TY  - JOUR
A1  - Pelz, Joerg O. W.
A1  - Chua, Terence C.
A1  - Esquivel, Jesus
A1  - Stojadinovic, Alexander
A1  - Doerfer, Joerg
A1  - Morris, David L.
A1  - Maeder, Uwe
A1  - Germer, Christoph-Thomas
A1  - Kerscher, Alexander G.
T1  - Evaluation of Best Supportive Care and Systemic Chemotherapy as Treatment Stratified according to the retrospective Peritoneal Surface Disease Severity Score (PSDSS) for Peritoneal Carcinomatosis of Colorectal Origin
N2  - Background: We evaluate the long-term survival of patients with peritoneal carcinomatosis (PC) treated with systemic chemotherapy regimens, and the impact of the of the retrospective peritoneal disease severity score (PSDSS) on outcomes. Methods: One hundred sixty-seven consecutive patients treated with PC from colorectal cancer between years 1987-2006 were identified from a prospective institutional database. These patients either received no chemotherapy, 5-FU/Leucovorin or Oxaliplatin/Irinotecan-based chemotherapy. Stratification was made according to the retrospective PSDSS that classifies PC patients based on clinically relevant factors. Survival analysis was performed using the Kaplan-Meier method and comparison with the log-rank test. Results: Median survival was 5 months (95% CI, 3-7 months) for patients who had no chemotherapy, 11 months (95% CI, 6-9 months) for patients treated with 5 FU/LV, and 12 months (95% CI, 4-20 months) for patients treated with Oxaliplatin/Irinotecan-based chemotherapy. Survival differed between patients treated with chemotherapy compared to those patients who did not receive chemotherapy (p = 0.026). PSDSS staging was identified as an independent predictor for survival on multivariate analysis [RR 2.8 (95%CI 1.5-5.4); p < 0.001]. Conclusion: A trend towards improved outcomes is demonstrated from treatment of patients with PC from colorectal cancer using modern systemic chemotherapy. The PSDSS appears to be a useful tool in patient selection and prognostication in PC of colorectal origin.
KW  - Krebs <Medizin>
KW  - peritoneal carcinomatosis
KW  - colorectal cancer
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67875
ER  - 
TY  - JOUR
A1  - Förster, Frank
A1  - Beisser, Daniela
A1  - Grohme, Markus A.
A1  - Liang, Chunguang
A1  - Mali, Brahim
A1  - Siegl, Alexander Matthias
A1  - Engelmann, Julia C.
A1  - Shkumatov, Alexander V.
A1  - Schokraie, Elham
A1  - Müller, Tobias
A1  - Schnölzer, Martina
A1  - Schill, Ralph O.
A1  - Frohme, Marcus
A1  - Dandekar, Thomas
T1  - Transcriptome analysis in tardigrade species reveals specific molecular pathways for stress adaptations
JF  - Bioinformatics and biology insights
N2  - Tardigrades have unique stress-adaptations that allow them to survive extremes of cold, heat, radiation and vacuum. To study this, encoded protein clusters and pathways from an ongoing transcriptome study on the tardigrade \(Milnesium\) \(tardigradum\) were analyzed using bioinformatics tools and compared to expressed sequence tags (ESTs) from \(Hypsibius\) \(dujardini\), revealing major pathways involved in resistance against extreme environmental conditions. ESTs are available on the Tardigrade Workbench along with software and databank updates. Our analysis reveals that RNA stability motifs for \(M.\) \(tardigradum\) are different from typical motifs known from higher animals. \(M.\) \(tardigradum\) and \(H.\) \(dujardini\) protein clusters and conserved domains imply metabolic storage pathways for glycogen, glycolipids and specific secondary metabolism as well as stress response pathways (including heat shock proteins, bmh2, and specific repair pathways). Redox-, DNA-, stress- and protein protection pathways complement specific repair capabilities to achieve the strong robustness of \(M.\) \(tardigradum\). These pathways are partly conserved in other animals and their manipulation could boost stress adaptation even in human cells. However, the unique combination of resistance and repair pathways make tardigrades and \(M.\) \(tardigradum\) in particular so highly stress resistant.
KW  - RNA
KW  - expressed sequence tag
KW  - cluster
KW  - protein familiy
KW  - adaption
KW  - tardigrada
KW  - transcriptome
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123089
N1  - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
VL  - 6
ER  - 
TY  - JOUR
A1  - Klammert, Uwe
A1  - Müller, Thomas D.
A1  - Hellmann, Tina V.
A1  - Wuerzler, Kristian K.
A1  - Kotzsch, Alexander
A1  - Schliermann, Anna
A1  - Schmitz, Werner
A1  - Kuebler, Alexander C.
A1  - Sebald, Walter
A1  - Nickel, Joachim
T1  - GDF-5 can act as a context-dependent BMP-2 antagonist
JF  - BMC Biology
N2  - Background
Bone morphogenetic protein (BMP)-2 and growth and differentiation factor (GDF)-5 are two related transforming growth factor (TGF)-β family members with important functions in embryonic development and tissue homeostasis. BMP-2 is best known for its osteoinductive properties whereas GDF-5—as evident from its alternative name, cartilage derived morphogenetic protein 1—plays an important role in the formation of cartilage. In spite of these differences both factors signal by binding to the same subset of BMP receptors, raising the question how these different functionalities are generated. The largest difference in receptor binding is observed in the interaction with the type I receptor BMPR-IA. GDF-5, in contrast to BMP-2, shows preferential binding to the isoform BMPR-IB, which is abrogated by a single amino acid (A57R) substitution. The resulting variant, GDF-5 R57A, represents a “BMP-2 mimic” with respect to BMP receptor binding. In this study we thus wanted to analyze whether the two growth factors can induce distinct signals via an identically composed receptor.

Results
Unexpectedly and dependent on the cellular context, GDF-5 R57A showed clear differences in its activity compared to BMP-2. In ATDC-5 cells, both ligands induced alkaline phosphatase (ALP) expression with similar potency. But in C2C12 cells, the BMP-2 mimic GDF-5 R57A (and also wild-type GDF-5) clearly antagonized BMP-2-mediated ALP expression, despite signaling in both cell lines occurring solely via BMPR-IA. The BMP-2- antagonizing properties of GDF-5 and GDF-5 R57A could also be observed in vivo when implanting BMP-2 and either one of the two GDF-5 ligands simultaneously at heterotopic sites.

Conclusions
Although comparison of the crystal structures of the GDF-5 R57A:BMPR-IAEC- and BMP-2:BMPR-IAEC complex revealed small ligand-specific differences, these cannot account for the different signaling characteristics because the complexes seem identical in both differently reacting cell lines. We thus predict an additional component, most likely a not yet identified GDF-5-specific co-receptor, which alters the output of the signaling complexes. Hence the presence or absence of this component then switches GDF-5′s signaling capabilities to act either similar to BMP-2 or as a BMP-2 antagonist. These findings might shed new light on the role of GDF-5, e.g., in cartilage maintenance and/or limb development in that it might act as an inhibitor of signaling events initiated by other BMPs.
KW  - growth and differentiation factor 5
KW  - ligand-receptor complex
KW  - crystal structure
KW  - antagonist
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-125550
VL  - 13
IS  - 77
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  - Reimer, Stanislaus
A1  - Lock, Johan F.
A1  - Flemming, Sven
A1  - Weich, Alexander
A1  - Widder, Anna
A1  - Plaßmeier, Lars
A1  - Döring, Anna
A1  - Hering, Ilona
A1  - Hankir, Mohammed K.
A1  - Meining, Alexander
A1  - Germer, Christoph-Thomas
A1  - Groneberg, Kaja
A1  - Seyfried, Florian
T1  - Endoscopic management of large leakages after upper gastrointestinal surgery
JF  - Frontiers in Surgery
N2  - Background
Endoscopic vacuum therapy (EVT) is an evidence-based option to treat anastomotic leakages of the upper gastrointestinal (GI) tract, but the technical challenges and clinical outcomes of patients with large defects remain poorly described.

Methods
All patients with leakages of the upper GI tract that were treated with endoscopic negative pressure therapy at our institution from 2012–2021 were analyzed. Patients with large defects (>30 mm) as an indicator of complex treatment were compared to patients with smaller defects (control group).

Results
Ninety-two patients with postoperative anastomotic or staplerline leakages were identified, of whom 20 (21.7%) had large defects. Compared to the control group, these patients required prolonged therapy (42 vs. 14 days, p < 0.001) and hospital stay (63 vs. 26 days, p < 0.001) and developed significantly more septic complications (40 vs. 17.6%, p = 0.027.) which often necessitated additional endoscopic and/or surgical/interventional treatments (45 vs. 17.4%, p = 0.007.) Nevertheless, a resolution of leakages was achieved in 80% of patients with large defects, which was similar compared to the control group (p = 0.42). Multiple leakages, especially on the opposite side, along with other local unfavorable conditions, such as foreign material mass, limited access to the defect or extensive necrosis occurred significantly more often in cases with large defects (p < 0.001).

Conclusions
Overall, our study confirms that EVT for leakages even from large defects of the upper GI tract is feasible in most cases but comes with significant technical challenges.
KW  - anastomotic leakage
KW  - endoluminal
KW  - vacuum-assisted closure
KW  - negative pressure
KW  - endoscopic
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274044
SN  - 2296-875X
VL  - 9
ER  - 
TY  - JOUR
A1  - Hautmann, Christopher
A1  - Döpfner, Manfred
A1  - Katzmann, Josepha
A1  - Schürmann, Stephanie
A1  - Wolff Metternich-Kaizman, Tanja
A1  - Jaite, Charlotte
A1  - Kappel, Viola
A1  - Geissler, Julia
A1  - Warnke, Andreas
A1  - Jacob, Christian
A1  - Hennighausen, Klaus
A1  - Haack-Dees, Barbara
A1  - Schneider-Momm, Katja
A1  - Philipsen, Alexandra
A1  - Matthies, Swantje
A1  - Rösler, Michael
A1  - Retz, Wolfgang
A1  - Gontard, Alexander von
A1  - Sobanski, Esther
A1  - Alm, Barbara
A1  - Hohmann, Sarah
A1  - Häge, Alexander
A1  - Poustka, Luise
A1  - Colla, Michael
A1  - Gentschow, Laura
A1  - Freitag, Christine M.
A1  - Becker, Katja
A1  - Jans, Thomas
T1  - Sequential treatment of ADHD in mother and child (AIMAC study): importance of the treatment phases for intervention success in a randomized trial
JF  - BMC Psychiatry
N2  - Background
The efficacy of parent-child training (PCT) regarding child symptoms may be reduced if the mother has attention-deficit/hyperactivity disorder (ADHD). The AIMAC study (ADHD in Mothers and Children) aimed to compensate for the deteriorating effect of parental psychopathology by treating the mother (Step 1) before the beginning of PCT (Step 2). This secondary analysis was particularly concerned with the additional effect of the Step 2 PCT on child symptoms after the Step 1 treatment.

Methods
The analysis included 143 mothers and children (aged 6–12 years) both diagnosed with ADHD. The study design was a two-stage, two-arm parallel group trial (Step 1 treatment group [TG]: intensive treatment of the mother including psychotherapy and pharmacotherapy; Step 1 control group [CG]: supportive counseling only for mother; Step 2 TG and CG: PCT). Single- and multi-group analyses with piecewise linear latent growth curve models were applied to test for the effects of group and phase. Child symptoms (e.g., ADHD symptoms, disruptive behavior) were rated by three informants (blinded clinician, mother, teacher).

Results
Children in the TG showed a stronger improvement of their disruptive behavior as rated by mothers than those in the CG during Step 1 (Step 1: TG vs. CG). In the CG, according to reports of the blinded clinician and the mother, the reduction of children’s disruptive behavior was stronger during Step 2 than during Step 1 (CG: Step 1 vs. Step 2). In the TG, improvement of child outcome did not differ across treatment steps (TG: Step 1 vs. Step 2).

Conclusions
Intensive treatment of the mother including pharmacotherapy and psychotherapy may have small positive effects on the child’s disruptive behavior. PCT may be a valid treatment option for children with ADHD regarding disruptive behavior, even if mothers are not intensively treated beforehand.

Trial registration
ISRCTN registry ISRCTN73911400. Registered 29 March 2007.
KW  - mothers
KW  - children
KW  - adult treatment
KW  - parent training
KW  - efficacy
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227930
VL  - 18
ER  - 
TY  - JOUR
A1  - Brand, Markus
A1  - Troya, Joel
A1  - Krenzer, Adrian
A1  - Saßmannshausen, Zita
A1  - Zoller, Wolfram G.
A1  - Meining, Alexander
A1  - Lux, Thomas J.
A1  - Hann, Alexander
T1  - Development and evaluation of a deep learning model to improve the usability of polyp detection systems during interventions
JF  - United European Gastroenterology Journal
N2  - Background
The efficiency of artificial intelligence as computer-aided detection (CADe) systems for colorectal polyps has been demonstrated in several randomized trials. However, CADe systems generate many distracting detections, especially during interventions such as polypectomies. Those distracting CADe detections are often induced by the introduction of snares or biopsy forceps as the systems have not been trained for such situations. In addition, there are a significant number of non-false but not relevant detections, since the polyp has already been previously detected. All these detections have the potential to disturb the examiner's work.

Objectives
Development and evaluation of a convolutional neuronal network that recognizes instruments in the endoscopic image, suppresses distracting CADe detections, and reliably detects endoscopic interventions.

Methods
A total of 580 different examination videos from 9 different centers using 4 different processor types were screened for instruments and represented the training dataset (519,856 images in total, 144,217 contained a visible instrument). The test dataset included 10 full-colonoscopy videos that were analyzed for the recognition of visible instruments and detections by a commercially available CADe system (GI Genius, Medtronic).

Results
The test dataset contained 153,623 images, 8.84% of those presented visible instruments (12 interventions, 19 instruments used). The convolutional neuronal network reached an overall accuracy in the detection of visible instruments of 98.59%. Sensitivity and specificity were 98.55% and 98.92%, respectively. A mean of 462.8 frames containing distracting CADe detections per colonoscopy were avoided using the convolutional neuronal network. This accounted for 95.6% of all distracting CADe detections.

Conclusions
Detection of endoscopic instruments in colonoscopy using artificial intelligence technology is reliable and achieves high sensitivity and specificity. Accordingly, the new convolutional neuronal network could be used to reduce distracting CADe detections during endoscopic procedures. Thus, our study demonstrates the great potential of artificial intelligence technology beyond mucosal assessment.
KW  - CADe
KW  - colonoscopy
KW  - deep learning
KW  - instrument
KW  - intervention
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312708
VL  - 10
IS  - 5
ER  - 
TY  - JOUR
A1  - Reimer, Stanislaus
A1  - Seyfried, Florian
A1  - Flemming, Sven
A1  - Brand, Markus
A1  - Weich, Alexander
A1  - Widder, Anna
A1  - Plaßmeier, Lars
A1  - Kraus, Peter
A1  - Döring, Anna
A1  - Hering, Ilona
A1  - Hankir, Mohammed K.
A1  - Meining, Alexander
A1  - Germer, Christoph-Thomas
A1  - Lock, Johan F.
A1  - Groneberg, Kaja
T1  - Evolution of endoscopic vacuum therapy for upper gastrointestinal leakage over a 10-year period: a quality improvement study
JF  - Surgical Endoscopy
N2  - Background
Endoscopic vacuum therapy (EVT) is an effective treatment option for leakage of the upper gastrointestinal (UGI) tract. The aim of this study was to evaluate the clinical impact of quality improvements in EVT management on patients’ outcome.

Methods
All patients treated by EVT at our center during 2012–2021 were divided into two consecutive and equal-sized cohorts (period 1 vs. period 2). Over time several quality improvement strategies were implemented including the earlier diagnosis and EVT treatment and technical optimization of endoscopy. The primary endpoint was defined as the composite score MTL30 (mortality, transfer, length-of-stay > 30 days). Secondary endpoints included EVT efficacy, complications, in-hospital mortality, length-of-stay (LOS) and nutrition status at discharge.

Results
A total of 156 patients were analyzed. During the latter period the primary endpoint MTL30 decreased from 60.8 to 39.0% (P = .006). EVT efficacy increased from 80 to 91% (P = .049). Further, the need for additional procedures for leakage management decreased from 49.9 to 29.9% (P = .013) and reoperations became less frequent (38.0% vs.15.6%; P = .001). The duration of leakage therapy and LOS were shortened from 25 to 14 days (P = .003) and 38 days to 25 days (P = .006), respectively. Morbidity (as determined by the comprehensive complication index) decreased from 54.6 to 46.5 (P = .034). More patients could be discharged on oral nutrition (70.9% vs. 84.4%, P = .043).

Conclusions
Our experience confirms the efficacy of EVT for the successful management of UGI leakage. Our quality improvement analysis demonstrates significant changes in EVT management resulting in accelerated recovery, fewer complications and improved functional outcome.
KW  - anastomotic leak
KW  - gastrointestinal perforation
KW  - esophageal perforation
KW  - endoluminal
KW  - vacuum-assisted closure
KW  - negative pressure
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323953
VL  - 36
IS  - 12
ER  - 
TY  - JOUR
A1  - Lux, Thomas J.
A1  - Banck, Michael
A1  - Saßmannshausen, Zita
A1  - Troya, Joel
A1  - Krenzer, Adrian
A1  - Fitting, Daniel
A1  - Sudarevic, Boban
A1  - Zoller, Wolfram G.
A1  - Puppe, Frank
A1  - Meining, Alexander
A1  - Hann, Alexander
T1  - Pilot study of a new freely available computer-aided polyp detection system in clinical practice
JF  - International Journal of Colorectal Disease
N2  - Purpose
Computer-aided polyp detection (CADe) systems for colonoscopy are already presented to increase adenoma detection rate (ADR) in randomized clinical trials. Those commercially available closed systems often do not allow for data collection and algorithm optimization, for example regarding the usage of different endoscopy processors. Here, we present the first clinical experiences of a, for research purposes publicly available, CADe system.

Methods
We developed an end-to-end data acquisition and polyp detection system named EndoMind. Examiners of four centers utilizing four different endoscopy processors used EndoMind during their clinical routine. Detected polyps, ADR, time to first detection of a polyp (TFD), and system usability were evaluated (NCT05006092).

Results
During 41 colonoscopies, EndoMind detected 29 of 29 adenomas in 66 of 66 polyps resulting in an ADR of 41.5%. Median TFD was 130 ms (95%-CI, 80–200 ms) while maintaining a median false positive rate of 2.2% (95%-CI, 1.7–2.8%). The four participating centers rated the system using the System Usability Scale with a median of 96.3 (95%-CI, 70–100).

Conclusion
EndoMind’s ability to acquire data, detect polyps in real-time, and high usability score indicate substantial practical value for research and clinical practice. Still, clinical benefit, measured by ADR, has to be determined in a prospective randomized controlled trial.
KW  - colonoscopy
KW  - polyp
KW  - artificial intelligence
KW  - deep learning
KW  - CADe
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324459
VL  - 37
IS  - 6
ER  - 
TY  - JOUR
A1  - Müller, Joachim
A1  - Brill, Stefan
A1  - Hagen, Rudolf
A1  - Moeltner, Alexander
A1  - Brockmeier, Steffi-Johanna
A1  - Stark, Thomas
A1  - Helbig, Silke
A1  - Maurer, Jan
A1  - Zahnert, Thomas
A1  - Zierhofer, Clemens
A1  - Nopp, Peter
A1  - Anderson, Ilona
T1  - Clinical Trial Results with the MED-EL Fine Structure Processing Coding Strategy in Experienced Cochlear Implant Users
JF  - ORL
N2  - Objectives: To assess the subjective and objective performance of the new fine structure processing strategy (FSP) compared to the previous generation coding strategies CIS+ and HDCIS. Methods: Forty-six adults with a minimum of 6 months of cochlear implant experience were included. CIS+, HDCIS and FSP were compared in speech perception tests in noise, pitch scaling and questionnaires. The randomized tests were performed acutely (interval 1) and again after 3 months of FSP experience (interval 3). The subjective evaluation included questionnaire 1 at intervals 1 and 3, and questionnaire 2 at interval 2, 1 month after interval 1. Results: Comparison between FSP and CIS+ showed that FSP performed at least as well as CIS+ in all speech perception tests, and outperformed CIS+ in vowel and monosyllabic word discrimination. Comparison between FSP and HDCIS showed that both performed equally well in all speech perception tests. Pitch scaling showed that FSP performed at least as well as HDCIS. With FSP, sound quality was at least as good and often better than with HDCIS. Conclusions: Results indicate that FSP performs better than CIS+ in vowel and monosyllabic word understanding. Subjective evaluation demonstrates strong user preferences for FSP when listening to speech and music.
KW  - pitch
KW  - CIS+
KW  - OPUS
KW  - fine structure processing
KW  - cochlear implant
KW  - coding strategy
KW  - speech perception
KW  - music
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196396
SN  - 0301-1569
SN  - 1423-0275
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  - 74
IS  - 4
ER  - 
TY  - JOUR
A1  - Schneider, Eberhard
A1  - Pliushch, Galyna
A1  - El Hajj, Nady
A1  - Galetzka, Danuta
A1  - Puhl, Alexander
A1  - Schorsch, Martin
A1  - Frauenknecht, Katrin
A1  - Riepert, Thomas
A1  - Tresch, Achim
A1  - Mueller, Annette M.
A1  - Coerdt, Wiltrud
A1  - Zechner, Ulrich
A1  - Haaf, Thomas
T1  - Spatial, temporal and interindividual epigenetic variation of functionally important DNA methylation patterns
N2  - DNA methylation is an epigenetic modification that plays an important role in gene regulation. It can be influenced by stochastic events, environmental factors and developmental programs. However, little is known about the natural variation of genespecific methylation patterns. In this study, we performed quantitative methylation analyses of six differentially methylated imprinted genes (H19, MEG3, LIT1, NESP55, PEG3 and SNRPN), one hypermethylated pluripotency gene (OCT4) and one hypomethylated tumor suppressor gene (APC) in chorionic villus, fetal and adult cortex, and adult blood samples. Both average methylation level and range of methylation variation depended on the gene locus, tissue type and/or developmental stage. We found considerable variability of functionally important methylation patterns among unrelated healthy individuals and a trend toward more similar methylation levels in monozygotic twins than in dizygotic twins. Imprinted genes showed relatively little methylation changes associated with aging in individuals who are >25 years. The relative differences in methylation among neighboring CpGs in the generally hypomethylated APC promoter may not only reflect stochastic fluctuations but also depend on the tissue type. Our results are consistent with the view that most methylation variation may arise after fertilization, leading to epigenetic mosaicism.
KW  - Medizin
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68371
ER  - 
TY  - JOUR
A1  - Mencacci, Niccoló E.
A1  - Isaias, Ioannis U.
A1  - Reich, Martin M.
A1  - Ganos, Christos
A1  - Plagnol, Vincent
A1  - Polke, James M.
A1  - Bras, Jose
A1  - Hersheson, Joshua
A1  - Stamelou, Maria
A1  - Pittman, Alan M.
A1  - Noyce, Alastair J.
A1  - Mok, Kin Y.
A1  - Opladen, Thomas
A1  - Kunstmann, Erdmute
A1  - Hodecker, Sybille
A1  - Münchau, Alexander
A1  - Volkmann, Jens
A1  - Samnick, Samuel
A1  - Sidle, Katie
A1  - Nanji, Tina
A1  - Sweeney, Mary G.
A1  - Houlden, Henry
A1  - Batla, Amit
A1  - Zecchinelli, Anna L.
A1  - Pezzoli, Gianni
A1  - Marotta, Giorgio
A1  - Lees, Andrew
A1  - Alegria, Paulo
A1  - Krack, Paul
A1  - Cormier-Dequaire, Florence
A1  - Lesage, Suzanne
A1  - Brice, Alexis
A1  - Heutink, Peter
A1  - Gasser, Thomas
A1  - Lubbe, Steven J.
A1  - Morris, Huw R.
A1  - Taba, Pille
A1  - Koks, Sulev
A1  - Majounie, Elisa
A1  - Gibbs, J. Raphael
A1  - Singleton, Andrew
A1  - Hardy, John
A1  - Klebe, Stephan
A1  - Bhatia, Kailash P.
A1  - Wood, Nicholas W.
T1  - Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers
JF  - Brain
N2  - GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([(123)I]N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
KW  - DOPA-responsive-dystonia
KW  - GCH1
KW  - Parkinson's disease
KW  - dopamine
KW  - exome sequencing
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121268
VL  - 137
IS  - 9
ER  - 
TY  - JOUR
A1  - Dech, Stefan
A1  - Holzwarth, Stefanie
A1  - Asam, Sarah
A1  - Andresen, Thorsten
A1  - Bachmann, Martin
A1  - Boettcher, Martin
A1  - Dietz, Andreas
A1  - Eisfelder, Christina
A1  - Frey, Corinne
A1  - Gesell, Gerhard
A1  - Gessner, Ursula
A1  - Hirner, Andreas
A1  - Hofmann, Matthias
A1  - Kirches, Grit
A1  - Klein, Doris
A1  - Klein, Igor
A1  - Kraus, Tanja
A1  - Krause, Detmar
A1  - Plank, Simon
A1  - Popp, Thomas
A1  - Reinermann, Sophie
A1  - Reiners, Philipp
A1  - Roessler, Sebastian
A1  - Ruppert, Thomas
A1  - Scherbachenko, Alexander
A1  - Vignesh, Ranjitha
A1  - Wolfmueller, Meinhard
A1  - Zwenzner, Hendrik
A1  - Kuenzer, Claudia
T1  - Potential and challenges of harmonizing 40 years of AVHRR data: the TIMELINE experience
JF  - Remote Sensing
N2  - Earth Observation satellite data allows for the monitoring of the surface of our planet at predefined intervals covering large areas. However, there is only one medium resolution sensor family in orbit that enables an observation time span of 40 and more years at a daily repeat interval. This is the AVHRR sensor family. If we want to investigate the long-term impacts of climate change on our environment, we can only do so based on data that remains available for several decades. If we then want to investigate processes with respect to climate change, we need very high temporal resolution enabling the generation of long-term time series and the derivation of related statistical parameters such as mean, variability, anomalies, and trends. The challenges to generating a well calibrated and harmonized 40-year-long time series based on AVHRR sensor data flown on 14 different platforms are enormous. However, only extremely thorough pre-processing and harmonization ensures that trends found in the data are real trends and not sensor-related (or other) artefacts. The generation of European-wide time series as a basis for the derivation of a multitude of parameters is therefore an extremely challenging task, the details of which are presented in this paper.
KW  - AVHRR
KW  - Earth Observation
KW  - harmonization
KW  - time series analysis
KW  - climate related trends
KW  - automatic processing
KW  - Europe
KW  - TIMELINE
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246134
SN  - 2072-4292
VL  - 13
IS  - 18
ER  - 
TY  - JOUR
A1  - Linsenmann, Thomas
A1  - Cattaneo, Andrea
A1  - März, Alexander
A1  - Weiland, Judith
A1  - Stetter, Christian
A1  - Nickl, Robert
A1  - Westermaier, Thomas
T1  - Combined frameless stereotactical biopsy and intraoperative cerebral angiography by 3D-rotational fluoroscopy with intravenous contrast administration: a feasibility study
JF  - BMC Medical Imaging
N2  - Background
Mobile 3-dimensional fluoroscopes are an integral part of modern neurosurgical operating theatres and can also be used in combination with free available image post processing to depict cerebral vessels. In preparation of stereotactic surgery, preoperative Computed Tomography (CT) may be required for image fusion. Contrast CT may be of further advantage for image fusion as it regards the vessel anatomy in trajectory planning. Time-consuming in-hospital transports are necessary for this purpose. Mobile 3D-fluoroscopes may be used to generate a CT equal preoperative data set without an in-hospital transport. This study was performed to determine the feasibility and image quality of intraoperative 3-dimensional fluoroscopy with intravenous contrast administration in combination with stereotactical procedures.

Methods
6 patients were included in this feasibility study. After fixation in a radiolucent Mayfield clamp a rotational fluoroscopy scan was performed with 50 mL iodine contrast agent. The image data sets were merged with the existing MRI images at a planning station and visually evaluated by two observer. The operation times were compared between the frame-based and frameless systems (“skin-to-skin” and “OR entry to exit”).

Results
The procedure proves to be safe. The entire procedure from fluoroscope positioning to the transfer to the planning station took 5–6 min with an image acquisition time of 24 s. In 5 of 6 cases, the fused imaging was able to reproduce the vascular anatomy accurately and in good quality. Both time end-points were significantly shorter compared to frame-based interventions.

Conclusion
The images could easily be transferred to the planning and navigation system and were successfully merged with the MRI data set. The procedure can be completely integrated into the surgical workflow. Preoperative CT imaging or transport under anaesthesia may even be replaced by this technique in the future. Furthermore, hemorrhages can be successfully visualized intraoperatively and might prevent time delays in emergencies.
KW  - 3 D rotational fluoroscopy
KW  - neurosurgery
KW  - stereotaxy
KW  - frameless systems
KW  - intraoperative imaging
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270370
VL  - 21
ER  - 
TY  - JOUR
A1  - Rayner, Christopher
A1  - Coleman, Jonathan R. I.
A1  - Purves, Kirstin L.
A1  - Hodsoll, John
A1  - Goldsmith, Kimberley
A1  - Alpers, Georg W.
A1  - Andersson, Evelyn
A1  - Arolt, Volker
A1  - Boberg, Julia
A1  - Bögels, Susan
A1  - Creswell, Cathy
A1  - Cooper, Peter
A1  - Curtis, Charles
A1  - Deckert, Jürgen
A1  - Domschke, Katharina
A1  - El Alaoui, Samir
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Grocholewski, Anja
A1  - Hahlweg, Kurt
A1  - Hamm, Alfons
A1  - Hedman, Erik
A1  - Heiervang, Einar R.
A1  - Hudson, Jennifer L.
A1  - Jöhren, Peter
A1  - Keers, Robert
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lavebratt, Catharina
A1  - Lee, Sang-hyuck
A1  - Lester, Kathryn J.
A1  - Lindefors, Nils
A1  - Margraf, Jürgen
A1  - Nauta, Maaike
A1  - Pané-Farré, Christiane A.
A1  - Pauli, Paul
A1  - Rapee, Ronald M.
A1  - Reif, Andreas
A1  - Rief, Winfried
A1  - Roberts, Susanna
A1  - Schalling, Martin
A1  - Schneider, Silvia
A1  - Silverman, Wendy K.
A1  - Ströhle, Andreas
A1  - Teismann, Tobias
A1  - Thastum, Mikael
A1  - Wannemüller, Andre
A1  - Weber, Heike
A1  - Wittchen, Hans-Ulrich
A1  - Wolf, Christiane
A1  - Rück, Christian
A1  - Breen, Gerome
A1  - Eley, Thalia C.
T1  - A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders
JF  - Translational Psychiatry
N2  - Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
KW  - Human behaviour
KW  - Personalized medicine
KW  - Prognostic markers
KW  - Psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225048
VL  - 9
IS  - 150
ER  - 
TY  - JOUR
A1  - Göbel, Kerstin
A1  - Pankratz, Susann
A1  - Asaridou, Chloi-Magdalini
A1  - Herrmann, Alexander M.
A1  - Bittner, Stefan
A1  - Merker, Monika
A1  - Ruck, Tobias
A1  - Glumm, Sarah
A1  - Langhauser, Friederike
A1  - Kraft, Peter
A1  - Krug, Thorsten F.
A1  - Breuer, Johanna
A1  - Herold, Martin
A1  - Gross, Catharina C.
A1  - Beckmann, Denise
A1  - Korb-Pap, Adelheid
A1  - Schuhmann, Michael K.
A1  - Kuerten, Stefanie
A1  - Mitroulis, Ioannis
A1  - Ruppert, Clemens
A1  - Nolte, Marc W.
A1  - Panousis, Con
A1  - Klotz, Luisa
A1  - Kehrel, Beate
A1  - Korn, Thomas
A1  - Langer, Harald F.
A1  - Pap, Thomas
A1  - Nieswandt, Bernhard
A1  - Wiendl, Heinz
A1  - Chavakis, Triantafyllos
A1  - Kleinschnitz, Christoph
A1  - Meuth, Sven G.
T1  - Blood coagulation factor XII drives adaptive immunity during neuroinflammation via CD87-mediated modulation of dendritic cells
JF  - Nature Communications
N2  - Aberrant immune responses represent the underlying cause of central nervous system (CNS) autoimmunity, including multiple sclerosis (MS). Recent evidence implicated the crosstalk between coagulation and immunity in CNS autoimmunity. Here we identify coagulation factor XII (FXII), the initiator of the intrinsic coagulation cascade and the kallikrein–kinin system, as a specific immune cell modulator. High levels of FXII activity are present in the plasma of MS patients during relapse. Deficiency or pharmacologic blockade of FXII renders mice less susceptible to experimental autoimmune encephalomyelitis (a model of MS) and is accompanied by reduced numbers of interleukin-17A-producing T cells. Immune activation by FXII is mediated by dendritic cells in a CD87-dependent manner and involves alterations in intracellular cyclic AMP formation. Our study demonstrates that a member of the plasmatic coagulation cascade is a key mediator of autoimmunity. FXII inhibition may provide a strategy to combat MS and other immune-related disorders.
KW  - blood coagulation
KW  - factor XII
KW  - neuroinflammation
KW  - dendric cells
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165503
VL  - 7
IS  - 11626
ER  - 
TY  - JOUR
A1  - Linsenmann, Thomas
A1  - März, Alexander
A1  - Dufner, Vera
A1  - Stetter, Christian
A1  - Weiland, Judith
A1  - Westermaier, Thomas
T1  - Optimization of radiation settings for angiography using 3D fluoroscopy for imaging of intracranial aneurysms
JF  - Computer Assisted Surgery
N2  - Mobile 3D fluoroscopes have become increasingly available in neurosurgical operating rooms. We recently reported its use for imaging cerebral vascular malformations and aneurysms. This study was conducted to evaluate various radiation settings for the imaging of cerebral aneurysms before and after surgical occlusion. Eighteen patients with cerebral aneurysms with the indication for surgical clipping were included in this prospective analysis. Before surgery the patients were randomized into one of three different scan protocols according (default settings of the 3D fluoroscope): Group 1: 110 kV, 80 mA (enhanced cranial mode), group 2: 120 kV, 64 mA (lumbar spine mode), group 3: 120 kV, 25 mA (head/neck settings). Prior to surgery, a rotational fluoroscopy scan (duration 24 s) was performed without contrast agent followed by another scan with 50 ml of intravenous iodine contrast agent. The image files of both scans were transferred to an Apple PowerMac(R) workstation, subtracted and reconstructed using OsiriX(R) MD 10.0 software. The procedure was repeated after clip placement. The image quality regarding preoperative aneurysm configuration and postoperative assessment of aneurysm occlusion and vessel patency was analyzed by 2 independent reviewers using a 6-grade scale. This technique quickly supplies images of adequate quality to depict intracranial aneurysms and distal vessel patency after aneurysm clipping. Regarding these features, a further optimization to our previous protocol seems possible lowering the voltage and increasing tube current. For quick intraoperative assessment, image subtraction seems not necessary. Thus, a native scan without a contrast agent is not necessary. Further optimization may be possible using a different contrast injection protocol.
KW  - 3D fluoroscopy
KW  - aneurysm
KW  - fluoroscopy
KW  - intraoperative imaging
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259251
VL  - 26
IS  - 1
ER  - 
TY  - JOUR
A1  - Castillo, Ruth
A1  - Wurdack, Mareike
A1  - Pauli, Thomas
A1  - Keller, Alexander
A1  - Feldhaar, Heike
A1  - Polidori, Carlo
A1  - Niehuis, Oliver
A1  - Schmitt, Thomas
T1  - Evidence for a chemical arms race between cuckoo wasps of the genus Hedychrum and their distantly related host apoid wasps
JF  - BMC Ecology and Evolution
N2  - Background
Brood parasites can exert strong selection pressure on their hosts. Many brood parasites escape their detection by mimicking sensory cues of their hosts. However, there is little evidence whether or not the hosts are able to escape the parasites’ mimicry by changing these cues. We addressed this question by analyzing cuticular hydrocarbon (CHC) profiles of Cerceris and Philanthus wasps and their brood parasites, cuckoo wasps mimicking the CHC profiles of their hosts. Some of these hosts use hydrocarbons to preserve their prey against fungal infestation and thus, they cannot significantly change their CHC composition in response to chemical mimicry by Hedychrum brood parasites.

Results
We found that the CHC overlap between brood parasites and their hosts was lower in case of host wasps not preserving their prey than in case of prey-preserving host wasps, whose CHC evolution is constrained. Furthermore, the CHC profiles in non-preserving host wasps is more strongly diversified in females than in males, thus in the sex that is chemically mimicked by brood parasites.

Conclusion
Our results provide evidence for a chemical arms race between those hosts that are liberated from stabilizing selection on their chemical template and their parasites.
KW  - chemical mimicry
KW  - philanthidae
KW  - hymenoptera
KW  - evolutionary arms race
KW  - cuticular hydrocarbons
KW  - chrysididae
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-301289
VL  - 22
IS  - 1
ER  - 
TY  - JOUR
A1  - Gottschalk, Michael G.
A1  - Richter, Jan
A1  - Ziegler, Christiane
A1  - Schiele, Miriam A.
A1  - Mann, Julia
A1  - Geiger, Maximilian J.
A1  - Schartner, Christoph
A1  - Homola, György A.
A1  - Alpers, Georg W.
A1  - Büchel, Christian
A1  - Fehm, Lydia
A1  - Fydrich, Thomas
A1  - Gerlach, Alexander L.
A1  - Gloster, Andrew T.
A1  - Helbig-Lang, Sylvia
A1  - Kalisch, Raffael
A1  - Kircher, Tilo
A1  - Lang, Thomas
A1  - Lonsdorf, Tina B.
A1  - Pané-Farré, Christiane A.
A1  - Ströhle, Andreas
A1  - Weber, Heike
A1  - Zwanzger, Peter
A1  - Arolt, Volker
A1  - Romanos, Marcel
A1  - Wittchen, Hans-Ulrich
A1  - Hamm, Alfons
A1  - Pauli, Paul
A1  - Reif, Andreas
A1  - Deckert, Jürgen
A1  - Neufang, Susanne
A1  - Höfler, Michael
A1  - Domschke, Katharina
T1  - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes
JF  - Translational Psychiatry
N2  - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.
KW  - human behaviour
KW  - molecular neuroscience
KW  - personalized medicine
KW  - predictive markers
KW  - psychiatric disorders
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479
VL  - 9
ER  - 
TY  - INPR
A1  - Braunschweig, Holger
A1  - Brückner, Tobias
A1  - Deißenberger, Andrea
A1  - Dewhurst, Rian
A1  - Gackstatter, Annika
A1  - Gärtner, Annalena
A1  - Hofmann, Alexander
A1  - Kupfer, Thomas
A1  - Prieschl, Dominic
A1  - Thiess, Torsten
A1  - Wang, Sunewang Rixin
T1  - Reaction of Dihalodiboranes(4) with N-Heterocyclic Silylenes: Facile Construction of 1-Aryl-2-Silyl-1,2-Diboraindanes
T2  - Chemistry, A European Journal
N2  - Dihalodiboranes(4) react with an N-heterocyclic silylene (NHSi) to generate NHSi-adducts of 1-aryl-2-silyl-1,2-diboraindanes as confirmed by X-ray crystallography, featuring the functionalization of both B–X (X = halogen) bonds and a C–H bond under mild conditions. Coordination of a third NHSi to the proposed 1,1-diaryl- 2,2-disilyldiborane(4) intermediates, generated by a two-fold B–X insertion, may be crucial for the C–H borylation that leads to the final products. Notably, our results demonstrate the first C–H borylation with a strong B–F bond activated by silylene insertion.
KW  - diborane
KW  - boron
KW  - silylenes
KW  - CH activation
KW  - bond activation
KW  - diboraindanes
KW  - diboranes
KW  - synthetic methods
KW  - borylation
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-153068
N1  - This is the pre-peer reviewed version of the following article: H. Braunschweig, T. Brückner, A. Deißenberger, R. D. Dewhurst, A. Gackstatter, A. Gärtner, A. Hofmann, T. Kupfer, D. Prieschl, T. Thiess, S. R. Wang, Reaction of Dihalodiboranes(4) with a N-Heterocyclic Silylene: Facile Construction of 1-Aryl-2-Silyl-1,2-Diboraindanes, Chem. Eur. J. 2017, 23, 9491., which has been published in final form at dx.doi.org/10.1002/chem.201702377. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving
ER  - 
TY  - JOUR
A1  - Pache, Florence
A1  - Zimmermann, Hanna
A1  - Mikolajczak, Janine
A1  - Schumacher, Sophie
A1  - Lacheta, Anna
A1  - Oertel, Frederike C.
A1  - Bellmann-Strobl, Judith
A1  - Jarius, Sven
A1  - Wildemann, Brigitte
A1  - Reindl, Markus
A1  - Waldman, Amy
A1  - Soelberg, Kerstin
A1  - Asgari, Nasrin
A1  - Ringelstein, Marius
A1  - Aktas, Orhan
A1  - Gross, Nikolai
A1  - Buttmann, Mathias
A1  - Ach, Thomas
A1  - Ruprecht, Klemens
A1  - Paul, Friedemann
A1  - Brandt, Alexander U.
T1  - MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: Afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients
JF  - Journal of Neuroinflammation
N2  - Background
Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been reported in patients with aquaporin-4 antibody (AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD). The objective of this study was to describe optic neuritis (ON)-induced neuro-axonal damage in the retina of MOG-IgG-positive patients in comparison with AQP4-IgG-positive NMOSD patients.

Methods
Afferent visual system damage following ON was bilaterally assessed in 16 MOG-IgG-positive patients with a history of ON and compared with that in 16 AQP4-IgG-positive NMOSD patients. In addition, 16 healthy controls matched for age, sex, and disease duration were analyzed. Study data included ON history, retinal optical coherence tomography, visual acuity, and visual evoked potentials.

Results
Eight MOG-IgG-positive patients had a previous diagnosis of AQP4-IgG-negative NMOSD with ON and myelitis, and eight of (mainly recurrent) ON. Twenty-nine of the 32 eyes of the MOG-IgG-positive patients had been affected by at least one episode of ON. Peripapillary retinal nerve fiber layer thickness (pRNFL) and ganglion cell and inner plexiform layer volume (GCIP) were significantly reduced in ON eyes of MOG-IgG-positive patients (pRNFL = 59 ± 23 μm; GCIP = 1.50 ± 0.34 mm3) compared with healthy controls (pRNFL = 99 ± 6 μm, p < 0.001; GCIP = 1.97 ± 0.11 mm3, p < 0.001). Visual acuity was impaired in eyes after ON in MOG-IgG-positive patients (0.35 ± 0.88 logMAR). There were no significant differences in any structural or functional visual parameters between MOG-IgG-positive and AQP4-IgG-positive patients (pRNFL: 59 ± 21 μm; GCIP: 1.41 ± 0.27 mm3; Visual acuity = 0.72 ± 1.09 logMAR). Importantly, MOG-IgG-positive patients had a significantly higher annual ON relapse rate than AQP4-IgG-positive patients (median 0.69 vs. 0.29 attacks/year, p = 0.004), meaning that on average a single ON episode caused less damage in MOG-IgG-positive than in AQP4-IgG-positive patients. pRNFL and GCIP loss correlated with the number of ON episodes in MOG-IgG-positive patients (p < 0.001), but not in AQP4-IgG-positive patients.

Conclusions
Retinal neuro-axonal damage and visual impairment after ON in MOG-IgG-positive patients are as severe as in AQP4-IgG-positive NMOSD patients. In MOG-IgG-positive patients, damage accrual may be driven by higher relapse rates, whereas AQP4-IgG-positive patients showed fewer but more severe episodes of ON. Given the marked damage in some of our MOG-IgG-positive patients, early diagnosis and timely initiation and close monitoring of immunosuppressive therapy are important.
KW  - Myelin oligodendrocyte glycoprotein antibodies (MOG-IgG)
KW  - aquaporin-4 antibodies (AQP4-IgG)
KW  - NMO-IgG
KW  - neuromyelitis optica
KW  - Devic syndrome
KW  - neuromyelitis optica spectrum disorders (NMOSD)
KW  - optic neuritis
KW  - optical coherence tomography
KW  - visual evoked potentials
KW  - visual acuity
KW  - retinal neuro-axonal damage
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165551
VL  - 13
IS  - 282
ER  - 
TY  - JOUR
A1  - Kunz, Meik
A1  - Liang, Chunguang
A1  - Nilla, Santosh
A1  - Cecil, Alexander
A1  - Dandekar, Thomas
T1  - The drug-minded protein interaction database (DrumPID) for efficient target analysis and drug development
JF  - Database
N2  - The drug-minded protein interaction database (DrumPID) has been designed to provide fast, tailored information on drugs and their protein networks including indications, protein targets and side-targets. Starting queries include compound, target and protein interactions and organism-specific protein families. Furthermore, drug name, chemical structures and their SMILES notation, affected proteins (potential drug targets), organisms as well as diseases can be queried including various combinations and refinement of searches. Drugs and protein interactions are analyzed in detail with reference to protein structures and catalytic domains, related compound structures as well as potential targets in other organisms. DrumPID considers drug functionality, compound similarity, target structure, interactome analysis and organismic range for a compound, useful for drug development, predicting drug side-effects and structure–activity relationships.
KW  - drug-minded protein
KW  - database
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147369
VL  - 2016
ER  - 
TY  - JOUR
A1  - Lichthardt, Sven
A1  - Kerscher, Alexander
A1  - Dietz, Ulrich A.
A1  - Jurowich, Christian
A1  - Kunzmann, Volker
A1  - von Rahden, Burkhard H. A.
A1  - Germer, Christoph-Thomas
A1  - Wiegering, Armin
T1  - Original article: role of adjuvant chemotherapy in a perioperative chemotherapy regimen for gastric cancer
JF  - BMC Cancer
N2  - Background

Multimodal treatment strategies – perioperative chemotherapy (CTx) and radical surgery – are currently accepted as treatment standard for locally advanced gastric cancer. However, the role of adjuvant postoperative CTx (postCTx) in addition to neoadjuvant preoperative CTx (preCTx) in this setting remains controversial.

Methods

Between 4/2006 and 12/2013, 116 patients with locally advanced gastric cancer were treated with preCTx. 72 patients (62 %), in whom complete tumor resection (R0, subtotal/total gastrectomy with D2-lymphadenectomy) was achieved, were divided into two groups, one of which receiving adjuvant therapy (n = 52) and one without (n = 20). These groups were analyzed with regard to survival and exclusion criteria for adjuvant therapy.

Results

Postoperative complications, as well as their severity grade, did not correlate with fewer postCTx cycles administered (p = n.s.). Long-term survival was shorter in patients receiving postCTx in comparison to patients without postCTx, but did not show statistical significance. In per protocol analysis by excluding two patients with perioperative death, a shorter 3-year survival rate was observed in patients receiving postCTx compared to patients without postCTx (3-year survival: 71.2 % postCTx group vs. 90.0 % non-postCTx group; p = 0.038).

Conclusion

These results appear contradicting to the anticipated outcome. While speculative, they question the value of post-CTx. Prospectively randomized studies are needed to elucidate the role of postCTx.
KW  - gastric cancer
KW  - chemotherapy
KW  - neoadjuvant
KW  - multimodal
KW  - complication
KW  - adjuvant
KW  - risk factor
KW  - survival
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147743
VL  - 16
IS  - 650
ER  - 
TY  - JOUR
A1  - Sessi, Paolo
A1  - Biswas, Rudro R.
A1  - Bathon, Thomas
A1  - Storz, Oliver
A1  - Wilfert, Stefan
A1  - Barla, Alessandro
A1  - Kokh, Konstantin A.
A1  - Tereshchenko, Oleg E.
A1  - Fauth, Kai
A1  - Bode, Matthias
A1  - Balatsky, Alexander V.
T1  - Dual nature of magnetic dopants and competing trends in topological insulators
JF  - Nature Communications
N2  - Topological insulators interacting with magnetic impurities have been reported to host several unconventional effects. These phenomena are described within the framework of gapping Dirac quasiparticles due to broken time-reversal symmetry. However, the overwhelming majority of studies demonstrate the presence of a finite density of states near the Dirac point even once topological insulators become magnetic. Here, we map the response of topological states to magnetic impurities at the atomic scale. We demonstrate that magnetic order and gapless states can coexist. We show how this is the result of the delicate balance between two opposite trends, that is, gap opening and emergence of a Dirac node impurity band, both induced by the magnetic dopants. Our results evidence a more intricate and rich scenario with respect to the once generally assumed, showing how different electronic and magnetic states may be generated and controlled in this fascinating class of materials.
KW  - magnetic properties and materials
KW  - topological insulators
KW  - magnetic dopants
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172704
VL  - 7
ER  - 
TY  - INPR
A1  - Englert, Lukas
A1  - Stoy, Andreas
A1  - Arrowsmith, Merle
A1  - Müssig, Jonas H.
A1  - Thaler, Melanie
A1  - Deißenberger, Andrea
A1  - Häfner, Alena
A1  - Böhnke, Julian
A1  - Hupp, Florian
A1  - Seufert, Jens
A1  - Mies, Jan
A1  - Damme, Alexander
A1  - Dellermann, Theresa
A1  - Hammond, Kai
A1  - Kupfer, Thomas
A1  - Radacki, Krzysztof
A1  - Thiess, Torsten
A1  - Braunschweig, Holger
T1  - Stable Lewis Base Adducts of Tetrahalodiboranes: Synthetic Methods and Structural Diversity
T2  - Chemistry - A European Journal
N2  - A series of 22 new bis(phosphine), bis(carbene) and bis(isonitrile) tetrahalodiborane adducts has been synthesized, either by direct adduct formation with highly sensitive B2X4 precursors (X = Cl, Br, I) or by ligand exchange at stable B2X4(SMe2)2 precursors (X = Cl, Br) with labile dimethylsulfide ligands. The isolated compounds have been fully characterized using NMR spectroscopic, (C,H,N)- elemental and, for 20 of these compounds, X-ray crystallographic analysis, revealing an unexpected variation in the bonding motifs. Besides the classical B2X4L2 diborane(6) adducts, some of the more sterically demanding carbene ligands induce a halide displacement leading to the first halide-bridged monocationic diboron species, [B2X3L2]A (A = BCl4, Br, I). Furthermore, low-temperature 1:1 reactions of B2Cl4 with sterically demanding N-heterocyclic carbenes led to the formation of kinetically unstable mono-adducts, one of which was structurally characterized. A comparison of the NMR and structural data of new and literature-known bis-adducts shows several trends pertaining to the nature of the halides and the stereoelectronic properties of the Lewis bases employed.
KW  - diborane(6)
KW  - Lewis-base adducts
KW  - ligand exchange
KW  - crystallography
KW  - NMR spectroscopy
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-184888
N1  - This is the pre-peer reviewed version of the following article: L. Englert, A. Stoy, M. Arrowsmith, J. H. Muessig, M. Thaler, A. Deißenberger, A. Häfner, J. Böhnke, F. Hupp, J. Seufert, J. Mies, A. Damme, T. Dellermann, K. Hammond, T. Kupfer, K. Radacki, T. Thiess, H. Braunschweig, Chem. Eur. J. 2019, 25, 8612. https://doi.org/10.1002/chem.201901437, which has been published in final form at https://doi.org/10.1002/chem.201901437. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
ER  - 
TY  - JOUR
A1  - Cecil, Alexander
A1  - Rikanovic, Carina
A1  - Ohlsen, Knut
A1  - Liang, Chunguang
A1  - Bernhardt, Jorg
A1  - Oelschlaeger, Tobias A.
A1  - Gulder, Tanja
A1  - Bringmann, Gerd
A1  - Holzgrabe, Ulrike
A1  - Unger, Matthias
A1  - Dandekar, Thomas
T1  - Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells
N2  - Background: Xenobiotics represent an environmental stress and as such are a source for antibiotics, including the isoquinoline (IQ) compound IQ-143. Here, we demonstrate the utility of complementary analysis of both host and pathogen datasets in assessing bacterial adaptation to IQ-143, a synthetic analog of the novel type N,C-coupled naphthyl-isoquinoline alkaloid ancisheynine. Results: Metabolite measurements, gene expression data and functional assays were combined with metabolic modeling to assess the effects of IQ-143 on Staphylococcus aureus, Staphylococcus epidermidis and human cell lines, as a potential paradigm for novel antibiotics. Genome annotation and PCR validation identified novel enzymes in the primary metabolism of staphylococci. Gene expression response analysis and metabolic modeling demonstrated the adaptation of enzymes to IQ-143, including those not affected by significant gene expression changes. At lower concentrations, IQ-143 was bacteriostatic, and at higher concentrations bactericidal, while the analysis suggested that the mode of action was a direct interference in nucleotide and energy metabolism. Experiments in human cell lines supported the conclusions from pathway modeling and found that IQ-143 had low cytotoxicity. Conclusions: The data suggest that IQ-143 is a promising lead compound for antibiotic therapy against staphylococci. The combination of gene expression and metabolite analyses with in silico modeling of metabolite pathways allowed us to study metabolic adaptations in detail and can be used for the evaluation of metabolic effects of other xenobiotics.
KW  - Staphylococcus aureus
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68802
ER  - 
TY  - JOUR
A1  - Klingelhoeffer, Chrístoph
A1  - Kämmerer, Ulrike
A1  - Koospal, Monika
A1  - Mühling, Bettina
A1  - Schneider, Manuela
A1  - Kapp, Michaela
A1  - Kübler, Alexander,
A1  - Germer, Christoph-Thomas
A1  - Otto, Christoph
T1  - Natural resistance to ascorbic acid induced oxidative stress is mainly mediated by catalase activity in human cancer cells and catalase-silencing sensitizes to oxidative stress
N2  - Background: Ascorbic acid demonstrates a cytotoxic effect by generating hydrogen peroxide, a reactive oxygen species (ROS) involved in oxidative cell stress. A panel of eleven human cancer cell lines, glioblastoma and carcinoma, were exposed to serial dilutions of ascorbic acid (5-100 mmol/L). The purpose of this study was to analyse the impact of catalase, an important hydrogen peroxide-detoxifying enzyme, on the resistance of cancer cells to ascorbic acid mediated oxidative stress. Methods: Effective concentration (EC50) values, which indicate the concentration of ascorbic acid that reduced the number of viable cells by 50%, were detected with the crystal violet assay. The level of intracellular catalase protein and enzyme activity was determined. Expression of catalase was silenced by catalase-specific short hairpin RNA (sh-RNA) in BT-20 breast carcinoma cells. Oxidative cell stress induced apoptosis was measured by a caspase luminescent assay. Results: The tested human cancer cell lines demonstrated obvious differences in their resistance to ascorbic acid mediated oxidative cell stress. Forty-five percent of the cell lines had an EC50>20 mmol/L and fifty-five percent had an EC50<20 mmol/L. With an EC50 of 2.6–5.5 mmol/L, glioblastoma cells were the most susceptible cancer cell lines analysed in this study. A correlation between catalase activity and the susceptibility to ascorbic acid was observed. To study the possible protective role of catalase on the resistance of cancer cells to oxidative cell stress, the expression of catalase in the breast carcinoma cell line BT-20, which cells were highly resistant to the exposure to ascorbic acid (EC50: 94,9 mmol/L), was silenced with specific sh-RNA. The effect was that catalase-silenced BT-20 cells (BT-20 KD-CAT) became more susceptible to high concentrations of ascorbic acid (50 and 100 mmol/L). Conclusions: Fifty-five percent of the human cancer cell lines tested were unable to protect themselves against oxidative stress mediated by ascorbic acid induced hydrogen peroxide production. The antioxidative enzyme catalase is important to protect cancer cells against cytotoxic hydrogen peroxide. Silenced catalase expression increased the susceptibility of the formerly resistant cancer cell line BT-20 to oxidative stress.
KW  - Medizin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75142
ER  - 
TY  - JOUR
A1  - Keller, Alexander
A1  - Foerster, Frank
A1  - Mueller, Tobias
A1  - Dandekar, Thomas
A1  - Schultz, Joerg
A1  - Wolf, Matthias
T1  - Including RNA secondary structures improves accuracy and robustness in reconstruction of phylogenetic trees
N2  - Background: In several studies, secondary structures of ribosomal genes have been used to improve the quality of phylogenetic reconstructions. An extensive evaluation of the benefits of secondary structure, however, is lacking. Results: This is the first study to counter this deficiency. We inspected the accuracy and robustness of phylogenetics with individual secondary structures by simulation experiments for artificial tree topologies with up to 18 taxa and for divergency levels in the range of typical phylogenetic studies. We chose the internal transcribed spacer 2 of the ribosomal cistron as an exemplary marker region. Simulation integrated the coevolution process of sequences with secondary structures. Additionally, the phylogenetic power of marker size duplication was investigated and compared with sequence and sequence-structure reconstruction methods. The results clearly show that accuracy and robustness of Neighbor Joining trees are largely improved by structural information in contrast to sequence only data, whereas a doubled marker size only accounts for robustness. Conclusions: Individual secondary structures of ribosomal RNA sequences provide a valuable gain of information content that is useful for phylogenetics. Thus, the usage of ITS2 sequence together with secondary structure for taxonomic inferences is recommended. Other reconstruction methods as maximum likelihood, bayesian inference or maximum parsimony may equally profit from secondary structure inclusion. Reviewers: This article was reviewed by Shamil Sunyaev, Andrea Tanzer (nominated by Frank Eisenhaber) and Eugene V. Koonin. Open peer review: Reviewed by Shamil Sunyaev, Andrea Tanzer (nominated by Frank Eisenhaber) and Eugene V. Koonin. For the full reviews, please go to the Reviewers’ comments section.
KW  - Phylogenie
KW  - phylogenetics
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-67832
ER  - 
TY  - JOUR
A1  - Harth, Stefan
A1  - Kotzsch, Alexander
A1  - Hu, Junli
A1  - Sebald, Walter
A1  - Mueller, Thomas D.
T1  - A Selection Fit Mechanism in BMP Receptor IA as a Possible Source for BMP Ligand-Receptor Promiscuity
N2  - Background: Members of the TGF-b superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. Principal Findings: In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor’s BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. Conclusions: Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors.
KW  - Physiologische Chemie
KW  - antigen binding antibody fragment (Fab)
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68497
ER  - 
TY  - JOUR
A1  - Kleinschnitz, Christoph
A1  - Grund, Henrike
A1  - Wingler, Kirstin
A1  - Armitage, Melanie E.
A1  - Jones, Emma
A1  - Mittal, Manish
A1  - Barit, David
A1  - Schwarz, Tobias
A1  - Geis, Christian
A1  - Kraft, Peter
A1  - Barthel, Konstanze
A1  - Schuhmann, Michael K.
A1  - Herrmann, Alexander M.
A1  - Meuth, Sven G.
A1  - Stoll, Guido
A1  - Meurer, Sabine
A1  - Schrewe, Anja
A1  - Becker, Lore
A1  - Gailus-Durner, Valerie
A1  - Fuchs, Helmut
A1  - Klopstock, Thomas
A1  - de Angelis, Martin Hrabe
A1  - Jandeleit-Dahm, Karin
A1  - Shah, Ajay M.
A1  - Weissmann, Norbert
A1  - Schmidt, Harald H. H. W.
T1  - Post-Stroke Inhibition of Induced NADPH Oxidase Type 4 Prevents Oxidative Stress and Neurodegeneration
N2  - Ischemic stroke is the second leading cause of death worldwide. Only one moderately effective therapy exists, albeit with contraindications that exclude 90% of the patients. This medical need contrasts with a high failure rate of more than 1,000 pre-clinical drug candidates for stroke therapies. Thus, there is a need for translatable mechanisms of neuroprotection and more rigid thresholds of relevance in pre-clinical stroke models. One such candidate mechanism is oxidative stress. However, antioxidant approaches have failed in clinical trials, and the significant sources of oxidative stress in stroke are unknown. We here identify NADPH oxidase type 4 (NOX4) as a major source of oxidative stress and an effective therapeutic target in acute stroke. Upon ischemia, NOX4 was induced in human and mouse brain. Mice deficient in NOX4 (Nox42/2) of either sex, but not those deficient for NOX1 or NOX2, were largely protected from oxidative stress, blood-brain-barrier leakage, and neuronal apoptosis, after both transient and permanent cerebral ischemia. This effect was independent of age, as elderly mice were equally protected. Restoration of oxidative stress reversed the stroke-protective phenotype in Nox42/2 mice. Application of the only validated low-molecular-weight pharmacological NADPH oxidase inhibitor, VAS2870, several hours after ischemia was as protective as deleting NOX4. The extent of neuroprotection was exceptional, resulting in significantly improved long-term neurological functions and reduced mortality. NOX4 therefore represents a major source of oxidative stress and novel class of drug target for stroke therapy.
KW  - Schlaganfall
Y1  - 2010
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68416
ER  - 
TY  - JOUR
A1  - Couch, Fergus J.
A1  - Wang, Xianshu
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Olswold, Curtis
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Fredericksen, Zachary
A1  - Barrowdale, Daniel
A1  - Dennis, Joe
A1  - Gaudet, Mia M.
A1  - Dicks, Ed
A1  - Kosel, Matthew
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Lee, Adam
A1  - Bacot, Françios
A1  - Vincent, Daniel
A1  - Hogervorst, Frans B. L.
A1  - Peock, Susan
A1  - Stoppa-Lyonnet, Dominique
A1  - Jakubowska, Anna
A1  - Radice, Paolo
A1  - Schmutzler, Rita Katharina
A1  - Domchek, Susan M.
A1  - Piedmonte, Marion
A1  - Singer, Christian F.
A1  - Friedman, Eitan
A1  - Thomassen, Mads
A1  - Hansen, Thomas V. O.
A1  - Neuhausen, Susan L.
A1  - Szabo, Csilla I.
A1  - Blanco, Ingnacio
A1  - Greene, Mark H.
A1  - Karlan, Beth Y.
A1  - Garber, Judy
A1  - Phelan, Catherine M.
A1  - Weitzel, Jeffrey N.
A1  - Montagna, Marco
A1  - Olah, Edith
A1  - Andrulis, Irene L.
A1  - Godwin, Andrew K.
A1  - Yannoukakos, Drakoulis
A1  - Goldgar, David E.
A1  - Caldes, Trinidad
A1  - Nevanlinna, Heli
A1  - Osorio, Ana
A1  - Terry, Mary Beth
A1  - Daly, Mary B.
A1  - van Rensburg, Elisabeth J.
A1  - Hamann, Ute
A1  - Ramus, Susan J.
A1  - Toland, Amanda Ewart
A1  - Caligo, Maria A.
A1  - Olopade, Olufunmilayo I.
A1  - Tung, Nadine
A1  - Claes, Kathleen
A1  - Beattie, Mary S.
A1  - Southey, Melissa C.
A1  - Imyanitov, Evgeny N.
A1  - Tischkowitz, Marc
A1  - Janavicius, Ramunas
A1  - John, Esther M.
A1  - Kwong, Ava
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Balmaña, Judith
A1  - Barkardottir, Rosa B.
A1  - Arun, Banu K.
A1  - Rennert, Gad
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Campbell, Ian
A1  - van der Hout, Annemarie H.
A1  - van Deurzen, Carolien H. M.
A1  - Seynaeve, Caroline
A1  - Garcia, Encarna B. Gómez
A1  - van Leeuwen, Flora E.
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Gille, Johannes J. P.
A1  - Ausems, Magreet G. E. M.
A1  - Blok, Marinus J.
A1  - Ligtenberg, Marjolinjin J. L.
A1  - Rookus, Matti A.
A1  - Devilee, Peter
A1  - Verhoef, Senno
A1  - van Os, Theo A. M.
A1  - Wijnen, Juul T.
A1  - Frost, Debra
A1  - Ellis, Steve
A1  - Fineberg, Elena
A1  - Platte, Radke
A1  - Evans, D. Gareth
A1  - Izatt, Luise
A1  - Eeles, Rosalind A.
A1  - Adlard, Julian
A1  - Eccles, Diana M.
A1  - Cook, Jackie
A1  - Brewer, Carole
A1  - Douglas, Fiona
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Side, Lucy E.
A1  - Donaldson, Alan
A1  - Houghton, Catherine
A1  - Rogers, Mark T.
A1  - Dorkins, Huw
A1  - Eason, Jacqueline
A1  - Gregory, Helen
A1  - McCann, Emma
A1  - Murray, Alex
A1  - Calender, Alain
A1  - Hardouin, Agnès
A1  - Berthet, Pascaline
A1  - Delnatte, Capucine
A1  - Nogues, Catherine
A1  - Lasset, Christine
A1  - Houdayer, Claude
A1  - Leroux,, Dominique
A1  - Rouleau, Etienne
A1  - Prieur, Fabienne
A1  - Damiola, Francesca
A1  - Sobol, Hagay
A1  - Coupier, Isabelle
A1  - Venat-Bouvet, Laurence
A1  - Castera, Laurent
A1  - Gauthier-Villars, Marion
A1  - Léoné, Mélanie
A1  - Pujol, Pascal
A1  - Mazoyer, Sylvie
A1  - Bignon, Yves-Jean
A1  - Zlowocka-Perlowska, Elzbieta
A1  - Gronwald, Jacek
A1  - Lubinski,, Jan
A1  - Durda, Katarzyna
A1  - Jaworska, Katarzyna
A1  - Huzarski, Tomasz
A1  - Spurdle, Amanda B.
A1  - Viel, Alessandra
A1  - Peissel, Bernhard
A1  - Bonanni, Bernardo
A1  - Melloni, Guilia
A1  - Ottini, Laura
A1  - Papi, Laura
A1  - Varesco, Liliana
A1  - Tibiletti, Maria Grazia
A1  - Peterlongo, Paolo
A1  - Volorio, Sara
A1  - Manoukian, Siranoush
A1  - Pensotti, Valeria
A1  - Arnold, Norbert
A1  - Engel, Christoph
A1  - Deissler, Helmut
A1  - Gadzicki, Dorothea
A1  - Gehrig, Andrea
A1  - Kast, Karin
A1  - Rhiem, Kerstin
A1  - Meindl, Alfons
A1  - Niederacher, Dieter
A1  - Ditsch, Nina
A1  - Plendl, Hansjoerg
A1  - Preisler-Adams, Sabine
A1  - Engert, Stefanie
A1  - Sutter, Christian
A1  - Varon-Mateeva, Raymenda
A1  - Wappenschmidt, Barbara
A1  - Weber, Bernhard H. F.
A1  - Arver, Brita
A1  - Stenmark-Askmalm, Marie
A1  - Loman, Niklas
A1  - Rosenquist, Richard
A1  - Einbeigi, Zakaria
A1  - Nathanson, Katherine L.
A1  - Rebbeck, Timothy R.
A1  - Blank, Stephanie V.
A1  - Cohn, David E.
A1  - Rodriguez, Gustavo C.
A1  - Small, Laurie
A1  - Friedlander, Michael
A1  - Bae-Jump, Victoria L.
A1  - Fink-Retter, Anneliese
A1  - Rappaport, Christine
A1  - Gschwantler-Kaulich, Daphne
A1  - Pfeiler, Georg
A1  - Tea, Muy-Kheng
A1  - Lindor, Noralane M.
A1  - Kaufman, Bella
A1  - Paluch, Shani Shimon
A1  - Laitman, Yael
A1  - Skytte, Anne-Bine
A1  - Gerdes, Anne-Marie
A1  - Pedersen, Inge Sokilde
A1  - Moeller, Sanne Traasdahl
A1  - Kruse, Torben A.
A1  - Jensen, Uffe Birk
A1  - Vijai, Joseph
A1  - Sarrel, Kara
A1  - Robson, Mark
A1  - Kauff, Noah
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Ozcelik, Hilmi
A1  - Ejlertsen, Bent
A1  - Nielsen, Finn C.
A1  - Jønson, Lars
A1  - Andersen, Mette K.
A1  - Ding, Yuan Chun
A1  - Steele, Linda
A1  - Foretova, Lenka
A1  - Teulé, Alex
A1  - Lazaro, Conxi
A1  - Brunet, Joan
A1  - Pujana, Miquel Angel
A1  - Mai, Phuong L.
A1  - Loud, Jennifer T.
A1  - Walsh, Christine
A1  - Lester, Jenny
A1  - Orsulic, Sandra
A1  - Narod, Steven A.
A1  - Herzog, Josef
A1  - Sand, Sharon R.
A1  - Tognazzo, Silvia
A1  - Agata, Simona
A1  - Vaszko, Tibor
A1  - Weaver, Joellen
A1  - Stravropoulou, Alexandra V.
A1  - Buys, Saundra S.
A1  - Romero, Atocha
A1  - de la Hoya, Miguel
A1  - Aittomäki, Kristiina
A1  - Muranen, Taru A.
A1  - Duran, Mercedes
A1  - Chung, Wendy K.
A1  - Lasa, Adriana
A1  - Dorfling, Cecilia M.
A1  - Miron, Alexander
A1  - Benitez, Javier
A1  - Senter, Leigha
A1  - Huo, Dezheng
A1  - Chan, Salina B.
A1  - Sokolenko, Anna P.
A1  - Chiquette, Jocelyne
A1  - Tihomirova, Laima
A1  - Friebel, Tara M.
A1  - Agnarsson, Bjarne A.
A1  - Lu, Karen H.
A1  - Lejbkowicz, Flavio
A1  - James, Paul A.
A1  - Hall, Per
A1  - Dunning, Alison M.
A1  - Tessier, Daniel
A1  - Cunningham, Julie
A1  - Slager, Susan L.
A1  - Chen, Wang
A1  - Hart, Steven
A1  - Stevens, Kristen
A1  - Simard, Jacques
A1  - Pastinen, Tomi
A1  - Pankratz, Vernon S.
A1  - Offit, Kenneth
A1  - Easton, Douglas F.
A1  - Chenevix-Trench, Georgia
A1  - Antoniou, Antonis C.
T1  - Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
JF  - PLOS Genetics
N2  - BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.
KW  - common variants
KW  - susceptibility alleles
KW  - genetic variants
KW  - modifiers
KW  - ZNF365
KW  - investigators
KW  - population
KW  - consortium
KW  - selection
KW  - subtypes
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-127947
SN  - 1553-7404
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Bittner, Stefan
A1  - Bobak, Nicole
A1  - Feuchtenberger, Martin
A1  - Herrmann, Alexander M
A1  - Göbel, Kerstin
A1  - Kinne, Raimund W
A1  - Hansen, Anker J
A1  - Budde, Thomas
A1  - Kleinschnitz, Christoph
A1  - Frey, Oliver
A1  - Tony, Hans-Peter
A1  - Wiendl, Heinz
A1  - Meuth, Sven G
T1  - Expression of K\(_2\)\(_P\)5.1 potassium channels on CD4\(^+\)T lymphocytes correlates with disease activity in rheumatoid arthritis patients
JF  - Arthritis Research & Therapy
N2  - Introduction

CD4+ T cells express K2P5.1 (TWIK-related acid-sensitive potassium channel 2 (TASK2); KCNK5), a member of the two-pore domain potassium channel family, which has been shown to influence T cell effector functions. Recently, it was shown that K2P5.1 is upregulated upon (autoimmune) T cell stimulation. The aim of this study was to correlate expression levels of K2P5.1 on T cells from patients with rheumatoid arthritis (RA) to disease activity in these patients.

Methods

Expression levels of K2P5.1 were measured by RT-PCR in the peripheral blood of 58 patients with RA and correlated with disease activity parameters (C-reactive protein levels, erythrocyte sedimentation rates, disease activity score (DAS28) scores). Twenty patients undergoing therapy change were followed-up for six months. Additionally, synovial fluid and synovial biopsies were investigated for T lymphocytes expressing K2P5.1.

Results

K2P5.1 expression levels in CD4+ T cells show a strong correlation to DAS28 scores in RA patients. Similar correlations were found for serological inflammatory parameters (erythrocyte sedimentation rate, C-reactive protein). In addition, K2P5.1 expression levels of synovial fluid-derived T cells are higher compared to peripheral blood T cells. Prospective data in individual patients show a parallel behaviour of K2P5.1 expression to disease activity parameters during a longitudinal follow-up for six months.

Conclusions

Disease activity in RA patients correlates strongly with K2P5.1 expression levels in CD4+ T lymphocytes in the peripheral blood in cross-sectional as well as in longitudinal observations. Further studies are needed to investigate the exact pathophysiological mechanisms and to evaluate the possible use of K2P5.1 as a potential biomarker for disease activity and differential diagnosis.
KW  - neurology
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-139334
VL  - 13
IS  - R21
ER  - 
TY  - JOUR
A1  - Duhr, Carolin D.
A1  - Kenn, Werner
A1  - Kickuth, Ralph
A1  - Kerscher, Alexander G.
A1  - Germer, Christoph-Thomas
A1  - Hahn, Dietbert
A1  - Pelz, Joerg O. W.
T1  - Optimizing of preoperative computed tomography for diagnosis in patients with peritoneal carcinomatosis
JF  - World Journal of Surgical Oncology
N2  - Background and Objective
This study evaluates whether Computer Tomography is an effective procedure for preoperative staging of patients with Peritoneal Carcinomatosis.

Method
A sample of 37 patients was analyzed with contrast enhanced abdominal Computer Tomography, followed by surgical staging. All Computer Tomography scans were evaluated 3 times by 2 radiologists with one radiologist reviewing 2 times. The efficacy of Computer Tomography was evaluated using the Spearman correlation coefficient. Correlations were analyzed by abdominopelvic region to assess results of the Peritoneal Carcinomatosis Index (PCI) aggregating the 13 regions. Surgical findings were compared to radiological findings.

Results
Results indicate high correlations between the surgical and radiological Peritoneal Carcinomatosis Indices. Analyses of the intra-class correlation between the first and second reading of one radiologist suggest high intra-observer reliability. Correlations by abdominopelvic region show higher values in the upper and middle regions and relatively lower values in the lower regions and the small bowel (correlation coefficients range between 0.418 and 0.726, p < 0.010; sensitivities range between 50% and 96%; and specificities range between 62% and 100%).

Conclusion
Computer Tomography represents an effective procedure in the preoperative staging of patients with PC. However, results by abdominopelvic region show lower correlation, therefore suggest lower efficacy. These results are supported by analyses of sensitivity and accuracy by lesion size. This suggests that Computer Tomography is an effective procedure for pre-operative staging but less for determining a tumor's accurate extent.
KW  - Carcinomatosis
KW  - diagnosis
KW  - PCI
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-138024
VL  - 9
IS  - 171
ER  - 
TY  - JOUR
A1  - Carsten A., Böger
A1  - Gorski, Mathias
A1  - Li, Man
A1  - Hoffmann, Michael M.
A1  - Huang, Chunmei
A1  - Yang, Qiong
A1  - Teumer, Alexander
A1  - Krane, Vera
A1  - O'Seaghdha, Conall M.
A1  - Kutalik, Zoltán
A1  - Wichmann, H.-Erich
A1  - Haak, Thomas
A1  - Boes, Eva
A1  - Coassin, Stefan
A1  - Coresh, Josef
A1  - Kollerits, Barbara
A1  - Haun, Margot
A1  - Paulweber, Bernhard
A1  - Köttgen, Anna
A1  - Li, Guo
A1  - Shlipak, Michael G.
A1  - Powe, Neil
A1  - Hwang, Shih-Jen
A1  - Dehghan, Abbas
A1  - Rivadeneira, Fernando
A1  - Uitterlinden, André
A1  - Hofman, Albert
A1  - Beckmann, Jacques S.
A1  - Krämer, Bernhard K.
A1  - Witteman, Jacqueline
A1  - Bochud, Murielle
A1  - Siscovick, David
A1  - Rettig, Rainer
A1  - Kronenberg, Florian
A1  - Wanner, Christoph
A1  - Thadhani, Ravi I.
A1  - Heid, Iris M.
A1  - Fox, Caroline S.
A1  - Kao, W.H.
T1  - Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD
JF  - PLoS Genetics
N2  - Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR < 60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
KW  - Chronic Kidney-disease
KW  - Stage renal-disease
KW  - Glomerular-filtration-rate
KW  - Diabetic-nephropathy
KW  - General-population
KW  - African-americans
KW  - Risk
KW  - Progression
KW  - Mortality
KW  - Variants
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-133758
VL  - 7
IS  - 9
ER  - 
TY  - JOUR
A1  - Antoniou, Antonis C.
A1  - Kuchenbaecker, Karoline B.
A1  - Soucy, Penny
A1  - Beesley, Jonathan
A1  - Chen, Xiaoqing
A1  - McGuffog, Lesley
A1  - Lee, Andrew
A1  - Barrowdale, Daniel
A1  - Healey, Sue
A1  - Sinilnikova, Olga M.
A1  - Caligo, Maria A.
A1  - Loman, Niklas
A1  - Harbst, Katja
A1  - Lindblom, Annika
A1  - Arver, Brita
A1  - Rosenquist, Richard
A1  - Karlsson, Per
A1  - Nathanson, Kate
A1  - Domchek, Susan
A1  - Rebbeck, Tim
A1  - Jakubowska, Anna
A1  - Lubinski, Jan
A1  - Jaworska, Katarzyna
A1  - Durda, Katarzyna
A1  - Zlowowcka-Perłowska, Elżbieta
A1  - Osorio, Ana
A1  - Durán, Mercedes
A1  - Andrés, Raquel
A1  - Benítez, Javier
A1  - Hamann, Ute
A1  - Hogervorst, Frans B.
A1  - van Os, Theo A.
A1  - Verhoef, Senno
A1  - Meijers-Heijboer, Hanne E. J.
A1  - Wijnen, Juul
A1  - Garcia, Encarna B. Gómez
A1  - Ligtenberg, Marjolijn J.
A1  - Kriege, Mieke
A1  - Collée, Margriet
A1  - Ausems, Margreet G. E. M.
A1  - Oosterwijk, Jan C.
A1  - Peock, Susan
A1  - Frost, Debra
A1  - Ellis, Steve D.
A1  - Platte, Radka
A1  - Fineberg, Elena
A1  - Evans, D. Gareth
A1  - Lalloo, Fiona
A1  - Jacobs, Chris
A1  - Eeles, Ros
A1  - Adlard, Julian
A1  - Davidson, Rosemarie
A1  - Cole, Trevor
A1  - Cook, Jackie
A1  - Paterson, Joan
A1  - Douglas, Fiona
A1  - Brewer, Carole
A1  - Hodgson, Shirley
A1  - Morrison, Patrick J.
A1  - Walker, Lisa
A1  - Rogers, Mark T.
A1  - Donaldson, Alan
A1  - Dorkins, Huw
A1  - Godwin, Andrew K.
A1  - Bove, Betsy
A1  - Stoppa-Lyonnet, Dominique
A1  - Houdayer, Claude
A1  - Buecher, Bruno
A1  - de Pauw, Antoine
A1  - Mazoyer, Sylvie
A1  - Calender, Alain
A1  - Léoné, Mélanie
A1  - Bressac-de Paillerets, Brigitte
A1  - Caron, Olivier
A1  - Sobol, Hagay
A1  - Frenay, Marc
A1  - Prieur, Fabienne
A1  - Ferrer, Sandra Fert
A1  - Mortemousque, Isabelle
A1  - Buys, Saundra
A1  - Daly, Mary
A1  - Miron, Alexander
A1  - Terry, Mary Beth
A1  - Hopper, John L.
A1  - John, Esther M.
A1  - Southey, Melissa
A1  - Goldgar, David
A1  - Singer, Christian F.
A1  - Fink-Retter, Anneliese
A1  - Muy-Kheng, Tea
A1  - Geschwantler Kaulich, Daphne
A1  - Hansen, Thomas V. O.
A1  - Nielsen, Finn C.
A1  - Barkardottir, Rosa B.
A1  - Gaudet, Mia
A1  - Kirchhoff, Tomas
A1  - Joseph, Vijai
A1  - Dutra-Clarke, Ana
A1  - Offit, Kenneth
A1  - Piedmonte, Marion
A1  - Kirk, Judy
A1  - Cohn, David
A1  - Hurteau, Jean
A1  - Byron, John
A1  - Fiorica, James
A1  - Toland, Amanda E.
A1  - Montagna, Marco
A1  - Oliani, Cristina
A1  - Imyanitov, Evgeny
A1  - Isaacs, Claudine
A1  - Tihomirova, Laima
A1  - Blanco, Ignacio
A1  - Lazaro, Conxi
A1  - Teulé, Alex
A1  - Del Valle, J.
A1  - Gayther, Simon A.
A1  - Odunsi, Kunle
A1  - Gross, Jenny
A1  - Karlan, Beth Y.
A1  - Olah, Edith
A1  - Teo, Soo-Hwang
A1  - Ganz, Patricia A.
A1  - Beattie, Mary S.
A1  - Dorfling, Cecelia M.
A1  - Jansen van Rensburg, Elizabeth
A1  - Diez, Orland
A1  - Kwong, Ava
A1  - Schmutzler, Rita K.
A1  - Wappenschmidt, Barbara
A1  - Engel, Christoph
A1  - Meindl, Alfons
A1  - Ditsch, Nina
A1  - Arnold, Norbert
A1  - Heidemann, Simone
A1  - Niederacher, Dieter
A1  - Preisler-Adams, Sabine
A1  - Gadzicki, Dorothea
A1  - Varon-Mateeva, Raymonda
A1  - Deissler, Helmut
A1  - Gehrig, Andrea
A1  - Sutter, Christian
A1  - Kast, Karin
A1  - Fiebig, Britta
A1  - Schäfer, Dieter
A1  - Caldes, Trinidad
A1  - de la Hoya, Miguel
A1  - Nevanlinna, Heli
A1  - Muranen, Taru A.
A1  - Lespérance, Bernard
A1  - Spurdle, Amanda B.
A1  - Neuhausen, Susan L.
A1  - Ding, Yuan C.
A1  - Wang, Xianshu
A1  - Fredericksen, Zachary
A1  - Pankratz, Vernon S.
A1  - Lindor, Noralane M.
A1  - Peterlongo, Paulo
A1  - Manoukian, Siranoush
A1  - Peissel, Bernard
A1  - Zaffaroni, Daniela
A1  - Bonanni, Bernardo
A1  - Bernard, Loris
A1  - Dolcetti, Riccardo
A1  - Papi, Laura
A1  - Ottini, Laura
A1  - Radice, Paolo
A1  - Greene, Mark H.
A1  - Loud, Jennifer T.
A1  - Andrulis, Irene L.
A1  - Ozcelik, Hilmi
A1  - Mulligan, Anna Marie
A1  - Glendon, Gord
A1  - Thomassen, Mads
A1  - Gerdes, Anne-Marie
A1  - Jensen, Uffe B.
A1  - Skytte, Anne-Bine
A1  - Kruse, Torben A.
A1  - Chenevix-Trench, Georgia
A1  - Couch, Fergus J.
A1  - Simard, Jacques
A1  - Easton, Douglas F.
T1  - Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers
JF  - Breast Cancer Research
N2  - Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). 
Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. 
Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10\(^{-4}\)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10\(^{-5}\), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10\(^{-5}\)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). 
Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.
KW  - investigators
KW  - genetic modifiers
KW  - mammographic density
KW  - susceptibility loci
KW  - ovarian cancer
KW  - hormone-related protein
KW  - genome-wide association
KW  - tumor subtypes
KW  - alleles
KW  - consortium
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130449
VL  - 14
IS  - R33
ER  - 
TY  - JOUR
A1  - Zeller, Mario
A1  - Müller, Alexander
A1  - Gutberlet, Marcel
A1  - Nichols, Thomas
A1  - Hahn, Dietbert
A1  - Köstler, Herbert
A1  - Bartsch, Andreas J.
T1  - Boosting BOLD fMRI by K-Space Density Weighted Echo Planar Imaging
JF  - PLoS ONE
N2  - Functional magnetic resonance imaging (fMRI) has become a powerful and influential method to non-invasively study neuronal brain activity. For this purpose, the blood oxygenation level-dependent (BOLD) effect is most widely used. T2* weighted echo planar imaging (EPI) is BOLD sensitive and the prevailing fMRI acquisition technique. Here, we present an alternative to its standard Cartesian recordings, i.e. k-space density weighted EPI, which is expected to increase the signal-to-noise ratio in fMRI data. Based on in vitro and in vivo pilot measurements, we show that fMRI by k-space density weighted EPI is feasible and that this new acquisition technique in fact boosted spatial and temporal SNR as well as the detection of local fMRI activations. Spatial resolution, spatial response function and echo time were identical for density weighted and conventional Cartesian EPI. The signal-to-noise ratio gain of density weighting can improve activation detection and has the potential to further increase the sensitivity of fMRI investigations.
KW  - data acquisition
KW  - density
KW  - echo planar imaging
KW  - functional magnetic resonance imaging
KW  - imaging techniques
KW  - matched filters
KW  - signal filtering
KW  - statistical data
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97233
ER  - 
TY  - JOUR
A1  - Wiegering, Armin
A1  - Isbert, Christoph
A1  - Dietz, Ulrich A.
A1  - Kunzmann, Volker
A1  - Ackermann, Sabine
A1  - Kerscher, Alexander
A1  - Maeder, Uwe
A1  - Flentje, Michael
A1  - Schlegel, Nicolas
A1  - Reibetanz, Joachim
A1  - Germer, Christoph-Thomas
A1  - Klein, Ingo
T1  - Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades
N2  - Background

The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival.

Methods

Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010.

Results

The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6% vs. 60%) and adjuvant chemotherapy (37.9% vs. 58.4%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60% to 79%.

Conclusion

In our study population, the implementation of treatment changes over the last decade improved the patient’s outcome significantly. Improvements were most evident for UICC stage III rectal cancer.
KW  - Rectal cancer
KW  - Improved survival
KW  - TME
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110606
ER  - 
TY  - JOUR
A1  - Hartmann, Stefan
A1  - Lessner, Grit
A1  - Mentzel, Thomas
A1  - Kübler, Alexander C.
A1  - Müller-Richter, Urs
T1  - An adult spindle cell rhabdomyosarcoma in the head and neck region with long-term survival: a case report
N2  - Introduction

Spindle cell rhabdomyosarcoma of the head and neck is a very rare tumor in adults. We report on one case with long-term survival.

Case presentation

A 41-year-old nonsmoking Caucasian man presented in June 2007 with a painless swelling under his tongue. A diagnosis of a soft tissue sarcoma, and a myofibrosarcoma in particular, was made via biopsy. After multimodal treatment, including local and systemic therapy, our patient remained disease-free until September 2010. The local recurrence was treated unsuccessfully with various chemotherapy regimens. In September 2011, our patient underwent surgical resection again, and a spindle cell rhabdomyosarcoma was diagnosed. To analyze the mismatch between the original diagnosis of a myofibrosarcoma and the second diagnosis, the two specimens were reassessed, and a final diagnosis of a spindle cell rhabdomyosarcoma was made. In 2012 and 2013, our patient suffered further recurrences that were surgically treated, and he is still alive with disease six years and 10 months after the initial diagnosis in June 2007.

Conclusions

In adults, the spindle cell rhabdomyosarcoma tumor is very rare in the head and neck region. In contrast to childhood tumors, spindle cell rhabdomyosarcoma in adulthood is often associated with a poor prognosis. In the present case, the radical surgical treatment might have helped to prolong the patient’s overall survival, which has lasted more than six years. To our knowledge, this is the longest overall survival reported so far for this tumor entity in the head and neck region.
KW  - Rhabdomyosarcoma
KW  - Spindle cell
KW  - Adult
KW  - Surgery
KW  - Head
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-110362
ER  - 
TY  - JOUR
A1  - Weber, Heike
A1  - Scholz, Claus Jürgen
A1  - Domschke, Katharina
A1  - Baumann, Christian
A1  - Klauke, Benedikt
A1  - Jacob, Christian P.
A1  - Maier, Wolfgang
A1  - Fritze, Jürgen
A1  - Bandelow, Borwin
A1  - Zwanzger, Peter Michael
A1  - Lang, Thomas
A1  - Fehm, Lydia
A1  - Ströhle, Andreas
A1  - Hamm, Alfons
A1  - Gerlach, Alexander L.
A1  - Alpers, Georg W.
A1  - Kircher, Tilo
A1  - Wittchen, Hans-Ulrich
A1  - Arolt, Volker
A1  - Pauli, Paul
A1  - Deckert, Jürgen
A1  - Reif, Andreas
T1  - Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder
N2  - Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype6gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype6gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
KW  - Medizin
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75830
ER  - 
TY  - THES
A1  - Hubert, Alexander Thomas Wilhelm
T1  - Funktionelle kardiale Magnet-Resonanz-Tomographie: Einfluss der alternativen Wahl des Narkosemittels Isofluran, Propofol sowie Propofol in Kombination mit Pancuronium auf die kardialen Funktionsparameter im Rattenmodell
N2  - Die Magnetresonanztomographie stellt den Goldstandard zur kardialen Funktionsdiagnostik dar und ermöglicht die nicht-invasive Analyse der Herzfunktion mit valider Bestimmung von Volumina, Flüssen sowie der Ejektionsfraktion in vivo. In unserer Arbeitsgruppe erfolgt eine stetige Weiterentwicklung der Methode am Rattenmodell, wobei regelhaft eine Narkose des Versuchtstiers notwendig ist. Im Rahmen meiner Arbeit wurde der Effekt verschiedener Narkoseformen auf die Herzfunktion untersucht. Dabei wurde eine Isoflurannarkose einer Narkose mittels Propofol sowie Propofol in Kombination mit Pancuronium gegenübergestellt. Hierbei zeigen sich teilweise deutliche Unterschiede in den kardialen Funktionsparametern während der Untersuchung. Hieraus ist zu folgern, dass ein sinnvoller Vergleich der Herzfunktion von Versuchsreihen mit unterschiedlicher Narkosetechnik problematisch ist. Dies unterstreicht die Wichtigkeit einer Festlegung der Narkosetechnik vor Beginn einer Versuchsreihe in der kardiovaskulären Forschung und deren Konstanthaltung über die gesamte Versuchsdauer.
N2  - Cardiac magnetic resonance imaging (MRI) is considered the current gold standard for in vivo-analysis of cardiac structure and function. Our workgroup is concentrating on developing cardiac MRI techniques in small animal models, which generally requires anaesthesia of the animal. In the current study, the effects of the narcotics Isoflurane vs. Propofol vs. Propofol in combination with Pancuronium on functional cardiac parameters measured by cardiac MRI were analyzed. The results reveal major differences of the acquired functional cardiac parameters in animals anaesthetized with Isoflurane, Propofol, or Propofol in combination with Pancuronium, respectively. This highlights the importance of establishing a specific anaesthesia technique and keeping it unchanged during an entire MRI study.
KW  - Kernspintomographie
KW  - Magnetresonanztomographie
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-94402
ER  - 
TY  - JOUR
A1  - Kosmala, Aleksander
A1  - Serfling, Sebastian E.
A1  - Dreher, Niklas
A1  - Lindner, Thomas
A1  - Schirbel, Andreas
A1  - Lapa, Constantin
A1  - Higuchi, Takahiro
A1  - Buck, Andreas K.
A1  - Weich, Alexander
A1  - Werner, Rudolf A.
T1  - Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography
JF  - Cancers
N2  - (1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs.
KW  - PET
KW  - [\(^{68}\)Ga]Ga-FAPI
KW  - theranostics
KW  - radioligand therapy
KW  - fibroblast activation protein
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275154
SN  - 2072-6694
VL  - 14
IS  - 11
ER  - 
TY  - JOUR
A1  - Lagler, Charlotte
A1  - El-Mesery, Mohamed
A1  - Kübler, Alexander Christian
A1  - Müller-Richter, Urs Dietmar Achim
A1  - Stühmer, Thorsten
A1  - Nickel, Joachim
A1  - Müller, Thomas Dieter
A1  - Wajant, Harald
A1  - Seher, Axel
T1  - The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent
JF  - PLoS ONE
N2  - Multiple myeloma (MM), a malignancy of the bone marrow, is characterized by a pathological increase in antibody-producing plasma cells and an increase in immunoglobulins (plasmacytosis). In recent years, bone morphogenetic proteins (BMPs) have been reported to be activators of apoptotic cell death in neoplastic B cells in MM. Here, we use bone morphogenetic protein 2 (BMP2) to show that the "apoptotic" effect of BMPs on human neoplastic B cells is dominated by anti-proliferative activities and cell cycle arrest and is apoptosis-independent. The anti-proliferative effect of BMP2 was analysed in the human cell lines KMS12-BM and L363 using WST-1 and a Coulter counter and was confirmed using CytoTox assays with established inhibitors of programmed cell death (zVAD-fmk and necrostatin-1). Furthermore, apoptotic activity was compared in both cell lines employing western blot analysis for caspase 3 and 8 in cells treated with BMP2 and FasL. Additionally, expression profiles of marker genes of different cell death pathways were analysed in both cell lines after stimulation with BMP2 for 48h using an RT-PCR-based array. In our experiments we observed that there was rather no reduction in absolute cell number, but cells stopped proliferating following treatment with BMP2 instead. The time frame (48–72 h) after BMP2 treatment at which a reduction in cell number is detectable is too long to indicate a directly BMP2-triggered apoptosis. Moreover, in comparison to robust apoptosis induced by the approved apoptotic factor FasL, BMP2 only marginally induced cell death. Consistently, neither the known inhibitor of apoptotic cell death zVAD-fmk nor the necroptosis inhibitor necrostatin-1 was able to rescue myeloma cell growth in the presence of BMP2.
KW  - apoptosis
KW  - gene expression
KW  - necrotic cell death
KW  - multiple myeloma
KW  - cell metabolism
KW  - cell cycle and cell division
KW  - B cells
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158993
VL  - 12
IS  - 10
ER  - 
TY  - JOUR
A1  - Walter, Steffen
A1  - Gruss, Sascha
A1  - Neidlinger, Jana
A1  - Stross, Isabelle
A1  - Hann, Alexander
A1  - Wagner, Martin
A1  - Seufferlein, Thomas
A1  - Walter, Benjamin
T1  - Evaluation of an Objective Measurement Tool for Stress Level Reduction by Individually Chosen Music During Colonoscopy—Results From the Study “ColoRelaxTone”
JF  - Frontiers in Medicine
N2  - Background and Aims: Colonoscopy as standard procedure in endoscopy is often perceived as uncomfortable for patients. Patient's anxiety is therefore a significant issue, which often lead to avoidance of participation of relevant examinations as CRC-screening. Non-pharmacological anxiety management interventions such as music might contribute to relaxation in the phase prior and during endoscopy. Although music's anxiolytic effects have been reported previously, no objective measurement of stress level reduction has been reported yet. Focus of this study was to evaluate the objective measurement of the state of relaxation in patients undergoing colonoscopy.
Methods: Prospective study (n = 196) performed at one endoscopic high-volume center. Standard colonoscopy was performed in control group. Interventional group received additionally self-chosen music over earphones. Facial Electromyography (fEMG) activity was obtained. Clinician Satisfaction with Sedation Instrument (CSSI) and Patients Satisfaction with Sedation Instrument (PSSI) was answered by colonoscopists and patients, respectively. Overall satisfaction with music accompanied colonoscopy was obtained if applicable.
Results: Mean difference measured by fEMG via musculus zygomaticus major indicated a significantly lower stress level in the music group [7.700(±5.560) μV vs. 4.820(±3.330) μV; p = 0.001]. Clinician satisfaction was significantly higher with patients listening to music [82.69(±15.04) vs. 87.3(±15.02) pts.; p = 0.001]. Patient's satisfaction was higher but did not differ significantly.
Conclusions: We conclude that self-chosen music contributes objectively to a reduced stress level for patients and therefore subjectively perceived satisfaction for endoscopists. Therefore, music should be considered as a non-pharmacological treatment method of distress reduction especially in the beginning of endoscopic procedures.
KW  - colonoscopy
KW  - anxiety
KW  - stress level
KW  - music
KW  - relaxation
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212337
VL  - 7
ER  - 
TY  - JOUR
A1  - Bencurova, Elena
A1  - Shityakov, Sergey
A1  - Schaack, Dominik
A1  - Kaltdorf, Martin
A1  - Sarukhanyan, Edita
A1  - Hilgarth, Alexander
A1  - Rath, Christin
A1  - Montenegro, Sergio
A1  - Roth, Günter
A1  - Lopez, Daniel
A1  - Dandekar, Thomas
T1  - Nanocellulose composites as smart devices with chassis, light-directed DNA Storage, engineered electronic properties, and chip integration
JF  - Frontiers in Bioengineering and Biotechnology
N2  - The rapid development of green and sustainable materials opens up new possibilities in the field of applied research. Such materials include nanocellulose composites that can integrate many components into composites and provide a good chassis for smart devices. In our study, we evaluate four approaches for turning a nanocellulose composite into an information storage or processing device: 1) nanocellulose can be a suitable carrier material and protect information stored in DNA. 2) Nucleotide-processing enzymes (polymerase and exonuclease) can be controlled by light after fusing them with light-gating domains; nucleotide substrate specificity can be changed by mutation or pH change (read-in and read-out of the information). 3) Semiconductors and electronic capabilities can be achieved: we show that nanocellulose is rendered electronic by iodine treatment replacing silicon including microstructures. Nanocellulose semiconductor properties are measured, and the resulting potential including single-electron transistors (SET) and their properties are modeled. Electric current can also be transported by DNA through G-quadruplex DNA molecules; these as well as classical silicon semiconductors can easily be integrated into the nanocellulose composite. 4) To elaborate upon miniaturization and integration for a smart nanocellulose chip device, we demonstrate pH-sensitive dyes in nanocellulose, nanopore creation, and kinase micropatterning on bacterial membranes as well as digital PCR micro-wells. Future application potential includes nano-3D printing and fast molecular processors (e.g., SETs) integrated with DNA storage and conventional electronics. This would also lead to environment-friendly nanocellulose chips for information processing as well as smart nanocellulose composites for biomedical applications and nano-factories.
KW  - nanocellulose
KW  - DNA storage
KW  - light-gated proteins
KW  - single-electron transistors
KW  - protein chip
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-283033
SN  - 2296-4185
VL  - 10
ER  - 
TY  - JOUR
A1  - Seher, Axel
A1  - Lagler, Charlotte
A1  - Stühmer, Thorsten
A1  - Müller-Richter, Urs Dietmar Achim
A1  - Kübler, Alexander Christian
A1  - Sebald, Walter
A1  - Müller, Thomas Dieter
A1  - Nickel, Joachim
T1  - Utilizing BMP-2 muteins for treatment of multiple myeloma
JF  - PLoS ONE
N2  - Multiple myeloma (MM) represents a haematological cancer characterized by the pathological hyper proliferation of antibody-producing B-lymphocytes. Patients typically suffer from kidney malfunction and skeletal disorders. In the context of MM, the transforming growth factor β (TGFβ) member Activin A was recently identified as a promoter of both accompanying symptoms. Because studies have shown that bone morphogenetic protein (BMP)-2-mediated activities are counteracted by Activin A, we analysed whether BMP2, which also binds to the Activin A receptors ActRII and ActRIIB but activates the alternative SMAD-1/5/8 pathway, can be used to antagonize Activin A activities, such as in the context of MM. Therefore three BMP2 derivatives were generated with modified binding activities for the type II (ActRIIB) and/or type I receptor (BMPRIA) showing either increased or decreased BMP2 activity. In the context of MM these BMP2 muteins show two functionalities since they act as a) an anti-proliferative/apoptotic agent against neoplastic B-cells, b) as a bone-formation promoting growth factor. The molecular basis of both activities was shown in two different cellular models to clearly rely on the properties of the investigated BMP2 muteins to compete for the binding of Activin A to the Activin type II receptors. The experimental outcome suggests new therapeutic strategies using BMP2 variants in the treatment of MM-related pathologies.
KW  - multiple myeloma
KW  - signaling
KW  - cell proliferation
KW  - cell binding
KW  - membrane receptor signaling
KW  - BMP
KW  - gene expression
KW  - B cell receptors
KW  - B cells
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158144
VL  - 12
IS  - 5
ER  - 
TY  - JOUR
A1  - Sadovnick, A. Dessa
A1  - Traboulsee, Anthony L.
A1  - Bernales, Cecily Q.
A1  - Ross, Jay P.
A1  - Forwell, Amanda L.
A1  - Yee, Irene M.
A1  - Guillot-Noel, Lena
A1  - Fontaine, Bertrand
A1  - Cournu-Rebeix, Isabelle
A1  - Alcina, Antonio
A1  - Fedetz, Maria
A1  - Izquierdo, Guillermo
A1  - Matesanz, Fuencisla
A1  - Hilven, Kelly
A1  - Dubois, Bénédicte
A1  - Goris, An
A1  - Astobiza, Ianire
A1  - Alloza, Iraide
A1  - Antigüedad, Alfredo
A1  - Vandenbroeck, Koen
A1  - Akkad, Denis A.
A1  - Aktas, Orhan
A1  - Blaschke, Paul
A1  - Buttmann, Mathias
A1  - Chan, Andrew
A1  - Epplen, Joerg T.
A1  - Gerdes, Lisa-Ann
A1  - Kroner, Antje
A1  - Kubisch, Christian
A1  - Kümpfel, Tania
A1  - Lohse, Peter
A1  - Rieckmann, Peter
A1  - Zettl, Uwe K.
A1  - Zipp, Frauke
A1  - Bertram, Lars
A1  - Lill, Christina M.
A1  - Fernandez, Oscar
A1  - Urbaneja, Patricia
A1  - Leyva, Laura
A1  - Alvarez-Cermeño, Jose Carlos
A1  - Arroyo, Rafael
A1  - Garagorri, Aroa M.
A1  - García-Martínez, Angel
A1  - Villar, Luisa M.
A1  - Urcelay, Elena
A1  - Malhotra, Sunny
A1  - Montalban, Xavier
A1  - Comabella, Manuel
A1  - Berger, Thomas
A1  - Fazekas, Franz
A1  - Reindl, Markus
A1  - Schmied, Mascha C.
A1  - Zimprich, Alexander
A1  - Vilariño-Güell, Carles
T1  - Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
JF  - G3: Genes Genomes Genetics
N2  - Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93–1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
KW  - multiple sclerosis
KW  - genetics
KW  - linkage
KW  - association
KW  - plasminogen
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165405
VL  - 6
IS  - 7
ER  - 
TY  - JOUR
A1  - Porubsky, Stefan
A1  - Popovic, Zoran V.
A1  - Badve, Sunil
A1  - Banz, Yara
A1  - Berezowska, Sabina
A1  - Borchert, Dietmar
A1  - Brüggemann, Monika
A1  - Gaiser, Timo
A1  - Graeter, Thomas
A1  - Hollaus, Peter
A1  - Huettl, Katrin S.
A1  - Kotrova, Michaela
A1  - Kreft, Andreas
A1  - Kugler, Christian
A1  - Lötscher, Fabian
A1  - Möller, Burkhard
A1  - Ott, German
A1  - Preissler, Gerhard
A1  - Roessner, Eric
A1  - Rosenwald, Andreas
A1  - Ströbel, Philipp
A1  - Marx, Alexander
T1  - Thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features: strong association with lymphomas and non-myasthenic autoimmune diseases
JF  - Cancers
N2  - Thymic hyperplasia (TH) with lymphoepithelial sialadenitis (LESA)-like features (LESA-like TH) has been described as a tumor-like, benign proliferation of thymic epithelial cells and lymphoid follicles. We aimed to determine the frequency of lymphoma and autoimmunity in LESA-like TH and performed retrospective analysis of cases with LESA-like TH and/or thymic MALT-lymphoma. Among 36 patients (21 males) with LESA-like TH (age 52 years, 32–80; lesion diameter 7.0 cm, 1–14.5; median, range), five (14%) showed associated lymphomas, including four (11%) thymic MALT lymphomas and one (3%) diffuse large B-cell lymphoma. One additional case showed a clonal B-cell-receptor rearrangement without evidence of lymphoma. Twelve (33%) patients (7 women) suffered from partially overlapping autoimmune diseases: systemic lupus erythematosus (n = 4, 11%), rheumatoid arthritis (n = 3, 8%), myasthenia gravis (n = 2, 6%), asthma (n = 2, 6%), scleroderma, Sjögren syndrome, pure red cell aplasia, Grave’s disease and anti-IgLON5 syndrome (each n = 1, 3%). Among 11 primary thymic MALT lymphomas, remnants of LESA-like TH were found in two cases (18%). In summary, LESA-like TH shows a striking association with autoimmunity and predisposes to lymphomas. Thus, a hematologic and rheumatologic workup should become standard in patients diagnosed with LESA-like TH. Radiologists and clinicians should be aware of LESA-like TH as a differential diagnosis for mediastinal mass lesions in patients with autoimmune diseases.
KW  - autoimmune disease
KW  - imaging
KW  - LESA
KW  - lymphoma
KW  - myasthenia
KW  - pathology
KW  - surgery
KW  - thymus
KW  - thymic epithelial tumor
KW  - thymitis
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223049
SN  - 2072-6694
VL  - 13
IS  - 2
ER  - 
TY  - JOUR
A1  - Hornick, Thomas
A1  - Richter, Anett
A1  - Harpole, William Stanley
A1  - Bastl, Maximilian
A1  - Bohlmann, Stephanie
A1  - Bonn, Aletta
A1  - Bumberger, Jan
A1  - Dietrich, Peter
A1  - Gemeinholzer, Birgit
A1  - Grote, Rüdiger
A1  - Heinold, Bernd
A1  - Keller, Alexander
A1  - Luttkus, Marie L.
A1  - Mäder, Patrick
A1  - Motivans Švara, Elena
A1  - Passonneau, Sarah
A1  - Punyasena, Surangi W.
A1  - Rakosy, Demetra
A1  - Richter, Ronny
A1  - Sickel, Wiebke
A1  - Steffan‐Dewenter, Ingolf
A1  - Theodorou, Panagiotis
A1  - Treudler, Regina
A1  - Werchan, Barbora
A1  - Werchan, Matthias
A1  - Wolke, Ralf
A1  - Dunker, Susanne
T1  - An integrative environmental pollen diversity assessment and its importance for the Sustainable Development Goals
JF  - Plants, People, Planet
N2  - Societal Impact Statement
Pollen relates to many aspects of human and environmental health, which protection and improvement are endorsed by the United Nations Sustainable Development Goals. By highlighting these connections in the frame of current challenges in monitoring and research, we discuss the need of more integrative and multidisciplinary pollen research related to societal needs, improving health of humans and our ecosystems for a sustainable future.
Summary
Pollen is at once intimately part of the reproductive cycle of seed plants and simultaneously highly relevant for the environment (pollinators, vector for nutrients, or organisms), people (food safety and health), and climate (cloud condensation nuclei and climate reconstruction). We provide an interdisciplinary perspective on the many and connected roles of pollen to foster a better integration of the currently disparate fields of pollen research, which would benefit from the sharing of general knowledge, technical advancements, or data processing solutions. We propose a more interdisciplinary and holistic research approach that encompasses total environmental pollen diversity (ePD) (wind and animal and occasionally water distributed pollen) at multiple levels of diversity (genotypic, phenotypic, physiological, chemical, and functional) across space and time. This interdisciplinary approach holds the potential to contribute to pressing human issues, including addressing United Nations Sustainable Development Goals, fostering social and political awareness of these tiny yet important and fascinating particles.
KW  - aerobiology
KW  - allergy
KW  - diversity
KW  - environmental monitoring
KW  - food safety
KW  - paleoecology
KW  - palynology
KW  - pollination
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276487
VL  - 4
IS  - 2
SP  - 110
EP  - 121
ER  - 
TY  - JOUR
A1  - Ampattu, Biju Joseph
A1  - Hagmann, Laura
A1  - Liang, Chunguang
A1  - Dittrich, Marcus
A1  - Schlüter, Andreas
A1  - Blom, Jochen
A1  - Krol, Elizaveta
A1  - Goesmann, Alexander
A1  - Becker, Anke
A1  - Dandekar, Thomas
A1  - Müller, Tobias
A1  - Schoen, Christoph
T1  - Transcriptomic buffering of cryptic genetic variation contributes to meningococcal virulence
JF  - BMC Genomics
N2  - Background:
Commensal bacteria like Neisseria meningitidis sometimes cause serious disease. However, genomic comparison of hyperinvasive and apathogenic lineages did not reveal unambiguous hints towards indispensable virulence factors. Here, in a systems biological approach we compared gene expression of the invasive strain MC58 and the carriage strain α522 under different ex vivo conditions mimicking commensal and virulence compartments to assess the strain-specific impact of gene regulation on meningococcal virulence.
Results:
Despite indistinguishable ex vivo phenotypes, both strains differed in the expression of over 500 genes under infection mimicking conditions. These differences comprised in particular metabolic and information processing genes as well as genes known to be involved in host-damage such as the nitrite reductase and numerous LOS biosynthesis genes. A model based analysis of the transcriptomic differences in human blood suggested ensuing metabolic flux differences in energy, glutamine and cysteine metabolic pathways along with differences in the activation of the stringent response in both strains. In support of the computational findings, experimental analyses revealed differences in cysteine and glutamine auxotrophy in both strains as well as a strain and condition dependent essentiality of the (p)ppGpp synthetase gene relA and of a short non-coding AT-rich repeat element in its promoter region.
Conclusions:
Our data suggest that meningococcal virulence is linked to transcriptional buffering of cryptic genetic variation in metabolic genes including global stress responses. They further highlight the role of regulatory elements for bacterial virulence and the limitations of model strain approaches when studying such genetically diverse species as N. meningitidis.
KW  - neisseria meningitidis
KW  - MITE
KW  - virulenceregulatory evolution
KW  - systems biology
KW  - metabolism
KW  - cryptic
KW  - genetic variation
KW  - stringent response
KW  - relA
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157534
VL  - 18
IS  - 282
ER  - 
TY  - JOUR
A1  - Rinaldetti, Sébastien
A1  - Pfirrmann, Markus
A1  - Manz, Kirsi
A1  - Guilhot, Joelle
A1  - Dietz, Christian
A1  - Panagiotidis, Panayiotidis
A1  - Spiess, Birgit
A1  - Seifarth, Wolfgang
A1  - Fabarius, Alice
A1  - Müller, Martin
A1  - Pagoni, Maria
A1  - Dimou, Maria
A1  - Dengler, Jolanta
A1  - Waller, Cornelius F.
A1  - Brümmendorf, Tim H.
A1  - Herbst, Regina
A1  - Burchert, Andreas
A1  - Janßen, Carsten
A1  - Goebeler, Maria Elisabeth
A1  - Jost, Philipp J.
A1  - Hanzel, Stefan
A1  - Schafhausen, Philippe
A1  - Prange-Krex, Gabriele
A1  - Illmer, Thomas
A1  - Janzen, Viktor
A1  - Klausmann, Martine
A1  - Eckert, Robert
A1  - Büschel, Gerd
A1  - Kiani, Alexander
A1  - Hofmann, Wolf-Karsten
A1  - Mahon, François-Xavier
A1  - Saussele, Susanne
T1  - Effect of ABCG2, OCT1, and ABCB1 (MDR1) Gene Expression on Treatment-Free Remission in a EURO-SKI Subtrial
JF  - Clinical Lymphoma, Myeloma & Leukemia
N2  - Within the EURO-SKI trial, 132 chronic phase CML patients discontinued imatinib treatment. RNA was isolated from peripheral blood in order to analyze the expression of MDR1, ABCG2 and OCT1. ABCG2 was predictive for treatment-free remission in Cox regression analysis. High transcript levels of the ABCG2 efflux transporter (>4.5 parts per thousand) were associated with a twofold higher risk of relapse. Introduction: Tyrosine kinase inhibitors (TKIs) can safely be discontinued in chronic myeloid leukemia (CML) patients with sustained deep molecular response. ABCG2 (breast cancer resistance protein), OCT1 (organic cation transporter 1), and ABCB1 (multidrug resistance protein 1) gene products are known to play a crucial role in acquired pharmacogenetic TKI resistance. Their influence on treatment-free remission (TFR) has not yet been investigated. Materials and Methods: RNA was isolated on the last day of TKI intake from peripheral blood leukocytes of 132 chronic phase CML patients who discontinued TKI treatment within the European Stop Tyrosine Kinase Inhibitor Study trial. Plasmid standards were designed including subgenic inserts of OCT1, ABCG2, and ABCB1 together with GUSB as reference gene. For expression analyses, quantitative real-time polymerase chain reaction was used. Multiple Cox regression analysis was performed. In addition, gene expression cutoffs for patient risk stratification were investigated. Results: The TFR rate of 132 patients, 12 months after TKI discontinuation, was 54% (95% confidence interval [CI], 46%-62%). ABCG2 expression (parts per thousand) was retained as the only significant variable (P=.02; hazard ratio, 1.04; 95% CI, 1.01-1.07) in multiple Cox regression analysis. Only for the ABCG2 efflux transporter, a significant cutoff was found (P=.04). Patients with an ABCG2/GUSB transcript level >4.5 parts per thousand (n=93) showed a 12-month TFR rate of 47% (95% CI, 37%-57%), whereas patients with low ABCG2 expression (<= 4.5 parts per thousand; n=39) had a 12-month TFR rate of 72% (95% CI, 55%-82%). Conclusion: In this study, we investigated the effect of pharmacogenetics in the context of a CML treatment discontinuation trial. The transcript levels of the efflux transporter ABCG2 predicted TFR after TKI discontinuation. (C) 2018 The Authors. Published by Elsevier Inc.
KW  - ABCG2
KW  - Biomarker
KW  - CML
KW  - Imatinib
KW  - Prediction
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226281
VL  - 18
IS  - 4
ER  - 
TY  - JOUR
A1  - Farmer, Adam D.
A1  - Strzelczyk, Adam
A1  - Finisguerra, Alessandra
A1  - Gourine, Alexander V.
A1  - Gharabaghi, Alireza
A1  - Hasan, Alkomiet
A1  - Burger, Andreas M.
A1  - Jaramillo, Andrés M.
A1  - Mertens, Ann
A1  - Majid, Arshad
A1  - Verkuil, Bart
A1  - Badran, Bashar W.
A1  - Ventura-Bort, Carlos
A1  - Gaul, Charly
A1  - Beste, Christian
A1  - Warren, Christopher M.
A1  - Quintana, Daniel S.
A1  - Hämmerer, Dorothea
A1  - Freri, Elena
A1  - Frangos, Eleni
A1  - Tobaldini, Eleonora
A1  - Kaniusas, Eugenijus
A1  - Rosenow, Felix
A1  - Capone, Fioravante
A1  - Panetsos, Fivos
A1  - Ackland, Gareth L.
A1  - Kaithwas, Gaurav
A1  - O'Leary, Georgia H.
A1  - Genheimer, Hannah
A1  - Jacobs, Heidi I. L.
A1  - Van Diest, Ilse
A1  - Schoenen, Jean
A1  - Redgrave, Jessica
A1  - Fang, Jiliang
A1  - Deuchars, Jim
A1  - Széles, Jozsef C.
A1  - Thayer, Julian F.
A1  - More, Kaushik
A1  - Vonck, Kristl
A1  - Steenbergen, Laura
A1  - Vianna, Lauro C.
A1  - McTeague, Lisa M.
A1  - Ludwig, Mareike
A1  - Veldhuizen, Maria G.
A1  - De Couck, Marijke
A1  - Casazza, Marina
A1  - Keute, Marius
A1  - Bikson, Marom
A1  - Andreatta, Marta
A1  - D'Agostini, Martina
A1  - Weymar, Mathias
A1  - Betts, Matthew
A1  - Prigge, Matthias
A1  - Kaess, Michael
A1  - Roden, Michael
A1  - Thai, Michelle
A1  - Schuster, Nathaniel M.
A1  - Montano, Nicola
A1  - Hansen, Niels
A1  - Kroemer, Nils B.
A1  - Rong, Peijing
A1  - Fischer, Rico
A1  - Howland, Robert H.
A1  - Sclocco, Roberta
A1  - Sellaro, Roberta
A1  - Garcia, Ronald G.
A1  - Bauer, Sebastian
A1  - Gancheva, Sofiya
A1  - Stavrakis, Stavros
A1  - Kampusch, Stefan
A1  - Deuchars, Susan A.
A1  - Wehner, Sven
A1  - Laborde, Sylvain
A1  - Usichenko, Taras
A1  - Polak, Thomas
A1  - Zaehle, Tino
A1  - Borges, Uirassu
A1  - Teckentrup, Vanessa
A1  - Jandackova, Vera K.
A1  - Napadow, Vitaly
A1  - Koenig, Julian
T1  - International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)
JF  - Frontiers in Human Neuroscience
N2  - Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.
KW  - transcutaneous vagus nerve stimulation
KW  - minimum reporting standards
KW  - guidelines & recommendations
KW  - transcutaneous auricular vagus nerve stimulation
KW  - transcutaneous cervical vagus nerve stimulation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234346
SN  - 1662-5161
VL  - 14
ER  - 
TY  - JOUR
A1  - Hennessen, Fabienne
A1  - Miethke, Marcus
A1  - Zaburannyi, Nestor
A1  - Loose, Maria
A1  - Lukežič, Tadeja
A1  - Bernecker, Steffen
A1  - Hüttel, Stephan
A1  - Jansen, Rolf
A1  - Schmiedel, Judith
A1  - Fritzenwanker, Moritz
A1  - Imirzalioglu, Can
A1  - Vogel, Jörg
A1  - Westermann, Alexander J.
A1  - Hesterkamp, Thomas
A1  - Stadler, Marc
A1  - Wagenlehner, Florian
A1  - Petković, Hrvoje
A1  - Herrmann, Jennifer
A1  - Müller, Rolf
T1  - Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin
JF  - Antibiotics
N2  - The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.
KW  - chelocardins
KW  - atypical tetracyclines
KW  - broad-spectrum antibiotics
KW  - clinical isolates
KW  - uropathogens
KW  - urinary tract infection (UTI)
KW  - resistance-breaking properties
KW  - mechanism of resistance
KW  - AcrAB-TolC efflux pump
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213149
SN  - 2079-6382
VL  - 9
IS  - 9
ER  - 
TY  - JOUR
A1  - Forchert, Leandra
A1  - Potapova, Ekaterina
A1  - Panetta, Valentina
A1  - Dramburg, Stephanie
A1  - Perna, Serena
A1  - Posa, Daniela
A1  - Resch‐Marat, Yvonne
A1  - Lupinek, Christian
A1  - Rohrbach, Alexander
A1  - Grabenhenrich, Linus
A1  - Icke, Katja
A1  - Bauer, Carl‐Peter
A1  - Hoffman, Ute
A1  - Forster, Johannes
A1  - Zepp, Fred
A1  - Schuster, Antje
A1  - Wahn, Ulrich
A1  - Keil, Thomas
A1  - Lau, Susanne
A1  - Vrtala, Susanne
A1  - Valenta, Rudolf
A1  - Matricardi, Paolo Maria
T1  - Der p 23‐specific IgE response throughout childhood and its association with allergic disease: A birth cohort study
JF  - Pediatric Allergy and Immunology
N2  - Background
The Dermatophagoides pteronyssinus molecule Der p 23 is a major allergen whose clinical relevance has been shown in cross‐sectional studies. We longitudinally analysed the trajectory of Der p 23‐specific IgE antibody (sIgE) levels throughout childhood and youth, their early‐life determinants and their clinical relevance for allergic rhinitis and asthma.
Methods
We obtained sera and clinical data of 191 participants of the German Multicentre Allergy Study, a prospective birth cohort. Serum samples from birth to 20 years of age with sIgE reactivity to Der p 23 in a customised semiquantitative microarray were newly analysed with a singleplex quantitative assay. Early mite exposure was assessed by measuring the average content of Der p 1 in house dust at 6 and 18 months.
Results
Der p 23‐sIgE levels were detected at least once in 97/191 participants (51%). Prevalence of Der p 23 sensitisation and mean sIgE levels increased until age 10 years, plateaued until age 13 years and were lowest at age 20 years. Asthma, allergic rhinitis (AR) and atopic dermatitis (AD) were more prevalent in Der p 23‐sensitised children, including those with monomolecular but persistent sensitisation (11/97, 11%). A higher exposure to mites in infancy and occurrence of AD before 5 years of age preceded the onset of Der p 23 sensitisation, which in turn preceded a higher incidence of asthma.
Conclusions
Der p 23 sensitisation peaks in late childhood and then decreases. It is preceded by early mite exposure and AD. Asthma and AR can occur in patients persistently sensitised to Der p 23 as the only mite allergen, suggesting the inclusion of molecular testing of Der p 23‐sIgE for subjects with clinical suspicion of HDM allergy but without sIgE to other major D.pt. allergens.
KW  - asthma
KW  - birth cohort
KW  - childhood
KW  - Der p 23
KW  - house dust mite allergy
KW  - IgE
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-287181
VL  - 33
IS  - 7
ER  - 
TY  - JOUR
A1  - Reichel, Thomas
A1  - Herz, Stefan
A1  - el Tabbakh, Mohammed
A1  - Bley, Thorsten Alexander
A1  - Plumhoff, Piet
A1  - Rueckl, Kilian
T1  - Less than 9.5-mm coracohumeral distance on axial magnetic resonance imaging scans predicts for subscapularis tear
JF  - JSES International
N2  - Background

Diagnosis of subscapularis (SSC) tendon lesions on magnetic resonance imaging (MRI) can be challenging. A small coracohumeral distance (CHD) has been associated with SSC tears. This study was designed to define a specific threshold value for CHD to predict SSC tears on axial MRI scans.

Methods

This retrospective study included 172 shoulders of 168 patients who underwent arthroscopic surgery for rotator cuff tear or glenohumeral instability. Diagnostic arthroscopy confirmed an SSC tear in 62 cases (36.0%, test group a), rotator cuff tear tears other than SSC in 71 cases (41.3%, control group b) and glenohumeral instability without any rotator cuff tear in 39 cases (22.7%, zero-sample group c). All patients had a preoperative MRI of the shoulder (1.5T or 3T). Minimum CHD was measured on axial fat-suppressed proton density-, T2-, or T1-weigthed sequences. Receiver operating characteristics analysis was used to determine the threshold value for CHD, and sensitivity and specificity were calculated.

Results

CHD measurement had a good interobserver reliability (Intraclass correlation coefficient 0.799). Mean CHD was highly significantly (P < .001) less for test group a (mean 7.3 mm, standard deviation ± 2.2) compared with control group b (mean 11.1 mm, standard deviation ± 2.3) or zero-sample group c (mean 13.6 mm, standard deviation ± 2.9). A threshold value of CHD <9.5 mm had a sensitivity of 83.6% and a specificity of 83.9% to predict SSC tears.

Conclusion

A CHD <9.5 mm on MRI is predictive of SSC lesions and a valuable tool to diagnose SSC tears.
KW  - subscapularis tear
KW  - coracohumeral distance
KW  - rotator cuff tear
KW  - coracohumeral impingement
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259118
VL  - 5
IS  - 3
ER  - 
TY  - JOUR
A1  - Klitsch, Alexander
A1  - Evdokimov, Dimitar
A1  - Frank, Johanna
A1  - Thomas, Dominique
A1  - Saffer, Nadine
A1  - Meyer zu Altenschildesche, Caren
A1  - Sisignano, Marco
A1  - Kampik, Daniel
A1  - Malik, Rayaz A.
A1  - Sommer, Claudia
A1  - Üçeyler, Nurcan
T1  - Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome
JF  - Journal of the Peripheral Nervous System
N2  - In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age‐matched female controls. After screening for dry eye disease, corneal LC were counted and sub‐classified as dendritic (dLC) and non‐dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.
KW  - corneal confocal microscopy
KW  - fibromyalgia syndrome
KW  - Langerhans cells
KW  - pain
KW  - small fiber neuropathy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214150
VL  - 25
IS  - 1
ER  - 
TY  - JOUR
A1  - Kiem, Dominik
A1  - Leisch, Michael
A1  - Neureiter, Daniel
A1  - Haslauer, Theresa
A1  - Egle, Alexander
A1  - Melchardt, Thomas
A1  - Topp, Max S.
A1  - Greil, Richard
T1  - Two cases of pancytopenia with Coombs-negative hemolytic anemia after chimeric antigen receptor T-cell therapy
JF  - International Journal of Molecular Sciences
N2  - Background: Chimeric antigen receptor (CAR) T-cells are changing the therapeutic landscape of hematologic malignancies. Severe side effects include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), but prolonged cytopenia has also been reported. The underlying mechanism for prolonged cytopenia is poorly understood so far. Cases: Severe pancytopenia with grade 2-3 anemia was marked 2–3 months after treatment. Laboratory evaluation revealed undetectable levels of haptoglobin with increased reticulocyte counts. Coomb's tests were negative, no schistocytes were detected on blood smear, and infectious causes were ruled out. Increased erythropoiesis without lymphoma infiltration was noted on bone marrow biopsy. A spontaneous increase in haptoglobin and hemoglobin levels was observed after several weeks. For one patient, peripheral CAR-T levels were monitored over time. We observed a decline at the same time as hemoglobin levels began to rise, implying a potential causality. Conclusion: To our knowledge, we describe the first two cases of Coombs-negative hemolytic anemia after CAR-T treatment for B-cell lymphoma. We encourage routine monitoring for hemolytic anemia after CAR-T treatment and also encourage further investigations on the underlying mechanism.
KW  - CAR T-cell
KW  - hemolytic anemia
KW  - prolonged cytopenia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284977
SN  - 1422-0067
VL  - 22
IS  - 11
ER  - 
TY  - JOUR
A1  - Wunder, Juliane
A1  - Pemp, Daniela
A1  - Cecil, Alexander
A1  - Mahdiani, Maryam
A1  - Hauptstein, René
A1  - Schmalbach, Katja
A1  - Geppert, Leo N.
A1  - Ickstadt, Katja
A1  - Esch, Harald L.
A1  - Dankekar, Thomas
A1  - Lehmann, Leane
T1  - Influence of breast cancer risk factors on proliferation and DNA damage in human breast glandular tissues: role of intracellular estrogen levels, oxidative stress and estrogen biotransformation
JF  - Archives of Toxicology
N2  - Breast cancer etiology is associated with both proliferation and DNA damage induced by estrogens. Breast cancer risk factors (BCRF) such as body mass index (BMI), smoking, and intake of estrogen-active drugs were recently shown to influence intratissue estrogen levels. Thus, the aim of the present study was to investigate the influence of BCRF on estrogen-induced proliferation and DNA damage in 41 well-characterized breast glandular tissues derived from women without breast cancer. Influence of intramammary estrogen levels and BCRF on estrogen receptor (ESR) activation, ESR-related proliferation (indicated by levels of marker transcripts), oxidative stress (indicated by levels of GCLC transcript and oxidative derivatives of cholesterol), and levels of transcripts encoding enzymes involved in estrogen biotransformation was identified by multiple linear regression models. Metabolic fluxes to adducts of estrogens with DNA (E-DNA) were assessed by a metabolic network model (MNM) which was validated by comparison of calculated fluxes with data on methoxylated and glucuronidated estrogens determined by GC- and UHPLC-MS/MS. Intratissue estrogen levels significantly influenced ESR activation and fluxes to E-DNA within the MNM. Likewise, all BCRF directly and/or indirectly influenced ESR activation, proliferation, and key flux constraints influencing E-DNA (i.e., levels of estrogens, CYP1B1, SULT1A1, SULT1A2, and GSTP1). However, no unambiguous total effect of BCRF on proliferation became apparent. Furthermore, BMI was the only BCRF to indeed influence fluxes to E-DNA (via congruent adverse influence on levels of estrogens, CYP1B1 and SULT1A2).
KW  - metabolic network model
KW  - estrogens
KW  - human breast
KW  - multiple linear regression
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265343
SN  - 1432-0738
VL  - 96
IS  - 2
ER  - 
TY  - JOUR
A1  - Nagler, Matthias
A1  - Nägele, Thomas
A1  - Gilli, Christian
A1  - Fragner, Lena
A1  - Korte, Arthur
A1  - Platzer, Alexander
A1  - Farlow, Ashley
A1  - Nordborg, Magnus
A1  - Weckwerth, Wolfram
T1  - Eco-Metabolomics and Metabolic Modeling: Making the Leap From Model Systems in the Lab to Native Populations in the Field
JF  - Frontiers in Plant Science
N2  - Experimental high-throughput analysis of molecular networks is a central approach to characterize the adaptation of plant metabolism to the environment. However, recent studies have demonstrated that it is hardly possible to predict in situ metabolic phenotypes from experiments under controlled conditions, such as growth chambers or greenhouses. This is particularly due to the high molecular variance of in situ samples induced by environmental fluctuations. An approach of functional metabolome interpretation of field samples would be desirable in order to be able to identify and trace back the impact of environmental changes on plant metabolism. To test the applicability of metabolomics studies for a characterization of plant populations in the field, we have identified and analyzed in situ samples of nearby grown natural populations of Arabidopsis thaliana in Austria. A. thaliana is the primary molecular biological model system in plant biology with one of the best functionally annotated genomes representing a reference system for all other plant genome projects. The genomes of these novel natural populations were sequenced and phylogenetically compared to a comprehensive genome database of A. thaliana ecotypes. Experimental results on primary and secondary metabolite profiling and genotypic variation were functionally integrated by a data mining strategy, which combines statistical output of metabolomics data with genome-derived biochemical pathway reconstruction and metabolic modeling. Correlations of biochemical model predictions and population-specific genetic variation indicated varying strategies of metabolic regulation on a population level which enabled the direct comparison, differentiation, and prediction of metabolic adaptation of the same species to different habitats. These differences were most pronounced at organic and amino acid metabolism as well as at the interface of primary and secondary metabolism and allowed for the direct classification of population-specific metabolic phenotypes within geographically contiguous sampling sites.
KW  - eco-metabolomics
KW  - in situ analysis
KW  - metabolomics
KW  - metabolic modeling
KW  - SNP
KW  - natural variation
KW  - Jacobian matrix
KW  - green systems biology
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-189560
SN  - 1664-462X
VL  - 9
IS  - 1556
ER  - 
TY  - JOUR
A1  - Cecil, Alexander
A1  - Gentschev, Ivaylo
A1  - Adelfinger, Marion
A1  - Dandekar, Thomas
A1  - Szalay, Aladar A.
T1  - Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models
JF  - Bioengineered
N2  - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients.
KW  - boolean modeling
KW  - oncolytic virus
KW  - human xenografted mouse models
KW  - cancer therapy
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200507
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Rosentreter, André
A1  - Lappas, Alexandra
A1  - Widder, Randolf Alexander
A1  - Alnawaiseh, Maged
A1  - Dietlein, Thomas Stefan
T1  - Conjunctival repair after glaucoma drainage device exposure using collagen-glycosaminoglycane matrices
JF  - BMC Ophthalmology
N2  - Background:
To report the results of the repair of conjunctival erosions resulting from glaucoma drainage device surgery using collagen-glycosaminoglycane matrices (CGM).

Methods:
Case series of 8 patients who underwent revision surgery due to conjunctival defects with exposed tubes through necrosis of the overlying scleral flap and conjunctiva after Baerveldt drainage device surgery. The defects were repaired by lateral displacement of the tube towards the sclera, with a slice of a CGM as a patch, covered by adjacent conjunctiva.

Result:
Successful, lasting closure (follow-up of 12 to 42 months) of the conjunctival defects was achieved without any side-effects or complications in all eight cases.

Conclusions:
Erosion of the drainage tube, creating buttonholes in the conjunctiva after implantation of glaucoma drainage devices, is a potentially serious problem. It can be managed successfully using a biodegradable CGM as a patch.
KW  - Ahmed
KW  - Baerveldt
KW  - biodegradable implant
KW  - collagen-glycosaminoglycane matrix (CGM)
KW  - conjunctival defect
KW  - episcleral drainage device
KW  - drainage tube
KW  - conjunctival repair
KW  - conjunctival hole
KW  - glaucoma drainage device
KW  - ologen implant
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175534
VL  - 18
IS  - 60
ER  - 
TY  - JOUR
A1  - Hann, Alexander
A1  - Graf, Louisa
A1  - Seufferlein, Thomas
A1  - Zizer, Eugen
T1  - Gastrointestinal Bleeding Diagnosed by Capsule Endoscopy – A Change towards More Patients with Bleeding-related Drugs
JF  - Journal of Advances in Medicine and Medical Research
N2  - Background: Video capsule endoscopy (VCE) is the standard procedure for a work-up of a suspected bleeding source after negative gastroscopy and colonoscopy. Popularity of this procedure increased in the last decade. In this work we aimed to identify the changes in patient characteristics and how those changes influence bleeding related findings. In particular the assumed higher risk of gastrointestinal bleeding of the new oral anticoagulants (nOAC) compared to phenprocoumon was of interest.

Methods: Consecutive VCE examinations performed at our center from January 2004 to March 2018 were identified retrospectively. Baseline characteristics of the patients, VCE results and treatment that was initiated were analyzed.

Results: 560 VCE were included in the analysis. The rate of VCE per month increased from 2.3/month in the period of January 2004 – December 2012 up to 5.0/month in January 2013 – March 2018. Accompanied by this increase the examined patients suffered from significantly more comorbidities (72 vs. 82%, p 0.001) and used a higher number of bleeding-related drugs (47 vs. 66%, p <0.001), especially nOACs. Age above 65 and bleeding-related drugs were significantly associated with angiodysplasias found on VCE examinations. NOACs and phenprocoumon showed no difference in their correlation to angiodysplasias.

Conclusion: This single center retrospective analysis revealed a steep increase in VCE examinations over the last years with an increase in the prevalence of comorbidities and the use of bleeding-related drugs. Interestingly, use of both nOACs and phenprocoumon did not result in a significant higher rate of angiodysplasias in the VCE.
KW  - video capsule endoscopy
KW  - small bowel bleeding
KW  - nOAC
KW  - VCE
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256687
SN  - 2456-8899
VL  - 32
IS  - 19
ER  - 
TY  - JOUR
A1  - Nees, Samuel
A1  - Kupfer, Thomas
A1  - Hofmann, Alexander
A1  - Braunschweig, Holger
T1  - Stabilisierung planarer Cyclopenten‐4‐yl‐Kationen durch Hyperkonjugation und π‐Delokalisierung
JF  - Angewandte Chemie
N2  - Theoretischen Untersuchungen zufolge stellt das planare Cyclopenten-4-yl-Kation das energetisch ungünstigste C\(_{5}\)H\(_{7}\)\(^{+}\)-Isomer dar und ist am ehesten als klassisches Carbokation zu beschreiben, wobei dessen Existenz experimentell bislang noch nicht nachgewiesen werden konnte. Durch Umsetzung sterisch überfrachteter Alane vom Typ Cp\(^{R}\)AlBr\(_{2}\) mit AlBr3 ist uns nun die Isolierung zweier stabiler Derivate des Cyclopenten-4-yl-Kations gelungen. Untersuchungen zu deren (elektronischer) Struktur (XRD, QM) offenbarten planare Geometrien und starke Hyperkonjugationswechselwirkungen zwischen den C-Al-σ-Bindungen und dem unbesetzten p-Orbital der kationischen sp\(^{2}\)-Kohlenstoffzentren. Die Analyse der Molekülorbitale (MOs), der Anisotropie der induzierten Stromdichte (ACID) sowie verschiedener Aromatizitätsdeskriptoren deuten hierbei auf ein hohes Maß an Delokalisierung und π-Aromatizität in diesen Systemen hin, was einer klassischen Beschreibung grundlegend widerspricht. Unsere Cyclopenten-4-yl-Kationen gehören somit zu den wenigen Beispielen aromatischer Carbocyclen, in denen eine Delokalisierung der π-Elektronen über gesättigte sp\(^{3}\)-Kohlenstoffatome hinweg beobachtet wird.
KW  - ACID
KW  - Carbokationen
KW  - Cyclopenten-4-yl-Kation
KW  - Hyperkonjugation
KW  - π-Aromatizität
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218456
VL  - 132
IS  - 42
SP  - 18971
EP  - 18978
ER  - 
TY  - JOUR
A1  - Nees, Samuel
A1  - Kupfer, Thomas
A1  - Hofmann, Alexander
A1  - Braunschweig, Holger
T1  - Planar Cyclopenten‐4‐yl Cations: Highly Delocalized π Aromatics Stabilized by Hyperconjugation
JF  - Angewandte Chemie International Edition
N2  - Theoretical studies predicted the planar cyclopenten‐4‐yl cation to be a classical carbocation, and the highest‐energy isomer of C\(_{5}\)H\(_{7}\)\(^{+}\). Hence, its existence has not been verified experimentally so far. We were now able to isolate two stable derivatives of the cyclopenten‐4‐yl cation by reaction of bulky alanes Cp\(^{R}\)AlBr\(_{2}\) with AlBr3. Elucidation of their (electronic) structures by X‐ray diffraction and quantum chemistry studies revealed planar geometries and strong hyperconjugation interactions primarily from the C−Al σ bonds to the empty p orbital of the cationic sp\(^{2}\) carbon center. A close inspection of the molecular orbitals (MOs) and of the anisotropy of current (induced) density (ACID), as well as the evaluation of various aromaticity descriptors indicated distinct aromaticity for these cyclopenten‐4‐yl derivatives, which strongly contrasts the classical description of this system. Here, strong delocalization of π electrons spanning the whole carbocycle has been verified, thus providing rare examples of π aromaticity involving saturated sp\(^{3}\) carbon atoms.
KW  - ACID
KW  - carbocations
KW  - cyclopenten-4-yl cation
KW  - hyperconjugation
KW  - π aromaticity
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218358
VL  - 59
IS  - 42
SP  - 18809
EP  - 18815
ER  - 
TY  - JOUR
A1  - Mayr, Antonia V.
A1  - Keller, Alexander
A1  - Peters, Marcell K.
A1  - Grimmer, Gudrun
A1  - Krischke, Beate
A1  - Geyer, Mareen
A1  - Schmitt, Thomas
A1  - Steffan‐Dewenter, Ingolf
T1  - Cryptic species and hidden ecological interactions of halictine bees along an elevational gradient
JF  - Ecology and Evolution
N2  - Changes of abiotic and biotic conditions along elevational gradients represent serious challenges to organisms which may promote the turnover of species, traits and biotic interaction partners. Here, we used molecular methods to study cuticular hydrocarbon (CHC) profiles, biotic interactions and phylogenetic relationships of halictid bees of the genus Lasioglossum along a 2,900 m elevational gradient at Mt. Kilimanjaro, Tanzania. We detected a strong species turnover of morphologically indistinguishable taxa with phylogenetically clustered cryptic species at high elevations, changes in CHC profiles, pollen resource diversity, and a turnover in the gut and body surface microbiome of bees. At high elevations, increased proportions of saturated compounds in CHC profiles indicate physiological adaptations to prevent desiccation. More specialized diets with higher proportions of low‐quality Asteraceae pollen imply constraints in the availability of food resources. Interactive effects of climatic conditions on gut and surface microbiomes, CHC profiles, and pollen diet suggest complex feedbacks among abiotic conditions, ecological interactions, physiological adaptations, and phylogenetic constraints as drivers of halictid bee communities at Mt. Kilimanjaro.
KW  - COI
KW  - cuticular chemistry
KW  - elevational gradient
KW  - Halictidae
KW  - microbiome metabarcoding
KW  - pollen metabarcoding
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238853
VL  - 11
IS  - 12
SP  - 7700
EP  - 7712
ER  - 
TY  - JOUR
A1  - Sauer, Alexander
A1  - Li, Mengxia
A1  - Holl-Wieden, Annette
A1  - Pabst, Thomas
A1  - Neubauer, Henning
T1  - Readout-segmented multi-shot diffusion-weighted MRI of the knee joint in patients with juvenile idiopathic arthritis
JF  - Pediatric Rheumatology
N2  - Background:
Diffusion-weighted MRI has been proposed as a new technique for imaging synovitis without intravenous contrast application. We investigated diagnostic utility of multi-shot readout-segmented diffusion-weighted MRI (multi-shot DWI) for synovial imaging of the knee joint in patients with juvenile idiopathic arthritis (JIA).

Methods:
Thirty-two consecutive patients with confirmed or suspected JIA (21 girls, median age 13 years) underwent routine 1.5 T MRI with contrast-enhanced T1w imaging (contrast-enhanced MRI) and with multi-shot DWI (RESOLVE, b-values 0–50 and 800 s/mm\(^2\)). Contrast-enhanced MRI, representing the diagnostic standard, and diffusion-weighted images at b = 800 s/mm\(^2\) were separately rated by three independent blinded readers at different levels of expertise for the presence and the degree of synovitis on a modified 5-item Likert scale along with the level of subjective diagnostic confidence.

Results:
Fourteen (44%) patients had active synovitis and joint effusion, nine (28%) patients showed mild synovial enhancement not qualifying for arthritis and another nine (28%) patients had no synovial signal alterations on contrast-enhanced imaging. Ratings by the 1st reader on contrast-enhanced MRI and on DWI showed substantial agreement (κ = 0.74). Inter-observer-agreement was high for diagnosing, or ruling out, active arthritis of the knee joint on contrast-enhanced MRI and on DWI, showing full agreement between 1st and 2nd reader and disagreement in one case (3%) between 1st and 3rd reader. In contrast, ratings in cases of absent vs. little synovial inflammation were markedly inconsistent on DWI. Diagnostic confidence was lower on DWI, compared to contrast-enhanced imaging.

Conclusion:
Multi-shot DWI of the knee joint is feasible in routine imaging and reliably diagnoses, or rules out, active arthritis of the knee joint in paediatric patients without the need of gadolinium-based i.v. contrast injection. Possibly due to “T2w shine-through” artifacts, DWI does not reliably differentiate non-inflamed joints from knee joints with mild synovial irritation.
KW  - diffusion-weighted MRI
KW  - juvenile idiopathic arthritis
KW  - synovitis
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158095
VL  - 15
IS  - 73
ER  - 
TY  - JOUR
A1  - Haussmann, Alexander
A1  - Schmidt, Martina E.
A1  - Illmann, Mona L.
A1  - Schröter, Marleen
A1  - Hielscher, Thomas
A1  - Cramer, Holger
A1  - Maatouk, Imad
A1  - Horneber, Markus
A1  - Steindorf, Karen
T1  - Meta-analysis of randomized controlled trials on yoga, psychosocial, and mindfulness-based interventions for cancer-related fatigue: What intervention characteristics are related to higher efficacy?
JF  - Cancers
N2  - Cancer-related fatigue (CRF) is a burdensome sequela of cancer treatments. Besides exercise, recommended therapies for CRF include yoga, psychosocial, and mindfulness-based interventions. However, interventions conducted vary widely, and not all show a significant effect. This meta-analysis aimed to explore intervention characteristics related to greater reductions in CRF. We included randomized controlled trials published before October 2021. Standardized mean differences were used to assess intervention efficacy for CRF and multimodel inference to explore intervention characteristics associated with higher efficacy. For the meta-analysis, we included 70 interventions (24 yoga interventions, 31 psychosocial interventions, and 15 mindfulness-based interventions) with 6387 participants. The results showed a significant effect of yoga, psychosocial, and mindfulness-based interventions on CRF but with high heterogeneity between studies. For yoga and mindfulness-based interventions, no particular intervention characteristic was identified to be advantageous for reducing CRF. Regarding psychosocial interventions, a group setting and work on cognition were related to higher intervention effects on CRF. The results of this meta-analysis suggest options to maximize the intervention effects of psychosocial interventions for CRF. The effects of yoga and mindfulness-based interventions for CRF appear to be independent of their design, although the limited number of studies points to the need for further research.
KW  - fatigue
KW  - cancer
KW  - psychosocial
KW  - mindfulness
KW  - yoga
KW  - quality of life
KW  - patient-reported outcomes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270753
SN  - 2072-6694
VL  - 14
IS  - 8
ER  - 
TY  - JOUR
A1  - Jobs, Alexander
A1  - Vonthein, Reinhard
A1  - König, Inke R.
A1  - Schäfer, Jane
A1  - Nauck, Matthias
A1  - Haag, Svenja
A1  - Fichera, Carlo Federico
A1  - Stiermaier, Thomas
A1  - Ledwoch, Jakob
A1  - Schneider, Alisa
A1  - Valentova, Miroslava
A1  - von Haehling, Stephan
A1  - Störk, Stefan
A1  - Westermann, Dirk
A1  - Lenz, Tobias
A1  - Arnold, Natalie
A1  - Edelmann, Frank
A1  - Seppelt, Philipp
A1  - Felix, Stephan
A1  - Lutz, Matthias
A1  - Hedwig, Felix
A1  - Borggrefe, Martin
A1  - Scherer, Clemens
A1  - Desch, Steffen
A1  - Thiele, Holger
T1  - Inferior vena cava ultrasound in acute decompensated heart failure: design rationale of the CAVA‐ADHF‐DZHK10 trial
JF  - ESC Heart Failure
N2  - Aims
Treating patients with acute decompensated heart failure (ADHF) presenting with volume overload is a common task. However, optimal guidance of decongesting therapy and treatment targets are not well defined. The inferior vena cava (IVC) diameter and its collapsibility can be used to estimate right atrial pressure, which is a measure of right‐sided haemodynamic congestion. The CAVA‐ADHF‐DZHK10 trial is designed to test the hypothesis that ultrasound assessment of the IVC in addition to clinical assessment improves decongestion as compared with clinical assessment alone.

Methods and results
CAVA‐ADHF‐DZHK10 is a randomized, controlled, patient‐blinded, multicentre, parallel‐group trial randomly assigning 388 patients with ADHF to either decongesting therapy guided by ultrasound assessment of the IVC in addition to clinical assessment or clinical assessment alone. IVC ultrasound will be performed daily between baseline and hospital discharge in all patients. However, ultrasound results will only be reported to treating physicians in the intervention group. Treatment target is relief of congestion‐related signs and symptoms in both groups with the additional goal to reduce the IVC diameter ≤21 mm and increase IVC collapsibility >50% in the intervention group. The primary endpoint is change in N‐terminal pro‐brain natriuretic peptide from baseline to hospital discharge. Secondary endpoints evaluate feasibility, efficacy of decongestion on other scales, and the impact of the intervention on clinical endpoints.

Conclusions
CAVA‐ADHF‐DZHK10 will investigate whether IVC ultrasound supplementing clinical assessment improves decongestion in patients admitted for ADHF.
KW  - acute decompensated heart failure
KW  - inferior vena cava
KW  - congestion
KW  - NT‐proBNP
KW  - ultrasound
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212692
VL  - 7
IS  - 3
SP  - 973
EP  - 983
ER  - 
TY  - JOUR
A1  - Kelm, Matthias
A1  - Reibetanz, Joachim
A1  - Kim, Mia
A1  - Schoettker, Kathrin
A1  - Brand, Markus
A1  - Meining, Alexander
A1  - Germer, Christoph-Thomas
A1  - Flemming, Sven
T1  - Kono-S anastomosis in Crohn’s disease: A retrospective study on postoperative morbidity and disease recurrence in comparison to the conventional side-to-side anastomosis
JF  - Journal of Clinical Medicine
N2  - Introduction: The rates of postoperative recurrence following ileocecal resection due to Crohn’s disease remain highly relevant. Despite this fact, while the Kono-S anastomosis technique initially demonstrated promising results, robust evidence is still lacking. This study aimed to analyze the short- and long-term outcomes of the Kono-S versus side-to-side anastomosis. Methods: A retrospective single-center study was performed including all patients who received an ileocecal resection between 1 January 2019 and 31 December 2021 at the Department of Surgery at the University Hospital of Wuerzburg. Patients who underwent conventional a side-to-side anastomosis were compared to those who received a Kono-S anastomosis. The short- and long-term outcomes were analyzed for all patients. Results: Here, 29 patients who underwent a conventional side-to-side anastomosis and 22 patients who underwent a Kono-S anastomosis were included. No differences were observed regarding short-term postoperative outcomes. The disease recurrence rate postoperatively was numerically lower following the Kono-S anastomosis (median Rutgeert score of 1.7 versus 2.5), with a relevantly increased rate of patients in remission (17.2% versus 31.8%); however, neither of these results reached statistical significance. Conclusion: The Kono-S anastomosis method is safe and feasible and potentially decreases the severity of postoperative disease remission.
KW  - Crohn’s disease
KW  - surgical therapy
KW  - ileocecal resection
KW  - Kono-S anastomosis
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297334
SN  - 2077-0383
VL  - 11
IS  - 23
ER  - 
TY  - JOUR
A1  - Herrmann, Johannes
A1  - Adam, Elisabeth Hannah
A1  - Notz, Quirin
A1  - Helmer, Philipp
A1  - Sonntagbauer, Michael
A1  - Ungemach-Papenberg, Peter
A1  - Sanns, Andreas
A1  - Zausig, York
A1  - Steinfeldt, Thorsten
A1  - Torje, Iuliu
A1  - Schmid, Benedikt
A1  - Schlesinger, Tobias
A1  - Rolfes, Caroline
A1  - Reyher, Christian
A1  - Kredel, Markus
A1  - Stumpner, Jan
A1  - Brack, Alexander
A1  - Wurmb, Thomas
A1  - Gill-Schuster, Daniel
A1  - Kranke, Peter
A1  - Weismann, Dirk
A1  - Klinker, Hartwig
A1  - Heuschmann, Peter
A1  - Rücker, Viktoria
A1  - Frantz, Stefan
A1  - Ertl, Georg
A1  - Muellenbach, Ralf Michael
A1  - Mutlak, Haitham
A1  - Meybohm, Patrick
A1  - Zacharowski, Kai
A1  - Lotz, Christopher
T1  - COVID-19 Induced Acute Respiratory Distress Syndrome — A Multicenter Observational Study
JF  - Frontiers in Medicine
N2  - Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS).
Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included.
Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay.
Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.
KW  - COVID-19
KW  - ARDS (acute respiratory distress syndrome)
KW  - intensive care medicine
KW  - pandemia
KW  - Germany
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219834
SN  - 2296-858X
VL  - 7
ER  - 
TY  - JOUR
A1  - Tanoey, Justine
A1  - Baechle, Christina
A1  - Brenner, Hermann
A1  - Deckert, Andreas
A1  - Fricke, Julia
A1  - Günther, Kathrin
A1  - Karch, André
A1  - Keil, Thomas
A1  - Kluttig, Alexander
A1  - Leitzmann, Michael
A1  - Mikolajczyk, Rafael
A1  - Obi, Nadia
A1  - Pischon, Tobias
A1  - Schikowski, Tamara
A1  - Schipf, Sabine M.
A1  - Schulze, Matthias B.
A1  - Sedlmeier, Anja
A1  - Moreno Velásquez, Ilais
A1  - Weber, Katharina S.
A1  - Völzke, Henry
A1  - Ahrens, Wolfgang
A1  - Gastell, Sylvia
A1  - Holleczek, Bernd
A1  - Jöckel, Karl-Heinz
A1  - Katzke, Verena
A1  - Lieb, Wolfgang
A1  - Michels, Karin B.
A1  - Schmidt, Börge
A1  - Teismann, Henning
A1  - Becher, Heiko
T1  - Birth order, Caesarean section, or daycare attendance in relation to child- and adult-onset type 1 diabetes: results from the German National Cohort
JF  - International Journal of Environmental Research and Public Health
N2  - (1) Background: Global incidence of type 1 diabetes (T1D) is rising and nearly half occurred in adults. However, it is unclear if certain early-life childhood T1D risk factors were also associated with adult-onset T1D. This study aimed to assess associations between birth order, delivery mode or daycare attendance and type 1 diabetes (T1D) risk in a population-based cohort and whether these were similar for childhood- and adult-onset T1D (cut-off age 15); (2) Methods: Data were obtained from the German National Cohort (NAKO Gesundheitsstudie) baseline assessment. Self-reported diabetes was classified as T1D if: diagnosis age ≤ 40 years and has been receiving insulin treatment since less than one year after diagnosis. Cox regression was applied for T1D risk analysis; (3) Results: Analyses included 101,411 participants (100 childhood- and 271 adult-onset T1D cases). Compared to “only-children”, HRs for second- or later-born individuals were 0.70 (95% CI = 0.50–0.96) and 0.65 (95% CI = 0.45–0.94), respectively, regardless of parental diabetes, migration background, birth year and perinatal factors. In further analyses, higher birth order reduced T1D risk in children and adults born in recent decades. Caesarean section and daycare attendance showed no clear associations with T1D risk; (4) Conclusions: Birth order should be considered in both children and adults’ T1D risk assessment for early detection.
KW  - perinatal
KW  - adult-onset
KW  - late-onset
KW  - autoimmune
KW  - delivery mode
KW  - sex
KW  - offspring
KW  - NAKO
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286216
SN  - 1660-4601
VL  - 19
IS  - 17
ER  - 
TY  - JOUR
A1  - Hetzer, Benjamin
A1  - Orth-Höller, Dorothea
A1  - Würzner, Reinhard
A1  - Kreidl, Peter
A1  - Lackner, Michaela
A1  - Müller, Thomas
A1  - Knabl, Ludwig
A1  - Geisler-Moroder, Daniel Rudolf
A1  - Mellmann, Alexander
A1  - Sesli, Özcan
A1  - Holzknecht, Jeanett
A1  - Noce, Damia
A1  - Akarathum, Noppadon
A1  - Chotinaruemol, Somporn
A1  - Prelog, Martina
A1  - Oberdorfer, Peninnah
T1  - “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study”
JF  - Antimicrobial Resistance & Infection Control
N2  - Background
Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants.

Methods
Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR.

Results
Forty-seven (33%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80%, ampicillin 72%, co-trimoxazole 66%, cefazoline 35%) almost matched those in parents. In 8 infants (6%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli.

Conclusion
One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.
KW  - Escherichia coli
KW  - antibiotic resistance
KW  - multiresistance
KW  - transmission
KW  - persistence
KW  - children
KW  - neonates
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320284
VL  - 8
ER  - 
TY  - JOUR
A1  - Däullary, Thomas
A1  - Imdahl, Fabian
A1  - Dietrich, Oliver
A1  - Hepp, Laura
A1  - Krammer, Tobias
A1  - Fey, Christina
A1  - Neuhaus, Winfried
A1  - Metzger, Marco
A1  - Vogel, Jörg
A1  - Westermann, Alexander J.
A1  - Saliba, Antoine-Emmanuel
A1  - Zdzieblo, Daniela
T1  - A primary cell-based in vitro model of the human small intestine reveals host olfactomedin 4 induction in response to Salmonella Typhimurium infection
JF  - Gut Microbes
N2  - Infection research largely relies on classical cell culture or mouse models. Despite having delivered invaluable insights into host-pathogen interactions, both have limitations in translating mechanistic principles to human pathologies. Alternatives can be derived from modern Tissue Engineering approaches, allowing the reconstruction of functional tissue models in vitro. Here, we combined a biological extracellular matrix with primary tissue-derived enteroids to establish an in vitro model of the human small intestinal epithelium exhibiting in vivo-like characteristics. Using the foodborne pathogen Salmonella enterica serovar Typhimurium, we demonstrated the applicability of our model to enteric infection research in the human context. Infection assays coupled to spatio-temporal readouts recapitulated the established key steps of epithelial infection by this pathogen in our model. Besides, we detected the upregulation of olfactomedin 4 in infected cells, a hitherto unrecognized aspect of the host response to Salmonella infection. Together, this primary human small intestinal tissue model fills the gap between simplistic cell culture and animal models of infection, and shall prove valuable in uncovering human-specific features of host-pathogen interplay.
KW  - intestinal enteroids
KW  - biological scaffold
KW  - Salmonella Typhimurium
KW  - OLFM4
KW  - NOTCH
KW  - filamentous Salmonella Typhimurium
KW  - bacterial migration
KW  - bacterial virulence
KW  - 3D tissue model
KW  - olfactomedin 4
KW  - infection
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350451
VL  - 15
IS  - 1
ER  - 
TY  - JOUR
A1  - Moris, Victoria C.
A1  - Christmann, Katharina
A1  - Wirtgen, Aline
A1  - Belokobylskij, Sergey A.
A1  - Berg, Alexander
A1  - Liebig, Wolf-Harald
A1  - Soon, Villu
A1  - Baur, Hannes
A1  - Schmitt, Thomas
A1  - Niehuis, Oliver
T1  - Cuticular hydrocarbons on old museum specimens of the spiny mason wasp, Odynerus spinipes (Hymenoptera: Vespidae: Eumeninae), shed light on the distribution and on regional frequencies of distinct chemotypes
JF  - Chemoecology
N2  - The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
KW  - cuticular hydrocarbons
KW  - chemotypes
KW  - dry-mounted samples
KW  - collections
KW  - distribution
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-306999
SN  - 0937-7409
SN  - 1423-0445
VL  - 31
IS  - 5
ER  - 
TY  - JOUR
A1  - Kern, Christian S.
A1  - Haags, Anja
A1  - Egger, Larissa
A1  - Yang, Xiaosheng
A1  - Kirschner, Hans
A1  - Wolff, Susanne
A1  - Seyller, Thomas
A1  - Gottwald, Alexander
A1  - Richter, Mathias
A1  - de Giovannini, Umberto
A1  - Rubio, Angel
A1  - Ramsey, Michael G.
A1  - Bocquet, François C.
A1  - Soubatch, Serguei
A1  - Tautz, F. Stefan
A1  - Puschnig, Peter
A1  - Moser, Simon
T1  - Simple extension of the plane-wave final state in photoemission: bringing understanding to the photon-energy dependence of two-dimensional materials
JF  - Physical Review Research
N2  - Angle-resolved photoemission spectroscopy (ARPES) is a method that measures orbital and band structure contrast through the momentum distribution of photoelectrons. Its simplest interpretation is obtained in the plane-wave approximation, according to which photoelectrons propagate freely to the detector. The photoelectron momentum distribution is then essentially given by the Fourier transform of the real-space orbital. While the plane-wave approximation is remarkably successful in describing the momentum distributions of aromatic compounds, it generally fails to capture kinetic-energy-dependent final-state interference and dichroism effects. Focusing our present study on quasi-freestanding monolayer graphene as the archetypical two-dimensional (2D) material, we observe an exemplary E\(_{kin}\)-dependent modulation of, and a redistribution of spectral weight within, its characteristic horseshoe signature around the \(\bar {K}\) and \(\bar {K´}\) points: both effects indeed cannot be rationalized by the plane-wave final state. Our data are, however, in remarkable agreement with ab initio time-dependent density functional simulations of a freestanding graphene layer and can be explained by a simple extension of the plane-wave final state, permitting the two dipole-allowed partial waves emitted from the C 2p\(_z\) orbitals to scatter in the potential of their immediate surroundings. Exploiting the absolute photon flux calibration of the Metrology Light Source, this scattered-wave approximation allows us to extract E\(_{kin}\)-dependent amplitudes and phases of both partial waves directly from photoemission data. The scattered-wave approximation thus represents a powerful yet intuitive refinement of the plane-wave final state in photoemission of 2D materials and beyond.
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350330
VL  - 5
IS  - 3
ER  - 
TY  - JOUR
A1  - Döhler, Ida
A1  - Röder, Daniel
A1  - Schlesinger, Tobias
A1  - Nassen, Christian Alexander
A1  - Germer, Christoph-Thomas
A1  - Wiegering, Armin
A1  - Lock, Johan Friso
T1  - Risk-adjusted perioperative bridging anticoagulation reduces bleeding complications without increasing thromboembolic events in general and visceral surgery
JF  - BMC Anesthesiology
N2  - Background
Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events.

Methods
We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality.

Results
A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed.

Conclusion
It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low.
KW  - low-molecular heparin
KW  - atrial fibrillation
KW  - postoperative bleeding
KW  - thromboembolism
KW  - anticoagulation
KW  - bridging
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357305
VL  - 23
ER  - 
TY  - JOUR
A1  - Hoernes, Thomas Philipp
A1  - Faserl, Klaus
A1  - Juen, Michael Andreas
A1  - Kremser, Johannes
A1  - Gasser, Catherina
A1  - Fuchs, Elisabeth
A1  - Shi, Xinying
A1  - Siewert, Aaron
A1  - Lindner, Herbert
A1  - Kreutz, Christoph
A1  - Micura, Ronald
A1  - Joseph, Simpson
A1  - Höbartner, Claudia
A1  - Westhof, Eric
A1  - Hüttenhofer, Alexander
A1  - Erlacher, Matthias David
T1  - Translation of non-standard codon nucleotides reveals minimal requirements for codon-anticodon interactions
JF  - Nature Communications
N2  - The precise interplay between the mRNA codon and the tRNA anticodon is crucial for ensuring efficient and accurate translation by the ribosome. The insertion of RNA nucleobase derivatives in the mRNA allowed us to modulate the stability of the codon-anticodon interaction in the decoding site of bacterial and eukaryotic ribosomes, allowing an in-depth analysis of codon recognition. We found the hydrogen bond between the N1 of purines and the N3 of pyrimidines to be sufficient for decoding of the first two codon nucleotides, whereas adequate stacking between the RNA bases is critical at the wobble position. Inosine, found in eukaryotic mRNAs, is an important example of destabilization of the codon-anticodon interaction. Whereas single inosines are efficiently translated, multiple inosines, e.g., in the serotonin receptor 5-HT2C mRNA, inhibit translation. Thus, our results indicate that despite the robustness of the decoding process, its tolerance toward the weakening of codon-anticodon interactions is limited.
KW  - chemical modification
KW  - nucleic acids
KW  - ribozymes
KW  - RNA
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-321067
VL  - 9
ER  - 
TY  - JOUR
A1  - Dörk, Thilo
A1  - Peterlongo, Peter
A1  - Mannermaa, Arto
A1  - Bolla, Manjeet K.
A1  - Wang, Qin
A1  - Dennis, Joe
A1  - Ahearn, Thomas
A1  - Andrulis, Irene L.
A1  - Anton-Culver, Hoda
A1  - Arndt, Volker
A1  - Aronson, Kristan J.
A1  - Augustinsson, Annelie
A1  - Beane Freeman, Laura E.
A1  - Beckmann, Matthias W.
A1  - Beeghly-Fadiel, Alicia
A1  - Behrens, Sabine
A1  - Bermisheva, Marina
A1  - Blomqvist, Carl
A1  - Bogdanova, Natalia V.
A1  - Bojesen, Stig E.
A1  - Brauch, Hiltrud
A1  - Brenner, Hermann
A1  - Burwinkel, Barbara
A1  - Canzian, Federico
A1  - Chan, Tsun L.
A1  - Chang-Claude, Jenny
A1  - Chanock, Stephen J.
A1  - Choi, Ji-Yeob
A1  - Christiansen, Hans
A1  - Clarke, Christine L.
A1  - Couch, Fergus J.
A1  - Czene, Kamila
A1  - Daly, Mary B.
A1  - dos-Santos-Silva, Isabel
A1  - Dwek, Miriam
A1  - Eccles, Diana M.
A1  - Ekici, Arif B.
A1  - Eriksson, Mikael
A1  - Evans, D. Gareth
A1  - Fasching, Peter A.
A1  - Figueroa, Jonine
A1  - Flyger, Henrik
A1  - Fritschi, Lin
A1  - Gabrielson, Marike
A1  - Gago-Dominguez, Manuela
A1  - Gao, Chi
A1  - Gapstur, Susan M.
A1  - García-Closas, Montserrat
A1  - García-Sáenz, José A.
A1  - Gaudet, Mia M.
A1  - Giles, Graham G.
A1  - Goldberg, Mark S.
A1  - Goldgar, David E.
A1  - Guenél, Pascal
A1  - Haeberle, Lothar
A1  - Haimann, Christopher A.
A1  - Håkansson, Niclas
A1  - Hall, Per
A1  - Hamann, Ute
A1  - Hartman, Mikael
A1  - Hauke, Jan
A1  - Hein, Alexander
A1  - Hillemanns, Peter
A1  - Hogervorst, Frans B. L.
A1  - Hooning, Maartje J.
A1  - Hopper, John L.
A1  - Howell, Tony
A1  - Huo, Dezheng
A1  - Ito, Hidemi
A1  - Iwasaki, Motoki
A1  - Jakubowska, Anna
A1  - Janni, Wolfgang
A1  - John, Esther M.
A1  - Jung, Audrey
A1  - Kaaks, Rudolf
A1  - Kang, Daehee
A1  - Kapoor, Pooja Middha
A1  - Khusnutdinova, Elza
A1  - Kim, Sung-Won
A1  - Kitahara, Cari M.
A1  - Koutros, Stella
A1  - Kraft, Peter
A1  - Kristensen, Vessela N.
A1  - Kwong, Ava
A1  - Lambrechts, Diether
A1  - Le Marchand, Loic
A1  - Li, Jingmei
A1  - Lindström, Sara
A1  - Linet, Martha
A1  - Lo, Wing-Yee
A1  - Long, Jirong
A1  - Lophatananon, Artitaya
A1  - Lubiński, Jan
A1  - Manoochehri, Mehdi
A1  - Manoukian, Siranoush
A1  - Margolin, Sara
A1  - Martinez, Elena
A1  - Matsuo, Keitaro
A1  - Mavroudis, Dimitris
A1  - Meindl, Alfons
A1  - Menon, Usha
A1  - Milne, Roger L.
A1  - Mohd Taib, Nur Aishah
A1  - Muir, Kenneth
A1  - Mulligan, Anna Marie
A1  - Neuhausen, Susan L.
A1  - Nevanlinna, Heli
A1  - Neven, Patrick
A1  - Newman, William G.
A1  - Offit, Kenneth
A1  - Olopade, Olufunmilayo I.
A1  - Olshan, Andrew F.
A1  - Olson, Janet E.
A1  - Olsson, Håkan
A1  - Park, Sue K.
A1  - Park-Simon, Tjoung-Won
A1  - Peto, Julian
A1  - Plaseska-Karanfilska, Dijana
A1  - Pohl-Rescigno, Esther
A1  - Presneau, Nadege
A1  - Rack, Brigitte
A1  - Radice, Paolo
A1  - Rashid, Muhammad U.
A1  - Rennert, Gad
A1  - Rennert, Hedy S.
A1  - Romero, Atocha
A1  - Ruebner, Matthias
A1  - Saloustros, Emmanouil
A1  - Schmidt, Marjanka K.
A1  - Schmutzler, Rita K.
A1  - Schneider, Michael O.
A1  - Schoemaker, Minouk J.
A1  - Scott, Christopher
A1  - Shen, Chen-Yang
A1  - Shu, Xiao-Ou
A1  - Simard, Jaques
A1  - Slager, Susan
A1  - Smichkoska, Snezhana
A1  - Southey, Melissa C.
A1  - Spinelli, John J.
A1  - Stone, Jennifer
A1  - Surowy, Harald
A1  - Swerdlow, Anthony J.
A1  - Tamimi, Rulla M.
A1  - Tapper, William J.
A1  - Teo, Soo H.
A1  - Terry, Mary Beth
A1  - Toland, Amanda E.
A1  - Tollenaar, Rob A. E. M.
A1  - Torres, Diana
A1  - Torres-Mejía, Gabriela
A1  - Troester, Melissa A.
A1  - Truong, Thérèse
A1  - Tsugane, Shoichiro
A1  - Untch, Michael
A1  - Vachon, Celine M.
A1  - van den Ouweland, Ans M. W.
A1  - van Veen, Elke M.
A1  - Vijai, Joseph
A1  - Wendt, Camilla
A1  - Wolk, Alicja
A1  - Yu, Jyh-Cherng
A1  - Zheng, Wei
A1  - Ziogas, Argyrios
A1  - Ziv, Elad
A1  - Dunnig, Alison
A1  - Pharaoh, Paul D. P.
A1  - Schindler, Detlev
A1  - Devilee, Peter
A1  - Easton, Douglas F.
T1  - Two truncating variants in FANCC and breast cancer risk
JF  - Scientific Reports
N2  - Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
KW  - oncology
KW  - risk factors
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222838
VL  - 9
ER  - 
TY  - JOUR
A1  - Kurabi, Arwa
A1  - Schaerer, Daniel
A1  - Noack, Volker
A1  - Bernhardt, Marlen
A1  - Pak, Kwang
A1  - Alexander, Thomas
A1  - Husseman, Jacob
A1  - Nguyen, Quyen
A1  - Harris, Jeffrey P.
A1  - Ryan, Allen F.
T1  - Active Transport of Peptides Across the Intact Human Tympanic Membrane
JF  - Scientific Reports
N2  - We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.
KW  - assay systems
KW  - biological models
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230929
VL  - 8
ER  -