 32\% had evidence for acute or chronic kidney disease during the index hospital stay. Either condition was mentioned in the discharge letter in 22\%, and 72\% were correctly coded according to ICD-10. At the study visit in the outpatient setting 35\% had impaired kidney function. Of 158 patients with kidney disease, 54 (34\%) were aware of CKD. Determinants of patient's awareness were severity of CKD (OR\(_{eGFR}\) 0.94; 95\%CI 0.92-0.96), obesity (OR 1.97; 1.07-3.64), history of heart failure (OR 1.99; 1.00-3.97), and mentioning of kidney disease in the index event's hospital discharge letter (OR 5.51; 2.35-12.9). Conclusions Although CKD is frequent in CHD, only one third of patients is aware of this condition. Patient's awareness was associated with kidney disease being mentioned in the hospital discharge letter. Future studies should examine how raising physician's awareness for kidney dysfunction may improve patient's awareness of CKD.}, language = {en} } @article{WagnerKraemerBlohmetal.2014, author = {Wagner, Martin and Kr{\"a}mer, Johannes and Blohm, Elisabeth and Vergho, Dorothee and Weidemann, Frank and Breunig, Frank and Wanner, Christoph}, title = {Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease}, doi = {10.1186/1471-2369-15-188}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111159}, year = {2014}, abstract = {Background: Impairments of health related quality of life (HRQoL) are frequently observed in Fabry disease (FD) and are known to be related to neuropathic pain and cardiovascular events. This study aimed to explore the role of chronic kidney disease (CKD) in a large cohort of patients with FD. Methods: In 96 patients (53\% female; age 40 ± 12 yrs) with genetically proven FD, HRQoL was assessed by the Medical Outcomes Study (SF-36) questionnaire. All patients were na{\"i}ve to enzyme replacement therapy. Three categories for kidney dysfunction were chosen, eGFR ≥/<60 ml/min/1.73 m2 or need of renal replacement therapy (RRT). Minor (e.g. arrhythmia, angina pectoris, etc.) and major (e.g. myocardial infarction, coronary artery bypass, stroke or implantable cardioverter-defibrillator) vascular events as well as pain and pain therapy were considered in linear regression analyses with the dimensions of HRQoL. Results: Ten patients (10\%) had impaired kidney function and a further nine were on RRT (9.4\%). Kidney function and pain emerged as the main factors associated with lower scores on the SF 36, in particular on physical components (PCS beta-coefficients for CKD -6.2, for RRT -11.8, for pain -9.1, p < 0.05, respectively), while controlling for gender, vascular event and pain-therapy. Relationships were found for mental aspects of HRQoL. Age and history of vascular events were not related to HRQoL. Conclusion: Cardiovascular events and pain are important factors related to HRQoL, social functioning and depression. Our study highlights impaired chronic kidney disease, in particular after initiation of RRT, as a strong determinant of reduced HRQoL in FD.}, language = {en} } @article{WagnerAshbyKurtzetal.2015, author = {Wagner, Martin and Ashby, Damien R. and Kurtz, Caroline and Alam, Ahsan and Busbridge, Mark and Raff, Ulrike and Zimmermann, Josef and Heuschmann, Peter U. and Wanner, Christoph and Schramm, Lothar}, title = {Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease}, series = {PLoS One}, volume = {10}, journal = {PLoS One}, number = {4}, doi = {10.1371/journal.pone.0123072}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125514}, pages = {e0123072}, year = {2015}, abstract = {Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003-2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53\% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7\%) and forty (16.1\%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define "high risk" populations in CKD.}, language = {en} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45\%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25\% distribution) in 6/87 (7\%) mouth epithelial cell samples, 31/88 (35\%) blood samples, and 9/27 (33\%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.}, language = {en} } @phdthesis{Vogg2023, author = {Vogg, Nora Johanna}, title = {Mass spectrometry-based quantification of steroids for the diagnostic workup of adrenal tumors}, doi = {10.25972/OPUS-29343}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-293438}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Tumors of the adrenal gland belong to the most frequent neoplasms in humans with a prevalence of 3-10 \% in adults. The aim of the diagnostic workup is the identification of potentially hormone-secreting and / or malignant tumors, because most of these tumors will require surgical resection. Malignant adrenocortical carcinomas (ACC) are very rare and associated with a poor prognosis in advanced stages, therefore, an early and accurate diagnosis is crucial. Within this thesis, two liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the quantification of steroids in different biomaterials were developed to improve the diagnostic workup of adrenal tumors. First, an LC-MS/MS method for the simultaneous quantification of cortisol and dexamethasone in serum samples after dexamethasone suppression test (DST) was developed, validated, and applied to 400 clinical samples. Newly established method-specific threshold concentrations for cortisol and dexamethasone increased DST specificity from 67.5 \% to 92.4 \% while preserving 100 \% sensitivity. Second, an LC-MS/MS method for the quantification of eleven urinary steroids was developed and validated to improve the differentiation between ACC and adrenocortical adenomas (ACA). A decision tree requiring only two steroids was trained for classification and tested based on 24 h urine samples from 268 patients with adrenal tumor. Malignancy was excluded with a negative predictive value of 100 \% in an independent validation cohort of 84 samples of 24-h urine. A newly proposed simplified diagnostic workflow with urinary steroid profiling as first tier test could obviate additional adrenal-specific imaging in 42 of 64 patients with ACA. The new DST method is already in clinical use at the University Hospital W{\"u}rzburg, whereas the classification model based on urinary steroid profiling will require prospective validation in a larger cohort.}, subject = {Nebennierentumor}, language = {en} } @phdthesis{Visan2003, author = {Visan, Ioana Andreea}, title = {The CD23 receptor-regulation of expression and signal transduction}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-5556}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2003}, abstract = {Bisher sind zwei Isoformen des humanen CD23 (CD23a und CD23b) beschrieben. Beide unterscheiden sich lediglich in 6-7 Resten im N-terminalen, zytoplasmatischen Anteil. CD23a wird ausschließlich auf B-Zellen exprimiert, w{\"a}hrend CD23b sowohl auf B-Zellen als auch auf Monozyten, eosinophilen Granulozyten, Makrophagen und zahlreichen anderen Zelltypen durch Stimulation mit IL-4 induziert werden kann. Die beiden Isoformen vermitteln wahrscheinlich unterschiedliche Funktionen. CD23a gilt als Isoform, welche vornehmlich mit der Endozytose von IgE-Immunkomplexen und der Vermittlung von Antigen-Pr{\"a}sentation auf B-Zellen assoziiert ist. CD23b besitzt ein Phagozytose-Motiv und scheint bei der Phagozytose IgE besetzter Partikel, der Freisetzung von Zytokinen und der Bildung von Peroxiden eine Rolle zu spielen. Fr{\"u}here Untersuchungen legen die Vermutung nahe, dass die beiden Isoformen zwei getrennte Signal{\"u}bertragungswege miteinander verbinden. Die Gegen{\"u}berstellung von Ereignissen, welche in Zellen, die nur eine einer oder beide Isoformen von CD23 besitzen, stattfinden, legt die Vermutung nahe, dass CD23b cAMP und iNOS hochreguliert, wohingegen CD23a einen Anstieg des intrazellul{\"a}ren Kalziums vermittelt. Im ersten Teil unserer Untersuchungen haben wir die Regulation der B-Zell-spezifischen Expression von CD23a analysiert. Pax-5 ist ein auf B-Zellen beschr{\"a}nkter Transkriptionsfaktor, welcher f{\"u}r die fr{\"u}he und sp{\"a}te B-Zellentwicklung von entscheidender Bedeutung ist. M{\"o}gliche Pax-5 Bindungsstellen wurden in den proximalen Abschnitten des CD23a Promotors vermutet. Die Analyse des CD23a Promotors ergab drei mutmaßliche Pax-5 Bindungsstellen mit mehr als 50\% Homologie zur Konsensus-Sequenz. Eine dieser Bindungsstellen, namens CD23-1, kann mit einer hochaffinen Pax-5 Bindungsstelle konkurrieren oder direkt das Pax-5 Protein in Elektromobilit{\"a}ts Experimenten (EMSA) binden. Das Einf{\"u}gen von Mutationen an dieser Stelle verhindert die Bindung. Ein weiterer Versuch, bei dem die gesamte L{\"a}nge des CD23a Promotors durch {\"u}berlappende Peptide in einem kompetitiven Verfahren gegen{\"u}ber hoch affinen Bindungsstellen getestet wurde, zeigt ebenso CD23-1 als die einzige Stelle, welche direkt Pax-5 binden kann. In weiteren Experimenten f{\"u}hrte die Expression von Pax-5 in 293 Zellen zu einer 7fachen Aktivierung eines CD23a Kernpromotor Konstrukts. Die Kotransfektion zusammen mit STAT6 zeigte, dass Pax-5 mit diesem Transkriptionsfaktor kooperiert, indem es die Transkriptionsrate eines vergr{\"o}ßerten CD23a Promotorkonstrukts erh{\"o}ht. Von besonderer Bedeutung ist die Tatsache, dass die ektope Expression von Pax-5 in der monozyt{\"a}ren Zelllinie U-937, die normalerweise nur die CD23b Isoform exprimiert, dann zu einer Expression von CD23a nach Stimulation mit IL-4 und PMA f{\"u}hrte. Unsere Ergebnisse legen nahe, dass Pax-5 in der auf B-Zellen beschr{\"a}nkten Expression der CD23 Isoform eine Schl{\"u}sselrolle zukommt. Im zweiten Teil des Projekts haben wir ein "Zwei-Hefen-Hybrid-System" (Cyto-Trap von Stratagene) verwendet, um nach zytoplasmatischen Interaktionspartnern f{\"u}r den CD23 Rezeptor zu suchen. Das System wurde modifiziert um eine hohe Effizienz an Transformation zu erzielen. Unterschiedliche „K{\"o}der"-Vektorkonstrukte wurden hergestellt. Das Screening wurde mittels einer humanen Milzbibliothek mit dem Zielvektor des Systems durchgef{\"u}hrt. Die anfangs benutzten Konstrukte -pSosCD23a und pSosCD23b - exprimierten sehr kurze (22 Aminos{\"a}uren) zytoplasmatischen Reste der Isoformen am C-terminalen Ende des Fusionsproteins (humanes SOS). Verbesserte Konstrukte (pSos CD23a+Linker und pSosCD23b+Linker) exprimierten den zytoplasmatischen Anteil von CD23a/b am N-terminalen Ende des humanen SOS und hatten folglich den N-terminalen Anteil als Andockstelle frei, entsprechend den Bedingungen in vivo. Eine flexible Verbindungsregion trennte die Fusionsproteine, um auf diese Weise die kurze Aminos{\"a}urekette deutlich „sichtbar" werden zu lassen. Ann{\"a}hernd drei Millionen Klone wurden mittels der verschiedenen Konstrukte untersucht. Dabei konnte keine tats{\"a}chlich positive Interaktion gefunden werden. Stattdessen fand sich eine vergleichsweise hohe Zahl falsch-positiver Klone. Diese wiederum wurden in einem zweiten "Zwei-Hefen-Hybrid-System" getestet. In Zukunft wird ein neues Konstrukt als K{\"o}der verwendet werden. Hierbei wurde ein Tyrosin-Rest im zytoplasmatischen Anteil von CD23a durch Glutamat ersetzt. Das System wurde bereits dazu verwendet, die Interaktion zwischen CD23 und p59fyn - einem Mitglied der Src-Familie von Proteinkinasen, welches mit CD23a assoziiert sein soll - zu testen. Jedoch konnte im CytoTrap "Zwei-Hefen-Hybrid-System" keine Wechselwirkung nachgewiesen werden. Zusammenfassend zeigt das zentrale Ergebnis der Arbeit, dass Pax-5 der Schl{\"u}sselregulator ist, der die B-Zell-spezifische Expression von CD23a erm{\"o}glicht. Zus{\"a}tzlich wurde ein "Zwei-Hefen-Hybrid-System" etabliert, mit dem zytoplasmatische Interaktionspartner f{\"u}r die CD23 Isoformen gefunden werden k{\"o}nnen.}, subject = {Antigen CD23}, language = {en} } @article{VetrivelZhangEngeletal.2022, author = {Vetrivel, Sharmilee and Zhang, Ru and Engel, Mareen and Oßwald, Andrea and Watts, Deepika and Chen, Alon and Wielockx, Ben and Sbiera, Silviu and Reincke, Martin and Riester, Anna}, title = {Characterization of adrenal miRNA-based dysregulations in Cushing's syndrome}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms23147676}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284394}, year = {2022}, abstract = {MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes.}, 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{VerruaFerranteFilopantietal.2014, author = {Verrua, Elisa and Ferrante, Emanuele and Filopanti, Marcello and Malchiodi, Elena and Sala, Elisa and Giavoli, Claudia and Arosio, Maura and Lania, Andrea Gerardo and Ronchi, Christina Lucia and Mantovani, Giovanna and Beck-Peccoz, Paolo and Spada, Anna}, title = {Reevaluation of Acromegalic Patients in Long-Term Remission according to Newly Proposed Consensus Criteria for Control of Disease}, series = {International Journal of Endocrinology}, journal = {International Journal of Endocrinology}, issn = {1687-8345}, doi = {10.1155/2014/581594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117790}, pages = {581594}, year = {2014}, abstract = {Acromegaly guidelines updated in 2010 revisited criteria of disease control: if applied, it is likely that a percentage of patients previously considered as cured might present postglucose GH nadir levels not adequately suppressed, with potential implications on management. This study explored GH secretion, as well as hormonal, clinical, neuroradiological, metabolic, and comorbid profile in a cohort of 40 acromegalic patients considered cured on the basis of the previous guidelines after a mean follow-up period of 17.2 years from remission, in order to assess the impact of the current criteria. At the last follow-up visit, in the presence of normal IGF-I concentrations, postglucose GH nadir was over 0.4 mu g/L in 11 patients (Group A) and below 0.4 mu g/L in 29 patients (Group B); moreover, Group A showed higher basal GH levels than Group B, whereas a significant decline of both GH and postglucose GH nadir levels during the follow-up was observed in Group B only. No differences in other evaluated parameters were found. These results seem to suggest that acromegalic patients considered cured on the basis of previous guidelines do not need a more intensive monitoring than patients who met the current criteria of disease control, supporting instead that the cut-off of 0.4 mcg/L might be too low for the currently used GH assay.}, language = {en} } @article{vanderVeenVlietstravanDussenetal.2020, author = {van der Veen, Sanne J. and Vlietstra, Wytze J. and van Dussen, Laura and van Kuilenburg, Andr{\´e} B.P. and Dijkgraaf, Marcel G. W. and Lenders, Malte and Brand, Eva and Wanner, Christoph and Hughes, Derralynn and Elliott, Perry M. and Hollak, Carla E. M. and Langeveld, Mirjam}, title = {Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms21165784}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285687}, year = {2020}, abstract = {Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50\% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.}, language = {en} } @phdthesis{vandenBerg2020, author = {van den Berg, Anne Maria}, title = {Age-related alterations of the immune system aggravate the myocardial aging process}, doi = {10.25972/OPUS-19362}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193622}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {The prevalence of cardiovascular diseases (CVD) increases dramatically with age. Nevertheless, most of the basic research in cardiology has been conducted on young healthy animals which may not necessarily reflect the situation observed in the clinic. The heart undergoes profound changes in elderly, including molecular alterations, myocardial hypertrophy, interstitial fibrosis and functional decline. To date, numerous approaches exist to explain mechanisms of the cardiac aging process whereupon inflammation and immune activity are of increasing interest. Myocardial aging is temporally associated with chronic low-grade systemic inflammation and accumulation of memory T-cells. However, a possible causal relationship between these two phenomena has not yet been investigated. Thus, aim of the present study was to assess how immunological mechanisms contribute to the myocardial aging process. Herein, the healthy murine heart was found to harbor all major resident leukocyte populations, including macrophages (CD45+CD11b+Ly6G-), granulocytes (CD45+ CD11b+Ly6G+), T-cells (CD45+CD11b-CD3e+), B-cells (CD45+CD11b-B220+) at frequencies that largely surpass those found in skeletal muscles. Age-related structural alterations and functional impairment occur simultaneously with significant shifts of the tissue resident leukocyte composition. Gene expression analyses performed on bulk myocardial samples revealed higher expression levels of TNF and INF- suggesting that in situ inflammation plays a role in the myocardial aging process. Aging was furthermore accompanied by a significant increase in size and cellularity of mediastinal, heart draining lymph nodes (med LN). Moreover, the med LNs harvested from aged mice showed a strong accumulation of effector-memory T-cells (CD44+CD62L-), mainly exhibiting a pro-inflammatory phenotype (Foxp3-, TNF+, IFN- γ+). None of these alterations were observed in popliteal lymph nodes of aged mice, indicating that they might be site-specific. Next, to go beyond mere associative evidence and examine underlying mechanisms, the myocardial aging process was comprehensively characterized in mice lacking B- (µMT) or CD4+ T-cells (CD4ko). Our analyses revealed that aged CD4+ T-cell-deficient, but not B-cell-deficient mice, exhibit a lower in situ inflammatory tone and preserved ventricular function, as compared to age-matched wild type controls. No differences in the expression levels of genes related to fibrosis were observed in the groups. Taken together, the results of this study indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. The T-cell-mediated immunosenescence profile might be particularly associated with age-related myocardial inflammation and functional decline, but not with tissue remodeling. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.}, language = {en} } @article{UttingerRiedmeierReibetanzetal.2022, author = {Uttinger, Konstantin L. and Riedmeier, Maria and Reibetanz, Joachim and Meyer, Thomas and Germer, Christoph Thomas and Fassnacht, Martin and Wiegering, Armin and Wiegering, Verena}, title = {Adrenalectomies in children and adolescents in Germany - a diagnose related groups based analysis from 2009-2017}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.914449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282280}, year = {2022}, abstract = {Background Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome. Methods This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included. Results A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1\%). The majority of patients were between 0 and 5 years old (52\% overall), while 11.1\% were between 6 and 11 and 38.8\% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56\%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29\% of all cases with the majority of affected patients being 12 years or older. 15\% were not defined regarding tumor behavior. Overall complication rate was 27\% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different "low volume" hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different "high volume" hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications. Conclusion Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.}, language = {en} } @article{UngethuemWiedmannWagneretal.2023, author = {Ungeth{\"u}m, K. and Wiedmann, S. and Wagner, M. and Leyh, R. and Ertl, G. and Frantz, S. and Geisler, T. and Karmann, W. and Prondzinsky, R. and Herdeg, C. and Noutsias, M. and Ludwig, T. and K{\"a}s, J. and Klocke, B. and Krapp, J. and Wood, D. and Kotseva, K. and St{\"o}rk, S. and Heuschmann, P. U.}, title = {Secondary prevention in diabetic and nondiabetic coronary heart disease patients: insights from the German subset of the hospital arm of the EUROASPIRE IV and V surveys}, series = {Clinical Research in Cardiology}, volume = {112}, journal = {Clinical Research in Cardiology}, number = {2}, doi = {10.1007/s00392-022-02093-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324037}, pages = {285-298}, year = {2023}, abstract = {Background Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012-13; and EA-V, 2016-17) in Germany. Methods The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years. The data collection in Germany was performed during a comprehensive baseline visit at study centers in W{\"u}rzburg (EA-IV, EA-V), Halle (EA-V), and T{\"u}bingen (EA-V). Results 384 EA-V participants (median age 69.0 years, 81.3\% male) and 536 EA-IV participants (median age 68.7 years, 82.3\% male) were examined. Comparing EA-IV and EA-V, no relevant differences in risk factor prevalence and lifestyle changes were observed with the exception of lower LDL cholesterol levels in EA-V. Prevalence of unrecognized diabetes was significantly lower in EA-V as compared to EA-IV (11.8\% vs. 19.6\%) while the proportion of prediabetes was similarly high in the remaining population (62.1\% vs. 61.0\%). Conclusion Between 2012 and 2017, a modest decrease in LDL cholesterol levels was observed, while no differences in blood pressure control and body weight were apparent in chronic CHD patients in Germany. Although the prevalence of unrecognized diabetes decreased in the later study period, the proportion of normoglycemic patients was low. As pharmacotherapy appeared fairly well implemented, stronger efforts towards lifestyle interventions, mental health programs and cardiac rehabilitation might help to improve risk factor profiles in chronic CHD patients.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and Homola, Gy{\"o}rgy A. and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure}, series = {ESC Heart Failure}, volume = {9}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312736}, pages = {2626-2634}, year = {2022}, abstract = {Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1\% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = -4.7; P < 0.001), alanine aminotransferase (T = -2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = -3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and G{\"o}pfert, Dennis and Homola, Gy{\"o}rgy and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients}, series = {Alzheimer's Research \& Therapy}, volume = {14}, journal = {Alzheimer's Research \& Therapy}, doi = {10.1186/s13195-022-01087-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300515}, year = {2022}, abstract = {Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1\% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60\% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.}, language = {en} } @article{TraubHusseiniWeber2021, author = {Traub, Jan and Husseini, Leila and Weber, Martin S.}, title = {B cells and antibodies as targets of therapeutic intervention in neuromyelitis optica spectrum disorders}, series = {Pharmaceuticals}, volume = {14}, journal = {Pharmaceuticals}, number = {1}, issn = {1424-8247}, doi = {10.3390/ph14010037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222957}, year = {2021}, abstract = {The first description of neuromyelitis optica by Eug{\`e}ne Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @article{TraubFreyStoerk2023, author = {Traub, Jan and Frey, Anna and St{\"o}rk, Stefan}, title = {Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications}, series = {Life}, volume = {13}, journal = {Life}, number = {2}, issn = {2075-1729}, doi = {10.3390/life13020329}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304869}, year = {2023}, abstract = {Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target.}, language = {en} } @article{TolstikAliGuoetal.2022, author = {Tolstik, Elen and Ali, Nairveen and Guo, Shuxia and Ebersbach, Paul and M{\"o}llmann, Dorothe and Arias-Loza, Paula and Dierks, Johann and Schuler, Irina and Freier, Erik and Debus, J{\"o}rg and Baba, Hideo A. and Nordbeck, Peter and Bocklitz, Thomas and Lorenz, Kristina}, title = {CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms23105345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284427}, year = {2022}, abstract = {Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient's prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90-96\%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.}, language = {en} }