TY  - JOUR
A1  - Sollfrank, Teresa
A1  - Hart, Daniel
A1  - Goodsell, Rachel
A1  - Foster, Jonathan
A1  - Tan, Tele
T1  - 3D visualization of movements can amplify motor cortex activation during subsequent motor imagery
JF  - Frontiers in Human Neuroscience
N2  - A repetitive movement practice by motor imagery (MI) can influence motor cortical excitability in the electroencephalogram (EEG). This study investigated if a realistic visualization in 3D of upper and lower limb movements can amplify motor related potentials during subsequent MI. We hypothesized that a richer sensory visualization might be more effective during instrumental conditioning, resulting in a more pronounced event related desynchronization (ERD) of the upper alpha band (10–12 Hz) over the sensorimotor cortices thereby potentially improving MI based brain-computer interface (BCI) protocols for motor rehabilitation. The results show a strong increase of the characteristic patterns of ERD of the upper alpha band components for left and right limb MI present over the sensorimotor areas in both visualization conditions. Overall, significant differences were observed as a function of visualization modality (VM; 2D vs. 3D). The largest upper alpha band power decrease was obtained during MI after a 3-dimensional visualization. In total in 12 out of 20 tasks the end-user of the 3D visualization group showed an enhanced upper alpha ERD relative to 2D VM group, with statistical significance in nine tasks.With a realistic visualization of the limb movements, we tried to increase motor cortex activation during subsequent MI. The feedback and the feedback environment should be inherently motivating and relevant for the learner and should have an appeal of novelty, real-world relevance or aesthetic value (Ryan and Deci, 2000; Merrill, 2007). Realistic visual feedback, consistent with the participant’s MI, might be helpful for accomplishing successful MI and the use of such feedback may assist in making BCI a more natural interface for MI based BCI rehabilitation.
KW  - 3-dimensional visualization
KW  - motor cortex activation
KW  - EEG
KW  - brain-computer interfaces
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126058
VL  - 9
IS  - 463
ER  - 
TY  - JOUR
A1  - Houben, Roland
A1  - Alimova, Pamela
A1  - Sarma, Bhavishya
A1  - Hesbacher, Sonja
A1  - Schulte, Carolin
A1  - Sarosi, Eva-Maria
A1  - Adam, Christian
A1  - Kervarrec, Thibault
A1  - Schrama, David
T1  - 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone inhibits MCPyV T antigen expression in Merkel cell carcinoma independent of Aurora kinase A
JF  - Cancers
N2  - Merkel cell carcinoma (MCC) is frequently caused by the Merkel cell polyomavirus (MCPyV), and MCPyV-positive tumor cells depend on expression of the virus-encoded T antigens (TA). Here, we identify 4-[(5-methyl-1H-pyrazol-3-yl)amino]-2H-phenyl-1-phthalazinone (PHT) — a reported inhibitor of Aurora kinase A — as a compound inhibiting growth of MCC cells by repressing noncoding control region (NCCR)-controlled TA transcription. Surprisingly, we find that TA repression is not caused by inhibition of Aurora kinase A. However, we demonstrate that β-catenin — a transcription factor repressed by active glycogen synthase kinase 3 (GSK3) — is activated by PHT, suggesting that PHT bears a hitherto unreported inhibitory activity against GSK3, a kinase known to function in promoting TA transcription. Indeed, applying an in vitro kinase assay, we demonstrate that PHT directly targets GSK3. Finally, we demonstrate that PHT exhibits in vivo antitumor activity in an MCC xenograft mouse model, suggesting a potential use in future therapeutic settings for MCC.
KW  - Merkel cell carcinoma
KW  - polyomavirus
KW  - large T antigen
KW  - phthalazinone pyrazole
KW  - glycogen synthase kinase 3
KW  - GSK3
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313547
SN  - 2072-6694
VL  - 15
IS  - 9
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Nusser, R.
A1  - Herzog, C.
T1  - 4-Bromoctavalen und zwei (Brommethylen)homobenzvalene anstelle eines erwarteten Bromoctabisvalens
N2  - No abstract available.
KW  - Organische Chemie
Y1  - 1988
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58409
ER  - 
TY  - JOUR
A1  - Wiedenmann, J.
A1  - Bocquillon, E.
A1  - Deacon, R.S.
A1  - Hartinger, S.
A1  - Herrmann, O.
A1  - Klapwijk, T.M.
A1  - Maier, L.
A1  - Ames, C.
A1  - Brüne, C.
A1  - Gould, C.
A1  - Oiwa, A.
A1  - Ishibashi, K.
A1  - Tarucha, S.
A1  - Buhmann, H.
A1  - Molenkamp, L.W.
T1  - 4π-periodic Josephson supercurrent in HgTe-based topological Josephson junctions
JF  - Nature Communications
N2  - The Josephson effect describes the generic appearance of a supercurrent in a weak link between two superconductors. Its exact physical nature deeply influences the properties of the supercurrent. In recent years, considerable efforts have focused on the coupling of superconductors to the surface states of a three-dimensional topological insulator. In such a material, an unconventional induced p-wave superconductivity should occur, with a doublet of topologically protected gapless Andreev bound states, whose energies vary 4π-periodically with the superconducting phase difference across the junction. In this article, we report the observation of an anomalous response to rf irradiation in a Josephson junction made of a HgTe weak link. The response is understood as due to a 4π-periodic contribution to the supercurrent, and its amplitude is compatible with the expected contribution of a gapless Andreev doublet. Our work opens the way to more elaborate experiments to investigate the induced superconductivity in a three-dimensional insulator.
KW  - Josephson effect
KW  - supercurrent
KW  - superconductors
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175353
VL  - 7
ER  - 
TY  - JOUR
A1  - Stopper, Helga
A1  - Pechan, R.
A1  - Schiffmann, D.
T1  - 5-azacytidine induces micronuclei in and morphological transformation of Syrian hamster embryo fibroblasts in the absence of unscheduled DNA synthesis
N2  - lt is known that 5-azacytidine (5-AC) induces tumors in several organs of rats and mice. The mechanisms of these effects are still poorly understood although it is known that 5-AC can be incorporated into DNA. Furthermore, it can inhibit DNA methylation. The known data on its clastogenic andjor gene mutation-inducing potential are still controversial. Therefore, we have investigated the kinds of genotoxic effects caused by 5-AC in Syrian hamster embryo (SHE) fibroblasts. Three different endp6ints (micronucleus formation, unscheduled DNA synthesis (UDS) and cell transforrnation) were assayed under similar conditions of metabolism and dose at target in this cell system. 5-AC induces morphological transformation of SHE cells, but not UDS. Therefore, 5-AC does not seem to cause repairable DNA lesions. Furthermore, our studies revealed that 5-AC is a potent inducer of mkronuclei in the SHE system. Immunocytochemical analysis revealed that a certain percentage of these contain kinetochores indicating that 5-AC may induce both clastogenic events and numerical chromosome changes.
KW  - Toxikologie
KW  - 5-Azacytidine
KW  - Micronuclei
KW  - Kinetochores
KW  - Unscheduled DNA synthesis
KW  - Cell transformation
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63443
ER  - 
TY  - JOUR
A1  - Karabeg, Margherita M.
A1  - Grauthoff, Sandra
A1  - Kollert, Sina Y.
A1  - Weidner, Magdalena
A1  - Heiming, Rebecca S.
A1  - Jansen, Friederike
A1  - Popp, Sandy
A1  - Kaiser, Sylvia
A1  - Lesch, Klaus-Peter
A1  - Sachser, Norbert
A1  - Schmitt, Angelika G.
A1  - Lewejohann, Lars
T1  - 5-HTT Deficiency Affects Neuroplasticity and Increases Stress Sensitivity Resulting in Altered Spatial Learning Performance in the Morris Water Maze but Not in the Barnes Maze
JF  - PLoS ONE
N2  - The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed.

While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice.

Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67-immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in naïve controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN.

Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM.
KW  - immediate early genes
KW  - learning curves
KW  - animal performance
KW  - animal behavior
KW  - serotonin
KW  - learning
KW  - mice
KW  - hippocampus
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129978
VL  - 8
IS  - 10
ER  - 
TY  - JOUR
A1  - Popp, Sandy
A1  - Schmitt-Böhrer, Angelika
A1  - Langer, Simon
A1  - Hofmann, Ulrich
A1  - Hommers, Leif
A1  - Schuh, Kai
A1  - Frantz, Stefan
A1  - Lesch, Klaus-Peter
A1  - Frey, Anna
T1  - 5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction
JF  - Journal of Clinical Medicine
N2  - Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
KW  - chronic heart failure
KW  - myocardial infarction
KW  - serotonin transporter deficient mice
KW  - anxiety
KW  - depression
KW  - behavior
KW  - inflammation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242739
SN  - 2077-0383
VL  - 10
IS  - 14
ER  - 
TY  - JOUR
A1  - Chen, Y.
A1  - Palm, F.
A1  - Lesch, K. P.
A1  - Gerlach, M.
A1  - Moessner, R.
A1  - Sommer, C.
T1  - 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, is responsible for complete Freund's adjuvant-induced thermal hyperalgesia in mice
N2  - Background: The role of serotonin (5-hydroxytrptamine, 5-HT) in the modulation of pain has been widely studied. Previous work led to the hypothesis that 5-hydroxyindolacetic acid (5-HIAA), a main metabolite of serotonin, might by itself influence pain thresholds. Results: In the present study, we investigated the role of 5-HIAA in inflammatory pain induced by intraplantar injection of complete Freund’s adjuvant (CFA) into the hind paw of mice. Wild-type mice were compared to mice deficient of the 5-HT transporter (5-HTT-/- mice) using behavioral tests for hyperalgesia and high-performance liquid chromatography (HPLC) to determine tissue levels of 5-HIAA. Wild-type mice reproducibly developed thermal hyperalgesia and paw edema for 5 days after CFA injection. 5-HTT-/- mice treated with CFA had reduced thermal hyperalgesia on day 1 after CFA injection and normal responses to heat hereafter. The 5-HIAA levels in spinal cord and sciatic nerve as measured with HPLC were lower in 5-HTT-/- mice than in wild-type mice after CFA injection. Pretreatment of wild-type mice with intraperitoneal injection of para-chlorophenylalanine (p-CPA), a serotonin synthesis inhibitor, resulted in depletion of the 5-HIAA content in spinal cord and sciatic nerve and decrease in thermal hyperalgesia in CFA injected mice. The application of exogenous 5-HIAA resulted in potentiation of thermal hyperalgesia induced by CFA in 5-HTT-/- mice and in wild-type mice pretreated with p- CPA, but not in wild-type mice without p-CPA pretreatment. Further, methysergide, a broad-spectrum serotonin receptor antagonist, had no effect on 5-HIAA-induced potentiation of thermal hyperalgesia in CFA-treated wildtype mice. Conclusion: Taken together, the present results suggest that 5-HIAA plays an important role in modulating peripheral thermal hyperalgesia in CFA induced inflammation, probably via a non-serotonin receptor mechanism.
KW  - Medizin
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-68858
ER  - 
TY  - JOUR
A1  - Blömer, Nadja
A1  - Pachel, Christina
A1  - Hofmann, Urlich
A1  - Nordbeck, Peter
A1  - Bauer, Wolfgang
A1  - Mathes, Denise
A1  - Frey, Anna
A1  - Bayer, Barbara
A1  - Vogel, Benjamin
A1  - Ertl, Georg
T1  - 5-Lipoxygenase facilitates healing after myocardial infarction
JF  - Basic Research in Cardiology
N2  - Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{−/−}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{−/−}\) bone marrow in 5-LOX\(^{−/−}\) animals), indicating that an altered function of 5-LOX\(^{−/−}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{−/−}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{−/−}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.
KW  - lipoxygenase
KW  - myocardial infarction
KW  - extracellular matrix remodeling
KW  - inflammation
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132602
VL  - 108
IS  - 4
ER  - 
TY  - JOUR
A1  - Schmid, Michael
A1  - Steinlein, Claus
A1  - Lomb, Christian
A1  - Sperling, Karl
A1  - Neitzel, Heidemarie
T1  - 5-Methylcytosine-Rich Heterochromatin in the Indian Muntjac
JF  - Cytogenetic and Genome Research
N2  - Two 5-methylcytosine (5-MeC)-rich heterochromatic regions were demonstrated in metaphase chromosomes of the Indian muntjac by indirect immunofluorescence using a monoclonal anti-5-MeC antibody. The metaphases were obtained from diploid and triploid cell lines. A major region is located in the ‘neck' of the 3;X fusion chromosome and can be detected after denaturation of the chromosomal DNA with UV-light irradiation for 1 h. It is located exactly at the border of the X chromosome and the translocated autosome 3. A minor region is found in the centromeric region of the free autosome 3 after denaturing the chromosomal DNA for 3 h or longer. The structure and possible function of the major hypermethylated region as barrier against spreading of the X-inactivation process into the autosome 3 is discussed.
KW  - heterochromatin
KW  - immunofluorescence
KW  - Indian muntjac
KW  - 5-Methylcytosine
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196701
SN  - 1424-8581
SN  - 1424-859X
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  - 147
IS  - 4
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Leß, Roland
A1  - Müller, Heinrich
T1  - 6,7-Dimethylene-2,4-diphenylbicyclo[3.2.l]oct-3-en-2-yl Anion : A Test for the Origin of the Unusual Properties of the Bicyclo[3.2.l]octa-3,6-dien-2-yl Anion
N2  - No abstract available
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-31547
ER  - 
TY  - JOUR
A1  - Li, Xiang
A1  - Samnick, Samuel
A1  - Lapa, Constantin
A1  - Israel, Ina
A1  - Buck, Andreas K.
A1  - Kreissl, Michael C.
A1  - Bauer, Wolfgang
T1  - 68Ga-DOTATATE PET/CT for the detection of inflammation of large arteries: correlation with18F-FDG, calcium burden and risk factors
N2  - Background: Ga-[1,4,7,10-tetraazacyclododecane-N,N0,N00,N000-tetraacetic acid]-d-Phe1,Tyr3-octreotate (DOTATATE) positron emission tomography (PET) is commonly used for the visualization of somatostatin receptor (SSTR)-positive neuroendocrine tumors. SSTR is also known to be expressed on macrophages, which play a major role in inflammatory processes in the walls of coronary arteries and large vessels. Therefore, imaging SSTR expression has the potential to visualize vulnerable plaques. We assessed 68Ga-DOTATATE accumulation in large vessels in comparison to 18F-2-fluorodeoxyglucose (FDG) uptake, calcified plaques (CPs), and cardiovascular risk factors. Methods: Sixteen consecutive patients with neuroendocrine tumors or thyroid cancer underwent both 68Ga-DOTATATE and 18F-FDG PET/CT for staging or restaging purposes. Detailed clinical data, including common cardiovascular risk factors, were recorded. For a separate assessment, they were divided into a high-risk and a low-risk group. In each patient, we calculated the maximum target-to-background ratio (TBR) of eight arterial segments. The correlation of the TBRmean of both tracers with risk factors including plaque burden was assessed. Results: The mean TBR of 68Ga-DOTATATE in all large arteries correlated significantly with the presence of CPs (r = 0.52; p < 0.05), hypertension (r = 0.60; p < 0.05), age (r = 0.56; p < 0.05), and uptake of 18F-FDG (r = 0.64; p < 0.01). There was one significant correlation between 18F-FDG uptake and hypertension (0.58; p < 0.05). Out of the 37 sites with the highest focal 68Ga-DOTATATE uptake, 16 (43.2%) also had focal 18F-FDG uptake. Of 39 sites with the highest 18F-FDG uptake, only 11 (28.2%) had a colocalized 68Ga-DOTATATE accumulation. Conclusions: In this series of cancer patients, we found a stronger association of increased 68Ga-DOTATATE uptake with known risk factors of cardiovascular disease as compared to 18F-FDG, suggesting a potential role for plaque imaging in large arteries. Strikingly, we found that focal uptake of 68Ga-DOTATATE and 18F-FDG does not colocalize in a significant number of lesions.
KW  - Medizin
KW  - Atherosclerotic plaque
KW  - 68Ga-DOTATATE
KW  - Somatostatin receptor
KW  - Cardiovascular risk factors
KW  - Macrophage
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-76231
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Schreck, M.
T1  - 7-Arylbicyclo[4.2.0]oct-1-ene - Synthese durch [2+2]-Cycloadditionen von 1,2-Cyclohexadien sowie 1-Methyl-1,2-cyclohexadien und thermische Äquilibrierung der exo/endo-Isomeren
T1  - 7-Arylbicyclo[4.2.0]oct-1-eaes - Synthesis by [2+2]Cycloadditions of 1,2-Cyclohexadiene and 1-Methyl-l,l-cyclohexadiene and Thermal Equilibration of the exo/endo Isomers
N2  - Das exo/endo--lsomerenverhältnis Ja: Jb bei der bekannten [2 + 2]-Cycloaddition von Styrol an 1,2-Cyclohexadien (2) wurde als tempcraturabhingiaaefunden. Der Einsatz von (Z)-Dcutcriostyrollicfene den Beweis der Zweistufiakeit dieser Reaktion, und das Diradikal 4 wird als wahrscheinlichste Zwischenstufe anaesehen. Erhitzen von Jb auf 140-170°C führte zur Binstellung des thermodynamischen Gleichgewichts mit Ja (Ja:3b = 93:7), wobei wieder das Diradikal4 als Zwischenstufe fungieren dürfte. Mit Hilfe kinetischer Messungen ermittelte man die Aktivierungsparameter für das System Ja~ 3b. - Aus 2 und den Abfangreagenzien p-Methoxystyrol, 1,1-Diphenylethylen sowie 1-Phenylpropen gingen mit bescheidenen Ausbeuten die Titelverbindungen 6a, b, 7 bzw. 8 hervor. Analoa zu 2 wurde sein l-Methylderivat 13 aus 6,6-Dibrom-1-methylbicyclo[3.1.0]hexan (9) durch Methyllithium freigesetzt. In Gegenwart von Styrol entstand neben den Abfanaprodukten 14a, b auch das Dimere 12 von lJ. - Die 1H-NMR-Spektren der Titelverbindungen belegen eine starre Halbsesselkonformation des Cyclohexentcils mit äquatorial anellienem Cyclobutanring.
N2  - The exofendo ratio of tbe isomers 3a, b formed in the kuown [2 + 2] cycloaddition of styrene to 1 ,2-cyclohexadiene (2) has been found to depend on the tempcrature. The utilization of (Z)deuteriostyrene provided the proof of the stepwise nature of this reaction with thc diradical 4 as the most probable intennediatc. Heating of 3b at l40-170°C established the thermodynamic equilibrium between Ja and Jb (3a:3b = 93:7) and again 4 is assumed to be the intermediatc. By means of kinetic measurements the activation parameten ofthe system 3a ~ Jb have been detcrmined. - From 2 and the trapping reagents p-metboxystyrene, 1,1-diphenylethylene, and 1-phenylpropene the title compounds 6a, b, 7, and 8, respectively, were formed in low yields. In analogy to 2 its 1-methyl derivative 13 has been generated from 6,6-dibromo-l-methylbicyclo[3.t.O]hexane (9) with methyUithium. From the reaction in the presence of styrcne the trappina products 14a, b were isolated in addition to the dimer ll of 13. - The 1H NMR spectra of the title compounds support a rigid halfchair conformation of the cyclohexene moiety with the cyclobutane ring ancllatcd equatorially.
KW  - Organische Chemie
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58352
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Leininger, Hartmut
T1  - 7-Azatetracyclo[4.1.0.0<sup>2,4</sup>.0<sup>3,5</sup>]heptan - ein neues Valenzisomeres des Azepins
N2  - No abstract available
Y1  - 1979
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30034
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Brunn, E.
A1  - Roth, W. R.
A1  - Lennartz, H.-W.
T1  - 7-Methyl- and 7-Phenylcyclohepta-1,3,5-trienes from Benzvalene Via 3,3a,4,5,6,6a-Hexahydro-4,5,6-methenocyclopentapyrazoles and Tetracyclo[4.1.0.0\(^{2,4}\).0\(^{3,5}\)]heptanes
N2  - No abstract available
KW  - Organische Chemie
Y1  - 1989
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58471
ER  - 
TY  - JOUR
A1  - Gunesch, Sandra
A1  - Hoffmann, Matthias
A1  - Kiermeier, Carolina
A1  - Fischer, Wolfgang
A1  - Pinto, Antonio F. M.
A1  - Maurice, Tangui
A1  - Maher, Pamela
A1  - Decker, Michael
T1  - 7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo
JF  - Redox Biology
N2  - Alzheimer's disease (AD) is a multifactorial disease and the most common form of dementia. There are no treatments to cure, prevent or slow down the progression of the disease. Natural products hold considerable interest for the development of preventive neuroprotectants to treat neurodegenerative disorders like AD, due to their low toxicity and general beneficial effects on human health with their anti-inflammatory and antioxidant features. In this work we describe regioselective synthesis of 7-O-ester hybrids of the flavonoid taxifolin with the phenolic acids cinnamic and ferulic acid, namely 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin. The compounds show pronounced overadditive neuroprotective effects against oxytosis, ferroptosis and ATP depletion in the murine hippocampal neuron HT22 cell model. Furthermore, 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin reduced LPS-induced neuroinflammation in BV-2 microglia cells as assessed by effects on the levels of NO, IL6 and TNFα. In all in vitro assays the 7-O-esters of taxifolin and ferulic or cinnamic acid showed strong overadditive activity, significantly exceeding the effects of the individual components and the equimolar mixtures thereof, which were almost inactive in all of the assays at the tested concentrations. In vivo studies confirmed this overadditive effect. Treatment of an AD mouse model based on the injection of oligomerized Aβ\(_{25-35}\) peptide into the brain to cause neurotoxicity and subsequently memory deficits with 7-O-cinnamoyltaxifolin or 7-O-feruloyltaxifolin resulted in improved performance in an assay for short-term memory as compared to vehicle and mice treated with the respective equimolar mixtures. These results highlight the benefits of natural product hybrids as a novel compound class with potential use for drug discovery in neurodegenerative diseases due to their pharmacological profile that is distinct from the individual natural components.
KW  - Alzheimer's disease
KW  - Natural product hybrids
KW  - Flavonoids
KW  - Phenolic acids
KW  - Microglia
KW  - In vivo studies
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202718
VL  - 29
ER  - 
TY  - JOUR
A1  - Leininger, H.
A1  - Kemmer, P.
A1  - Beck, K.
A1  - Christl, M.
T1  - 7-Thiatetracyclo[4.1.0.0\(^{2,4}\).0\(^{3,5}\)]heptan (Benzvalensulfid) - Synthese und Reaktionen
N2  - No abstract available
KW  - Organische Chemie
Y1  - 1982
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58113
ER  - 
TY  - JOUR
A1  - Grunicke, H.
A1  - Pyerin, W.
A1  - Eisenbrand, G.
A1  - Havemann, K.
A1  - Rabes, H. M.
A1  - Molling, K.
A1  - Schwab, M.
A1  - Lutz, Werner K.
A1  - Wahrendorf, J.
A1  - Schirrmacher, V.
T1  - 7th International Symposium of the Division of Experimental Cancer Research (AEK) of the German Cancer Society : [Meeting report]
N2  - No abstract available
KW  - Toxikologie
Y1  - 1994
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60651
ER  - 
TY  - JOUR
A1  - Lohse, M. J.
A1  - Klotz, Karl-Norbert
A1  - Lindenborn Fotinos, J.
A1  - Reddington, M.
A1  - Schwabe, U.
A1  - Olsson, R. A.
T1  - 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) - a selective high affinity antagonist radioligand for A\(_1\) adenosine receptors
N2  - The properties of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) as an antagonist ligand for A\(_1\) adenosirre receptors were examined and conipared with other radioligands for this receptor. DPCPX competitively antagonized both the inhibition of adenylate cyclase activity via A\(_1\) adenosirre receptors and the stimulationvia A\(_2\) adenosirre receptors. The K\(_i\)-values of this antagonism were 0.45 nM at the A\(_1\) receptor of rat fat cells, and 330 nM at the A\(_2\) receptor of human platelets, giving a more than 700-fold A\(_1\)-selectivity. A similar A\(_1\)-selectivity was determined in radioligand binding studies. Even at high concentrations, DPCPX did not significantly inhibit the soluble cAMPphosphodiesterase activity of human platelets. [\(^3\)H]DPCPX (105 Ci/mmol) bound in a saturable manner with high affinity to A\(_1\) receptors in membranes of bovine brain and heart, and rat brain and fat cells (K\(_D\) -values 50-190 pM). Its nonspecific binding was about 1% of total at K\(_D\) , except in bovine myocardial membranes (about 10%). Binding studies with bovine myocardial membranes allowed the analysis of both the high and low agonist affinity states of this receptor in a tissue with low receptor density. The binding properties of [\(^3\)H]DPCPX appear superior to those of other agonist and antagonist radioligands for the A\(_1\) receptor.
KW  - Toxikologie
KW  - Adenosine receptors
KW  - Adenylate cyclase
KW  - Phosphodiesterase
KW  - Xanthines
KW  - Radioligands
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-60246
ER  - 
TY  - JOUR
A1  - Wiese, D.
A1  - Tacke, Reinhold
A1  - Wannagat, U.
T1  - 9,9-Dimethyl-10-(3-dimethylaminopropyl)-9-silaacridan, ein Sila-Analogon des Dimetacrins, und strukturverwandte Verbindungen
T1  - 9,9-Dimethyl-10-(3-dimethylaminopropyl)-9-silaacridane,a Sila-Analogue of Dimetacrine, and Structurally Related Compounds
N2  - Das Sila-Dimetacrin (3a), ein Sila-Analogon des Psychopharmakons Dimetacrin (2), und sein N,N-Diethylderivat 3 b sowie sein 3-Chlorderivat 3 c wurden, von den o-Halogenanilinen 4 a- c ausgehend, über die teilweise unbekannten Stufen 5 a- c bis 10a- d synthetisiert, in ihren Eigenschaften beschrieben und in ihrer Struktur über Elementaranalysen, \(^1\)H-NMR- und Massenspektren sichergestellt. Die Synthese des Zwischenproduktes Bis(2-bromphenyl)amin (9a) konnte optimiert werden.
N2  - Sila-dimetacrine (Ja), a sila-analogue of the psychotropic drug dimetacrine (2), and its N,N-diethyl derivative 3 b as well as its 3-chloro derivative 3 c were synthesized from o-haloanilines 4 a- c via the - partially unknown - intermediates S a- c to 10 a- d. Their properties are described and their structure is confirmed by eiemental analysis, \(^1\)H-NMR, and mass spectroscopy. The preparation of the intermediate bis(2-bromophenyl)amine (9a) could be improved.
KW  - Anorganische Chemie
Y1  - 1981
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63691
ER  - 
TY  - JOUR
A1  - Gerhard-Hartmann, Elena
A1  - Goergen, Helen
A1  - Bröckelmann, Paul J.
A1  - Mottok, Anja
A1  - Steinmüller, Tabea
A1  - Grund, Johanna
A1  - Zamò, Alberto
A1  - Ben-Neriah, Susana
A1  - Sasse, Stephanie
A1  - Borchmann, Sven
A1  - Fuchs, Michael
A1  - Borchmann, Peter
A1  - Reinke, Sarah
A1  - Engert, Andreas
A1  - Veldman, Johanna
A1  - Diepstra, Arjan
A1  - Klapper, Wolfram
A1  - Rosenwald, Andreas
T1  - 9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial
JF  - British Journal of Haematology
N2  - High programmed cell death 1 ligand 1 (PD-L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin- and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti-PD-1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD-L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti-PD-1-based first-line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced-stage or r/r cHL. All but two cases (97%) showed PD-L1 expression by the tumour cells in variable amounts. While MHC-I was rarely expressed in >50% of HRSC, MHC-II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD-L1 and MHC-I/II expression on early response to the highly effective anti-PD-1-based NIVAHL first-line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti-PD-1 first-line cHL treatment.
KW  - fluorescence in situ hybridisation
KW  - major histocompatibility complex
KW  - immune checkpoint blockade
KW  - classical Hodgkin lymphoma
KW  - CD274
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258358
VL  - 196
IS  - 1
ER  - 
TY  - JOUR
A1  - Hesselbach, Robert
T1  - <<Nous sommes en guerre sanitaire contre le COVID-19>> – A Corpus-based Approach of Official French, Italian, and Spanish Social Media Discourse in the Light of the Coronavirus Crisis
JF  - promptus - Würzburger Beiträge zur Romanistik
N2  - France, Italy, and Spain are three Romance-speaking countries which – at least in Europe – have been affected to a very high degree by the consequences of the Corona pandemic. This paper examines discursive strategies on social media (Twitter and Facebook) by the three heads of government/state of the aforementioned countries – namely Emmanuel Macron (France), Giuseppe Conte (Italy), and Pedro Sánchez (Spain)- from a corpuslinguistic point of view. For this purpose, a corpus was created which contains all Twitter and Facebook messages posted by these heads of government/state from the beginning of February until the end of April 2020. By applying corpus-linguistic methods we find that all three politicians consciously use social media to sensitize, inform, and – in view of a dramatic pandemic situation – unite their respective populations behind them.
KW  - corpus linguistics
KW  - coronavirus
KW  - Covid-19
KW  - political discourse
KW  - social media
KW  - lexical  co-occurrences
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244251
VL  - 6
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Buchner, Wolfgang
T1  - <sup>13</sup>C-NMR-Spektren von Tetracyclo[4.1.0.0<sup>2,4</sup>.0<sup>3,5</sup>]heptanen, Tetracyclo[5.1.0.0<sup>2,4</sup>.0<sup>3,5</sup>]octanen und Tricyclo[4.1.0.0<sup>2,7</sup>]hept-3-enen. Ungewöhnliche beta- und gamma-Substituenteneffekte
N2  - No abstract available
Y1  - 1978
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-30087
ER  - 
TY  - JOUR
A1  - Nose, Naoko
A1  - Nogami, Suguru
A1  - Koshino, Kazuhiro
A1  - Chen, Xinyu
A1  - Werner, Rudolf A.
A1  - Kashima, Soki
A1  - Rowe, Steven P.
A1  - Lapa, Constantin
A1  - Fukuchi, Kazuki
A1  - Higuchi, Takahiro
T1  - [18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species
JF  - Scientific Reports
N2  - Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.
KW  - biomarkers
KW  - molecular medicine
KW  - stem-cell research
KW  - stem cells
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260590
VL  - 11
IS  - 1
ER  - 
TY  - JOUR
A1  - Breun, Maria
A1  - Monoranu, Camelia M.
A1  - Kessler, Almuth F.
A1  - Matthies, Cordula
A1  - Löhr, Mario
A1  - Hagemann, Carsten
A1  - Schirbel, Andreas
A1  - Rowe, Steven P.
A1  - Pomper, Martin G.
A1  - Buck, Andreas K.
A1  - Wester, Hans-Jürgen
A1  - Ernestus, Ralf-Ingo
A1  - Lapa, Constantin
T1  - [\(^{68}\)Ga]-Pentixafor PET/CT for CXCR4-mediated imaging of vestibular schwannomas
JF  - Frontiers in Oncology
N2  - We have recently demonstrated CXCR4 overexpression in vestibular schwannomas (VS). This study investigated the feasibility of CXCR4-directed positron emission tomography/computed tomography (PET/CT) imaging of VS using the radiolabeled chemokine ligand [\(^{68}\)Ga]Pentixafor.

Methods: 4 patients with 6 primarily diagnosed or pre-treated/observed VS were enrolled. All subjects underwent [\(^{68}\)Ga]Pentixafor PET/CT prior to surgical resection. Images were analyzed visually and semi-quantitatively for CXCR4 expression including calculation of tumor-to-background ratios (TBR). Immunohistochemistry served as standard of reference in three patients.

Results: [\(^{68}\)Ga]Pentixafor PET/CT was visually positive in all cases. SUV\(_{mean}\) and SUV\(_{max}\) were 3.0 ± 0.3 and 3.8 ± 0.4 and TBR\(_{mean}\) and TBR\(_{max}\) were 4.0 ± 1.4 and 5.0 ± 1.7, respectively. Histological analysis confirmed CXCR4 expression in tumors.

Conclusion: Non-invasive imaging of CXCR4 expression using [\(^{68}\)Ga]Pentixafor PET/CT of VS is feasible and could prove useful for in vivo assessment of CXCR4 expression.
KW  - vestibular schwannoma
KW  - CXCR4
KW  - PET/CT
KW  - molecular imaging
KW  - Pentixafor
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201863
VL  - 9
IS  - 503
ER  - 
TY  - JOUR
A1  - Lapa, Constantin
A1  - Schreder, Martin
A1  - Schirbel, Andreas
A1  - Samnick, Samuel
A1  - Kortüm, Klaus Martin
A1  - Herrmann, Ken
A1  - Kropf, Saskia
A1  - Einsele, Herrmann
A1  - Buck, Andreas K.
A1  - Wester, Hans-Jürgen
A1  - Knop, Stefan
A1  - Lückerath, Katharina
T1  - [\(^{68}\)Ga]Pentixafor-PET/CT for imaging of chemokine receptor CXCR4 expression in multiple myeloma - comparison to [\(^{18}\)F]FDG and laboratory values
JF  - Theranostics
N2  - Chemokine (C-X-C motif) receptor 4 (CXCR4) is a key factor for tumor growth and metastasis in several types of human cancer including multiple myeloma (MM). Proof-of-concept of CXCR4-directed radionuclide therapy in MM has recently been reported. This study assessed the diagnostic performance of the CXCR4-directed radiotracer [\(^{68}\)Ga]Pentixafor in MM and a potential role for stratifying patients to CXCR4-directed therapies.

Thirty-five patients with MM underwent [\(^{68}\)Ga]Pentixafor-PET/CT for evaluation of eligibility for endoradiotherapy. In 19/35 cases, [\(^{18}\)F]FDG-PET/CT for correlation was available. Scans were compared on a patient and on a lesion basis. Tracer uptake was correlated with standard clinical parameters of disease activity.

[\(^{68}\)Ga]Pentixafor-PET detected CXCR4-positive disease in 23/35 subjects (66%). CXCR4-positivity at PET was independent from myeloma subtypes, cytogenetics or any serological parameters and turned out as a negative prognostic factor. In the 19 patients in whom a comparison to [\(^{18}\)F]FDG was available, [\(^{68}\)Ga]Pentixafor-PET detected more lesions in 4/19 (21%) subjects, [\(^{18}\)F]FDG proved superior in 7/19 (37%). In the remaining 8/19 (42%) patients, both tracers detected an equal number of lesions. [\(^{18}\)F]FDG-PET positivity correlated with [\(^{68}\)Ga]Pentixafor-PET positivity (p=0.018).

[\(^{68}\)Ga]Pentixafor-PET provides further evidence that CXCR4 expression frequently occurs in advanced multiple myeloma, representing a negative prognostic factor and a potential target for myeloma specific treatment. However, selecting patients for CXCR4 directed therapies and prognostic stratification seem to be more relevant clinical applications for this novel imaging modality, rather than diagnostic imaging of myeloma.
KW  - medicine
KW  - multiple myeloma
KW  - FDG
KW  - molecular imaging
KW  - CXCR4
KW  - PET
KW  - radionuclide therapy
KW  - theranostics
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172106
VL  - 7
IS  - 1
ER  - 
TY  - JOUR
A1  - Ewing, William C.
A1  - Dellermann, Theresa
A1  - Angel Wong, Y. T.
A1  - Mattock, James D.
A1  - Vargas, Alfredo
A1  - Bryce, David L.
A1  - Dewhurst, Rian D.
A1  - Braunschweig, Holger
T1  - \(\pi\)‐Complexes of Diborynes with Main Group Atoms
JF  - Chemistry – An Asian Journal
N2  - We present herein an in‐depth study of complexes in which a molecule containing a boron‐boron triple bond is bound to tellurate cations. The analysis allows the description of these salts as true π complexes between the B−B triple bond and the tellurium center. These complexes thus extend the well‐known Dewar‐Chatt‐Duncanson model of bonding to compounds made up solely of p block elements. Structural, spectroscopic and computational evidence is offered to argue that a set of recently reported heterocycles consisting of phenyltellurium cations complexed to diborynes bear all the hallmarks of \(\pi\)‐complexes in the \(\pi\)‐complex/metallacycle continuum envisioned by Joseph Chatt. Described as such, these compounds are unique in representing the extreme of a metal‐free continuum with conventional unsaturated three‐membered rings (cyclopropenes, azirenes, borirenes) occupying the opposite end.
KW  - boron
KW  - main group elements
KW  - solid-state NMR
KW  - \(\pi\) interactions
KW  - multiple bonds
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214677
VL  - 15
IS  - 10
SP  - 1553
EP  - 1557
ER  - 
TY  - JOUR
A1  - Lapa, Constantin
A1  - Garcia-Velloso, Maria J.
A1  - Lückerath, Katharina
A1  - Samnick, Samuel
A1  - Schreder, Martin
A1  - Otero, Paula Rodriguez
A1  - Schmid, Jan-Stefan
A1  - Herrmann, Ken
A1  - Knop, Stefan
A1  - Buck, Andreas K.
A1  - Einsele, Hermann
A1  - San-Miguel, Jesus
A1  - Kortüm, Klaus Martin
T1  - \(^{11}\)C-methionine-PET in multiple myeloma: a combined study from two different institutions
JF  - Theranostics
N2  - \(^{11}\)C-methionine (MET) has recently emerged as an accurate marker of tumor burden and disease activity in patients with multiple myeloma (MM). This dual-center study aimed at further corroboration of the superiority of MET as positron emission tomography (PET) tracer for staging and re-staging MM, as compared to \(^{18}\)F-2`-deoxy-2`-fluoro-D-glucose (FDG).
78 patients with a history of solitary plasmacytoma (n=4), smoldering MM (SMM, n=5), and symptomatic MM (n=69) underwent both MET- and FDG-PET/computed tomography (CT) at the University Centers of Würzburg, Germany and Navarra, Spain. Scans were compared on a patient and on a lesion basis. Inter-reader agreement was also evaluated. In 2 patients, tumor biopsies for verification of discordant imaging results were available.
MET-PET detected focal lesions (FL) in 59/78 subjects (75.6%), whereas FDG-PET/CT showed lesions in only 47 patients (60.3%; p<0.01), accordingly disease activity would have been missed in 12 patients. Directed biopsies of discordant results confirmed MET-PET/CT results in both cases.
MET depicted more FL in 44 patients (56.4%; p<0.01), whereas in two patients (2/78), FDG proved superior. In the remainder (41.0%, 32/78), both tracers yielded comparable results. Inter-reader agreement for MET was higher than for FDG (κ = 0.82 vs κ = 0.72).
This study demonstrates higher sensitivity of MET in comparison to standard FDG to detect intra- and extramedullary MM including histologic evidence of FDG-negative, viable disease exclusively detectable by MET-PET/CT. MET holds the potential to replace FDG as functional imaging standard for staging and re-staging of MM.
KW  - medicine
KW  - PET/CT
KW  - \(^{11}\)C-methionine
KW  - multiple myeloma
KW  - FDG
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172038
VL  - 7
IS  - 11
ER  - 
TY  - JOUR
A1  - Lückerath, Katharina
A1  - Lapa, Constantin
A1  - Albert, Christa
A1  - Herrmann, Ken
A1  - Jörg, Gerhard
A1  - Samnick, Samuel
A1  - Einsele, Herrmann
A1  - Knop, Stefan
A1  - Buck, Andreas K.
T1  - \(^{11}\)C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma
JF  - Oncotarget
N2  - Multiple myeloma (MM) remains an essentially incurable hematologic malignancy. However, new treatment modalities and novel drugs have been introduced and thus additional tools for therapy monitoring are increasingly needed. Therefore, we evaluated the radiotracers \(^{11}\)C-Methionine (paraprotein-biosynthesis) and \(^{18}\)F-FDG (glucose-utilization) for monitoring response to anti-myeloma-therapy and outcome prediction. Influence of proteasome-inhibition on radiotracer-uptake of different MM cell-lines and patient-derived CD138\(^{+}\) plasma cells was analyzed and related to tumor-biology. Mice xenotransplanted with MM. 1S tumors underwent MET- and FDG-\(\mu\)PET. Tumor-to-background ratios before and after 24 h, 8 and 15 days treatment with bortezomib were correlated to survival. Treatment reduced both MET and FDG uptake; changes in tracer-retention correlated with a switch from high to low CD138-expression. In xenotransplanted mice, MET-uptake significantly decreased by 30-79% as early as 24 h after bortezomib injection. No significant differences were detected thus early with FDG. This finding was confirmed in patient-derived MM cells. Importantly, early reduction of MET-but not FDG-uptake correlated with improved survival and reduced tumor burden in mice. Our results suggest that MET is superior to FDG in very early assessment of response to anti-myeloma-therapy. Early changes in MET-uptake have predictive potential regarding response and survival. MET-PET holds promise to individualize therapies in MM in future.
KW  - positron emission tomography
KW  - imaging techniques
KW  - experience
KW  - \(^{11}\)C-Methionine-PET
KW  - treatment response
KW  - molecular imaging
KW  - multiple myeloma
KW  - management
KW  - \(^{18}\)F-FDG PET/CT
KW  - bone disease
KW  - stem-cell transplantation
KW  - esophagogastric junction
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148688
VL  - 6
IS  - 10
ER  - 
TY  - JOUR
A1  - Christl, Manfred
T1  - \(^{13}\)-NMR-Spektren von Bicyclo[n.1.0]kohlenwasserstoffen
N2  - No abstract available
KW  - Organische Chemie
Y1  - 1975
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57977
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Warren, J. D.
A1  - Hawkins, B. L.
A1  - Roberts, J. D.
T1  - \(^{13}\)C and \(^{15}\)N Nuclear Magnetic Resonance Spectroscopy of Nitrile Oxides and Related Reaction Products : Unexpected \(^{13}\)C and \(^{15}\)N Nuclear Magnetic Resonance Parameters of 2,4,6-Trimethylbenzonitrile Oxide
N2  - No abstract available
KW  - Organische Chemie
Y1  - 1973
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-57894
ER  - 
TY  - JOUR
A1  - Christl, Manfred
A1  - Herzog, C.
T1  - \(^{13}\)C-NMR-Spektroskopie: Besondere Hochfeldeffekte in Bicyclo[4.1.1]- und Tricyclo[5.1.0.0\(^{2,8}\)]octan-Systemen (1,3-Cycloheptadien-Effekt) und besondere Tieffeldeffekte in Dihalogenbicyclo[2.1.1]hex-2-enen (Cyclopenten-Effekt)
N2  - No abstract available
KW  - Organische Chemie
Y1  - 1986
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-58334
ER  - 
TY  - JOUR
A1  - Beykan, Seval
A1  - Dam, Jan S.
A1  - Eberlein, Uta
A1  - Kaufmann, Jens
A1  - Kjærgaard, Benedict
A1  - Jødal, Lars
A1  - Bouterfa, Hakim
A1  - Bejot, Romain
A1  - Lassmann, Michael
A1  - Jensen, Svend Borup
T1  - \(^{177}\)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model
JF  - EJNMMI Research
N2  - Background

\(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.

Results

\(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.

Conclusions

The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.
KW  - lutetium-177
KW  - JR11
KW  - antagonist
KW  - dosimetry
KW  - neuroendocrine tumor (NET)
KW  - OPS201
KW  - pig model
KW  - PRRT
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146888
VL  - 6
IS  - 50
ER  - 
TY  - JOUR
A1  - Morales-Lozano, Maria I.
A1  - Viering, Oliver
A1  - Samnick, Samuel
A1  - Rodriguez-Otero, Paula
A1  - Buck, Andreas K.
A1  - Marcos-Jubilar, Maria
A1  - Rasche, Leo
A1  - Prieto, Elena
A1  - Kortüm, K. Martin
A1  - San-Miguel, Jesus
A1  - Garcia-Velloso, Maria J.
A1  - Lapa, Constantin
T1  - \(^{18}\)F-FDG and \(^{11}\)C-methionine PET/CT in newly diagnosed multiple myeloma patients: comparison of volume-based PET biomarkers
JF  - Cancers
N2  - \(^{11}\)C-methionine (\(^{11}\)C-MET) is a new positron emission tomography (PET) tracer for the assessment of disease activity in multiple myeloma (MM) patients, with preliminary data suggesting higher sensitivity and specificity than \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG). However, the value of tumor burden biomarkers has yet to be investigated. Our goals were to corroborate the superiority of \(^{11}\)C-MET for MM staging and to compare its suitability for the assessment of metabolic tumor burden biomarkers in comparison to \(^{18}\)F-FDG. Twenty-two patients with newly diagnosed, treatment-naïve symptomatic MM who had undergone \(^{11}\)C-MET and \(^{18}\)F-FDG PET/CT were evaluated. Standardized uptake values (SUV) were determined and compared with total metabolic tumor volume (TMTV) for both tracers: total lesion glycolysis (TLG) and total lesion \(^{11}\)C-MET uptake (TLMU). PET-derived values were compared to Revised International Staging System (R-ISS), cytogenetic, and serologic MM markers such as M component, beta 2 microglobulin (B2M), serum free light chains (FLC), albumin, and lactate dehydrogenase (LDH). In 11 patients (50%), \(^{11}\)C-MET detected more focal lesions (FL) than FDG (p < 0.01). SUVmax, SUVmean, SUVpeak, TMTV, and TLMU were also significantly higher in \(^{11}\)C-MET than in \(^{18}\)F-FDG (p < 0.05, respectively). \(^{11}\)C-MET PET biomarkers had a better correlation with tumor burden (bone marrow plasma cell infiltration, M component; p < 0.05 versus p = n.s. respectively). This pilot study suggests that \(^{11}\)C-MET PET/CT is a more sensitive marker for the assessment of myeloma tumor burden than \(^{18}\)F-FDG. Its implications for prognosis evaluation need further investigation.
KW  - multiple myeloma
KW  - methionine
KW  - total lesion glycolysis (TLG)
KW  - metabolic tumor volume (MTV)
KW  - total lesion methionine uptake (TLMU)
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203686
SN  - 2072-6694
VL  - 12
IS  - 4
ER  - 
TY  - JOUR
A1  - Werner, Rudolf A.
A1  - Derlin, Thorsten
A1  - Lapa, Constantin
A1  - Sheikbahaei, Sara
A1  - Higuchi, Takahiro
A1  - Giesel, Frederik L.
A1  - Behr, Spencer
A1  - Drzezga, Alexander
A1  - Kimura, Hiroyuki
A1  - Buck, Andreas K.
A1  - Bengel, Frank M.
A1  - Pomper, Martin G.
A1  - Gorin, Michael A.
A1  - Rowe, Steven P.
T1  - \(^{18}\)F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging
JF  - Theranostics
N2  - Prostate-specific membrane antigen (PSMA)-targeted PET imaging for prostate cancer with \(^{68}\)Ga-labeled compounds has rapidly become adopted as part of routine clinical care in many parts of the world. However, recent years have witnessed the start of a shift from \(^{68}\)Ga- to \(^{18}\)F-labeled PSMA-targeted compounds. The latter imaging agents have several key advantages, which may lay the groundwork for an even more widespread adoption into the clinic. First, facilitated delivery from distant suppliers expands the availability of PET radiopharmaceuticals in smaller hospitals operating a PET center but lacking the patient volume to justify an onsite \(^{68}\)Ge/\(^{68}\)Ga generator. Thus, such an approach meets the increasing demand for PSMA-targeted PET imaging in areas with lower population density and may even lead to cost-savings compared to in-house production. Moreover, \(^{18}\)F-labeled radiotracers have a higher positron yield and lower positron energy, which in turn decreases image noise, improves contrast resolution, and maximizes the likelihood of detecting subtle lesions. In addition, the longer half-life of 110 min allows for improved delayed imaging protocols and flexibility in study design, which may further increase diagnostic accuracy. Moreover, such compounds can be distributed to sites which are not allowed to produce radiotracers on-site due to regulatory issues or to centers without access to a cyclotron. In light of these advantageous characteristics, \(^{18}\)F-labeled PSMA-targeted PET radiotracers may play an important role in both optimizing this transformative imaging modality and making it widely available. We have aimed to provide a concise overview of emerging \(^{18}\)F-labeled PSMA-targeted radiotracers undergoing active clinical development. Given the wide array of available radiotracers, comparative studies are needed to firmly establish the role of the available \(^{18}\)F-labeled compounds in the field of molecular PCa imaging, preferably in different clinical scenarios.
KW  - Radiofluorine
KW  - prostate-specific membrane antigen
KW  - prostate cancer
KW  - \(^{18}\)F
KW  - PSMA
KW  - \(^{68}\)Ga
KW  - theranostics
KW  - radioligand therapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202559
SN  - 1838-7640
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Hertlein, Tobias
A1  - Sturm, Volker
A1  - Jakob, Peter
A1  - Ohlsen, Knut
T1  - \(^{19}\)F Magnetic Resonance Imaging of Perfluorocarbons for the Evaluation of Response to Antibiotic Therapy in a Staphylococcus aureus Infection Model
JF  - PLoS ONE
N2  - Background
The emergence of antibiotic resistant bacteria in recent decades has highlighted the importance of developing new drugs to treat infections. However, in addition to the design of new drugs, the development of accurate preclinical testing methods is essential. In vivo imaging technologies such as bioluminescence imaging (BLI) or magnetic resonance imaging (MRI) are promising approaches. In a previous study, we showed the effectiveness of \(^{19}\)F MRI using perfluorocarbon (PFC) emulsions for detecting the site of Staphylococcus aureus infection. In the present follow-up study, we investigated the use of this method for in vivo visualization of the effects of antibiotic therapy.

Methods/Principal findings
Mice were infected with S. aureus Xen29 and treated with 0.9% NaCl solution, vancomycin or linezolid. Mock treatment led to the highest bioluminescence values during infection followed by vancomycin treatment. Counting the number of colony-forming units (cfu) at 7 days post-infection (p.i.) showed the highest bacterial burden for the mock group and the lowest for the linezolid group. Administration of PFCs at day 2 p.i. led to the accumulation of \(^{19}\)F at the rim of the abscess in all mice (in the shape of a hollow sphere), and antibiotic treatment decreased the \(^{19}\)F signal intensity and volume. Linezolid showed the strongest effect. The BLI, cfu, and MRI results were comparable.

Conclusions
\(^{19}\)F-MRI with PFCs is an effective non-invasive method for assessing the effects of antibiotic therapy in vivo. This method does not depend on pathogen specific markers and can therefore be used to estimate the efficacy of antibacterial therapy against a broad range of clinically relevant pathogens, and to localize sites of infection.
KW  - staphylococcus aureus
KW  - abscesses
KW  - vancomycin
KW  - antibiotics
KW  - magnetic resonance imaging
KW  - emulsions
KW  - bioluminescence imaging
KW  - in vivo imaging
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130113
VL  - 8
IS  - 5
ER  - 
TY  - JOUR
A1  - Lapa, Constantin
A1  - Lückerath, Katharina
A1  - Kleinlein, Irene
A1  - Monoranu, Camelia Maria
A1  - Linsenmann, Thomas
A1  - Kessler, Almuth F.
A1  - Rudelius, Martina
A1  - Kropf, Saskia
A1  - Buck, Andreas K.
A1  - Ernestus, Ralf-Ingo
A1  - Wester, Hans-Jürgen
A1  - Löhr, Mario
A1  - Herrmann, Ken
T1  - \(^{68}\)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma
JF  - Theranostics
N2  - Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand \(^{68}\)Ga-Pentixafor.
15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent \(^{68}\)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-\(^{18}\)F-fluoroethyl)-L-tyrosine (\(^{18}\)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUV\(_{max}\), SUV\(_{mean}\)). Tumor-to-background ratios (TBR) were calculated for both PET probes. \(^{68}\)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples.
\(^{68}\)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUV\(_{mean}\) and SUV\(_{max}\) of 3.0±1.5 and 3.9±2.0 respectively. Respective values for \(^{18}\)F-FET were 4.4±2.0 (SUV\(_{mean}\)) and 5.3±2.3 (SUV\(_{max}\)). TBR for SUV\(_{mean}\) and SUV\(_{max}\) were higher for \(^{68}\)Ga-Pentixafor than for \(^{18}\)F-FET (SUV\(_{mean}\) 154.0±90.7 vs. 4.1±1.3; SUV\(_{max}\) 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high \(^{68}\)Ga-Pentixafor uptake; regions of the same tumor without apparent \(^{68}\)Ga-Pentixafor uptake showed no or low receptor expression.
In this pilot study, \(^{68}\)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, \(^{68}\)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy.
KW  - imaging
KW  - chemokine receptor-4
KW  - glioblastoma
KW  - positron emission tomography/computed tomography
KW  - \(^{68}\)Ga-Pentixafor
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-168174
VL  - 6
IS  - 3
ER  - 
TY  - JOUR
A1  - Goettel, James T.
A1  - Gao, Haopeng
A1  - Dotzauer, Simon
A1  - Braunschweig, Holger
T1  - \(^{Me}\)CAAC=N\(^{-}\): A Cyclic (Alkyl)(Amino)Carbene Imino Ligand
JF  - Chemistry – A European Journal
N2  - A cyclic (alkyl)(amino)carbene (CAAC) has been shown to react with a covalent azide similar to the Staudinger reaction. The reaction of \(^{Me}\)CAAC with trimethylsilyl azide afforded the N‐silylated 2‐iminopyrrolidine (\(^{Me}\)CAAC=NSiMe\(_{3}\)), which was fully characterized. This compound undergoes hydrolysis to afford the 2‐iminopyrrolidine and trimethylsiloxane which co‐crystallize as a hydrogen‐bonded adduct. The N‐silylated 2‐iminopyrrolidine was used to transfer the novel pyrrolidine‐2‐iminato ligand onto both main‐group and transition‐metal centers. The reaction of the tetrabromodiborane bis(dimethyl sulfide) adduct with two equivalents of \(^{Me}\)CAAC=NSiMe\(_{3}\) afforded the disubstituted diborane. The reaction of \(^{Me}\)CAAC=NSiMe\(_{3}\) with TiCl\(_{4}\) and CpTiCl\(_{3}\) afforded \(^{Me}\)CAAC=NTiCl\(_{3}\) and \(^{Me}\)CAAC=NTiCl\(_{2}\)Cp, respectively.
KW  - boron
KW  - carbenes
KW  - imide ligands
KW  - nitrogen ligands
KW  - titanium
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212662
VL  - 26
IS  - 5
ER  - 
TY  - JOUR
A1  - Zopf, Kathrin
A1  - Frey, Kathrin R.
A1  - Kienitz, Tina
A1  - Ventz, Manfred
A1  - Bauer, Britta
A1  - Quinkler, Marcus
T1  - \(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency
JF  - Endocrine Connections
N2  - Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR).
Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH.
Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented.
Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)).
Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC.
KW  - medicine
KW  - adrenal crisis
KW  - adrenal insufficiency
KW  - cortisol
KW  - hydrocortisone
KW  - polyglandular autoimmune syndrome
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173276
VL  - 6
IS  - 8
ER  - 
TY  - JOUR
A1  - Allert, Stefanie
A1  - Förster, Toni M.
A1  - Svensson, Carl-Magnus
A1  - Richardson, Jonathan P.
A1  - Pawlik, Tony
A1  - Hebecker, Betty
A1  - Rudolphi, Sven
A1  - Juraschitz, Marc
A1  - Schaller, Martin
A1  - Blagojevic, Mariana
A1  - Morschhäuser, Joachim
A1  - Figge, Marc Thilo
A1  - Jacobsen, Ilse D.
A1  - Naglik, Julian R.
A1  - Kasper, Lydia
A1  - Mogavero, Selene
A1  - Hube, Bernhard
T1  - \(Candida\) \(albicans\)-Induced Epithelial Damage Mediates Translocation through Intestinal Barriers
JF  - mBio
N2  - Life-threatening systemic infections often occur due to the translocation of pathogens across the gut barrier and into the bloodstream. While the microbial and host mechanisms permitting bacterial gut translocation are well characterized, these mechanisms are still unclear for fungal pathogens such as Candida albicans, a leading cause of nosocomial fungal bloodstream infections. In this study, we dissected the cellular mechanisms of translocation of C. albicans across intestinal epithelia in vitro and identified fungal genes associated with this process. We show that fungal translocation is a dynamic process initiated by invasion and followed by cellular damage and loss of epithelial integrity. A screen of >2,000 C. albicans deletion mutants identified genes required for cellular damage of and translocation across enterocytes. Correlation analysis suggests that hypha formation, barrier damage above a minimum threshold level, and a decreased epithelial integrity are required for efficient fungal translocation. Translocation occurs predominantly via a transcellular route, which is associated with fungus-induced necrotic epithelial damage, but not apoptotic cell death. The cytolytic peptide toxin of C. albicans, candidalysin, was found to be essential for damage of enterocytes and was a key factor in subsequent fungal translocation, suggesting that transcellular translocation of C. albicans through intestinal layers is mediated by candidalysin. However, fungal invasion and low-level translocation can also occur via non-transcellular routes in a candidalysin-independent manner. This is the first study showing translocation of a human-pathogenic fungus across the intestinal barrier being mediated by a peptide toxin. IMPORTANCE Candida albicans, usually a harmless fungus colonizing human mucosae, can cause lethal bloodstream infections when it manages to translocate across the intestinal epithelium. This can result from antibiotic treatment, immune dysfunction, or intestinal damage (e.g., during surgery). However, fungal processes may also contribute. In this study, we investigated the translocation process of C. albicans using in vitro cell culture models. Translocation occurs as a stepwise process starting with invasion, followed by epithelial damage and loss of epithelial integrity. The ability to secrete candidalysin, a peptide toxin deriving from the hyphal protein Ece1, is key: C. albicans hyphae, secreting candidalysin, take advantage of a necrotic weakened epithelium to translocate through the intestinal layer.
KW  - Candida albicans
KW  - candidalysin
KW  - host cell damage
KW  - host cell invasion
KW  - intestinal barrier
KW  - necrosis
KW  - translocation
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221084
VL  - 9
IS  - 3
ER  - 
TY  - JOUR
A1  - Kühlhorn, Franziska
A1  - Rath, Matthias
A1  - Schmoeckel, Katrin
A1  - Cziupka, Katharina
A1  - Nguyen, Huu Hung
A1  - Hildebrandt, Petra
A1  - Hünig, Thomas
A1  - Sparwasser, Tim
A1  - Huehn, Jochen
A1  - Pötschke, Christian
A1  - Bröker, Barbara M.
T1  - \(Foxp3^+\) Regulatory T Cells Are Required for Recovery from Severe Sepsis
JF  - PLoS ONE
N2  - The role of regulatory T cells (Tregs) in bacterial sepsis remains controversial because antibody-mediated depletion experiments gave conflicting results. We employed DEREG mice (DEpletion of REGulatory T cells) and a caecal ligation and puncture model to elucidate the role of \(CD4^+Foxp3^+\) Tregs in sepsis. In DEREG mice natural Tregs can be visualized easily and selectively depleted by diphtheria toxin because the animals express the diphtheria toxin receptor and enhanced green fluorescent protein as a fusion protein under the control of the foxp3 locus. We confirmed rapid Treg-activation and an increased ratio of Tregs to Teffs in sepsis. Nevertheless, 24 h after sepsis induction, Treg-depleted and control mice showed equally strong inflammation, immune cell immigration into the peritoneum and bacterial dissemination. During the first 36 h of disease survival was not influenced by Treg-depletion. Later, however, only Treg-competent animals recovered from the insult. We conclude that the suppressive capacity of Tregs is not sufficient to control overwhelming inflammation and early mortality, but is a prerequisite for the recovery from severe sepsis.
KW  - CD4(+)CD25(+)
KW  - toll-like receptors
KW  - TGF-BETA
KW  - mediated suppression
KW  - polymicrobial sepsis
KW  - improves survival
KW  - adoptive transfer
KW  - infected mice
KW  - in-vivo
KW  - CD4(+)
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130940
VL  - 8
IS  - 5
ER  - 
TY  - JOUR
A1  - Breyer, Maximilian
A1  - Grüner, Julia
A1  - Klein, Alexandra
A1  - Finke, Laura
A1  - Klug, Katharina
A1  - Sauer, Markus
A1  - Üçeyler, Nurcan
T1  - \(In\) \(vitro\) characterization of cells derived from a patient with the GLA variant c.376A>G (p.S126G) highlights a non-pathogenic role in Fabry disease
JF  - Molecular Genetics and Metabolism Reports
N2  - Highlights
• The GLA variant S126G is not associated with Fabry symptoms in the presented case
• S126G has no effect on α-GAL A activity or Gb3 levels in this patient
• S126G sensory neurons show no electrophysiological abnormalities

Abstract
Fabry disease (FD) is a life-limiting disorder characterized by intracellular globotriaosylceramide (Gb3) accumulations. The underlying α-galactosidase A (α-GAL A) deficiency is caused by variants in the gene GLA. Variants of unknown significance (VUS) are frequently found in GLA and challenge clinical management. Here, we investigated a 49-year old man with cryptogenic lacunar cerebral stroke and the chance finding of the VUS S126G, who was sent to our center for diagnosis and initiation of a costly and life-long FD-specific treatment. We combined clinical examination with in vitro investigations of dermal fibroblasts (HDF), induced pluripotent stem cells (iPSC), and iPSC-derived sensory neurons. We analyzed α-GAL A activity in iPSC, Gb3 accumulation in all three cell types, and action potential firing in sensory neurons. Neurological examination and small nerve fiber assessment was normal except for reduced distal skin innervation. S126G iPSC showed normal α-GAL A activity compared to controls and no Gb3 deposits were found in all three cell types. Baseline electrophysiological characteristics of S126G neurons showed no difference compared to healthy controls as investigated by patch-clamp recordings. We pioneer multi-level cellular characterization of the VUS S126G using three cell types derived from a patient and provide further evidence for the benign nature of S126G in GLA, which is of great importance in the management of such cases in clinical practice.
KW  - Fabry disease
KW  - variants of unknown significance
KW  - C.376A>G (p.S126G)
KW  - globotriaosylceramide
KW  - induced pluripotent stem cells
KW  - sensory neurons
KW  - disease model
KW  - α-Galactosidase A
Y1  - 2024
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350295
SN  - 22144269
VL  - 38
ER  - 
TY  - JOUR
A1  - Pötters, Wilhelm
ED  - Hornung, Christoph
ED  - Lambrecht, Gabriella-Maria
ED  - Sendner, Annika
T1  - \(Spagna\) in Dantes poetischer Kosmologie
JF  - Kommunikation und Repräsentation in den romanischen Kulturen. Festschrift für Gerhard Penzkofer
N2  - Verstreut über den ganzen Text der Göttlichen Komödie kommen verschiedene geographische Namen vor, die sich auf Spanien beziehen. In mehreren dieser Fälle hat Dante die im wörtlichen Schriftsinn verwendeten toponymischen Zeichen als Elemente hermetisch wirkender Aussagen und damit offenbar als Indizien einer verborgenen Botschaft konzipiert. Zum Nachweis dieser These soll in den folgenden Betrachtungen erkundet werden, welche Funktion den im wissenschaftlichen Weltbild des Dichters verankerten spanischen Land- und Städtenamen in der Komposition des Epos zukommt. Damit möchte ich meinem Kollegen und Freund Gerhard Penzkofer für die vielen anregenden Gespräche danken, die wir – in den Jahren der gemeinsamen Tätigkeit in der Würzburger Romanistik – vor allem über cosas de España führen konnten. Da der vorliegende Band unter den von seiner Lehre inspirierten Leitbegriffen Kommunikation und Repräsentation steht, bietet es sich am Schluss an, die beiden Konzepte mit den vom Dichter diskutierten Termini sensus litteralis und sensus allegoricus in Beziehung zu setzen.
KW  - Dante
KW  - Spanien
KW  - Dante, Alighieri
KW  - Dante, Alighieri : Divina commedia
KW  - Göttliche Komödie
KW  - Spanien
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-152077
UR  - https://www.avm-verlag.de/detailview?no=5477-055
SN  - 9783954770557
PB  - AVM.edition
CY  - München
ER  - 
TY  - JOUR
A1  - Jannasch, Maren
A1  - Weigel, Tobias
A1  - Engelhardt, Lisa
A1  - Wiezoreck, Judith
A1  - Gaetzner, Sabine
A1  - Walles, Heike
A1  - Schmitz, Tobias
A1  - Hansmann, Jan
T1  - \({In}\) \({vitro}\) chemotaxis and tissue remodeling assays quantitatively characterize foreign body reaction
JF  - ALTEX - Alternatives to Animal Experimentation
N2  - Surgical implantation of a biomaterial triggers foreign-body-induced fibrous encapsulation. Two major mechanisms of this complex physiological process are (I) chemotaxis of fibroblasts from surrounding tissue to the implant region, followed by (II) tissue remodeling. As an alternative to animal studies, we here propose a process-aligned \({in}\) \({vitro}\) test platform to investigate the material dependency of fibroblast chemotaxis and tissue remodeling mediated by material-resident macrophages.
Embedded in a biomimetic three-dimensional collagen hydrogel, chemotaxis of fibroblasts in the direction of macrophage-material-conditioned cell culture supernatant was analyzed by live cell imaging. A combination of statistical analysis with a complementary parameterized random walk model allowed quantitative and qualitative characterization of the cellular walk process. We thereby identified an increasing macrophage-mediated chemotactic potential ranking of biomaterials from glass over polytetrafluorethylene to titanium. To address long-term effects of biomaterial-resident macrophages on fibroblasts in a three-dimensional microenvironment, we further studied tissue remodeling by applying macrophage-material-conditioned medium on fibrous \({in}\) \({vitro}\) tissue models. A high correlation of the \({in}\) \({vitro}\) tissue model to state of the art \({in}\) \({vivo}\) study data was found. Titanium exhibited a significantly lower tissue remodeling capacity compared to polytetrafluorethylene. With this approach, we identified a material dependency of both chemotaxis and tissue remodeling processes, strengthening knowledge on their specific contribution to the foreign body reaction.
KW  - medicine
KW  - foreign body reaction
KW  - fibroblast chemotaxis
KW  - tissue remodeling
KW  - in vitro
KW  - quanititative characterization
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172080
VL  - 34
IS  - 2
ER  - 
TY  - JOUR
T1  - \({ZZ}\) -> l(+)l(-)l '(+)l '(-) cross-section measurements and search for anomalous triple gauge couplings in 13 TeV \({pp}\) collisions with the ATLAS detector
JF  - Physical Review D
N2  - Measurements of ZZ production in the l(+)l(-)l'(+)l'(-) channel in proton-proton collisions at 13 TeV center-of-mass energy at the Large Hadron Collider are presented. The data correspond to 36.1 fb(-1) of collisions collected by the ATLAS experiment in 2015 and 2016. Here l and l ' stand for electrons or muons. Integrated and differential ZZ -> l(+)l(-)l'(+)l'(-) cross sections with Z -> l(+)l(-) candidate masses in the range of 66 GeV to 116 GeV are measured in a fiducial phase space corresponding to the detector acceptance and corrected for detector effects. The differential cross sections are presented in bins of twenty observables, including several that describe the jet activity. The integrated cross section is also extrapolated to a total phase space and to all standard model decays of Z bosons with mass between 66 GeV and 116 GeV, resulting in a value of 17.3 +/- 0.9 [+/- 0.6(start) +/- 0.5 (syst) +/- 0.6 (lumi)] pb. The measurements are found to be in good agreement with the standard model. A search for neutral triple gauge couplings is performed using the transverse momentum distribution of the leading Z boson candidate. No evidence for such couplings is found and exclusion limits are set on their parameters.
KW  - Parton Distributions
KW  - Events
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225844
VL  - 97
IS  - 3
ER  - 
TY  - JOUR
A1  - Massih, Bita
A1  - Veh, Alexander
A1  - Schenke, Maren
A1  - Mungwa, Simon
A1  - Seeger, Bettina
A1  - Selvaraj, Bhuvaneish T.
A1  - Chandran, Siddharthan
A1  - Reinhardt, Peter
A1  - Sterneckert, Jared
A1  - Hermann, Andreas
A1  - Sendtner, Michael
A1  - Lüningschrör, Patrick
T1  - A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS
JF  - Frontiers in Cell and Developmental Biology
N2  - The signals that coordinate and control movement in vertebrates are transmitted from motoneurons (MNs) to their target muscle cells at neuromuscular junctions (NMJs). Human NMJs display unique structural and physiological features, which make them vulnerable to pathological processes. NMJs are an early target in the pathology of motoneuron diseases (MND). Synaptic dysfunction and synapse elimination precede MN loss suggesting that the NMJ is the starting point of the pathophysiological cascade leading to MN death. Therefore, the study of human MNs in health and disease requires cell culture systems that enable the connection to their target muscle cells for NMJ formation. Here, we present a human neuromuscular co-culture system consisting of induced pluripotent stem cell (iPSC)-derived MNs and 3D skeletal muscle tissue derived from myoblasts. We used self-microfabricated silicone dishes combined with Velcro hooks to support the formation of 3D muscle tissue in a defined extracellular matrix, which enhances NMJ function and maturity. Using a combination of immunohistochemistry, calcium imaging, and pharmacological stimulations, we characterized and confirmed the function of the 3D muscle tissue and the 3D neuromuscular co-cultures. Finally, we applied this system as an in vitro model to study the pathophysiology of Amyotrophic Lateral Sclerosis (ALS) and found a decrease in neuromuscular coupling and muscle contraction in co-cultures with MNs harboring ALS-linked SOD1 mutation. In summary, the human 3D neuromuscular cell culture system presented here recapitulates aspects of human physiology in a controlled in vitro setting and is suitable for modeling of MND.
KW  - NMJ–neuromuscular junction
KW  - motoneuron (MN)
KW  - skeletal muscle
KW  - iPSC (induced pluripotent stem cells)
KW  - 3D cell culture
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304161
SN  - 2296-634X
VL  - 11
ER  - 
TY  - JOUR
A1  - Schneider, Verena
A1  - Kruse, Daniel
A1  - Bernardelli de Mattos, Ives
A1  - Zöphel, Saskia
A1  - Tiltmann, Kendra-Kathrin
A1  - Reigl, Amelie
A1  - Khan, Sarah
A1  - Funk, Martin
A1  - Bodenschatz, Karl
A1  - Groeber-Becker, Florian
T1  - A 3D in vitro model for burn wounds: monitoring of regeneration on the epidermal level
JF  - Biomedicines
N2  - Burns affect millions every year and a model to mimic the pathophysiology of such injuries in detail is required to better understand regeneration. The current gold standard for studying burn wounds are animal models, which are under criticism due to ethical considerations and a limited predictiveness. Here, we present a three-dimensional burn model, based on an open-source model, to monitor wound healing on the epidermal level. Skin equivalents were burned, using a preheated metal cylinder. The healing process was monitored regarding histomorphology, metabolic changes, inflammatory response and reepithelialization for 14 days. During this time, the wound size decreased from 25% to 5% of the model area and the inflammatory response (IL-1β, IL-6 and IL-8) showed a comparable course to wounding and healing in vivo. Additionally, the topical application of 5% dexpanthenol enhanced tissue morphology and the number of proliferative keratinocytes in the newly formed epidermis, but did not influence the overall reepithelialization rate. In summary, the model showed a comparable healing process to in vivo, and thus, offers the opportunity to better understand the physiology of thermal burn wound healing on the keratinocyte level.
KW  - skin models
KW  - open-source epidermis
KW  - wound model
KW  - impedance spectroscopy
KW  - wound physiology
KW  - burn wound
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246068
SN  - 2227-9059
VL  - 9
IS  - 9
ER  - 
TY  - JOUR
A1  - Kiesel, Matthias
A1  - Beyers, Inga
A1  - Kalisz, Adam
A1  - Joukhadar, Ralf
A1  - Wöckel, Achim
A1  - Herbert, Saskia-Laureen
A1  - Curtaz, Carolin
A1  - Wulff, Christine
T1  - A 3D printed model of the female pelvis for practical education of gynecological pelvic examination
JF  - 3D Printing in Medicine
N2  - Background
Pelvic palpation is a core component of every Gynecologic examination. It requires vigorous training, which is difficult due to its intimate nature, leading to a need of simulation. Up until now, there are mainly models available for mere palpation which do not offer adequate visualization of the concerning anatomical structures. In this study we present a 3D printed model of the female pelvis. It can improve both the practical teaching of gynecological pelvic examination for health care professionals and the spatial understanding of the relevant anatomy.

Methods
We developed a virtual, simplified model showing selected parts of the female pelvis. 3D printing was used to create a physical model.

Results
The life-size 3D printed model has the ability of being physically assembled step by step by its users. Consequently, it improves teaching especially when combining it with commercial phantoms, which are built solely for palpation training. This is achieved by correlating haptic and visual sensations with the resulting feedback received.

Conclusion
The presented 3D printed model of the female pelvis can be of aid for visualizing and teaching pelvic anatomy and examination to medical staff. 3D printing provides the possibility of creating, multiplying, adapting and sharing such data worldwide with little investment of resources. Thus, an important contribution to the international medical community can be made for training this challenging examination.
KW  - gynecology
KW  - pelvic examination
KW  - pelvic palpation
KW  - 3D printing
KW  - FDM
KW  - SLA
KW  - teaching
KW  - visualization
KW  - education
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313347
VL  - 8
ER  - 
TY  - JOUR
A1  - Schmitt, Joachim
A1  - Lindner, Nathalie
T1  - A 3‐week multimodal intervention involving high‐intensity interval training in female cancer survivors: a randomized controlled trial
JF  - Physiological Reports
N2  - To compare the effects of a 3‐week multimodal rehabilitation involving supervised high‐intensity interval training (HIIT) on female breast cancer survivors with respect to key variables of aerobic fitness, body composition, energy expenditure, cancer‐related fatigue, and quality of life to those of a standard multimodal rehabilitation program. A randomized controlled trial design was administered. Twenty‐eight women, who had been treated for cancer were randomly assigned to either a group performing exercise of low‐to‐moderate intensity (LMIE; n = 14) or a group performing high‐intensity interval training (HIIT; n = 14) as part of a 3‐week multimodal rehabilitation program. No adverse events related to the exercise were reported. Work economy improved following both HIIT and LMIE, with improved peak oxygen uptake following LMIE. HIIT reduced mean total body fat mass with no change in body mass, muscle or fat‐free mass (best P < 0.06). LMIE increased muscle and total fat‐free body mass. Total energy expenditure (P = 0.45) did not change between the groups, whereas both improved quality of life to a similar high extent and lessened cancer‐related fatigue. This randomized controlled study demonstrates that HIIT can be performed by female cancer survivors without adverse health effects. Here, HIIT and LMIE both improved work economy, quality of life and cancer‐related fatigue, body composition or energy expenditure. Since the outcomes were similar, but HIIT takes less time, this may be a time‐efficient strategy for improving certain aspects of the health of female cancer survivors.
KW  - high-intensity interval training
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146455
VL  - 4
IS  - 3
ER  - 
TY  - JOUR
A1  - Sperlich, Billy
A1  - Hahn, Lea-Sofie
A1  - Edel, Antonia
A1  - Behr, Tino
A1  - Helmprobst, Julian
A1  - Leppich, Robert
A1  - Wallmann-Sperlich, Birgit
A1  - Holmberg, Hans-Christer
T1  - A 4-week intervention involving mobile-based daily 6-minute micro-sessions of functional high-intensity circuit training improves strength and quality of life, but not cardio-respiratory fitness of young untrained adults
JF  - Frontiers in Physiology
N2  - The present study was designed to assess the psycho-physiological responses of physically untrained individuals to mobile-based multi-stimulating, circuit-like, multiple-joint conditioning (Circuit\(_{HIIT}\)) performed either once (1xCircuitHIIT) or twice (2xCircuit\(_{HIIT}\)) daily for 4 weeks. In this single-center, two-arm randomized, controlled study, 24 men and women (age: 25 ± 5 years) first received no training instructions for 4 weeks and then performed 4 weeks of either 1xCircuitHIIT or 2xCircuit\(_{HIIT}\) (5 men and 7 women in each group) daily. The 1xCircuitHIIT and 2xCircuit\(_{HIIT}\) participants carried out 90.7 and 85.7% of all planned training sessions, respectively, with average heart rates during the 6-min sessions of 74.3 and 70.8% of maximal heart rate. Body, fat and fat-free mass, and metabolic rate at rest did not differ between the groups or between time-points of measurement. Heart rate while running at 6 km⋅h\(^{-1}\) declined after the intervention in both groups. Submaximal and peak oxygen uptake, the respiratory exchange ratio and heart rate recovery were not altered by either intervention. The maximal numbers of push-ups, leg-levers, burpees, 45°-one-legged squats and 30-s skipping, as well as perception of general health improved in both groups. Our 1xCircuit\(_{HIIT}\) or 2xCircuit\(_{HIIT}\) interventions improved certain parameters of functional strength and certain dimensions of quality of life in young untrained individuals. However, they were not sufficient to enhance cardio-respiratory fitness, in particular peak oxygen uptake.
KW  - aerobic fitness
KW  - body composition
KW  - functional training
KW  - mHealth
KW  - power training
KW  - V800
KW  - wearable
KW  - web-based apps
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176565
VL  - 9
IS  - 423
ER  -