TY  - JOUR
A1  - Üçeyler, Nurcan
A1  - Schröter, Nils
A1  - Kafke, Waldemar
A1  - Kramer, Daniela
A1  - Wanner, Christoph
A1  - Weidemann, Frank
A1  - Sommer, Claudia
T1  - Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease
JF  - PLoS ONE
N2  - 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.
KW  - biopsy
KW  - neuropathy
KW  - Fabry disease
KW  - renal system
KW  - immunofluorescence
KW  - enzyme replacement therapy
KW  - skin diseases
KW  - nerve fibers
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178856
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Üçeyler, Nurcan
A1  - Kahn, Ann-Kathrin
A1  - Kramer, Daniela
A1  - Zeller, Daniel
A1  - Casanova-Molla, Jordi
A1  - Wanner, Christoph
A1  - Weidemann, Frank
A1  - Katsarava, Zaza
A1  - Sommer, Claudia
T1  - Impaired small fiber conduction in patients with Fabry disease: a neurophysiological case–control study
JF  - BMC Neurology
N2  - 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.
KW  - Fabry disease
KW  - Pain-related evoked potentials
KW  - Small fiber neuropathy
KW  - A-delta fibers
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96527
UR  - http://www.biomedcentral.com/1471-2377/13/47
ER  - 
TY  - JOUR
A1  - Zopf, Kathrin
A1  - Frey, Kathrin R.
A1  - Kienitz, Tina
A1  - Ventz, Manfred
A1  - Bauer, Britta
A1  - Quinkler, Marcus
T1  - \(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency
JF  - Endocrine Connections
N2  - 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.
KW  - medicine
KW  - adrenal crisis
KW  - adrenal insufficiency
KW  - cortisol
KW  - hydrocortisone
KW  - polyglandular autoimmune syndrome
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173276
VL  - 6
IS  - 8
ER  - 
TY  - JOUR
A1  - Zinman, Bernard
A1  - Inzucchi, Silvio E.
A1  - Lachin, John M.
A1  - Wanner, Christoph
A1  - Ferrari, Roberto
A1  - Fitchett, David
A1  - Bluhmki, Erich
A1  - Hantel, Stefan
A1  - Kempthorne-Rawson, Joan
A1  - Newman, Jennifer
A1  - Johansen, Odd Erik
A1  - Woerle, Hans-Juergen
A1  - Broedl, Uli C.
T1  - Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME (TM))
JF  - Cardiovascular Diabetology
N2  - 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.
KW  - glycemic control
KW  - blood pressure
KW  - macrovascular
KW  - doule blind
KW  - chronic kidney disease
KW  - type-1 diabetes mellitus
KW  - safety
KW  - metformin
KW  - add-on
KW  - albuminuria
KW  - sulfonylurea
KW  - efficacy
KW  - canagliflozin
KW  - microvascular
KW  - SGLT2 inhibitor
KW  - type 2 diabetes
KW  - body weight
KW  - empagliflozin
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-116036
SN  - 1475-2840
VL  - 13
IS  - 102
ER  - 
TY  - JOUR
A1  - Zhao, De-Wei
A1  - Yu, Mang
A1  - Hu, Kai
A1  - Wang, Wei
A1  - Yang, Lei
A1  - Wang, Ben-Jie
A1  - Gao, Xiao-Hong
A1  - Guo, Yong-Ming
A1  - Xu, Yong-Qing
A1  - Wei, Yu-Shan
A1  - Tian, Si-Miao
A1  - Yang, Fan
A1  - Wang, Nan
A1  - Huang, Shi-Bo
A1  - Xie, Hui
A1  - Wei, Xiao-Wei
A1  - Jiang, Hai-Shen
A1  - Zang, Yu-Qiang
A1  - Ai, Jun
A1  - Chen, Yuan-Liang
A1  - Lei, Guang-Hua
A1  - Li, Yu-Jin
A1  - Tian, Geng
A1  - Li, Zong-Sheng
A1  - Cao, Yong
A1  - Ma, Li
T1  - Prevalence of Nontraumatic Osteonecrosis of the Femoral Head and its Associated Risk Factors in the Chinese Population: Results from a Nationally Representative Survey
JF  - Chinese Medical Journal
N2  - 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.
KW  - nontraumatic osteonecrosis of the femoral head
KW  - risk factors
KW  - idiopathic osteonecrosis
KW  - early-stage osteonecrosis
KW  - implantation
KW  - bone
KW  - marrow
KW  - follow-up
KW  - intake
KW  - avascular necrosis
KW  - occupational-status
KW  - cigarette smoking
KW  - alcohol
KW  - prevalence
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138482
VL  - 128
IS  - 21
ER  - 
TY  - JOUR
A1  - Yurdadogan, Tino
A1  - Malsch, Carolin
A1  - Kotseva, Kornelia
A1  - Wood, David
A1  - Leyh, Rainer
A1  - Ertl, Georg
A1  - Karmann, Wolfgang
A1  - Müller-Scholden, Lara
A1  - Morbach, Caroline
A1  - Breuning, Margret
A1  - Wagner, Martin
A1  - Gelbrich, Götz
A1  - Bots, Michiel L.
A1  - Heuschmann, Peter U.
A1  - Störk, Stefan
T1  - Functional versus morphological assessment of vascular age in patients with coronary heart disease
JF  - Scientific Reports
N2  - 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.
KW  - arterial stiffening
KW  - atherosclerosis
KW  - calcification
KW  - carotid artery disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265810
VL  - 11
IS  - 1
ER  - 
TY  - JOUR
A1  - Winter, Patrick M.
A1  - Andelovic, Kristina
A1  - Kampf, Thomas
A1  - Hansmann, Jan
A1  - Jakob, Peter Michael
A1  - Bauer, Wolfgang Rudolf
A1  - Zernecke, Alma
A1  - Herold, Volker
T1  - Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch
JF  - Journal of Cardiovascular Magnetic Resonance
N2  - 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.
KW  - 4D flow
KW  - pulse wave velocity
KW  - wall shear stress
KW  - radial
KW  - self-navigation
KW  - mouse
KW  - aortic arch
KW  - atherosclerosis
KW  - mice
KW  - flow
KW  - plaque
KW  - CMR
KW  - quantification
KW  - microscopy
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259152
VL  - 23
IS  - 1
ER  - 
TY  - JOUR
A1  - Winter, Patrick
A1  - Kampf, Thomas
A1  - Helluy, Xavier
A1  - Gutjahr, Fabian T.
A1  - Meyer, Cord B.
A1  - Rommel, Eberhard
A1  - Bauer, Wolfgang R.
A1  - Jakob, Peter M.
A1  - Herold, Volker
T1  - Fast retrospectively triggered local pulse-wave velocity measurements in mice with CMR-microscopy using a radial trajectory
JF  - Journal of Cardiovascular Magnetic Resonance
N2  - 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.
KW  - pulse-wave velocity
KW  - mouse
KW  - self-gating
KW  - phase-contrast CMR
KW  - non-triggered
KW  - retrospective
KW  - radial
KW  - aorta
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-96602
UR  - http://jcmr-online.com/content/15/1/88
ER  - 
TY  - JOUR
A1  - Winter, Patrick
A1  - Andelovic, Kristina
A1  - Kampf, Thomas
A1  - Gutjahr, Fabian Tobias
A1  - Heidenreich, Julius
A1  - Zernecke, Alma
A1  - Bauer, Wolfgang Rudolf
A1  - Jakob, Peter Michael
A1  - Herold, Volker
T1  - Fast self-navigated wall shear stress measurements in the murine aortic archusing radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T
JF  - Journal of Cardiovascular Magnetic Resonance
N2  - 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.
KW  - 4D flow
KW  - WSS
KW  - OSI
KW  - Self-navigation
KW  - Mouse
KW  - Aortic arch
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201120
VL  - 21
ER  - 
TY  - JOUR
A1  - Williams, Tatjana
A1  - Machann, Wolfram
A1  - Kühler, Leif
A1  - Hamm, Henning
A1  - Müller-Höcker, Josef
A1  - Zimmer, Michael
A1  - Ertl, Georg
A1  - Ritter, Oliver
A1  - Beer, Meinrad
A1  - Schönberger, Jost
T1  - Novel desmoplakin mutation: juvenile biventricular cardiomyopathy with left ventricular non-compaction and acantholytic palmoplantar keratoderma
JF  - Clinical Research in Cardiology
N2  - 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.
KW  - Desmoplakin
KW  - Juvenile biventricular cardiomyopathy
KW  - Palmoplantar keratoderma
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141198
VL  - 100
IS  - 12
ER  - 
TY  - JOUR
A1  - Wiegering, Verena
A1  - Riedmeier, Maria
A1  - Thompson, Lester D. R.
A1  - Virgone, Calogero
A1  - Redlich, Antje
A1  - Kuhlen, Michaela
A1  - Gultekin, Melis
A1  - Yalcin, Bilgehan
A1  - Decarolis, Boris
A1  - Härtel, Christoph
A1  - Schlegel, Paul-Gerhardt
A1  - Fassnacht, Martin
A1  - Timmermann, Beate
T1  - Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature
JF  - Clinical and Translational Radiation Oncology
N2  - 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.
KW  - pediatric adrenocortical cancer
KW  - pediatric adrenocortical carcinoma
KW  - pediatric adrenocortical tumor
KW  - radiotherapy
KW  - therapy
KW  - treatment
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300472
VL  - 35
ER  - 
TY  - CHAP
A1  - Werner, Rudolf
A1  - Wakabayashi, Hiroshi
A1  - Jahns, Roland
A1  - Ergün, Süleyman
A1  - Jahns, Valerie
A1  - Higuchi, Takahiro
T1  - PET-Guided Histological Characterization of Myocardial Infiltrating Cells in a Rat Model of Myocarditis
T2  - European Heart Journal - Cardiovascular Imaging
N2  - No abstract available.
KW  - Myokarditis
KW  - positron emission tomography
KW  - myocarditis
KW  - PET
KW  - 18F-FDG
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161127
SN  - 2047-2404
N1  - This is a pre-copyedited, author-produced version of an article accepted for publication in European Heart Journal Cardiovascular Imaging following peer review. The version of record . Eur Heart J Cardiovasc Imaging. ISSN: 2047-2404. Supplement, vol. 18, i1-i3, May 2017 is available online at: 10.1093/ehjci/jex071.
VL  - 18
IS  - Supplement
PB  - Oxford University Press
ER  - 
TY  - JOUR
A1  - Werner, Rudolf
A1  - Schmid, Jan-Stefan
A1  - Higuchi, Takahiro
A1  - Javadi, Mehrbod S.
A1  - Rowe, Steven P.
A1  - Märkl, Bruno
A1  - Aulmann, Christoph
A1  - Fassnacht, Martin
A1  - Kroiß, Matthias
A1  - Reiners, Christoph
A1  - Buck, Andreas
A1  - Kreissl, Michael
A1  - Lapa, Constantin
T1  - Predictive value of \(^{18}\)F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib
JF  - Journal of Nuclear Medicine
N2  - 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.
KW  - positron emission tomography
KW  - Medullärer Schilddrüsenkrebs
KW  - Positronen-Emissions-Tomografie
KW  - medullary thyroid carcinoma
KW  - tyrosine kinase inhibitor
KW  - vandetanib
KW  - 2- deoxy-2-(18F)fluoro-D-glucose
KW  - 18F-FDG
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161256
SN  - 0161-5505
N1  - This research was originally published in JNM. Rudolf A. Werner, Jan-Stefan Schmid, Takahiro Higuchi, Mehrbod S. Javadi, Steven P. Rowe, Bruno Märkl, Christoph Aulmann, Martin Fassnacht, Matthias Kroiss, Christoph Reiners, Andreas K. Buck, Michael C. Kreissl, Constantin Lapa. Predictive value of 18F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib. J Nucl Med. May 1, 2018;vol. 59 no. 5: 756-761. © SNMMI.
ER  - 
TY  - CHAP
A1  - Werner, Rudolf
A1  - Higuchi, Takahiro
A1  - Muegge, Dirk
A1  - Javadi, Mehrbod S.
A1  - Märkl, Bruno
A1  - Aulmann, Christoph
A1  - Buck, Andreas K.
A1  - Fassnacht, Martin
A1  - Lapa, Constantin
A1  - Kreissl, Michael C.
T1  - Predictive value of FDG-PET in patients with advanced medullary thyroid cancer undergoing vandetanib treatment
T2  - Journal of Nuclear Medicine
N2  - 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.
KW  - 18F-FDG
KW  - vandetanib
KW  - TKI
KW  - PET
KW  - positron emission tomography
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161147
UR  - http://jnm.snmjournals.org/content/58/supplement_1/169
SN  - 0161-5505
N1  - This  research  was  originally  published  in  JNM. 
Rudolf  A.  Werner,  Takahiro  Higuchi, Dirk O. Muegge, Mehrbod S. Javadi, B. Märkl, C. Aulmann, Andreas K. Buck, Martin Fassnacht,  Constantin  Lapa, Michael  C.  Kreissl. 
Predictive  value  of  FDG-PET  in patients with advanced medullary thyroid cancer undergoing vandetanib treatment. J Nucl Med. May 1, 2017; vol. 58 no. supplement 1:169. © SNMMI.
VL  - 58
IS  - no. supplement 1
ER  - 
TY  - JOUR
A1  - Werner, Rudolf A.
A1  - Sayehli, Cyrus
A1  - Hänscheid, Heribert
A1  - Higuchi, Takahiro
A1  - Serfling, Sebastian E.
A1  - Fassnacht, Martin
A1  - Goebeler, Maria-Elisabeth
A1  - Buck, Andreas K.
A1  - Kroiss, Matthias
T1  - Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma
JF  - European Journal of Nuclear Medicine and Molecular Imaging
N2  - No abstract available.
KW  - papillary thyroid carcinoma (PTC)
KW  - selpercatinib
KW  - radioiodine
KW  - combination
KW  - thyroid carcinoma (TC)
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324435
VL  - 50
IS  - 6
ER  - 
TY  - JOUR
A1  - Werner, Rudolf A.
A1  - Eissler, Christoph
A1  - Hayakawa, Nobuyuki
A1  - Arias-Loza, Paula
A1  - Wakabayashi, Hiroshi
A1  - Javadi, Mehrbod S.
A1  - Chen, Xinyu
A1  - Shinaji, Tetsuya
A1  - Lapa, Constantin
A1  - Pelzer, Theo
A1  - Higuchi, Takahiro
T1  - Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated \(^{18}\)F-FDG PET
JF  - Scientific Reports
N2  - 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.
KW  - diabetic cardiomyopathy
KW  - personalized treatment
KW  - precision medicine
KW  - ZDF rats
KW  - ECG
KW  - PET
KW  - \(^{18}\)F-fluorodeoxyglucose
KW  - \(^{18}\)F-FDG
KW  - diabetes
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171765
VL  - 8
IS  - 17631
ER  - 
TY  - JOUR
A1  - Werner, Rudolf A.
A1  - Bundschuh, Ralph A.
A1  - Higuchi, Takahiro
A1  - Javadi, Mehrbod S.
A1  - Rowe, Steven P.
A1  - Zsótér, Norbert
A1  - Kroiss, Matthias
A1  - Fassnacht, Martin
A1  - Buck, Andreas K.
A1  - Kreissl, Michael C.
A1  - Lapa, Constantin
T1  - Volumetric and Texture Analysis of Pretherapeutic \(^{18}\)F-FDG PET can Predict Overall Survival in Medullary Thyroid Cancer Patients Treated with Vandetanib
JF  - Endocrine
N2  - 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.
KW  - personalized medicine
KW  - Positronen-Emissions-Tomografie
KW  - medullary thyroid carcinoma
KW  - tyrosine kinase inhibitor
KW  - TKI
KW  - vandetanib
KW  - 18F-FDG
KW  - positron emission tomography
KW  - 2-deoxy-2-(18F)fluoro-D-glucose
KW  - PET
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-167910
SN  - 1355-008X
ER  - 
TY  - JOUR
A1  - Wendlinger, Simone
A1  - Wohlfarth, Jonas
A1  - Kreft, Sophia
A1  - Siedel, Claudia
A1  - Kilian, Teresa
A1  - Dischinger, Ulrich
A1  - Heppt, Markus V.
A1  - Wistuba-Hamprecht, Kilian
A1  - Meier, Friedegund
A1  - Goebeler, Matthias
A1  - Schadendorf, Dirk
A1  - Gesierich, Anja
A1  - Kosnopfel, Corinna
A1  - Schilling, Bastian
T1  - Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma
JF  - Cancers
N2  - 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.
KW  - melanoma
KW  - eosinophils
KW  - biomarker
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275137
SN  - 2072-6694
VL  - 14
IS  - 9
ER  - 
TY  - JOUR
A1  - Weiß, Martin
A1  - Gründahl, Marthe
A1  - Deckert, Jürgen
A1  - Eichner, Felizitas A.
A1  - Kohls, Mirjam
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
A1  - Hein, Grit
T1  - Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men
JF  - Scientific Reports
N2  - 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 Würzburg, 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.
KW  - anxiety
KW  - depression
KW  - human behaviour
KW  - quality of life
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357858
VL  - 13
ER  - 
TY  - JOUR
A1  - Weiß, Emil
A1  - Ramos, Gustavo Campos
A1  - Delgobo, Murilo
T1  - Myocardial-Treg crosstalk: How to tame a wolf
JF  - Frontiers in Immunology
N2  - 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.
KW  - Tregs (regulatory T cells)
KW  - Foxp3
KW  - myocardial infarction
KW  - heart
KW  - fibrosis
KW  - T-cells
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275591
SN  - 1664-3224
VL  - 13
ER  - 
TY  - JOUR
A1  - Weismann, Dirk
A1  - Schneider, Andreas
A1  - Höybye, Charlotte
T1  - Clinical aspects of symptomatic hyponatremia
JF  - Endocrine Connections
N2  - 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.
KW  - hyponatremia
KW  - clinical
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-162936
VL  - 5
IS  - 5
ER  - 
TY  - JOUR
A1  - Weismann, Dirk
A1  - Möckel, Martin
A1  - Paeth, Heiko
A1  - Slagman, Anna
T1  - Modelling variations of emergency attendances using data on community mobility, climate and air pollution
JF  - Scientific Reports
N2  - 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.
KW  - cardiovascular diseases
KW  - environmental health
KW  - environmental impact
KW  - preclinical research
KW  - preventive medicine
KW  - reproductive disorders
KW  - respiratory signs and symptoms
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357578
VL  - 13
ER  - 
TY  - JOUR
A1  - Weigand, Isabel
A1  - Ronchi, Cristina L.
A1  - Vanselow, Jens T.
A1  - Bathon, Kerstin
A1  - Lenz, Kerstin
A1  - Herterich, Sabine
A1  - Schlosser, Andreas
A1  - Kroiss, Matthias
A1  - Fassnacht, Martin
A1  - Calebiro, Davide
A1  - Sbiera, Silviu
T1  - PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser\(^{114}\) phosphorylation
JF  - Science Advances
N2  - 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.
KW  - mutation triggers
KW  - phosphorylation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270445
VL  - 7
IS  - 8
ER  - 
TY  - JOUR
A1  - Weigand, Isabel
A1  - Ronchi, Cristina L.
A1  - Rizk-Rabin, Marthe
A1  - Dalmazi, Guido Di
A1  - Wild, Vanessa
A1  - Bathon, Kerstin
A1  - Rubin, Beatrice
A1  - Calebiro, Davide
A1  - Beuschlein, Felix
A1  - Bertherat, Jérôme
A1  - Fassnacht, Martin
A1  - Sbiera, Silviu
T1  - Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas
JF  - Scientific Reports
N2  - 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.
KW  - kinases
KW  - immunohistochemistry
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157952
VL  - 7
IS  - 49
ER  - 
TY  - THES
A1  - Weigand, Isabel
T1  - Consequences of Protein Kinase A mutations in adrenocortical cells and tumours
T1  - Auswirkungen von Proteinkinase A Mutationen in Zellen und Tumoren der Nebenniere
N2  - 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.
N2  - Das adrenale Cushing Syndrom, ausgelöst durch ein Kortisol-sekretierendes Nebennierenadenom (CPA), ist eine potentiell letale Erkrankung mit einer geringen Inzidenz. Schon lange ist bekannt, dass der Proteinkinase A (PKA)-Signalweg maßgeblich die Sekretion von Steroidhormonen in der Nebenniere reguliert. In ihrer inaktiven Form ist die PKA ein Heterotetramer aus zwei katalytischen und zwei regulatorischen Untereinheiten, welches über die Bindung des second messengers cAMP und die daraus resultierende Konformationsänderung aktiviert wird. Kürzlich wurden in etwa 40 % der CPAs, somatische Mutationen in der katalytischen Untereinheit a (Ca) der PKA identifiziert. Diese Mutation verhindert die Bindung der regulatorischen Untereinheiten, was zu einer konstitutiven Aktivierung des PKA-Signalwegs führt. Unabhängig davon war bereits einige Jahre zuvor erkannt worden, dass in einem Teil der CPAs die regulatorische Untereinheit IIb (RIIb) der PKA in geringerem Maße exprimiert wird. Ein Zusammenhang zwischen dieser verringerten Proteinmenge an RIIb und den Mutationen in Ca war bisher nicht bekannt. In dieser Dissertation konnte gezeigt werden, dass zwischen den Mutationen in Ca und der verringerten Proteinmenge von RIIb in CPAs, jedoch nicht in anderen Tumorentitäten der Nebenniere, ein klarer Zusammenhang besteht. Darüber hinaus wurde gezeigt, dass auch die Zonen der normalen Nebenniere ein spezifisches Muster der Proteinkinase A Untereinheiten exprimieren. Zusätzlich konnten in in vitro Versuchen Caspasen identifiziert werden, die maßgeblich am Abbau von RIIb beteiligt sind. Durch Mutagenese-Experimente und den Austausch der Inhibitory-Sequenzen der regulatorischen Untereinheiten RIa und RIIb, konnte die Phosphorylierung von Ser114 an RIIb als essentiell für den Abbau identifiziert werden. Darüber hinaus wurden mittels LC-MS/MS neue RIIb Interaktionspartner in Zellen der Nebennierenrinde identifiziert, die sich in der An-oder Abwesenheit der Ca L206R Mutante unterscheiden. Ferner konnte für RIIb eine inhibierende Rolle, speziell in der Kortisol-Sekretion von Nebennierenrindenzellen, gezeigt werden. Dies stellt eine bislang unbekannte Funktion von RIIb dar, die das Verständnis der komplexen Regulierung von PKA als Schlüsselregulator in vielen Zellen verbessert.
KW  - Cushing-Syndrom
KW  - protein kinase a
KW  - cushing's syndrome
KW  - tumour
KW  - signalling
KW  - adrenal gland
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-160646
ER  - 
TY  - JOUR
A1  - Weidemann, Frank
A1  - Sanchez-Nino, Maria D.
A1  - Politei, Juan
A1  - Oliveira, João-Paulo
A1  - Wanner, Christoph
A1  - Warnock, David G.
A1  - Oritz, Alberto
T1  - Fibrosis: a key feature of Fabry disease with potential therapeutic implications
JF  - Orphanet Journal of Rare Diseases
N2  - 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.
KW  - Fabry
KW  - fibrosis
KW  - podocyte
KW  - Lyso-Gb3
KW  - kidney
KW  - enzyme replacement therapy
KW  - alpha-galactosidase-A
KW  - focal semental glomerulosclerosis
KW  - cardiovascular magnetic-resonance
KW  - left-ventricular hypertrophy
KW  - biopsy findings
KW  - agalsidase-beta
KW  - natural-history data
KW  - cardiac energy metabolism
KW  - randomized controlled trial
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124773
SN  - 1750-1172
VL  - 8
IS  - 116
ER  - 
TY  - JOUR
A1  - Weidemann, F.
A1  - Niemann, M.
A1  - Stork, S.
A1  - Breunig, F.
A1  - Beer, M.
A1  - Sommer, C.
A1  - Herrmann, S.
A1  - Ertl, G.
A1  - Wanner, C.
T1  - Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications
JF  - Journal of Internal Medicine
N2  - 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.
KW  - Fabry disease
KW  - α-galactosidase A
KW  - dialysis
KW  - prognosis
KW  - stroke
KW  - sudden cardiac death
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132075
VL  - 247
IS  - 4
ER  - 
TY  - JOUR
A1  - Weich, Alexander
A1  - Werner, Rudolf A.
A1  - Buck, Andreas K.
A1  - Hartrampf, Philipp E.
A1  - Serfling, Sebastian E.
A1  - Scheurlen, Michael
A1  - Wester, Hans-Jürgen
A1  - Meining, Alexander
A1  - Kircher, Stefan
A1  - Higuchi, Takahiro
A1  - Pomper, Martin G.
A1  - Rowe, Steven P.
A1  - Lapa, Constantin
A1  - Kircher, Malte
T1  - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas
JF  - Diagnostics
N2  - 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-naïve 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.
KW  - CXCR4
KW  - NET
KW  - NEC
KW  - <sup>68</sup>Ga-Pentixafor
KW  - <sup>18</sup>F-FDG
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231
SN  - 2075-4418
VL  - 11
IS  - 4
ER  - 
TY  - THES
A1  - Weber, Justus C.
T1  - Development and preclinical assessment of ROR2-specific CAR-T cells for the treatment of clear cell renal cell carcinoma and multiple myeloma
T1  - Entwicklung und präklinische Evaluation ROR2-spezifischer CAR-T Zellen  zur Behandlung des klarzelligen Nierenzellkarzinoms und des Multiplen Myeloms
N2  - 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.
N2  - Adoptive Immuntherapie mit T-Zellen, die chimäre Antigenrezeptoren (CAR) exprimieren, ist ein effektiver Behandlungsansatz für Chemotherapie-resistente Blutkrebserkrankungen. Die Übertragung dieses Konzepts auf weitere Krebsarten erfordert die Identifikation und Charakterisierung neuer Zielstrukturen für die CAR-T Zelltherapie. ROR1 und ROR2, die beiden Mitglieder der Familie der Rezeptortyrosinkinase-ähnlichen Orphan-Rezeptoren, werden auf einer Vielzahl von Tumoren überexprimiert und korrelieren mit einer schlechten Prognose und höherer Krebs-Invasivität. Kürzlich konnte ROR1 als Zielstruktur für die CAR-T Zelltherapie bestätigt werden und die Effektivität und Sicherheit ROR1 spezifischer CAR-T Zellen wird derzeit im Rahmen klinischer Phase-I Studien näher untersucht. Aus diesem Grund waren wir daran interessiert, das therapeutische Potenzial ROR2-spezifischer Zelltherapie zu untersuchen. Als Modellsysteme hierfür wählten wir das Nierenzellkarzinom und das Multiple Myelom als repräsentative hämatologische und solide Krebserkrankungen mit hohem medizinischem Bedarf aus. 
Unsere Daten zeigen, dass ROR2 häufig auf Zelllinien und primären Tumorproben des klarzelligen Nierenzellkarzinoms und des Multiplen Myeloms vorkommt. Um die Effektivität ROR2-spezifischer CAR-T Zellen zu untersuchen, wurden zwei CAR Konstrukte mit zehnfach unterschiedlichen Bindungsaffinitäten für dasselbe Epitop von ROR2 hergestellt. Beide Zellprodukte zeigten hohe, antigen-spezifische Antitumor-Reaktivität in vitro – insbesondere im Hinblick auf Tumorzell-Lyse, Sekretion der Zytokine Interleukin-2 (IL-2) und 
Interferon gamma (IFNγ) und T-Zell Proliferation. In vivo beobachteten wir langanhaltende Antitumor-Effektivität durch ROR2-spezifische CAR-T Zellen, sowie signifikante Überlebensvorteile und langfristige T-Zell Persistenz. Außerdem beobachteten wir, sowohl in vitro als auch in vivo, einen Trend zu stärkerer Antitumor-Effektivität von T-Zellen, die den CAR mit höherer Affinität für ROR2 exprimierten. 
Im Rahmen einer präklinischen Toxikologie-Studie analysierten wir die Expression von ROR2 im gesunden Gewebe, die Kreuz-Reaktivität ROR2-spezifischer CAR-T Zellen und deren 
Sicherheit durch adoptiven T-Zell Transfer in immun-defiziente Mäuse.  Unsere Daten zeigen, dass ROR2 in H. sapiens und M. musculus gleichermaßen exprimiert wird und ROR2 Expression war insbesondere in den weiblichen und männlichen Reproduktionsorganen und Teilen des Gastrointestinaltrakts detektierbar. Wir konnten außerdem zeigen, dass CAR-T Zellen, die menschliches ROR2 erkennen, vergleichbare Antitumor-Reaktivität gegen Zellen, die murines ROR2 exprimieren, auslösen. Unsere in vivo Analysen zeigten temporäre Anreicherung und Aktivierung ROR2-spezifischer CAR-T Zellen in gut durchbluteten Geweben, wie Lunge, Leber und Milz, in der Abwesenheit klinischer Anzeichen für Toxizität oder histologisch nachweisbarer Gewebsschädigungen. 
Um die Risiken immunologischer Nebenwirkungen und die damit einhergehende Abstoßung ROR2-spezifischer CAR-T Zellen zu reduzieren, humanisierten wir die CAR Bindedomäne. Unsere Daten zeigen, dass humanisierte ROR2-spezifische CAR-T Zellen vergleichbare Spezifität und Funktionalität gegen ROR2-positive Tumorzellen in vitro aufweisen. 
Insgesamt zeigen unsere Daten, dass ROR2 eine häufig auftretende Zielstruktur auf der Oberfläche von RCC und MM Zellen ist und diese in präklinischen Modellen effektiv mittels ROR2-spezifischer CAR-T Zellen adressiert werden kann. Unsere vorläufigen Toxizitätsdaten deuten darauf hin, dass ROR2-spezifische CAR-T Zellen ein vorteilhaftes Sicherheitsprofil aufweisen. Alles in allem unterstützen diese Daten das Potenzial der klinischen Entwicklung ROR2-spezifischer CAR-T Zellen als Zellprodukte mit breit gefächerter Anwendbarkeit.
KW  - CAR-T-Zell-Therapie
KW  - Immuntherapie
KW  - CAR-T cell
KW  - ROR2
KW  - cell therapy
KW  - cancer therapy
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-310399
ER  - 
TY  - JOUR
A1  - Warnock, David G.
A1  - Ortiz, Alberto
A1  - Mauer, Michael
A1  - Linthorst, Gabor E.
A1  - Oliveira, João P.
A1  - Serra, Andreas L.
A1  - Maródi, László
A1  - Mignani, Renzo
A1  - Vujkovac, Bojan
A1  - Beitner-Johnson, Dana
A1  - Lemay, Roberta
A1  - Cole, J. Alexander
A1  - Svarstad, Einar
A1  - Waldek, Stephen
A1  - Germain, Dominique P.
A1  - Wanner, Christoph
T1  - Renal outcomes of agalsidase beta treatment for Fabry disease: role of proteinuria and timing of treatment initiation
JF  - Nephrology Dialysis Transplantation
N2  - 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.
KW  - proteinuria
KW  - enzyme replacement therapy
KW  - alpha galactosidase
KW  - Fabry disease
KW  - genetic renal disease
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124697
VL  - 27
IS  - 3
ER  - 
TY  - JOUR
A1  - Wanner, Christoph
A1  - Feldt-Rasmussen, Ulla
A1  - Jovanovic, Ana
A1  - Linhart, Aleš
A1  - Yang, Meng
A1  - Ponce, Elvira
A1  - Brand, Eva
A1  - Germain, Dominique P.
A1  - Hughes, Derralynn A.
A1  - Jefferies, John L.
A1  - Martins, Anna Maria
A1  - Nowak, Albina
A1  - Vujkovac, Bojan
A1  - Weidemann, Frank
A1  - West, Michael L.
A1  - Ortiz, Alberto
T1  - Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis
JF  - ESC Heart Failure
N2  - 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.
KW  - Agalsidase beta
KW  - Enzyme replacement therapy
KW  - Fabry disease
KW  - Cardiomyopathy
KW  - Kidney function
KW  - Female patients
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235963
VL  - 7
IS  - 3
ER  - 
TY  - JOUR
A1  - Wagner, Martin
A1  - Wanner, Christoph
A1  - Schich, Martin
A1  - Kotseva, Kornelia
A1  - Wood, David
A1  - Hartmann, Katrin
A1  - Fette, Georg
A1  - Rücker, Viktoria
A1  - Oezkur, Mehmet
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
T1  - 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
JF  - BMC Nephrology
N2  - 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.
KW  - coronary heart disease
KW  - ICD-coding of CKD
KW  - chronic kidney disease
KW  - patients’ awareness
KW  - physicians’ awareness
KW  - EUROASPIRE survey
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158387
VL  - 18
IS  - 321
ER  - 
TY  - JOUR
A1  - Wagner, Martin
A1  - Krämer, Johannes
A1  - Blohm, Elisabeth
A1  - Vergho, Dorothee
A1  - Weidemann, Frank
A1  - Breunig, Frank
A1  - Wanner, Christoph
T1  - Kidney function as an underestimated factor for reduced health related quality of life in patients with Fabry disease
N2  - 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 naïve 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.
KW  - Quality of life
KW  - SF-36
KW  - Chronic kidney disease
KW  - Fabry disease
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-111159
UR  - http://www.biomedcentral.com/1471-2369/15/188
ER  - 
TY  - JOUR
A1  - Wagner, Martin
A1  - Ashby, Damien R.
A1  - Kurtz, Caroline
A1  - Alam, Ahsan
A1  - Busbridge, Mark
A1  - Raff, Ulrike
A1  - Zimmermann, Josef
A1  - Heuschmann, Peter U.
A1  - Wanner, Christoph
A1  - Schramm, Lothar
T1  - Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease
JF  - PLoS One
N2  - 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.
KW  - diabetes mellitus
KW  - inflammation
KW  - type 2 diabetes
KW  - hemoglobin
KW  - chronic kidney disease
KW  - anemia
KW  - ferritin
KW  - proteinuria
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125514
VL  - 10
IS  - 4
ER  - 
TY  - JOUR
A1  - Wagenhäuser, Laura
A1  - Rickert, Vanessa
A1  - Sommer, Claudia
A1  - Wanner, Christoph
A1  - Nordbeck, Peter
A1  - Rost, Simone
A1  - Üçeyler, Nurcan
T1  - X-chromosomal inactivation patterns in women with Fabry disease
JF  - Molecular Genetics & Genomic Medicine
N2  - 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.
KW  - Fabry disease
KW  - Fabry genotype
KW  - Fabry phenotype
KW  - female Fabry patients
KW  - X-chromosomal inactivation
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312795
VL  - 10
IS  - 9
ER  - 
TY  - THES
A1  - Vogg, Nora Johanna
T1  - Mass spectrometry-based quantification of steroids for the diagnostic workup of adrenal tumors
T1  - Massenspektrometrische Quantifizierung von Steroiden zur Diagnostik von Nebennierentumoren
N2  - 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 Würzburg, whereas the classification model based on urinary steroid profiling will require prospective validation in a larger cohort.
N2  - Nebennierentumoren gehören zu den häufigsten Neoplasmen beim Menschen und treten mit einer Prävalenz von 3–10 % bei Erwachsenen über 50 Jahren auf. Häufig wird die Raumforderung zufällig im Rahmen einer bildgebenden Untersuchung erkannt. Die meisten dieser sogenannten Inzidentalome sind gutartige und hormoninaktive Nebennierenrindenadenome (ACA), die keine therapeutische Intervention erfordern. Das Ziel der Nebennierentumor-Diagnostik ist die Abklärung potentieller Hormonaktivität und Malignität, denn diese Tumoren müssen zum Großteil operativ entfernt werden. Hormonaktive Tumoren können benigne oder maligne sein und sind durch die autonome Sekretion von Steroidhormonen charakterisiert. Maligne Nebennierenrindenkarzinome (ACC) sind sehr selten, aber aggressiv und mit einer schlechten Prognose im fortgeschrittenen Tumorstadium assoziiert. Da die therapeutischen Möglichkeiten für das ACC limitiert sind, ist eine schnelle und sichere Diagnostik erforderlich. Im Rahmen dieser Doktorarbeit wurden zwei Flüssigchromatographie-Tandemmassenspektrometrie (LC-MS/MS) Methoden zur Quantifizierung von Steroiden in Biomaterialien entwickelt, um damit die Diagnostik von Nebennierentumoren zu verbessern.
Der 1 mg-Dexamethason-Hemmtest (DST) ist ein häufig durchgeführter Screening-Test zur Untersuchung auf autonome Cortisolsekretion. Dabei wird die Supprimierbarkeit der Cortisolsekretion durch die orale Einnahme von Dexamethason überprüft. Eine LC-MS/MS Methode zur simultanen Quantifizierung von Cortisol und Dexamethason im Serum wurde entwickelt, validiert und zur Messung von 400 DST-Patientenproben genutzt. Durch methodenspezifische Schwellenwertkonzentrationen für Cortisol und Dexamethason konnte die klinische Testspezifität von 67.5 % auf 92.4 % bei unveränderter Sensitivität von 100.0 % erhöht werden.
Der zweite Teil dieser Arbeit befasst sich mit der Verbesserung der Unterscheidung von ACC und ACA. Dafür wurde eine LC-MS/MS Methode zur Quantifizierung von elf Steroiden im Urin entwickelt und validiert. Über die Messung von 24 h Sammelurinproben von 268 Nebennierenrindentumor-Patienten wurde ein Klassifikationsmodell, das auf nur zwei Steroiden basiert, trainiert und getestet. Sowohl die analytische Methode als auch das Klassifikationsmodell wurden hinsichtlich Robustheit und Zeiteffizienz optimiert, um sich möglichst gut in die klinische Routine implementieren zu lassen. Außerdem lag der Fokus auf einer einfachen, nachvollziehbaren und direkten Datenauswertung und -interpretation. Als ein Hauptergebnis konnte Malignität in einer unabhängigen Validierungskohorte von 84 Patienten mit einem negativen prädiktiven Wert von 100 % ausgeschlossen werden. Nach einem vereinfachten diagnostischen Schema mit der Urin-Steroid-Analytik als erstem Screening-Test könnte bei 42 von 64 Patienten mit ACA auf eine zusätzliche nebennierenspezifische Bildgebung verzichtet werden. Des Weiteren wurden erstmals Spontanurinproben als Surrogatmatrix für 24 h Sammelurin in der Validierungskohorte getestet. Dabei unterschied sich der positive prädiktive Wert der Spontanurine mit 86.7 % kaum von den 87.5 % der 24-h Sammelurine, während auch mit Spontanurin ein negativer prädiktiver Wert von 100 % erzielt werden konnte, was einen wichtigen Schritt in die Richtung einer vereinfachten Probensammlung darstellt.
Sowohl die simultane Quantifizierung von Cortisol und Dexamethason als auch die 24-h Urin-Steroid-Methode haben ihre Eignung für die klinische Routineanwendung bewiesen. Der Transfer der Urinmethode auf den deutlich einfacheren Spontanurin erfordert jedoch eine prospektive Validierung in einer größeren Patientenkohorte. Die neue DST-Methode wurde bereits im September 2021 in die klinische Routine am Universitätsklinikum Würzburg eingeführt.
KW  - Nebennierentumor
KW  - HPLC-MS
KW  - Steroide
KW  - adrenal incidentaloma
KW  - adrenocortical carcinoma
KW  - adrenocortical adenoma
KW  - dexamethasone suppression test
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-293438
N1  - A revised version of this manuscript has been published in Clinica Chimica Acta 2023
ER  - 
TY  - THES
A1  - Visan, Ioana Andreea
T1  - The CD23 receptor-regulation of expression and signal transduction
N2  - 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, während 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-Präsentation 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. Frühere Untersuchungen legen die Vermutung nahe, dass die beiden Isoformen zwei getrennte Signalübertragungswege miteinander verbinden. Die Gegenüberstellung 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 intrazellulären 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 beschränkter Transkriptionsfaktor, welcher für die frühe und späte B-Zellentwicklung von entscheidender Bedeutung ist. Mögliche 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 Elektromobilitäts Experimenten (EMSA) binden. Das Einfügen von Mutationen an dieser Stelle verhindert die Bindung. Ein weiterer Versuch, bei dem die gesamte Länge des CD23a Promotors durch überlappende Peptide in einem kompetitiven Verfahren gegenüber hoch affinen Bindungsstellen getestet wurde, zeigt ebenso CD23-1 als die einzige Stelle, welche direkt Pax-5 binden kann. In weiteren Experimenten führte 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 vergrößerten CD23a Promotorkonstrukts erhöht. Von besonderer Bedeutung ist die Tatsache, dass die ektope Expression von Pax-5 in der monozytären Zelllinie U-937, die normalerweise nur die CD23b Isoform exprimiert, dann zu einer Expression von CD23a nach Stimulation mit IL-4 und PMA führte. Unsere Ergebnisse legen nahe, dass Pax-5 in der auf B-Zellen beschränkten Expression der CD23 Isoform eine Schlüsselrolle zukommt. Im zweiten Teil des Projekts haben wir ein “Zwei-Hefen-Hybrid-System“ (Cyto-Trap von Stratagene) verwendet, um nach zytoplasmatischen Interaktionspartnern für den CD23 Rezeptor zu suchen. Das System wurde modifiziert um eine hohe Effizienz an Transformation zu erzielen. Unterschiedliche „Köder“-Vektorkonstrukte wurden hergestellt. Das Screening wurde mittels einer humanen Milzbibliothek mit dem Zielvektor des Systems durchgeführt. Die anfangs benutzten Konstrukte –pSosCD23a und pSosCD23b – exprimierten sehr kurze (22 Aminosäuren) 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 Aminosäurekette deutlich „sichtbar“ werden zu lassen. Annähernd drei Millionen Klone wurden mittels der verschiedenen Konstrukte untersucht. Dabei konnte keine tatsächlich 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 Köder 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 Schlüsselregulator ist, der die B-Zell-spezifische Expression von CD23a ermöglicht. Zusätzlich wurde ein “Zwei-Hefen-Hybrid-System“ etabliert, mit dem zytoplasmatische Interaktionspartner für die CD23 Isoformen gefunden werden können.
N2  - Two isoforms of human CD23 (CD23a and CD23b) have been described. They differ by only 6-7 residues in the N-terminal cytoplasmic tail. CD23a is restrictively expressed on B-cells while CD23b is inducible on B-cells, as well as monocytes, eosinophils, macrophages and a variety of other cell types, after IL-4 stimulation. The two isoforms seems to have different functions. CD23a appears to be the isoform associated with endocytosis of IgE immune complexes and mediating antigen presentation on B-cells. CD23b has a phagocytosis motif and seems to be involved in the phagocytosis of IgE-coated particles, cytokine release and the generation of superoxides. Previous studies indicate that the two isoforms connect to different signal transduction pathways. Comparing the cells that express only one or both CD23 isoforms suggests that CD23b is involved in upregulating cAMP and iNOS, whereas CD23a mediates an increase in intracellular calcium. In the main part of the study we investigated how the CD23a B-cell specific expression is regulated. Pax-5 is a B-cell restricted transcription factor with an essential role in early and late B-cell development. Putative Pax-5 binding sites have been predicted in the CD23a proximal promoter. Analyses of the CD23a promoter revealed three putative Pax-5 binding sites with more than 50% homology to the consensus sequence. One of these sites, named CD23-1 can compete a high affinity Pax-5 binding site or can directly bind Pax-5 protein in electrophoretic mobility shift assays. Introducing mutations into this site abrogates the binding. A different approach, in which overlapping peptides covering the length of the CD23a promoter were tested in competition assays against a high affinity binding site, also revealed CD23-1 as the only site that directly binds Pax-5 protein. Expression of Pax-5 in 293 cells resulted in a 7-fold activation of a CD23a core promoter construct. Co-transfection together with STAT6 showed that Pax-5 cooperates with this transcription factor in enhancing the level of transcription of a CD23a extended promoter construct. Most importantly, ectopic expression of Pax-5 in the monocytic cell line U-937 that regularly expresses only the CD23b isoform enabled a significant CD23a expression after stimulation with IL-4 and PMA. Our results suggest that Pax-5 is a key regulator of the B-cell restricted expression of the CD23a isoform. In the second part of the project, we used a yeast two-hybrid system (CytoTrapTM from Stratagene) in order to look for cytoplasmic interaction partners for the CD23 receptor. The system was established in order to reach a high efficiency of transformation and different bait vector constructs were made. The screening was performed using a human spleen library cloned in the target vector of the system. The first bait constructs used (pSosCD23a and pSosCD23b) expressed the very short (22 amino acids) cytoplasmic tails of the isoforms at the C-terminal end of the fusion protein (human SOS). Improved bait constructs, (pSosCD23a+Linker and pSos CD23b+Linker) expressed the cytoplasmic tail of CD23a/b at the N-terminal side of the human SOS and had in consequence the N-terminal part free as a bait, as it occurs in vivo. A flexible linker region separated the fusion proteins in order to make the small amino acid bait chain more obvious. Approximately three million library clones were screened with these various constructs. No “true positive” interaction was detected. A relatively high number of “false positive” clones were obtained and checked in another two-hybrid system. A new bait construct, in which the tyrosine residue in the cytoplasmic tail of CD23a was replaced by a glutamic acid residue will be used for future screening. The system was also used in order to test the interaction between CD23 and p59fyn, a member of the Src family of protein kinases that was mentioned to associate with CD23a. No interaction was detected by using the CytoTrap two-hybrid system. In conclusion, the key result of the study demonstrates that Pax-5 is a main regulator of the B-cell specific expression of the CD23a isoform. In addition, a two-hybrid system was established and employed in order to look for cytoplasmic interaction partners for CD23.
KW  - Antigen CD23
KW  - Promotor <Genetik>
KW  - Genregulation
KW  - CD23
KW  - Pax-5
KW  - Zwei-Hefen-Hybrid-System
KW  - Promotor Regulation
KW  - CD23
KW  - Pax-5
KW  - promoter regulation
KW  - two-hybrid system
Y1  - 2003
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-5556
ER  - 
TY  - JOUR
A1  - Vetrivel, Sharmilee
A1  - Zhang, Ru
A1  - Engel, Mareen
A1  - Oßwald, Andrea
A1  - Watts, Deepika
A1  - Chen, Alon
A1  - Wielockx, Ben
A1  - Sbiera, Silviu
A1  - Reincke, Martin
A1  - Riester, Anna
T1  - Characterization of adrenal miRNA-based dysregulations in Cushing's syndrome
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - cortisol
KW  - ACTH
KW  - miRNA
KW  - Cushing's
KW  - hypercortisolism
KW  - pituitary
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284394
SN  - 1422-0067
VL  - 23
IS  - 14
ER  - 
TY  - JOUR
A1  - Vetrivel, Sharmilee
A1  - Zhang, Ru
A1  - Engel, Mareen
A1  - Altieri, Barbara
A1  - Braun, Leah
A1  - Osswald, Andrea
A1  - Bidlingmaier, Martin
A1  - Fassnacht, Martin
A1  - Beuschlein, Felix
A1  - Reincke, Martin
A1  - Chen, Alon
A1  - Sbiera, Silviu
A1  - Riester, Anna
T1  - Circulating microRNA Expression in Cushing’s Syndrome
JF  - Frontiers in Endocrinology
N2  - 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.
KW  - cortisol
KW  - ACTH
KW  - miRNA
KW  - biomarker
KW  - cortisol-producing adenoma
KW  - miR-182-5p
KW  - hypercortisolism
KW  - miR-183 cluster
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229761
SN  - 1664-2392
VL  - 12
ER  - 
TY  - JOUR
A1  - Verrua, Elisa
A1  - Ferrante, Emanuele
A1  - Filopanti, Marcello
A1  - Malchiodi, Elena
A1  - Sala, Elisa
A1  - Giavoli, Claudia
A1  - Arosio, Maura
A1  - Lania, Andrea Gerardo
A1  - Ronchi, Christina Lucia
A1  - Mantovani, Giovanna
A1  - Beck-Peccoz, Paolo
A1  - Spada, Anna
T1  - Reevaluation of Acromegalic Patients in Long-Term Remission according to Newly Proposed Consensus Criteria for Control of Disease
JF  - International Journal of Endocrinology
N2  - 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.
KW  - IGF-I
KW  - glucose tolerance test
KW  - growth hormone deficiency
KW  - body mass index
KW  - oral glucose
KW  - GH response
KW  - mortality
KW  - immunoassays
KW  - statement
KW  - diagnosis
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-117790
SN  - 1687-8345
ER  - 
TY  - JOUR
A1  - van der Veen, Sanne J.
A1  - Vlietstra, Wytze J.
A1  - van Dussen, Laura
A1  - van Kuilenburg, André B.P.
A1  - Dijkgraaf, Marcel G. W.
A1  - Lenders, Malte
A1  - Brand, Eva
A1  - Wanner, Christoph
A1  - Hughes, Derralynn
A1  - Elliott, Perry M.
A1  - Hollak, Carla E. M.
A1  - Langeveld, Mirjam
T1  - Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - Fabry disease
KW  - enzyme replacement therapy
KW  - anti-drug antibodies
KW  - prediction model
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285687
SN  - 1422-0067
VL  - 21
IS  - 16
ER  - 
TY  - THES
A1  - van den Berg, Anne Maria
T1  - Age-related alterations of the immune system aggravate the myocardial aging process
T1  - Altersabhängige Veränderungen des Immunsystems verstärken den Alterungsprozess des Myokards
N2  - 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.
N2  - Die Prävalenz kardiovaskulärer Erkrankungen nimmt mit dem Alter dramatisch zu. Dennoch wurde der größte Anteil der kardiologischen Grundlagenforschung bisher an jungen, gesunden Tieren durchgeführt. Dies spiegelt nicht zwangsläufig die in der Klinik beobachtete Situation wieder. Das Herz durchläuft während des Alterns einen tiefgreifenden Wandel, einschließlich molekularer Veränderungen, Hypertrophie des Myokards, interstitieller Fibrose und funktioneller Verschlechterung. Bis heute gibt es zahlreiche Ansätze, um die Mechanismen hinter dem kardialen Alterungsprozess zu erklären. Insbesondere Inflammation und Immunaktivität sind von zunehmendem Interesse. Das Altern des Myokards korreliert zeitlich mit geringer chronischer, systemischer Entzündungsaktivität und einer Akkumulation von Gedächtnis-T-Zellen. Trotzdem wurde ein kausaler Zusammenhang zwischen beiden Vorgängen bisher nicht tiefergehend untersucht. Ziel dieser Studie war es festzustellen, wie immunologische Mechanismen zum kardialen Alterungsprozess beitragen.
Im Rahmen dieser Arbeit konnte gezeigt werden, dass gesunde Maus Herzen alle bedeutenden, gewebeansässigen Leukozyten einschließlich Makrophagen (CD45+CD11b+Ly6G-), Granulozyten (CD45+ CD11b+Ly6G+), T-Zellen (CD45+CD11b-CD3e+) und B-Zellen (CD45+CD11b-B220+) beherbergen und dies in einer deutliche höherer Anzahl als die Skelettmuskulatur. Altersabhängige, strukturelle Veränderungen und funktionelle Verschlechterung treten zeitgleich mit signifikanten Veränderungen in der Zusammensetzung der ansässigen Leukozyten auf. Untersuchungen der Genexpression an Myokardproben ergaben ein erhöhtes Level der TNF und INF- Expression, was darauf hinweist, dass in-situ Inflammation eine Rolle im myokardialen Alterungsprozess spielt. Darüber hinaus zeigten mediastinale Lymphknoten im Alter eine deutliche Größenzunahme sowie einen signifikanten Anstieg der Zellzahl. In mediastinalen Lymphknoten von alten Mäusen konnte außerdem eine starke Akkumulation von Effektor-Gedächtnis-T-Zellen (CD44+CD62L-) nachgewiesen werden, welche vorwiegend einen pro-inflammatorischen Phänotyp (Foxp3-, TNF+, IFN-γ+) aufwiesen. Keine dieser Veränderungen konnte in poplitealen Lymphknoten gezeigt werden, was darauf hindeutet, dass es sich um einen ortsspezifischen Prozess handeln könnte. 
Um über eine rein assoziative Evidenz hinaus zu gehen und zugrundeliegende Vorgänge zu analysieren, wurde der myokardiale Alterungsprozess umfassend an Mäusen ohne B- Zellen (µMT) oder CD4+ T-Zellen (CD4ko) charakterisiert. Die Untersuchungen ergaben, dass alte Mäuse ohne CD4+ T-Zellen verglichen zu gleichalterigen Wildtyp Tieren einen geringeren inflammatorischen Tonus in-situ entwickeln. Diese Veränderung war für Mäuse ohne B-Zellen nicht zu beobachten. Keinen Unterschied gab es in den Versuchsgruppen hingegen bei der Expression von Genen, die mit Fibrose assoziiert sind.
Zusammenfassend weisen die Ergebnisse dieser Arbeit darauf hin, dass auf das Herz gerichtete Immunantworten im Alter spontan, auch ohne eindeutigen Gewebeschaden oder eine begleitende Infektion, auftreten können. Das T-Zell vermittelte Profil des alternden Immunsystems kann teilweise mit der altersabhängigen Entzündung des Myokards sowie funktionellen Einschränkung assoziiert sein, weniger jedoch mit dem Remodeling Prozess. Diese Beobachtungen geben neuen Aufschluss über die aufkommende Rolle von T-Zellen in Erkrankungen des Myokards, welche vor allem die ältere Bevölkerung betreffen.
KW  - Aging
KW  - Heart
KW  - Immunsystem
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193622
ER  - 
TY  - JOUR
A1  - Uttinger, Konstantin L.
A1  - Riedmeier, Maria
A1  - Reibetanz, Joachim
A1  - Meyer, Thomas
A1  - Germer, Christoph Thomas
A1  - Fassnacht, Martin
A1  - Wiegering, Armin
A1  - Wiegering, Verena
T1  - Adrenalectomies in children and adolescents in Germany – a diagnose related groups based analysis from 2009-2017
JF  - Frontiers in Endocrinology
N2  - 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.
KW  - pediatric
KW  - neuroblastoma – diagnosis
KW  - therapy
KW  - adrenocortical adenocarcinoma
KW  - outcome
KW  - volume
KW  - adrenalectomia
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-282280
SN  - 1664-2392
VL  - 13
ER  - 
TY  - JOUR
A1  - Ungethüm, K.
A1  - Wiedmann, S.
A1  - Wagner, M.
A1  - Leyh, R.
A1  - Ertl, G.
A1  - Frantz, S.
A1  - Geisler, T.
A1  - Karmann, W.
A1  - Prondzinsky, R.
A1  - Herdeg, C.
A1  - Noutsias, M.
A1  - Ludwig, T.
A1  - Käs, J.
A1  - Klocke, B.
A1  - Krapp, J.
A1  - Wood, D.
A1  - Kotseva, K.
A1  - Störk, S.
A1  - Heuschmann, P. U.
T1  - 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
JF  - Clinical Research in Cardiology
N2  - 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 Würzburg (EA-IV, EA-V), Halle (EA-V), and Tübingen (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.
KW  - coronary heart disease
KW  - diabetes mellitus
KW  - secondary prevention
KW  - EUROASPIRE
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324037
VL  - 112
IS  - 2
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Otto, Markus
A1  - Sell, Roxane
A1  - Homola, György A.
A1  - Steinacker, Petra
A1  - Oeckl, Patrick
A1  - Morbach, Caroline
A1  - Frantz, Stefan
A1  - Pham, Mirko
A1  - Störk, Stefan
A1  - Stoll, Guido
A1  - Frey, Anna
T1  - Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure
JF  - ESC Heart Failure
N2  - 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.
KW  - Glial fibrillary acidic protein
KW  - GFAP
KW  - Chronic heart failure
KW  - Cognitive decline
KW  - Memory dysfunction
KW  - Brain atrophy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312736
VL  - 9
IS  - 4
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Otto, Markus
A1  - Sell, Roxane
A1  - Göpfert, Dennis
A1  - Homola, György
A1  - Steinacker, Petra
A1  - Oeckl, Patrick
A1  - Morbach, Caroline
A1  - Frantz, Stefan
A1  - Pham, Mirko
A1  - Störk, Stefan
A1  - Stoll, Guido
A1  - Frey, Anna
T1  - Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients
JF  - Alzheimer's Research & Therapy
N2  - 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.
KW  - Alzheimer’s dementia
KW  - heart failure
KW  - cognitive impairment
KW  - neurofilament light chain
KW  - phosphorylated tau protein
KW  - renal function
KW  - age
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300515
VL  - 14
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Husseini, Leila
A1  - Weber, Martin S.
T1  - B cells and antibodies as targets of therapeutic intervention in neuromyelitis optica spectrum disorders
JF  - Pharmaceuticals
N2  - The first description of neuromyelitis optica by Eugène 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.
KW  - neuromyelitis optica spectrum disorders
KW  - B cells
KW  - antibodies
KW  - eculizumab
KW  - ravulizumab
KW  - inebilizumab
KW  - tocilizumab
KW  - satralizumab
KW  - ublituximab
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222957
SN  - 1424-8247
VL  - 14
IS  - 1
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Grondey, Katja
A1  - Gassenmaier, Tobias
A1  - Schmitt, Dominik
A1  - Fette, Georg
A1  - Frantz, Stefan
A1  - Boivin-Jahns, Valérie
A1  - Jahns, Roland
A1  - Störk, Stefan
A1  - Stoll, Guido
A1  - Reiter, Theresa
A1  - Hofmann, Ulrich
A1  - Weber, Martin S.
A1  - Frey, Anna
T1  - Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - myocardial infarction
KW  - STEMI
KW  - glial fibrillary acidic protein
KW  - GFAP
KW  - neurofilament light chain
KW  - NfL
KW  - glial damage
KW  - cardiac magnetic resonance imaging
KW  - MRI
KW  - infarction size
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288261
SN  - 1422-0067
VL  - 23
IS  - 18
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Frey, Anna
A1  - Störk, Stefan
T1  - Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications
JF  - Life
N2  - 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.
KW  - neuroinflammation
KW  - cognitive impairment
KW  - dementia
KW  - myocardial infarction
KW  - heart failure
KW  - hypertension
KW  - coronary artery disease
KW  - atrial fibrillation
KW  - cardiac arrest
KW  - aortic valve stenosis
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304869
SN  - 2075-1729
VL  - 13
IS  - 2
ER  - 
TY  - JOUR
A1  - Tolstik, Elen
A1  - Ali, Nairveen
A1  - Guo, Shuxia
A1  - Ebersbach, Paul
A1  - Möllmann, Dorothe
A1  - Arias-Loza, Paula
A1  - Dierks, Johann
A1  - Schuler, Irina
A1  - Freier, Erik
A1  - Debus, Jörg
A1  - Baba, Hideo A.
A1  - Nordbeck, Peter
A1  - Bocklitz, Thomas
A1  - Lorenz, Kristina
T1  - CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - coherent anti-Stokes Raman scattering (CARS) microscopy
KW  - Raman micro-spectroscopy
KW  - cardiovascular diseases
KW  - Fabry Disease (FD)
KW  - Gb3 and lyso-Gb3 biomarkers
KW  - multivariate data analysis
KW  - immunohistochemistry
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284427
SN  - 1422-0067
VL  - 23
IS  - 10
ER  - 
TY  - JOUR
A1  - Toepfer, Martin
A1  - Corovic, Hamo
A1  - Fette, Georg
A1  - Klügl, Peter
A1  - Störk, Stefan
A1  - Puppe, Frank
T1  - Fine-grained information extraction from German transthoracic echocardiography reports
JF  - BMC Medical Informatics and Decision Making
N2  - Background
Information extraction techniques that get structured representations out of unstructured data make a large amount of clinically relevant information about patients accessible for semantic applications. These methods typically rely on standardized terminologies that guide this process. Many languages and clinical domains, however, lack appropriate resources and tools, as well as evaluations of their applications, especially if detailed conceptualizations of the domain are required. For instance, German transthoracic echocardiography reports have not been targeted sufficiently before, despite of their importance for clinical trials. This work therefore aimed at development and evaluation of an information extraction component with a fine-grained terminology that enables to recognize almost all relevant information stated in German transthoracic echocardiography reports at the University Hospital of Würzburg.

Methods
A domain expert validated and iteratively refined an automatically inferred base terminology. The terminology was used by an ontology-driven information extraction system that outputs attribute value pairs. The final component has been mapped to the central elements of a standardized terminology, and it has been evaluated according to documents with different layouts.

Results
The final system achieved state-of-the-art precision (micro average.996) and recall (micro average.961) on 100 test documents that represent more than 90 % of all reports. In particular, principal aspects as defined in a standardized external terminology were recognized with f 1=.989 (micro average) and f 1=.963 (macro average). As a result of keyword matching and restraint concept extraction, the system obtained high precision also on unstructured or exceptionally short documents, and documents with uncommon layout.

Conclusions
The developed terminology and the proposed information extraction system allow to extract fine-grained information from German semi-structured transthoracic echocardiography reports with very high precision and high recall on the majority of documents at the University Hospital of Würzburg. Extracted results populate a clinical data warehouse which supports clinical research.
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125509
VL  - 15
IS  - 91
ER  - 
TY  - JOUR
A1  - Tiffe, Theresa
A1  - Wagner, Martin
A1  - Rücker, Viktoria
A1  - Morbach, Caroline
A1  - Gelbrich, Götz
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
T1  - Control of cardiovascular risk factors and its determinants in the general population – findings from the STAAB cohort study
JF  - BMC Cardiovascular Disorders
N2  - Background:
While data from primary care suggest an insufficient control of vascular risk factors, little is known about vascular risk factor control in the general population. We therefore aimed to investigate the adoption of adequate risk factor control and its determinants in the general population free of cardiovascular disease (CVD).

Methods:
Data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) Cohort Study, a population-based study of inhabitants aged 30 to 79 years from the general population of Würzburg (Germany), were used. Proportions of participants without established CVD meeting targets for risk factor control recommended by 2016 ESC guideline were identified. Determinants of the accumulation of insufficiently controlled vascular risk factors (three or more) were assessed.

Results:
Between December 2013 and April 2015, 1379 participants without CVD were included; mean age was 53.1 ± 11.9 years and 52.9% were female; 30.8% were physically inactive, 55.2% overweight, 19.3% current smokers. Hypertension, dyslipidemia, and diabetes mellitus were prevalent in 31.8%, 57.6%, and 3.9%, respectively. Treatment goals were not reached despite medication in 52.7% of hypertensive, in 37.3% of hyperlipidemic and in 44.0% of diabetic subjects. Insufficiently controlled risk was associated with male sex (OR 1.94, 95%CI 1.44–2.61), higher age (OR for 30–39 years vs. 70–79 years 4.01, 95%CI 1.94–8.31) and lower level of education (OR for primary vs. tertiary 2.15, 95%CI 1.48–3.11).

Conclusions:
In the general population, prevalence of vascular risk factors was high. We found insufficient identification and control of vascular risk factors and a considerable potential to improve adherence to cardiovascular guidelines for primary prevention. Further studies are needed to identify and overcome patient- and physician-related barriers impeding successful control of vascular risk factors in the general population.
KW  - population-based study
KW  - prevalence
KW  - risk factor control
KW  - guideline adherence
KW  - primary prevention
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159391
VL  - 17
IS  - 276
ER  - 
TY  - JOUR
A1  - Tiffe, Theresa
A1  - Morbach, Caroline
A1  - Rücker, Viktoria
A1  - Gelbrich, Götz
A1  - Wagner, Martin
A1  - Faller, Hermann
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
T1  - Impact of patient beliefs on blood pressure control in the general population: findings from the population-based STAAB cohort study
JF  - International Journal of Hypertension
N2  - Background. 
Effective antihypertensive treatment depends on patient compliance regarding prescribed medications. We assessed the impact of beliefs related towards antihypertensive medication on blood pressure control in a population-based sample treated for hypertension. 

Methods. 
We used data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) study investigating 5000 inhabitants aged 30 to 79 years from the general population of Würzburg, Germany. The Beliefs about Medicines Questionnaire German Version (BMQ-D) was provided in a subsample without established cardiovascular diseases (CVD) treated for hypertension. We evaluated the association between inadequately controlled hypertension (systolic RR >140/90 mmHg; >140/85 mmHg in diabetics) and reported concerns about and necessity of antihypertensive medication. 

Results. 
Data from 293 participants (49.5% women, median age 64 years [quartiles 56.0; 69.0]) entered the analysis. Despite medication, half of the participants (49.8%) were above the recommended blood pressure target. Stratified for sex, inadequately controlled hypertension was less frequent in women reporting higher levels of concerns (OR 0.36; 95%CI 0.17-0.74), whereas no such association was apparent in men. We found no association for specific-necessity in any model.
 
Conclusion. 
Beliefs regarding the necessity of prescribed medication did not affect hypertension control. An inverse association between concerns about medication and inappropriately controlled hypertension was found for women only. Our findings highlight that medication-related beliefs constitute a serious barrier of successful implementation of treatment guidelines and underline the role of educational interventions taking into account sex-related differences.
KW  - hypertension
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200992
VL  - 2019
ER  - 
TY  - JOUR
A1  - Tamburello, Mariangela
A1  - Altieri, Barbara
A1  - Sbiera, Iuliu
A1  - Sigala, Sandra
A1  - Berruti, Alfredo
A1  - Fassnacht, Martin
A1  - Sbiera, Silviu
T1  - FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma
JF  - Endocrine
N2  - FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.
KW  - FGF-pathway
KW  - FGFR
KW  - FGFR-inhibitors
KW  - adrenocortical development
KW  - adrenocortical tumors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324420
VL  - 77
IS  - 3
ER  - 
TY  - JOUR
A1  - Störk, Stefan
A1  - Bernhardt, Alexandra
A1  - Böhm, Michael
A1  - Brachmann, Johannes
A1  - Dagres, Nikolaos
A1  - Frantz, Stefan
A1  - Hindricks, Gerd
A1  - Köhler, Friedrich
A1  - Zeymer, Uwe
A1  - Rosenkranz, Stephan
A1  - Angermann, Christiane
A1  - Aßmus, Birgit
T1  - Pulmonary artery sensor system pressure monitoring to improve heart failure outcomes (PASSPORT-HF): rationale and design of the PASSPORT-HF multicenter randomized clinical trial
JF  - Clinical Research in Cardiology
N2  - Background
Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients.

Objectives
PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points.

Methods and results
The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression.

Conclusions
PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care.

Trial registration
ClinicalTrials.gov; NCT04398654, 13-MAY-2020.
KW  - heart failure
KW  - pulmonary artery pressure
KW  - remote monitoring
KW  - CardioMEMS™ HF-System
KW  - randomized controlled trial
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324026
VL  - 111
IS  - 11
ER  - 
TY  - JOUR
A1  - Stritt, Simon
A1  - Nurden, Paquita
A1  - Favier, Remi
A1  - Favier, Marie
A1  - Ferioli, Silvia
A1  - Gotru, Sanjeev K.
A1  - van Eeuwijk, Judith M.M.
A1  - Schulze, Harald
A1  - Nurden, Alan T.
A1  - Lambert, Michele P.
A1  - Turro, Ernest
A1  - Burger-Stritt, Stephanie
A1  - Matsushita, Masayuki
A1  - Mittermeier, Lorenz
A1  - Ballerini, Paola
A1  - Zierler, Susanna
A1  - Laffan, Michael A.
A1  - Chubanov, Vladimir
A1  - Gudermann, Thomas
A1  - Nieswandt, Bernhard
A1  - Braun, Attila
T1  - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture
JF  - Nature Communications
N2  - Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
KW  - Cytoskeleton
KW  - homeostasisIon channels
KW  - thrombopoiesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173843
VL  - 7
ER  - 
TY  - JOUR
A1  - Steinbrunn, Torsten
A1  - Chatterjee, Manik
A1  - Bargou, Ralf C.
A1  - Stühmer, Thorsten
T1  - Efficient Transient Transfection of Human Multiple Myeloma Cells by Electroporation - An Appraisal
JF  - PLoS ONE
N2  - Cell lines represent the everyday workhorses for in vitro research on multiple myeloma (MM) and are regularly employed in all aspects of molecular and pharmacological investigations. Although loss-of-function studies using RNA interference in MM cell lines depend on successful knockdown, no well-established and widely applied protocol for efficient transient transfection has so far emerged. Here, we provide an appraisal of electroporation as a means to introduce either short-hairpin RNA expression vectors or synthesised siRNAs into MM cells. We found that electroporation using siRNAs was much more efficient than previously anticipated on the basis of transfection efficiencies deduced from EGFP-expression off protein expression vectors. Such knowledge can even confidently be exploited in "hard-to-transfect" MM cell lines to generate large numbers of transient knockdown phenotype MM cells. In addition, special attention was given to developing a protocol that provides easy implementation, good reproducibility and manageable experimental costs.
KW  - cell cultures
KW  - green fluorescent protein
KW  - oligonucleotides
KW  - multiple myeloma
KW  - plasmid construction
KW  - transfection
KW  - small interfering RNAs
KW  - electroporation
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119616
VL  - 9
IS  - 6
ER  - 
TY  - JOUR
A1  - Sommer, Kim K.
A1  - Amr, Ali
A1  - Bavendiek, Udo
A1  - Beierle, Felix
A1  - Brunecker, Peter
A1  - Dathe, Henning
A1  - Eils, Jürgen
A1  - Ertl, Maximilian
A1  - Fette, Georg
A1  - Gietzelt, Matthias
A1  - Heidecker, Bettina
A1  - Hellenkamp, Kristian
A1  - Heuschmann, Peter
A1  - Hoos, Jennifer D. E.
A1  - Kesztyüs, Tibor
A1  - Kerwagen, Fabian
A1  - Kindermann, Aljoscha
A1  - Krefting, Dagmar
A1  - Landmesser, Ulf
A1  - Marschollek, Michael
A1  - Meder, Benjamin
A1  - Merzweiler, Angela
A1  - Prasser, Fabian
A1  - Pryss, Rüdiger
A1  - Richter, Jendrik
A1  - Schneider, Philipp
A1  - Störk, Stefan
A1  - Dieterich, Christoph
T1  - Structured, harmonized, and interoperable integration of clinical routine data to compute heart failure risk scores
JF  - Life
N2  - Risk prediction in patients with heart failure (HF) is essential to improve the tailoring of preventive, diagnostic, and therapeutic strategies for the individual patient, and effectively use health care resources. Risk scores derived from controlled clinical studies can be used to calculate the risk of mortality and HF hospitalizations. However, these scores are poorly implemented into routine care, predominantly because their calculation requires considerable efforts in practice and necessary data often are not available in an interoperable format. In this work, we demonstrate the feasibility of a multi-site solution to derive and calculate two exemplary HF scores from clinical routine data (MAGGIC score with six continuous and eight categorical variables; Barcelona Bio-HF score with five continuous and six categorical variables). Within HiGHmed, a German Medical Informatics Initiative consortium, we implemented an interoperable solution, collecting a harmonized HF-phenotypic core data set (CDS) within the openEHR framework. Our approach minimizes the need for manual data entry by automatically retrieving data from primary systems. We show, across five participating medical centers, that the implemented structures to execute dedicated data queries, followed by harmonized data processing and score calculation, work well in practice. In summary, we demonstrated the feasibility of clinical routine data usage across multiple partner sites to compute HF risk scores. This solution can be extended to a large spectrum of applications in clinical care.
KW  - medical informatics initiative
KW  - HiGHmed
KW  - medical data integration center
KW  - clinical routine data
KW  - heart failure
KW  - risk prediction scores
KW  - semantic interoperability
KW  - openEHR
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275239
SN  - 2075-1729
VL  - 12
IS  - 5
ER  - 
TY  - JOUR
A1  - Sherif, Mohammad A.
A1  - Ince, Hüseyin
A1  - Maniuc, Octavian
A1  - Reiter, Therese
A1  - Voelker, Wolfram
A1  - Ertl, Georg
A1  - Öner, Alper
T1  - Two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation
JF  - BMC Cardiovascular Disorders
N2  - Background: Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we examined the accuracy of a novel method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus. 
Methods: We evaluated the theoretical impact of the measurement of the annulus diameter and area using the circumcircle of a triangle method on the decision to perform the procedure and choice of the prosthesis size. Results: Sixty-three consecutive patients were scheduled for TAVI. Mean age was 82 +/- 4 years, and 25 patients (55.6 %) were female. Mean aortic annulus diameter was 20.3 +/- 2.2 mm assessed by TEE on the mid-esophageal long-axis view and 23.9 +/- 2.3 mm using CT (p < 0.001). There was a tendency for the TEE derived areas using the new method to be higher (p < 0.001). The TEE measurements were on average 42.33 mm(2) higher than the CT measurements without an evidence of a systematic over-or under-sizing (p = 1.00). Agreement between TEE and CT chosen valve sizes was good overall (kappa = 0.67 and weighted kappa = 0.71). For patients who turned out to have no AR, the two methods agreed in 84.6 % of patients. 
Conclusions: CT remanis the gold standard in sizing of the aortic valve annulus. Nevertheless, sizing of the aortic valve annulus using TEE derived area may be helpful. The impact of integration of this method in the algorithm of aortic annulus sizing on the outcome of patients undergoing TAVI should be examined in future studies.
KW  - multicenter
KW  - TAVI
KW  - impact
KW  - complex
KW  - anatomy
KW  - dimensions
KW  - regurgitation
KW  - root
KW  - sizing
KW  - echocardiography
KW  - multidetector computed-tomography
KW  - replacement
KW  - outcomes
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136002
VL  - 15
IS  - 181
ER  - 
TY  - JOUR
A1  - Sherif, Mohammad A.
A1  - Herold, Joerg
A1  - Voelker, Wolfram
A1  - Maniuc, Octavian
A1  - Ertl, Georg
A1  - Praast, Christian
A1  - Braun-Dullaeus, Ruediger Christian
T1  - Feasibility of a new method using two-dimensional transesophageal echocardiography for aortic annular sizing in patients undergoing transcatheter aortic valve implantation; a case-control study
JF  - BMC Cardiovascular Disorders
N2  - Background: 
Accurate preoperative assessment of the aortic annulus dimension is crucial for successful transcatheter aortic valve implantation (TAVI). In this study we validated a new method using two-dimensional transesophageal echocardiography (2D-TEE) for measurement of the aortic annulus prior to TAVI. 

Methods: 
We analysed 124 patients who underwent successful TAVI using a self-expandable prosthesis, divided equally into two groups; in the study group we used the cross sectional short axis 2D-TEE for measurement of the aortic annulus and in the control group we used the long axis 2D-TEE. 

Results: 
Both groups were comparable regarding the clinical parameters. On the other hand, patients in the study group had less left ventricular ejection fraction (38.9 % versus 45.6 %, p = 0.01). The aortic valve annulus was, although not statistically significant, smaller in the study group (21.58 versus 23.28 mm, p = 0.25). Post procedural quantification of the aortic regurgitation revealed that only one patient in both groups had severe aortic regurgitation (AR), in this patient the valve was implanted deep. The incidence of significant AR was higher in the control group (29.0 % versus 12.9 %, p = 0.027). 

Conclusions: 
Sizing of the aortic valve annulus using cross-sectional 2D-TEE offers a safe and plausible method for patients undergoing TAVI using the self-expandable prosthesis and is significantly superior to using long axis 2D-TEE.
KW  - paravalvular regurgitation
KW  - multicenter
KW  - management
KW  - sizing
KW  - echocardiography
KW  - replacement
KW  - tomography
KW  - guidelines
KW  - outcomes
KW  - impact
KW  - recommendations
KW  - stenosis
KW  - TAVI
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148328
VL  - 15
IS  - 78
ER  - 
TY  - JOUR
A1  - Shemer, Yuval
A1  - Mekies, Lucy N.
A1  - Ben Jehuda, Ronen
A1  - Baskin, Polina
A1  - Shulman, Rita
A1  - Eisen, Binyamin
A1  - Regev, Danielle
A1  - Arbustini, Eloisa
A1  - Gerull, Brenda
A1  - Gherghiceanu, Mihaela
A1  - Gottlieb, Eyal
A1  - Arad, Michael
A1  - Binah, Ofer
T1  - Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes
JF  - International Journal of Molecular Sciences
N2  - LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.
KW  - LMNA
KW  - dilated cardiomyopathy
KW  - iPSC-CMs
KW  - electrophysiology
KW  - arrhythmia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285673
SN  - 1422-0067
VL  - 22
IS  - 15
ER  - 
TY  - JOUR
A1  - Seyfried, Florian
A1  - von Rahden, Burkhard H.
A1  - Miras, Alexander D.
A1  - Gasser, Martin
A1  - Maeder, Uwe
A1  - Kunzmann, Volker
A1  - Germer, Christoph-Thomas
A1  - Pelz, Jörg O. W.
A1  - Kerscher, Alexander G.
T1  - Incidence, time course and independent risk factors for metachronous peritoneal carcinomatosis of gastric origin – a longitudinal experience from a prospectively collected database of 1108 patients
JF  - BMC Cancer
N2  - Background
Comprehensive evidence on the incidence, time course and independent risk factors of metachronous peritoneal carcinomatosis (metaPC) in gastric cancer patients treated with curative intent in the context of available systemic combination chemotherapies is lacking.

Methods
Data from a prospectively collected single-institutional Center Cancer Registry with 1108 consecutive patients with gastric adenocarcinoma (GC), clinical, histological and survival data were analyzed for independent risk factors and prognosis with focus on the development of metaPC. Findings were then stratified to the time periods of treatment with surgery alone, 5-Fluorouracil-only and contemporary combined systemic perioperative chemotherapy strategies, respectively.

Results
Despite R0 D2 gastrectomy (n = 560), 49.6% (±5.4%) of the patients were diagnosed with tumour recurrence and 15.5% (±1.8%) developed metaPC after a median time of 17.7 (15.1-20.3) months after surgery resulting in a tumour related mortality of 100% with a median survival of 3.0 months (2.1 – 4.0). Independent risk factors for the development of metaPC were serosa positive T-category, nodal positive-status, signet cell and undifferentiated gradings (G3/G4). Contemporary systemic combination chemotherapy did not improve the incidence and prognosis of metaPC (p = 0.54).

Conclusions
Despite significant improvements in the overall survival for the complete cohort with gastric cancer over time, those patients with metaPC did not experience the same benefits. The lack of change in the incidence, and persistent poor prognosis of metaPC after curative surgery expose the need for further prevention and/or improved treatment options for this devastating condition.
KW  - recurrence survival
KW  - metachronous
KW  - peritoneal carcinomatosis
KW  - gastric cancer
KW  - risk factors
KW  - perioperative chemotherapy
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125014
VL  - 15
IS  - 73
ER  - 
TY  - JOUR
A1  - Seydelmann, Nora
A1  - Liu, Dan
A1  - Krämer, Johannes
A1  - Drechsler, Christiane
A1  - Hu, Kai
A1  - Nordbeck, Peter
A1  - Schneider, Andreas
A1  - Störk, Stefan
A1  - Bijnens, Bart
A1  - Ertl, Georg
A1  - Wanner, Christoph
A1  - Weidemann, Frank
T1  - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease
JF  - Journal of the American Heart Association
N2  - Background
High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression.

Methods and Results
For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression.

Conclusions
hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients.
KW  - biomarker
KW  - cardiomyopathy
KW  - fabry disease
KW  - myocardial fibrosis
KW  - troponin T
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165682
VL  - 5
IS  - e002839
ER  - 
TY  - JOUR
A1  - Serfling, Sebastian E.
A1  - Lapa, Constantin
A1  - Dreher, Niklas
A1  - Hartrampf, Philipp E.
A1  - Rowe, Steven P.
A1  - Higuchi, Takahiro
A1  - Schirbel, Andreas
A1  - Weich, Alexander
A1  - Hahner, Stefanie
A1  - Fassnacht, Martin
A1  - Buck, Andreas K.
A1  - Werner, Rudolf A.
T1  - Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT
JF  - Molecular Imaging and Biology
N2  - Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.

Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.

Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.

Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
KW  - CXCR4
KW  - C-X-C motif chemokine receptor 4
KW  - PET
KW  - [68Ga]PentixaFor
KW  - [177Lu]/[90Y]PentixaTher
KW  - theranostics
KW  - endoradiotherapy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324622
VL  - 24
IS  - 4
ER  - 
TY  - JOUR
A1  - Seidlmayer, Lea K.
A1  - Mages, Christine
A1  - Berbner, Annette
A1  - Eder-Negrin, Petra
A1  - Arias-Loza, Paula Anahi
A1  - Kaspar, Mathias
A1  - Song, Moshi
A1  - Dorn, Gerald W.
A1  - Kohlhaas, Michael
A1  - Frantz, Stefan
A1  - Maack, Christoph
A1  - Gerull, Brenda
A1  - Dedkova, Elena N.
T1  - Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes
JF  - Frontiers in Physiology
N2  - Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP\(_3\)) by activating their membrane-bound receptors. We have previously demonstrated that IP\(_3\)-mediated sarcoplasmic reticulum (SR) Ca\(^{2+}\) release results in mitochondrial Ca\(^{2+}\) uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP\(_3\)-mediated SR/mitochondrial feedback in ventricular myocytes.
Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca\(^{2+}\) uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates.
Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca\(^{2+}\) uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca\(^{2+}\) uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca\(^{2+}\) uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca\(^{2+}\) uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca\(^{2+}\) uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions.
Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP\(_3\)-mediated SR Ca\(^{2+}\) release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP\(_3\)R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).
KW  - mitofusin 2
KW  - IP3
KW  - SR/mitochondria metabolic feedback
KW  - mitochondrial mRyR1
KW  - ATP generation
KW  - endothelin-1
KW  - Mfn2 KO mice
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199141
SN  - 1664-042X
VL  - 10
IS  - 733
ER  - 
TY  - JOUR
A1  - Schupp, Nicole
A1  - Stopper, Helga
A1  - Heidland, August
T1  - DNA Damage in Chronic Kidney Disease: Evaluation of Clinical Biomarkers
JF  - Oxidative Medicine and Cellular Longevity
N2  - Patients with chronic kidney disease (CKD) exhibit an increased cancer risk compared to a healthy control population. To be able to estimate the cancer risk of the patients and to assess the impact of interventional therapies thereon, it is of particular interest to measure the patients’ burden of genomic damage. Chromosomal abnormalities, reduced DNA repair, and DNA lesions were found indeed in cells of patients with CKD. Biomarkers for DNA damage measurable in easily accessible cells like peripheral blood lymphocytes are chromosomal aberrations, structural DNA lesions, and oxidatively modified DNA bases. In this review the most common methods quantifying the three parameters mentioned above, the cytokinesis-block micronucleus assay, the comet assay, and the quantification of 8-oxo-7,8-dihydro-2′-deoxyguanosine, are evaluated concerning the feasibility of the analysis and regarding the marker’s potential to predict clinical outcomes.
KW  - chronic kidney disease
KW  - cancer risk
KW  - DNA damage
KW  - biomarkers
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166569
VL  - 2016
IS  - 3592042
ER  - 
TY  - JOUR
A1  - Schreiber, Laura M.
A1  - Lohr, David
A1  - Baltes, Steffen
A1  - Vogel, Ulrich
A1  - Elabyad, Ibrahim A.
A1  - Bille, Maya
A1  - Reiter, Theresa
A1  - Kosmala, Aleksander
A1  - Gassenmaier, Tobias
A1  - Stefanescu, Maria R.
A1  - Kollmann, Alena
A1  - Aures, Julia
A1  - Schnitter, Florian
A1  - Pali, Mihaela
A1  - Ueda, Yuichiro
A1  - Williams, Tatiana
A1  - Christa, Martin
A1  - Hofmann, Ulrich
A1  - Bauer, Wolfgang
A1  - Gerull, Brenda
A1  - Zernecke, Alma
A1  - Ergün, Süleyman
A1  - Terekhov, Maxim
T1  - Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research
JF  - Frontiers in Cardiovascular Medicine
N2  - A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.
KW  - ultrahigh-field MRI
KW  - large animal models
KW  - translational research
KW  - research infrastructure
KW  - heart
KW  - organoid
KW  - pig
KW  - cardiovascular MRI
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-317398
SN  - 2297-055X
VL  - 10
ER  - 
TY  - JOUR
A1  - Schrader, Nikolas
A1  - Riese, Thorsten
A1  - Kurlbaum, Max
A1  - Meybohm, Patrick
A1  - Kredel, Markus
A1  - Surat, Güzin
A1  - Scherf-Clavel, Oliver
A1  - Strate, Alexander
A1  - Pospiech, Andreas
A1  - Hoppe, Kerstin
T1  - Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis
JF  - Antibiotics
N2  - Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness.
KW  - therapeutic drug monitoring
KW  - piperacillin/tazobactam
KW  - personalized antimicrobial therapy
KW  - antimicrobial stewardship
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250052
SN  - 2079-6382
VL  - 10
IS  - 12
ER  - 
TY  - JOUR
A1  - Schneider, Andreas
A1  - Schneider, Markus P.
A1  - Scharnagl, Hubert
A1  - Jardine, Alan G.
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Predicting erythropoietin resistance in hemodialysis patients with type 2 diabetes
JF  - BMC Nephrology
N2  - Background: Resistance to ESAs (erythropoietin stimulating agents) is highly prevalent in hemodialysis patients with diabetes and associated with an increased mortality. The aim of this study was to identify predictors for ESA resistance and to develop a prediction model for the risk stratification in these patients.
Methods: A post-hoc analysis was conducted of the 4D study, including 1015 patients with type 2 diabetes undergoing hemodialysis. Determinants of ESA resistance were identified by univariate logistic regression analyses. Subsequently, multivariate models were performed with stepwise inclusion of significant predictors from clinical parameters, routine laboratory and specific biomarkers.
Results: In the model restricted to clinical parameters, male sex, shorter dialysis vintage, lower BMI, history of CHF, use of ACE-inhibitors and a higher heart rate were identified as independent predictors of ESA resistance. In regard to routine laboratory markers, lower albumin, lower iron saturation, higher creatinine and higher potassium levels were independently associated with ESA resistance. With respect to specific biomarkers, higher ADMA and CRP levels as well as lower Osteocalcin levels were predictors of ESA resistance.
Conclusions: Easily obtainable clinical parameters and routine laboratory parameters can predict ESA resistance in diabetic hemodialysis patients with good discrimination. Specific biomarkers did not meaningfully further improve the risk prediction of ESA resistance. Routinely assessed data can be used in clinical practice to stratify patients according to the risk of ESA resistance, which may help to assign appropriate treatment strategies.
KW  - type 2 diabetes
KW  - heodialysis patients
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128695
VL  - 14
IS  - 67
ER  - 
TY  - JOUR
A1  - Schneider, Andreas
A1  - Schneider, Markus P.
A1  - Krieter, Detlef H.
A1  - Genser, Bernd
A1  - Scharnagl, Hubert
A1  - Stojakovic, Tatjana
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Effect of high-flux dialysis on circulating FGF-23 levels in end-stage renal disease patients: results from a randomized trial
JF  - PLoS ONE
N2  - Background 
In patients undergoing maintenance hemodialysis (HD), increased levels of circulating fibroblast growth factor-23 (FGF-23) are independently associated with cardiovascular events and mortality. Interventional strategies aiming to reduce levels of FGF-23 in HD patients are of particular interest. The purpose of the current study was to compare the impact of high-flux versus low-flux HD on circulating FGF-23 levels. 

Methods 
We conducted a post-hoc analysis of the MINOXIS study, including 127 dialysis patients randomized to low-flux (n = 62) and high-flux (n = 65) HD for 52 weeks. Patients with valid measures for FGF-23 investigated baseline and after 52 weeks were included. 

Results 
Compared to baseline, a significant increase in FGF-23 levels after one year of low-flux HD was observed (Delta plasma FGF-23: +4026 RU/ml; p < 0.001). In contrast, FGF-23 levels remained stable in the high flux group (Delta plasma FGF-23: +373 RU/ml, p = 0.70). The adjusted difference of the absolute change in FGF-23 levels between the two treatment groups was statistically significant (p < 0.01). 

Conclusions 
Over a period of 12 months, high-flux HD was associated with stable FGF-23 levels, whereas the low-flux HD group showed an increase of FGF-23. However, the implications of the different FGF 23 time-trends in patients on high flux dialysis, as compared to the control group, remain to be explored in specifically designed clinical trials.
KW  - chronic kidney disease
KW  - left ventricular hypertrophy
KW  - phosphate homeostasis
KW  - hemodialysis
KW  - mortality
KW  - fibroblast growth factor-23
KW  - mineral metabolism
KW  - parathyroid hormone
KW  - cardiovascular events
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148559
VL  - 10
IS  - 5
ER  - 
TY  - JOUR
A1  - Schneider, Andreas
A1  - Gutjahr-Lengsfeld, Lena
A1  - Ritz, Eberhard
A1  - Scharnagl, Hubert
A1  - Gelbrich, Götz
A1  - Pilz, Stefan
A1  - Macdougall, Iain C.
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients
JF  - Nephron Clinical Practice
N2  - Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.
KW  - dialysis
KW  - erythropoietin
KW  - diabetes
KW  - epidemiology
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511
SN  - 1660-2110
N1  - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL  - 128
IS  - 1-2
ER  - 
TY  - JOUR
A1  - Schmitz, Sophia M.
A1  - Storms, Sebastian
A1  - Koch, Alexander
A1  - Stier, Christine
A1  - Kroh, Andreas
A1  - Rheinwalt, Karl P.
A1  - Schipper, Sandra
A1  - Hamesch, Karim
A1  - Ulmer, Tom F.
A1  - Neumann, Ulf P.
A1  - Alizai, Patrick H.
T1  - Insulin resistance is the main characteristic of metabolically unhealthy obesity (MUO) associated with NASH in patients undergoing bariatric surgery
JF  - Biomedicines
N2  - (1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36–74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.
KW  - NAFLD
KW  - metabolically unhealthy obesity
KW  - obesity surgery
KW  - insulin resistance
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319213
SN  - 2227-9059
VL  - 11
IS  - 6
ER  - 
TY  - THES
A1  - Schlereth, Florian
T1  - Expression of the DHEA/DHEAS-Shuttle in cell lines and foetal tissue of human liver, adrenal and cartilage
T1  - Expression des DHEA/DHEAS-Shuttles in Zelllinien und fötalem Gewebe der menschlichen Leber, Nebenniere und Knorpel
N2  - DHEA is a precursor for the male and female sex hormones testosterone and estradiol, which are mainly secreted from the testes and the ovary, respectively. In addition, epidemiological studies showed that low serum levels of DHEA and DHEAS correlate with the incidence of autoimmune disease, cancer and cardiovascular disease. In vitro, DHEA and DHEAS influenced glucose metabolism in a favourable manner. However, positive effects of DHEA substitution were only significant adrenal insufficiency in women.
Steroid sulphotransferase 2A1 (SULT2A1) is the responsible enzyme for sulphonation of DHEA to DHEAS which is thought to be the inactive form of DHEA. In this role, SULT2A1 acts as a central regulator of steroid synthesis because sulphonation of DHEA withdraws the substrate for further downstream conversion. Another essential cofactor for sulphonation is PAPS, which is produced by the enzyme PAPS synthase (PAPSS) from ATP and anorganic sulphate. PAPSS exists in the different isoforms PAPSS1 and PAPSS2 and splice variants PAPSS2a and PAPSS2b. Changes in PAPSS activity are thought to influence sulphonation of DHEA significantly. However, neither regulation of PAPSS nor its influence on SULT2A1 have been investigated in human cell lines or humans.
The main goal of this thesis was to analyze the enzyme expression of the DHEA/DHEA shuttle, i.e. mRNA and protein of SULT2A1, PAPSS1 and PAPSS2, in various human cell lines. Furthermore, I investigated which cell line could serve as a suitable model for further research regarding regulation of SULT2A1, PAPSS1 and PAPSS2.
Here, I could show that the enzymes of the DHEA/DHEAS shuttle were expressed in the human adrenal cell line NCI-h295R as both mRNA and protein. In enzyme assays, I was able to prove conversion of DHEA to DHEAS as well as to different other steroids. However, applying Trilostane, a potent inhibitor of CYP3B, effectively directed conversion of DHEA to DHEAS. Using these findings, future experiments can investigate for example the influence of certain cytokines or endocrine disruptors on expression and activity of PAPSS1/2 and on sulphonation of DHEA. In particular, the relatively equal expression of PAPSS1 and PAPSS2 will enable us to do knock down experiments with siRNA to elucidate how the activity of one enzyme changes when the other one fails.
Sulphonation of DHEA by SULT2A1 is thought to happen in the cytoplasm or more precisely in the Golgi apparatus. However, experiments in transfected cells have shown both a cytoplasmatic and a nuclear localisation when both enzymes were expressed at the same time. Immunocytochemistry revealed the same results in the adrenal cell line NCI-h295R, where both enzymes were expressed strongly in the nucleus. The physiological role is not clear and requires further research. Presumably, sulphate is activated in the nucleus. However, one could also speculate that a shift of PAPSS to the nucleus could generate a reservoir, which can be activated by re-localisation to the cytoplasm when more PAPS is needed.
Expression of SULT2A1 in some foetal tissues has been investigated earlier. Whilst in adult human cartilage PAPSS1 is predominant, in newly born hamsters PAPSS2 is more abundantly expressed. The expression of PAPSS isoforms in highly sulphonating tissue has not been investigated in humans, so far. This work demonstrated a differential expression of SULT2A1, PAPSS1 and PAPSS2 in adult and foetal liver, adrenal and foetal cartilage tissue. In adult and foetal adrenal expression was similar. However, foetal and adult liver differed in the expression of SULT2A1, which was expressed much more in adult tissue. Most importantly, in foetal cartilage there was only a low expression of SULT2A1 and PAPS seems to mostly provided by PAPSS1, which was considerably higher expressed in cartilage than in other tissues. In contrast, PAPSS2 was mainly expressed in adult and foetal adrenal.
Additionally, we reported a case of a female patient who had been investigated for hyperandrogenism. Two mutations in the PAPSS2 gene had led to massively reduced serum levels of DHEAS. One heterozygous mutation in the domain of the APS kinase of the PAPSS2 protein leads to substitution of one amino acid at position 48 (T48R). In vitro experiments showed a residual activity of 6% for this mutation. A second mutation in the ATP sulphurylase domain of PAPSS2 was found. The introduction of thymidine instead of cytidine leads to a stop codon, which is presumed to truncate the protein at position 329 (R329X). In vitro, no residual activity was seen for this mutation. The lack of PAPS reduces sulphonation of DHEA but also sulphonation of proteoglycanes, which leads to skeletal abnormalities. The abundance of DHEA enables massive downstream conversion to androgens leading to clinical features of hyperandrogenism. Regarding the bone abnormalities, it is interesting and surprising that activity of PAPSS1 compensated to a great extent in cartilage but was not able to keep up a more considerable sulphonation of DHEA. Possibly, the subcellular localisation might play a role in this scenario.
N2  - DHEA ist eine Vorstufe der männlichen und weiblichen Sexualhormone Testosteron bzw. Oestradiol, welche hauptsächlich in den Testes bzw. Ovarien gebildet werden, aber auch in der Körperperipherie aus DHEA gebildet werden können. Desweiteren konnte in epidemiologischen Studien gezeigt werden, dass niedrige Spiegel von DHEA und DHEAS mit dem Auftreten von Autoimmunerkrankungen, Tumorerkrankungen und Herz-Kreislauf-Erkrankungen korrelieren. In vitro konnten beispielsweise günstige Effekte auf den Glukose-Stoffwechsel nachgewiesen werden. Allerdings konnte eine klinisch sinnvolle Gabe von DHEA nur im Rahmen einer Substitution bei Nebenniereninsuffizienz bei Frauen nachgewiesen werden. 
Verantwortlich für die Sulfonierung von DHEA ist vor allem die Steroid Sulfotransferase 2A1 (SULT2A1). DHEAS wird als inaktivierte Form von DHEA angesehen. SULT2A1 fungiert als zentraler Regulator der Steroid-Synthese, da durch Sulfonierung von DHEA zu DHEAS der weiteren Konversion das Substrat entzogen wird. Für diese Sulfonierung ist PAPS ein essentieller Kofaktor. Das Enzym PAPS-Synthase, von welchem unterschiedliche Splice-Varianten und Isoformen (PAPSS1 und PAPSS2a/b) vorliegen, stellen PAPS aus ATP und anorganischem Sulfat her. Eine Änderung der Aktivität der PAPS-Synthase kann vermutlich die Aktivität der DHEA Sulfotransferase maßgeblich beeinflussen. Weder die Regulation der PAPS Synthase noch deren Wirkung auf SULT2A1 wurden bisher in menschlichen Zelllinien oder beim Menschen untersucht.
Hauptziel dieser Arbeit war die Analyse der Enzymexpression des DHEA/DHEAS Shuttles (mRNA und Protein von SULT2A1, PAPSS1, PAPSS2) in verschiedenen humanen Zelllinien. Ferner wurde untersucht, ob eine der Zelllinien als Modell geeignet ist, die Regulation von SULT2A1 sowie insbesondere PAPSS1 und PAPSS2 in bestimmten pathophysiologischen Situationen zu untersuchen.
Hier konnte gezeigt werden, dass insbesondere die adrenale Zelllinie NCI-h295R die Enzyme des DHEA/DHEAS Shuttles sowohl als mRNA als auch als Protein exprimiert. Mittels Enzym-Assay konnte eine Konversion von DHEA zu DHEAS und verschiedenen weiteren Steroiden nachgewiesen werden. Eine Hemmung der CYP3B-abhängigen Konversion mittels Trilostane unterdrückt die Bildung von weiteren Androgenen in NCI-h295R Zellen allerdings effektiv, sodass DHEA größtenteils zu DHEAS konvertiert wurde. Hieraus ergeben sich vielfältige Möglichkeiten, z.B. den Einfluss von Zytokinen oder von endokrinen Disruptoren auf die Sulfonierung von DHEA und auf die Expression von PAPSS1/2 zu untersuchen. Insbesondere kann aufgrund der ähnlichen Expression von PAPSS1 und PAPSS2 in dieser Zelllinie untersucht werden, welche Auswirkung ein Ausschalten eines Enzyms mittels siRNA auf das jeweils andere hat.
Die Sulfonierung von DHEA durch SULT2A1 geschieht im Zytoplasma bzw. im Golgi Apparat. Allerdings haben Untersuchungen an transfizierten Zelllinien gezeigt, dass PAPSS1 bzw. PAPSS2 sowohl im Plasma als auch nukleär vorliegen können, wenn beide gleichzeitig exprimiert waren. Mittels Immunzytochemie konnten diese Ergebnisse auch in der Zelllinie NCI-h295R nachgewiesen werden. Beide Enzyme sind auch hier vor allem nukleär exprimiert. Der physiologische Hintergrund dieser Lokalisierung ist nicht geklärt und erfordert weitere Erforschung. Vermutlich erfolgt die Sulfat-Aktivierung also im Nukleus. Möglicherweise stellt die Verlagerung der Enzyme in den Nukleus aber auch eine Reserve der PAPS Synthese dar, die durch Rückverlagerung ins Zytoplasma dort rasch zusätzliches PAPS zur Verfügung stellen kann.
Die Expression der DHEA Sulfotransferase wurde bereits in einigen fötalen Geweben untersucht. Während in adultem Knorpel beim Menschen die Expression von PAPSS1 dominiert, wird z.B. im Knorpel von neugeborenen Hamstern vor allem PAPSS2 gebildet. Welche Isoform von PAPSS in welchen fötalen Geweben beim Menschen dominiert, wurde bislang nicht untersucht. In dieser Arbeit konnte mittels Realtime PCR eine differenzierte Expression von SULT2A1, PAPSS1 und PAPSS2 in fötalen Geweben nachgewiesen werden. In adultem und fötalem Gewebe der Nebennieren zeigte sich ein ähnliches Expressionsmuster. Während allerdings in der adulten Leber viel SULT2A1 vorhanden ist, konnte nur eine deutlich niedrigere Expression in fötalem Gewebe gezeigt werden. In fötalem Knorpel findet sich kaum SULT2A1. Dagegen wird in fötalem Knorpel deutlich mehr PAPSS1 gebildet als in adultem und fötalem Leber- bzw. Nebennieren-Gewebe. PAPSS2 ist sowohl beim Erwachsenen als auch beim Fötus hauptsächlich in der Nebenniere exprimiert. Auffällig ist eine relativ geringe Expression in der fötalen Leber.
Ergänzend wird in dieser Arbeit eine Patientin mit Hyperandrogenismus vorgestellt, bei der zwei Mutationen im PAPSS2 Gen zu einem massiv erniedrigten DHEAS Spiegel geführt hatten. Eine heterozygote Mutation liegt im Bereich der APS-Kinase von PAPSS2 und führt zum Austausch einer Aminosäure an Position 48 im PAPSS2a Protein (T48R). In vitro konnte für diese Mutation eine Reduktion der Aktivität auf 6% nachgewiesen werden. Eine zweite Mutation fand sich in der ATP Sulfurylase Domäne von PAPSS2. Durch einen Nukleosid-Austausch (Thymidin statt Cytidin) entsteht ein Stop-Codon, was vermutlich an Position 329 zum Abbruch des Proteins führt (R329X). In vitro konnte für diese Mutation (R329X) keine Aktivität nachgewiesen werden. Durch das Fehlen von PAPS ist die Sulfonierung von Proteoglykanen im Knorpel gestört, was zu Skelettveränderungen führt. Vor allem aber kommt es durch das Fehlen der Inaktivierung von DHEA zu DHEAS zu einem Überangebot an DHEA. Dieses wird zu aktiven Androgenen konvertiert und verursacht klinisch einen Hyperandrogenismus. Interessant und überraschend ist, dass die PAPSS1-Aktivität im Knorpel eine gewisse Sulfonierung der Proteoglykane ermöglicht. Im Gegensatz dazu trägt PAPSS1 offensichtlich kaum zur Sulfonierung von DHEA bei, da der DHEAS Spiegel extrem niedrig ist. Möglicherweise spielt hier auch die subzelluläre Lokalisation der PAPS Synthase eine entscheidende Rolle.
KW  - Dehydroepiandrosteron
KW  - Zelllinie
KW  - Phosphoadenosinphosphosulfat
KW  - DHEA
KW  - PAPSS2
KW  - adrenal
KW  - cell lines
KW  - DHEA-Sulfotransferase
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-102068
ER  - 
TY  - JOUR
A1  - Schick, Martin Alexander
A1  - Baar, Wolfgang
A1  - Bruno, Raphael Romano
A1  - Wollborn, Jakob
A1  - Held, Christopher
A1  - Schneider, Reinhard
A1  - Flemming, Sven
A1  - Schlegel, Nicolas
A1  - Roewer, Norbert
A1  - Neuhaus, Winfried
A1  - Wunder, Christian
T1  - Balanced hydroxyethylstarch (HES 130/0.4) impairs kidney function in-vivo without inflammation
JF  - PLoS One
N2  - Volume therapy is a standard procedure in daily perioperative care, and there is an ongoing discussion about the benefits of colloid resuscitation with hydroxyethylstarch (HES). In sepsis HES should be avoided due to a higher risk for acute kidney injury (AKI). Results of the usage of HES in patients without sepsis are controversial. Therefore we conducted an animal study to evaluate the impact of 6% HES 130/0.4 on kidney integrity with sepsis or under healthy conditions Sepsis was induced by standardized Colon Ascendens Stent Peritonitis (sCASP). sCASP-group as well as control group (C) remained untreated for 24 h. After 18 h sCASP+HES group (sCASP+VOL) and control+HES (C+VOL) received 50 ml/KG balanced 6% HES (VOL) 130/0.4 over 6h. After 24h kidney function was measured via Inulin- and PAH-Clearance in re-anesthetized rats, and serum urea, creatinine (crea), cystatin C and Neutrophil gelatinase-associated lipocalin (NGAL) as well as histopathology were analysed. In vitro human proximal tubule cells (PTC) were cultured +/- lipopolysaccharid (LPS) and with 0.1–4.0% VOL. Cell viability was measured with XTT-, cell toxicity with LDH-test. sCASP induced severe septic AKI demonstrated divergent results regarding renal function by clearance or creatinine measure focusing on VOL. Soleley HES (C+VOL) deteriorated renal function without sCASP. Histopathology revealed significantly derangements in all HES groups compared to control. In vitro LPS did not worsen the HES induced reduction of cell viability in PTC cells. For the first time, we demonstrated, that application of 50 ml/KG 6% HES 130/0.4 over 6 hours induced AKI without inflammation in vivo. Severity of sCASP induced septic AKI might be no longer susceptible to the way of volume expansion
KW  - colloids
KW  - kidneys
KW  - histopathology
KW  - blood
KW  - creatinine
KW  - sepsis
KW  - urine
KW  - inflammation
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126068
VL  - 10
IS  - 9
ER  - 
TY  - JOUR
A1  - Schick, Martin A.
A1  - Baar, Wolfgang
A1  - Flemming, Sven
A1  - Schlegel, Nicolas
A1  - Wollborn, Jakob
A1  - Held, Christopher
A1  - Schneider, Reinhard
A1  - Brock, Robert W.
A1  - Roewer, Norbert
A1  - Wunder, Christian
T1  - Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model
JF  - Intensive Care Medicine Experimental
N2  - Background
Up to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring.

Methods
Anaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days.

Results
All sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days.

Conclusions
The presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI.
KW  - CASP
KW  - animal model
KW  - acute kidney injury
KW  - sepsis
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126111
VL  - 2
IS  - 34
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Tryfonidou, Marianna A.
A1  - Weigand, Isabel
A1  - Grinwis, Guy C. M.
A1  - Broeckx, Bart
A1  - Herterich, Sabine
A1  - Allolio, Bruno
A1  - Deutschbein, Timo
A1  - Fassnacht, Martin
A1  - Meij, Björn P.
T1  - Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas
JF  - Plos One
N2  - Purpose

Cushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs.

Methods

Presence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas.

Results

None of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours.

Conclusions

Canine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed.
KW  - cytoplasmic staining
KW  - dogs
KW  - adenomas
KW  - pituitary gland
KW  - pituitary adenomas
KW  - nuclear staining
KW  - mutation
KW  - protein expression
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148020
VL  - 11
IS  - 12
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Ronchi, Cristina L.
A1  - Leich, Ellen
A1  - Henzel, Katharina
A1  - Rosenwald, Andreas
A1  - Allolio, Bruno
A1  - Fassnacht, Martin
T1  - Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence?
JF  - PLoS ONE
N2  - Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors.
KW  - adenomas
KW  - cancer diagnosis
KW  - cancer detection
KW  - carcinogenesis
KW  - carcinomas
KW  - chromosomes
KW  - genetic loci
KW  - malignant tumors
KW  - notch signaling
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97218
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Kunz, Meik
A1  - Weigand, Isabel
A1  - Deutschbein, Timo
A1  - Dandekar, Thomas
A1  - Fassnacht, Martin
T1  - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight
JF  - Cancers
N2  - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.
KW  - Cushing’s disease
KW  - pathogenesis
KW  - somatic mutations
KW  - deubiquitinases
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194
SN  - 2072-6694
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Dexneit, Thomas
A1  - Reichardt, Sybille D.
A1  - Michel, Kai D.
A1  - van den Brandt, Jens
A1  - Schmull, Sebastian
A1  - Kraus, Luitgard
A1  - Beyer, Melanie
A1  - Mlynski, Robert
A1  - Wortmann, Sebastian
A1  - Allolio, Bruno
A1  - Reichardt, Holger M.
A1  - Fassnacht, Martin
T1  - Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\)
JF  - PLoS One
N2  - Background: 

Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). 

Objective: 

We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice.
 
Methods: 

Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers. 

Results: 

Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5% vs 3.4 +/- 1.5%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5%; * p < 0.05). 

Conclusion: 

Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers.
KW  - Systemic-Lupus-Erythematosus
KW  - Immunological Self-Tolerance
KW  - Multiple-Sclerosis
KW  - Suppressive Function
KW  - Autoimmune-Diseases
KW  - FoxP3 Expression
KW  - Dendritic Cells
KW  - Immune-System
KW  - Sex-Hormones
KW  - Antigen 4
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140822
VL  - 6
IS  - 9
ER  - 
TY  - JOUR
A1  - Sbiera, Iuliu
A1  - Kircher, Stefan
A1  - Altieri, Barbara
A1  - Lenz, Kerstin
A1  - Hantel, Constanze
A1  - Fassnacht, Martin
A1  - Sbiera, Silviu
A1  - Kroiss, Matthias
T1  - Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications
JF  - Frontiers in Endocrinology
N2  - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.
KW  - normal adrenal glands
KW  - adrenocortical tumors
KW  - FGF-pathway
KW  - FGFR
KW  - RNA Expression
KW  - RNAScope
KW  - unsupervised clustering
KW  - patient survival
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251953
SN  - 1664-2392
VL  - 12
ER  - 
TY  - JOUR
A1  - Sbiera, Iuliu
A1  - Kircher, Stefan
A1  - Altieri, Barbara
A1  - Fassnacht, Martin
A1  - Kroiss, Matthias
A1  - Sbiera, Silviu
T1  - Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?
JF  - Cancers
N2  - A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.
KW  - adrenocortical tissues
KW  - EMT
KW  - epithelial markers
KW  - mesenchymal markers
KW  - recurrence-free survival
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236486
SN  - 2072-6694
VL  - 13
IS  - 7
ER  - 
TY  - THES
A1  - Sbiera, Iuliu
T1  - Possible role of epithelial to mesenchymal transition and its associated FGF/FGFR pathway in adrenocortical carcinoma
T1  - Mögliche Rolle des epithelial-mesenchymalen Transition und des damit verbundenen FGF/FGFR-Signalwegs beim Nebennierenrindenkarzinom
N2  - Recent studies have hinted to an involvement of epithelial to mesenchymal transition, a mechanism often associated with metastasis in epithelial cancers, in adrenocortical carcinoma. In addition, the knowledge about the FGF/FGFR pathway in pathogenesis of the adrenal gland, a pathway often associated with the epithelial to mesenchymal transition, is sparse and fragmented. 
	We assessed, in a large number of normal, benign and malignant adrenocortical tissues (a total of 181 different samples), the expression of canonical and novel epithelial and mesenchymal markers and compared it with their expression in typical epithelial and mesenchymal tissues.  In addition, we also quantified the expression of most members of the FGF/FGFR pathway in adrenocortical tissues and compared it against well-studied epithelial and mesenchymal tissues as well as between malignant and not malignant adrenocortical tissues, in order to assess the possible connection to epithelial to mesenchymal transition and find possible drug targets. Surprisingly, both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers (e.g. E-Cadhering or EpCAM) but strongly expressed mesenchymal markers (e.g. N-Cadherin or SLUG), suggesting a higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues, reminiscent of the adrenocortical origin from the intermediate mesoderm. Despite their ubiquitous expression in all adrenocortical tissues, mesenchymal markers had a variable expression in adrenocortical carcinoma, associating either directly or inversely with different clinical markers of tumor aggressiveness.  Lymph node infiltration was associated with high expression of SLUG (p = 0.04), and at the same time low expression of N-cadherin (p = 0.001), and the same pattern was observed for venous infiltration of tumoral tissue, Weiss score of tumor malignancy or Ki67 proliferation marker. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16 out of the 94 studied FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesenchymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by using two different quantification methods in both frozen and paraffin embedded tissue material. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis (High FGFR1 expression was associated with a shorter overall patient survival of 84 vs 148 months (HR=1.8, 95% CI: 1.01-3.25) as well as a shorter resection free survival of 25 vs 75 months ((HR=2.93, 95% CI: 1.25-6.84), while high FGFR4 was associated with a much shorter overall survival of 50 vs 155 months (HR=2.44, 95% CI: 1.41-4.22).
	 In conclusion, epithelial to mesenchymal transition does not seem to play a role in adrenocortical carcinoma tumor progression, and the FGF/FGFR pathway, even if it is probably not related to EMT, is nonetheless associated with tumor aggressiveness. Furthermore, quantification of FGF receptors may enable a stratification of adrenocortical carcinoma for the use of FGFR inhibitors in future clinical trials.
N2  - Jüngste Studien weisen auf eine Beteiligung der epithelial-mesenchymalen Transition, ein Mechanismus der oft mit Metastasen bei Epithelkarzinomen assoziiert ist, beim Nebennierenrindenkarzinom hin. Darüber hinaus gibt es kaum Kenntnisse über die Rolle des FGF/FGFR-Signalweges in der Pathogenese der Nebenniere, ein Signalweg, der oft mit der epithelial-mesenchymalen Transition in Verbindung gebracht wird.
	 Wir haben hier an einer großen Anzahl von normalen, gutartigen und bösartigen Nebennierenrindengewebeproben (insgesamt 181 Proben) die Expression von kanonischen und anderen epithelialen und mesenchymalen Markern untersucht und mit ihrer Expression in typischen epithelialen und mesenchymalen Geweben verglichen. Darüber hinaus, haben wir auch die Expression der meisten Mitglieder des FGF/FGFR-Signalwegs in Nebennierenrindengeweben quantifiziert und mit gut definierten epithelialen und mesenchymalen Geweben verglichen sowie zwischen bösartigen und nicht bösartigen Nebennierenrindengeweben, um die mögliche Verbindung zu epithelialer-mesenchymaler Transition zu finden und mögliche therapeutische Ziele zu identifizieren. Überraschenderweise konnte weder in normalem noch in neoplastischem Nebennierenrindengewebe die Expression von epithelialen Markern (z. B. E-Cadherin oder EpCAM) nachgewiesen werden. In beiden Geweben wurde aber eine starke Expression mesenchymaler Marker (z. B. N-Cadherin oder SLUG) gefunden, was auf eine größere Ähnlichkeit von Nebennierenrindengeweben zu mesenchymalen im Vergleich zu epithelialen Geweben hindeutet. Dies könnte mit der Entwicklung des Nebennierenrinden-gewebes aus dem intermediären Mesoderm erklärt werden. Trotz ihrer ubiquitären Expression in allen Nebennierenrindengeweben, hatten mesenchymale Marker eine variable Expression in Nebennierenrindenkarzinomen, die entweder direkt oder indirekt mit verschiedenen klinischen Markern der Tumoraggressivität assoziiert waren. Die Lymphknoteninfiltration war mit einer hohen Expression von SLUG (p = 0,04) und einer niedrigen Expression von N-Cadherin (p = 0,001) verbunden. Das gleiche Muster wurde für die venöse Infiltration von Tumorgewebe, dem Weiss-Score oder dem Ki67-Proliferationsmarker beobachtet. Signifikante Unterschiede in der Expression von 16 der 94 untersuchten Gene, die mit dem FGF-Rezeptorsignalweg in Verbindung stehen, wurden beim Vergleich von bösartigen und gutartigen Nebennierentumoren gefunden. Gene, die an der Gewebedifferenzierung und Metastasierung durch epithelial-mesenchymale Transition beteiligt sind, waren dabei am stärksten verändert. Die therapeutisch relevante FGF-Rezeptoren 1 und 4 waren bei malignen im Vergleich zu gutartigen Nebennierenrindentumoren 4,6- bzw. 6,0-fach hochreguliert. Dies wurde durch Verwendung zweier unabhängiger Quantifizierungsmethoden sowohl in gefrorenem als auch in paraffineingebettetem Gewebematerial bestätigt. Eine hohe Expression von FGFR1 und 4 war signifikant mit einer schlechteren Prognose verbunden. Eine hohe FGFR1-Expression war mit einem kürzeren Gesamtüberleben der Patienten von 84 vs. 148 Monaten (HR = 1,8; 95%CI: 1,01-3,25) sowie einem kürzeren resektions-freien Überleben von 25 vs. 75 Monaten (HR = 2,93; 95%CI: 1,25-6,84) verbunden, während eine höhere FGFR4-Expression mit einem viel kürzeren Gesamtüberleben von 50 vs. 155 Monaten assoziiert war (HR = 2,44; 95%CI: 1,41-4.22)). 
	Zusammenfassend lässt sich sagen, dass der Mechanismus der epithelial-mesenchymalen Transition keine Rolle bei der Tumorprogression des Nebennierenrindenkarzinoms zu spielen schein. Es konnte außerdem gezeigt werden, dass der FGF/FGFR-Signalweg, auch wenn er wahrscheinlich nicht mit der EMT zusammenhängt, mit der Aggressivität der Tumoren assoziiert. Die Untersuchung der Expression der FGF-Rezeptoren könnte für die Stratifizierung des Nebennierenrindenkarzinoms, zwecks Verwendung von FGFR-Inhibitoren in zukünftigen klinischen Studien, benutzt werden.
KW  - Nebennierenrindenkrebs
KW  - Fibroblastenwachstumsfaktor
KW  - adrenocortical carcinoma
KW  - epithelial to mesenchymal transition
KW  - fibroblast growth factors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-277454
ER  - 
TY  - JOUR
A1  - Salman Haider, Malik
A1  - Schreiner, Jochen
A1  - Kendl, Sabine
A1  - Kroiss, Matthias
A1  - Luxenhofer, Robert
T1  - A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models
JF  - Macromolecular Bioscience
N2  - Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
KW  - adrenocortical carcinoma
KW  - amphiphilic block copolymer
KW  - NCI-H295R
KW  - poly(2-oxazoline)
KW  - solubility enhancement
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206224
VL  - 20
IS  - 1
ER  - 
TY  - JOUR
A1  - Salinger, Tim
A1  - Hu, Kai
A1  - Liu, Dan
A1  - Taleh, Scharoch
A1  - Herrmann, Sebastian
A1  - Oder, Daniel
A1  - Gensler, Daniel
A1  - Müntze, Jonas
A1  - Ertl, Georg
A1  - Lorenz, Kristina
A1  - Frantz, Stefan
A1  - Weidemann, Frank
A1  - Nordbeck, Peter
T1  - Association between Comorbidities and Progression of Transvalvular Pressure Gradients in Patients with Moderate and Severe Aortic Valve Stenosis
JF  - Cardiology Research and Practice
N2  - Background. Fast progression of the transaortic mean gradient (P-mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. Methods. This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index >= 30 Kg/m(2), and history of smoking) were analyzed. Patients were divided into slow (P-mean < 5 mmHg/year) or fast (P-mean >= 5 mmHg/year) progression groups. Results. A total of 402 patients (mean age 78 +/- 9.4 years, 58% males) were included in the study. Mean follow-up duration was 3.4 +/- 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 +/- 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 +/- 1.5 vs 2.9 +/- 1.7; P = 0.036). Patients in slow progression group had more often coronary heart disease (49.2% vs 33.6%; P = 0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 +/- 32.6 mg/dl vs 110.8 +/- 36.6 mg/dl; P = 0.005). Conclusion. These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.
KW  - Valvular heart-desease
KW  - Prognostic impact
KW  - Risk-factors
KW  - Chronic heart-failure
KW  - Prevalence
KW  - mild
KW  - statins
KW  - therapy
KW  - mortality
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227291
ER  - 
TY  - JOUR
A1  - Salinger, Tim
A1  - Hu, Kai
A1  - Liu, Dan
A1  - Herrmann, Sebastian
A1  - Lorenz, Kristina
A1  - Ertl, Georg
A1  - Nordbeck, Peter
T1  - Cardiac amyloidosis mimicking severe aortic valve stenosis - a case report demonstrating diagnostic pitfalls and role of dobutamine stress echocardiography
JF  - BMC Cardiovascular Disorders
N2  - Background
Aortic valve stenosis is a common finding diagnosed with high sensitivity in transthoracic echocardiography, but the examiner often finds himself confronted with uncertain results in patients with moderate pressure gradients and concomitant systolic heart failure. While patients with true-severe low-gradient aortic valve stenosis with either reduced or preserved left ventricular systolic function are primarily candidates for valve replacement, there is a relevant proportion of patients with pseudo-severe aortic valve stenosis anticipated not to benefit but actually rather deteriorate by interventional therapy or surgery.

Case presentation
In this article we present a case report of a male patient with pseudo-severe aortic valve stenosis due to cardiac amyloidosis highlighting the diagnostic schedule. The patient underwent stress echocardiography because of discrepant findings in transthoracic echocardiography and cardiac catheterization regarding the severity of aortic valve stenosis. After evaluation of the results, it became clear that he had a need for optimum heart failure medication and implantation of a cardiac resynchronization therapy defibrillator.

Conclusion
Due to the pitfalls in conventional as well as invasive diagnostics at rest, Stress echocardiography should be considered part of the standard optimum diagnostic spectrum in all unclear or borderline cases in order to confirm the correct diagnosis and constitute optimal therapy.
KW  - aortic valve stenosis (AS)
KW  - case report
KW  - pseudo-severe AS
KW  - low-gradient AS
KW  - dobutamine stress echocardiography
KW  - cardiac amyloidosis
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171109
VL  - 17
IS  - 86
ER  - 
TY  - JOUR
A1  - Sailer, Clara Odilia
A1  - Wiedemann, Sophia Julia
A1  - Strauss, Konrad
A1  - Schnyder, Ingeborg
A1  - Fenske, Wiebke Kristin
A1  - Christ-Crain, Mirjam
T1  - Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers
JF  - Endocrine Connections
N2  - Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.
KW  - TNF-alpha
KW  - interleukin-8
KW  - interleukin-6
KW  - copeptin
KW  - hyperosmolality
KW  - Hyperosmotic Stress
KW  - Interleukin-6
KW  - Expression
KW  - Protein
KW  - Neurons
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227204
VL  - 8
IS  - 9
ER  - 
TY  - JOUR
A1  - Sahiti, Floran
A1  - Morbach, Caroline
A1  - Cejka, Vladimir
A1  - Tiffe, Theresa
A1  - Wagner, Martin
A1  - Eichner, Felizitas A.
A1  - Gelbrich, Götz
A1  - Heuschmann, Peter U.
A1  - Störk, Stefan
T1  - Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study
JF  - Journal of Human Hypertension
N2  - Myocardial work is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops, and has been validated against invasively derived pressure-volume measurements. Myocardial work is described by its components (global constructive work [GCW], global wasted work [GWW]) and indices (global work index [GWI], global work efficiency [GWE]). Applying this innovative concept, we characterized the prevalence and severity of subclinical left ventricular compromise in the general population and estimated its association with cardiovascular (CV) risk factors. Within the Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study we comprehensively phenotyped a representative sample of the population of Würzburg, Germany, aged 30-79 years. Indices of myocardial work were determined in 1929 individuals (49.3% female, mean age 54 ± 12 years). In multivariable analysis, hypertension was associated with a mild increase in GCW, but a profound increase in GWW, resulting in higher GWI and lower GWE. All other CV risk factors were associated with lower GCW and GWI, but not with GWW. The association of hypertension and obesity with GWI was stronger in women. We conclude that traditional CV risk factors impact selectively and gender-specifically on left ventricular myocardial performance, independent of systolic blood pressure. Quantifying active systolic and diastolic compromise by derivation of myocardial work advances our understanding of pathophysiological processes in health and cardiac disease.
KW  - myocardial work
KW  - left ventricular performance
KW  - cardiovascular risk factors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271770
SN  - 1476-5527
VL  - 36
IS  - 3
ER  - 
TY  - JOUR
A1  - Sahiti, Floran
A1  - Morbach, Caroline
A1  - Cejka, Vladimir
A1  - Albert, Judith
A1  - Eichner, Felizitas A.
A1  - Gelbrich, Götz
A1  - Heuschmann, Peter U.
A1  - Störk, Stefan
T1  - Left Ventricular Remodeling and Myocardial Work: Results From the Population-Based STAAB Cohort Study
JF  - Frontiers in Cardiovascular Medicine
N2  - Introduction: Left ventricular (LV) dilatation and LV hypertrophy are acknowledged precursors of myocardial dysfunction and ultimately of heart failure, but the implications of abnormal LV geometry on myocardial function are not well-understood. Non-invasive LV myocardial work (MyW) assessment based on echocardiography-derived pressure-strain loops offers the opportunity to study detailed myocardial function in larger cohorts. We aimed to assess the relationship of LV geometry with MyW indices in general population free from heart failure.
Methods and Results: We report cross-sectional baseline data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of the general population of Würzburg, Germany, aged 30–79 years. MyW analysis was performed in 1,926 individuals who were in sinus rhythm and free from valvular disease (49.3% female, 54 ± 12 years). In multivariable regression, higher LV volume was associated with higher global wasted work (GWW) (+0.5 mmHg% per mL/m\(^2\), p < 0.001) and lower global work efficiency (GWE) (−0.02% per mL/m\(^2\), p < 0.01), while higher LV mass was associated with higher GWW (+0.45 mmHg% per g/m\(^2\), p < 0.001) and global constructive work (GCW) (+2.05 mmHg% per g/m\(^2\), p < 0.01) and lower GWE (−0.015% per g/m\(^2\), p < 0.001). This was dominated by the blood pressure level and also observed in participants with normal LV geometry and concomitant hypertension.
Conclusion: Abnormal LV geometric profiles were associated with a higher amount of wasted work, which translated into reduced work efficiency. The pattern of a disproportionate increase in GWW with higher LV mass might be an early sign of hypertensive heart disease.
KW  - myocardial work
KW  - myocardial work efficiency
KW  - left ventricular geometry
KW  - left ventricular mass
KW  - LV dilatation
KW  - left ventricular geometric abnormality
KW  - left ventricular remodeling
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240480
SN  - 2297-055X
VL  - 8
ER  - 
TY  - JOUR
A1  - Sack, Stefan
A1  - Wende, Christian Michael
A1  - Nägele, Herbert
A1  - Katz, Amos
A1  - Bauer, Wolfgang Rudolf
A1  - Barr, Craig Scott
A1  - Malinowski, Klaus
A1  - Schwacke, Harald
A1  - Leyva, Francisco
A1  - Proff, Jochen
A1  - Berdyshev, Sergey
A1  - Paul, Vincent
T1  - Potential value of automated daily screening of cardiac resynchronization therapy defibrillator diagnostics for prediction of major cardiovascular events: results from Home-CARE (Home Monitoring in Cardiac Resynchronization Therapy) study
JF  - European Journal of Heart Failure
N2  - Aim

To investigate whether diagnostic data from implanted cardiac resynchronization therapy defibrillators (CRT-Ds) retrieved automatically at 24 h intervals via a Home Monitoring function can enable dynamic prediction of cardiovascular hospitalization and death.

Methods and results

Three hundred and seventy-seven heart failure patients received CRT-Ds with Home Monitoring option. Data on all deaths and hospitalizations due to cardiovascular reasons and Home Monitoring data were collected prospectively during 1-year follow-up to develop a predictive algorithm with a predefined specificity of 99.5%. Seven parameters were included in the algorithm: mean heart rate over 24 h, heart rate at rest, patient activity, frequency of ventricular extrasystoles, atrial–atrial intervals (heart rate variability), right ventricular pacing impedance, and painless shock impedance. The algorithm was developed using a 25-day monitoring window ending 3 days before hospitalization or death. While the retrospective sensitivities of the individual parameters ranged from 23.6 to 50.0%, the combination of all parameters was 65.4% sensitive in detecting cardiovascular hospitalizations and deaths with 99.5% specificity (corresponding to 1.83 false-positive detections per patient-year of follow-up). The estimated relative risk of an event was 7.15-fold higher after a positive predictor finding than after a negative predictor finding.

Conclusion

We developed an automated algorithm for dynamic prediction of cardiovascular events in patients treated with CRT-D devices capable of daily transmission of their diagnostic data via Home Monitoring. This tool may increase patients’ quality of life and reduce morbidity, mortality, and health economic burden, it now warrants prospective studies.
KW  - Remote device monitoring
KW  - Multiparameter predictor
KW  - Cardiovascular hospitalizations
KW  - Heart failure
KW  - Home monitoring
KW  - Cardiac resynchronization therapy defibrillator
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141709
VL  - 13
IS  - 9
ER  - 
TY  - JOUR
A1  - Rücker, Viktoria
A1  - Keil, Ulrich
A1  - Fitzgerald, Anthony P
A1  - Malzahn, Uwe
A1  - Prugger, Christof
A1  - Ertl, Georg
A1  - Heuschmann, Peter U
A1  - Neuhauser, Hannelore
T1  - Predicting 10-Year Risk of Fatal Cardiovascular Disease in Germany: An Update Based on the SCORE-Deutschland Risk Charts
JF  - PLoS ONE
N2  - Estimation of absolute risk of cardiovascular disease (CVD), preferably with population-specific risk charts, has become a cornerstone of CVD primary prevention. Regular recalibration of risk charts may be necessary due to decreasing CVD rates and CVD risk factor levels. The SCORE risk charts for fatal CVD risk assessment were first calibrated for Germany with 1998 risk factor level data and 1999 mortality statistics. We present an update of these risk charts based on the SCORE methodology including estimates of relative risks from SCORE, risk factor levels from the German Health Interview and Examination Survey for Adults 2008–11 (DEGS1) and official mortality statistics from 2012. Competing risks methods were applied and estimates were independently validated. Updated risk charts were calculated based on cholesterol, smoking, systolic blood pressure risk factor levels, sex and 5-year age-groups. The absolute 10-year risk estimates of fatal CVD were lower according to the updated risk charts compared to the first calibration for Germany. In a nationwide sample of 3062 adults aged 40–65 years free of major CVD from DEGS1, the mean 10-year risk of fatal CVD estimated by the updated charts was lower by 29% and the estimated proportion of high risk people (10-year risk > = 5%) by 50% compared to the older risk charts. This recalibration shows a need for regular updates of risk charts according to changes in mortality and risk factor levels in order to sustain the identification of people with a high CVD risk.
KW  - fatal cardiovascular disease
KW  - SCORE
KW  - Germany
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166804
VL  - 11
IS  - 9
ER  - 
TY  - JOUR
A1  - Rothe, Hansjörg
A1  - Brandenburg, Vincent
A1  - Haun, Margot
A1  - Kollerits, Barbara
A1  - Kronenberg, Florian
A1  - Ketteler, Markus
A1  - Wanner, Christoph
T1  - Ecto-5 ' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients - Data from the German Calciphylaxis Registry
JF  - PLoS One
N2  - Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before.

Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex.

Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA.

Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
KW  - single nucleotide polymorphisms
KW  - calcification
KW  - medical dialysis
KW  - genotyping
KW  - cancer risk factors
KW  - vitamin D
KW  - chronic kidney disease
KW  - melanoma
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171817
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Rosenstock, Julio
A1  - Perkovic, Vlado
A1  - Alexander, John H.
A1  - Cooper, Mark E.
A1  - Marx, Nikolaus
A1  - Pencina, Michael J.
A1  - Toto, Robert D.
A1  - Wanner, Christoph
A1  - Zinman, Bernard
A1  - Baanstra, David
A1  - Pfarr, Egon
A1  - Mattheus, Michaela
A1  - Broedl, Uli C.
A1  - Woerle, Hans-Jürgen
A1  - George, Jyothis T.
A1  - von Eynatten, Maximilian
A1  - McGuire, Darren K.
T1  - Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin - (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk
JF  - Cardiovascular Diabetology
N2  - Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. 

Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. 

Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. 

Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.
KW  - Diabetes mellitus
KW  - type 2
KW  - Cardiovascular diseases
KW  - Diabetic nephropathies
KW  - Dipeptidyl-peptidase IV inhibitors
KW  - Linagliptin
KW  - Clinical trial
KW  - phase IV
KW  - Research design
KW  - Treatment outcome
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226996
VL  - 17
ER  - 
TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Sbiera, Silviu
A1  - Volante, Marco
A1  - Steinhauer, Sonja
A1  - Scott-Wild, Vanessa
A1  - Altieri, Barbara
A1  - Kroiss, Matthias
A1  - Bala, Margarita
A1  - Papotti, Mauro
A1  - Deutschbein, Timo
A1  - Terzolo, Massimo
A1  - Fassnacht, Martin
A1  - Allolio, Bruno
T1  - CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma
N2  - Background

Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins.

Objective

To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC.

Material and Methods

CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples).

Results

CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01).

Conclusion

CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment.
KW  - CYP2W1
KW  - cancer treatment
KW  - adrenal glands
KW  - carcinomas
KW  - drug therapy
KW  - hormones
KW  - immune response
KW  - immunohistochemistry techniques
KW  - surgical oncology
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113096
ER  - 
TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Leich, Ellen
A1  - Sbiera, Silviu
A1  - Weismann, Dirk
A1  - Rosenwald, Andreas
A1  - Allolio, Bruno
A1  - Fassnacht, Martin
T1  - Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways
JF  - Neoplasia
N2  - The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors.
KW  - kinase
KW  - comparative genomic hybridization
KW  - high-resolution analysis
KW  - Cushings syndrome
KW  - neutral loss
KW  - tumors
KW  - serum
KW  - expression
KW  - carcinoma
KW  - catenin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134953
VL  - 14
IS  - 3
ER  - 
TY  - JOUR
A1  - Ronchi, Cristina L.
A1  - Altieri, Barbara
T1  - Special issue: Present and future of personalised medicine for endocrine cancers
JF  - Journal of Personalized Medicine
N2  - No abstract available
KW  - personalised medicine
KW  - endocrine cancer
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270705
SN  - 2075-4426
VL  - 12
IS  - 5
ER  - 
TY  - JOUR
A1  - Rogowski-Lehmann, Natalie
A1  - Geroula, Aikaterini
A1  - Prejbisz, Aleksander
A1  - Timmers, Henri J. L. M.
A1  - Megerle, Felix
A1  - Robledo, Mercedes
A1  - Fassnacht, Martin
A1  - Fliedner, Stephanie M. J.
A1  - Reincke, Martin
A1  - Stell, Anthony
A1  - Januszewicz, Andrzej
A1  - Lenders, Jacques W. M.
A1  - Eisenhofer, Graeme
A1  - Beuschlein, Felix
T1  - Missed clinical clues in patients with pheochromocytoma/paraganglioma discovered by imaging
JF  - Endocrine Connections
N2  - Background: Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure. Objective: To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL). Design: Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P<0.001), found to have larger tumors (P=0.003) and higher metanephrine and normetanephrine levels at diagnosis (P=0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P< 0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed. Precis: Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.
KW  - pheochromocytoma
KW  - paraganglioma
KW  - imaging
KW  - signs and symptoms
KW  - prospective
KW  - Biochemical-Diagnosis
KW  - Plasma
KW  - MASS
KW  - Normetanephrine
KW  - Metanephrine
KW  - Paraganglioma
KW  - Society
KW  - Utility
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226481
VL  - 7
IS  - 11
ER  - 
TY  - JOUR
A1  - Rodriguez-Rozada, Silvia
A1  - Frantz, Stefan
A1  - Tovote, Philip
T1  - Cardiac optogenetics: regulating brain states via the heart
JF  - Signal Transduction and Targeted Therapy
N2  - No abstract available.
KW  - cardiology
KW  - neurology
KW  - neuroscience
KW  - systems biology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357625
VL  - 8
ER  - 
TY  - JOUR
A1  - Riedmeier, Maria
A1  - Decarolis, Boris
A1  - Haubitz, Imme
A1  - Müller, Sophie
A1  - Uttinger, Konstantin
A1  - Börner, Kevin
A1  - Reibetanz, Joachim
A1  - Wiegering, Armin
A1  - Härtel, Christoph
A1  - Schlegel, Paul-Gerhardt
A1  - Fassnacht, Martin
A1  - Wiegering, Verena
T1  - Adrenocortical carcinoma in childhood: a systematic review
JF  - Cancers
N2  - Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89%). Most patients were diagnosed with localized disease, whereas 23% had metastasis at primary diagnosis. Only 72% of the patients achieved complete resection. In 334 children (23%), recurrent disease was reported: 81% — local recurrence, 19% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.
KW  - pediatric adrenocortical cancer
KW  - pediatric adrenocortical adenoma
KW  - pediatric adrenocortical tumor
KW  - prognostic factors
KW  - therapy
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248507
SN  - 2072-6694
VL  - 13
IS  - 21
ER  - 
TY  - JOUR
A1  - Riedl, Katharina A.
A1  - Kampf, Thomas
A1  - Herold, Volker
A1  - Behr, Volker C.
A1  - Bauer, Wolfgang R.
T1  - Wall shear stress analysis using 17.6 Tesla MRI: A longitudinal study in ApoE\(^{-/-}\)mice with histological analysis
JF  - PLoS One
N2  - This longitudinal study was performed to evaluate the feasibility of detecting the interaction between wall shear stress (WSS) and plaque development. 20 ApoE\(^{-/-}\)mice were separated in 12 mice with Western Diet and 8 mice with Chow Diet. Magnetic resonance (MR) scans at 17.6 Tesla and histological analysis were performed after one week, eight and twelve weeks. Allin vivoMR measurements were acquired using a flow sensitive phase contrast method for determining vectorial flow. Histological sections were stained with Hematoxylin and Eosin, Elastica van Gieson and CD68 staining. Data analysis was performed using Ensight and a Matlab-based "Flow Tool". The body weight of ApoE\(^{-/-}\)mice increased significantly over 12 weeks. WSS values increased in the Western Diet group over the time period; in contrast, in the Chow Diet group the values decreased from the first to the second measurement point. Western Diet mice showed small plaque formations with elastin fragmentations after 8 weeks and big plaque formations after 12 weeks; Chow Diet mice showed a few elastin fragmentations after 8 weeks and small plaque formations after 12 weeks. Favored by high-fat diet, plaque formation results in higher values of WSS. With wall shear stress being a known predictor for atherosclerotic plaque development, ultra highfield MRI can serve as a tool for studying the causes and beginnings of atherosclerosis.
KW  - phase-contrast MRI
KW  - flow patterns
KW  - blood flow
KW  - apolipoprotein-E
KW  - atheriosclerosis
KW  - mouse
KW  - mice
KW  - quantification
KW  - association
KW  - lesions
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229318
VL  - 15
IS  - 8
ER  - 
TY  - JOUR
A1  - Rickert, V.
A1  - Wagenhäuser, L.
A1  - Nordbeck, P.
A1  - Wanner, C.
A1  - Sommer, C.
A1  - Rost, S.
A1  - Üçeyler, N.
T1  - Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure
JF  - Journal of Internal Medicine
N2  - Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.

Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.

Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).

Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
KW  - Fabry disease
KW  - Fabry genotype
KW  - Fabry phenotype
KW  - lyso‐Gb3
KW  - α‐GalA 3D‐structure
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218125
VL  - 288
IS  - 5
SP  - 593
EP  - 604
ER  -