TY - JOUR
A1 - Koehler, Viktoria Florentine
A1 - Adam, Pia
A1 - Fuss, Carmina Teresa
A1 - Jiang, Linmiao
A1 - Berg, Elke
A1 - Frank-Raue, Karin
A1 - Raue, Friedhelm
A1 - Hoster, Eva
A1 - Knösel, Thomas
A1 - Schildhaus, Hans-Ulrich
A1 - Negele, Thomas
A1 - Siebolts, Udo
A1 - Lorenz, Kerstin
A1 - Allelein, Stephanie
A1 - Schott, Matthias
A1 - Spitzweg, Christine
A1 - Kroiss, Matthias
T1 - Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis
JF - Cancers
N2 - Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.
KW - medullary thyroid cancer
KW - rearranged during transfection
KW - variant
KW - multi-tyrosine kinase inhibitor
KW - survival
KW - treatment outcome
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281776
SN - 2072-6694
VL - 14
IS - 14
ER -
TY - JOUR
A1 - Chubanov, Vladimir
A1 - Ferioli, Silvia
A1 - Wisnowsky, Annika
A1 - Simmons, David G.
A1 - Leitzinger, Christin
A1 - Einer, Claudia
A1 - Jonas, Wenke
A1 - Shymkiv, Yuriy
A1 - Gudermann, Thomas
A1 - Bartsch, Harald
A1 - Braun, Attila
A1 - Akdogan, Banu
A1 - Mittermeier, Lorenz
A1 - Sytik, Ludmila
A1 - Torben, Friedrich
A1 - Jurinovic, Vindi
A1 - van der Vorst, Emiel P. C.
A1 - Weber, Christian
A1 - Yildirim, Önder A.
A1 - Sotlar, Karl
A1 - Schürmann, Annette
A1 - Zierler, Susanna
A1 - Zischka, Hans
A1 - Ryazanov, Alexey G.
T1 - Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
JF - eLife
N2 - Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.
KW - signalling pathways
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164987
VL - 5
ER -
TY - JOUR
A1 - Kirscher, Lorenz
A1 - Deán-Ben, Xosé Luis
A1 - Scadeng, Miriam
A1 - Zaremba, Angelika
A1 - Zhang, Qian
A1 - Kober, Christina
A1 - Fehm, Thomas Felix
A1 - Razansky, Daniel
A1 - Ntziachristos, Vasilis
A1 - Stritzker, Jochen
A1 - Szalay, Aladar A.
T1 - Doxycycline Inducible Melanogenic Vaccinia Virus as Theranostic Anti-Cancer Agent
JF - Theranostics
N2 - We reported earlier the diagnostic potential of a melanogenic vaccinia virus based system in magnetic resonance (MRI) and optoacoustic deep tissue imaging (MSOT). Since melanin overproduction lead to attenuated virus replication, we constructed a novel recombinant vaccinia virus strain (rVACV), GLV-1h462, which expressed the key enzyme of melanogenesis (tyrosinase) under the control of an inducible promoter-system. In this study melanin production was detected after exogenous addition of doxycycline in two different tumor xenograft mouse models. Furthermore, it was confirmed that this novel vaccinia virus strain still facilitated signal enhancement as detected by MRI and optoacoustic tomography. At the same time we demonstrated an enhanced oncolytic potential compared to the constitutively melanin synthesizing rVACV system.
KW - reporter gene
KW - oncolysis
KW - molecular imaging
KW - virotherapy
Y1 - 2015
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-124987
VL - 5
IS - 10
ER -
TY - JOUR
A1 - Barth, Thomas F. E.
A1 - Herrmann, Tobias S.
A1 - Tappe, Dennis
A1 - Stark, Lorenz
A1 - Grüner, Beate
A1 - Buttenschoen, Klaus
A1 - Hillenbrand, Andreas
A1 - Juchems, Markus
A1 - Henne-Bruns, Doris
A1 - Kern, Petra
A1 - Seitz, Hanns M.
A1 - Möller, Peter
A1 - Rausch, Robert L.
A1 - Kern, Peter
A1 - Deplazes, Peter
T1 - Sensitive and Specific Immunohistochemical Diagnosis of Human Alveolar Echinococcosis with the Monoclonal Antibody Em2G11
JF - PLoS Neglected Tropical Diseases
N2 - Background: Alveolar echinococcosis (AE) is caused by the metacestode stage of Echinococcus multilocularis. Differential diagnosis with cystic echinococcosis (CE) caused by E. granulosus and AE is challenging. We aimed at improving diagnosis of AE on paraffin sections of infected human tissue by immunohistochemical testing of a specific antibody.
Methodology/Principal Findings: We have analysed 96 paraffin archived specimens, including 6 cutting needle biopsies and 3 fine needle aspirates, from patients with suspected AE or CE with the monoclonal antibody (mAb) Em2G11 specific for the Em2 antigen of E. multilocularis metacestodes. In human tissue, staining with mAb Em2G11 is highly specific for E. multilocularis metacestodes while no staining is detected in CE lesions. In addition, the antibody detects small particles of E. multilocularis (spems) of less than 1 mm outside the main lesion in necrotic tissue, liver sinusoids and lymphatic tissue most probably caused by shedding of parasitic material. The conventional histological diagnosis based on haematoxylin and eosin and PAS stainings were in accordance with the immunohistological diagnosis using mAb Em2G11 in 90 of 96 samples. In 6 samples conventional subtype diagnosis of echinococcosis had to be adjusted when revised by immunohistology with mAb Em2G11.
Conclusions/Significance: Immunohistochemistry with the mAb Em2G11 is a new, highly specific and sensitive diagnostic tool for AE. The staining of small particles of E. multilocularis (spems) outside the main lesion including immunocompetent tissue, such as lymph nodes, suggests a systemic effect on the host.
KW - cells
KW - multilocularis
KW - antigen
Y1 - 2012
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-135371
VL - 6
IS - 10
ER -
TY - JOUR
A1 - Lorenz, Delia
A1 - Musacchio, Thomas
A1 - Kunstmann, Erdmute
A1 - Grauer, Eva
A1 - Pluta, Natalie
A1 - Stock, Annika
A1 - Speer, Christian P.
A1 - Hebestreit, Helge
T1 - A case report of Sanfilippo syndrome - the long way to diagnosis
JF - BMC Neurology
N2 - Background
Mucopolysaccharidosis type III (Sanfilippo syndrome) is a lysosomal storage disorder, caused by a deficiency in the heparan-N-sulfatase enzyme involved in the catabolism of the glycosaminoglycan heparan sulfate. It is characterized by early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild somatic features. In this patient group with a broad clinical spectrum a significant genotype-phenotype correlation with some mutations leading to a slower progressive, attenuated course has been demonstrated.
Case presentation
Our patient had complications in the neonatal period and was diagnosed with Mucopolysaccharidosis IIIa only at the age of 28 years. He was compound heterozygous for the variants p.R245H and p.S298P, the latter having been shown to lead to a significantly milder phenotype.
Conclusions
The diagnostic delay is even more prolonged in this patient population with comorbidities and a slowly progressive course of the disease.
KW - Mucopolysaccharidosis IIIa
KW - diagnostic delay
KW - genotype-phenotype correlation
KW - p.S298P
KW - p.R245H
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300465
VL - 22
IS - 1
ER -
TY - JOUR
A1 - Breitenbach, Tim
A1 - Lorenz, Kristina
A1 - Dandekar, Thomas
T1 - How to steer and control ERK and the ERK signaling cascade exemplified by looking at cardiac insufficiency
JF - International Journal of Molecular Sciences
N2 - Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK\(^{Thr188}\) phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.
KW - optimal pharmacological modulation
KW - efficient intervention points
KW - ERK signaling
KW - optimal treatment strategies
KW - optimal drug targeting
KW - optimal drug combination
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285164
SN - 1422-0067
VL - 20
IS - 9
ER -
TY - JOUR
A1 - Müller, Stefanie H.
A1 - Girard, Simon L.
A1 - Hopfner, Franziska
A1 - Merner, Nancy D.
A1 - Bourassa, Cynthia V.
A1 - Lorenz, Delia
A1 - Clark, Lorraine N.
A1 - Tittmann, Lukas
A1 - Soto-Ortolaza, Alexandra I.
A1 - Klebe, Stephan
A1 - Hallett, Mark
A1 - Schneider, Susanne A.
A1 - Hodgkinson, Colin A.
A1 - Lieb, Wolfgang
A1 - Wszolek, Zbigniew K.
A1 - Pendziwiat, Manuela
A1 - Lorenzo-Betancor, Oswaldo
A1 - Poewe, Werner
A1 - Ortega-Cubero, Sara
A1 - Seppi, Klaus
A1 - Rajput, Alex
A1 - Hussl, Anna
A1 - Rajput, Ali H.
A1 - Berg, Daniela
A1 - Dion, Patrick A.
A1 - Wurster, Isabel
A1 - Shulman, Joshua M.
A1 - Srulijes, Karin
A1 - Haubenberger, Dietrich
A1 - Pastor, Pau
A1 - Vilariño-Güell, Carles
A1 - Postuma, Ronald B.
A1 - Bernard, Geneviève
A1 - Ladwig, Karl-Heinz
A1 - Dupré, Nicolas
A1 - Jankovic, Joseph
A1 - Strauch, Konstantin
A1 - Panisset, Michel
A1 - Winkelmann, Juliane
A1 - Testa, Claudia M.
A1 - Reischl, Eva
A1 - Zeuner, Kirsten E.
A1 - Ross, Owen A.
A1 - Arzberger, Thomas
A1 - Chouinard, Sylvain
A1 - Deuschl, Günther
A1 - Louis, Elan D.
A1 - Kuhlenbäumer, Gregor
A1 - Rouleau, Guy A.
T1 - Genome-wide association study in essential tremor identifies three new loci
JF - Brain
N2 - We conducted a genome-wide association study of essential tremor, a common movement disorder characterized mainly by a postural and kinetic tremor of the upper extremities. Twin and family history studies show a high heritability for essential tremor. The molecular genetic determinants of essential tremor are unknown. We included 2807 patients and 6441 controls of European descent in our two-stage genome-wide association study. The 59 most significantly disease-associated markers of the discovery stage were genotyped in the replication stage. After Bonferroni correction two markers, one (rs10937625) located in the serine/threonine kinase STK32B and one (rs17590046) in the transcriptional coactivator PPARGC1A were associated with essential tremor. Three markers (rs12764057, rs10822974, rs7903491) in the cell-adhesion molecule CTNNA3 were significant in the combined analysis of both stages. The expression of STK32B was increased in the cerebellar cortex of patients and expression quantitative trait loci database mining showed association between the protective minor allele of rs10937625 and reduced expression in cerebellar cortex. We found no expression differences related to disease status or marker genotype for the other two genes. Replication of two lead single nucleotide polymorphisms of previous small genome-wide association studies (rs3794087 in SLC1A2, rs9652490 in LINGO1) did not confirm the association with essential tremor.
KW - quality-control
KW - disease
KW - tool
KW - movement disorders
KW - genome-wide association study
KW - tremor
KW - genetics
KW - essential tremor
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186541
VL - 139
ER -
TY - JOUR
A1 - Stritt, Simon
A1 - Nurden, Paquita
A1 - Favier, Remi
A1 - Favier, Marie
A1 - Ferioli, Silvia
A1 - Gotru, Sanjeev K.
A1 - van Eeuwijk, Judith M.M.
A1 - Schulze, Harald
A1 - Nurden, Alan T.
A1 - Lambert, Michele P.
A1 - Turro, Ernest
A1 - Burger-Stritt, Stephanie
A1 - Matsushita, Masayuki
A1 - Mittermeier, Lorenz
A1 - Ballerini, Paola
A1 - Zierler, Susanna
A1 - Laffan, Michael A.
A1 - Chubanov, Vladimir
A1 - Gudermann, Thomas
A1 - Nieswandt, Bernhard
A1 - Braun, Attila
T1 - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture
JF - Nature Communications
N2 - Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
KW - Cytoskeleton
KW - homeostasisIon channels
KW - thrombopoiesis
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173843
VL - 7
ER -
TY - JOUR
A1 - Butt, Elke
A1 - Stempfle, Katrin
A1 - Lister, Lorenz
A1 - Wolf, Felix
A1 - Kraft, Marcella
A1 - Herrmann, Andreas B.
A1 - Viciano, Cristina Perpina
A1 - Weber, Christian
A1 - Hochhaus, Andreas
A1 - Ernst, Thomas
A1 - Hoffmann, Carsten
A1 - Zernecke, Alma
A1 - Frietsch, Jochen J.
T1 - Phosphorylation-dependent differences in CXCR4-LASP1-AKT1 interaction between breast cancer and chronic myeloid leukemia
JF - Cells
N2 - The serine/threonine protein kinase AKT1 is a downstream target of the chemokine receptor 4 (CXCR4), and both proteins play a central role in the modulation of diverse cellular processes, including proliferation and cell survival. While in chronic myeloid leukemia (CML) the CXCR4 is downregulated, thereby promoting the mobilization of progenitor cells into blood, the receptor is highly expressed in breast cancer cells, favoring the migratory capacity of these cells. Recently, the LIM and SH3 domain protein 1 (LASP1) has been described as a novel CXCR4 binding partner and as a promoter of the PI3K/AKT pathway. In this study, we uncovered a direct binding of LASP1, phosphorylated at S146, to both CXCR4 and AKT1, as shown by immunoprecipitation assays, pull-down experiments, and immunohistochemistry data. In contrast, phosphorylation of LASP1 at Y171 abrogated these interactions, suggesting that both LASP1 phospho-forms interact. Finally, findings demonstrating different phosphorylation patterns of LASP1 in breast cancer and chronic myeloid leukemia may have implications for CXCR4 function and tyrosine kinase inhibitor treatment.
KW - LASP1
KW - CXCR4
KW - AKT1
KW - CML
KW - breast cancer
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200638
SN - 2073-4409
VL - 9
IS - 2
ER -
TY - JOUR
A1 - Brosge, Felix
A1 - Lorenz, Thomas
A1 - Helten, Holger
A1 - Bolm, Carsten
T1 - BN- and BO-Doped Inorganic–Organic Hybrid Polymers with Sulfoximine Core Units
JF - Chemistry - A European Journal
N2 - While polysulfones constitute a class of well‐established, highly valuable applied materials, knowledge about polymers based on the related sulfoximine group is very limited. We have employed functionalized diaryl sulfoximines and a p ‐phenylene bisborane as building blocks for unprecedented BN‐ and BO‐doped alternating inorganic–organic hybrid copolymers. While the former were accessed by a facile silicon/boron exchange protocol, the synthesis of polymers with main‐chain B–O linkages was achieved by salt elimination.
KW - boron
KW - hybrid materials
KW - polymers
KW - sulfoimines
KW - sulfur
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206194
VL - 25
IS - 55
ER -
TY - THES
A1 - Lorenz, Thomas
T1 - Conjugated Polymers with BN Units in the Main Chain
T1 - Konjugierte Polymere mit BN-Einheiten in der Hauptkette
N2 - In recent years PI-conjugated organoboron polymers and BN-doped polycyclic aromatic hydrocarbons have attracted a lot of interest due to their great potential in organic electronics. However, there are only few known examples of conjugated polymers with BN units in their main chain. Within this work silazane cleavage with silicon-boron (Si/B) exchange for the synthesis of a novel class of inorganic-organic hybrid polymers is demonstrated. These polymers consist of alternating NBN and para-phenylene units in the main chain. Photophysical studies and TD-DFT calculations for the polymer and molecular model systems were carried out, revealing a low extent of PI-conjugation across the NBN units. The new polymers can be used as macromolecular polyligands by a cross-linking reaction with a ZrIV compound. In the next chapter the synthesis and characterization of the first poly(p-phenylene iminoborane) is presented. This novel inorganic–organic hybrid polymer can be described as a BN analogue of the well-known poly(p-phenylene vinylene) (PPV) and is also accessible using the previously described Si/B exchange as synthetic strategy. Photophysical investigations and TD-DFT calculations on the polymer and corresponding model oligomers provide clear evidence for PI-conjugation across the B=N units and extension of the conjugation path with increasing chain length. Furthermore, a possible application of Si/B exchange for the synthesis of polysulfoximines was explored. Herein, diaryl sulfoximines and a p-phenylene bisborane serve as building blocks for new BN- and BO-doped alternating inorganic–organic hybrid copolymers. While the BN-linked polymers were accessible by a facile silicon/boron exchange protocol, the synthesis of polymers with B–O linkages in the main chain is achieved by salt elimination. In the last chapter the concept of Si/B exchange was investigated for the synthesis of BP-linked oligomers. Herein oligomers with sterically less demanding substituents (substituents: 2,4,6-trimethylphenyl or 2,4,6-tri-iso-propylphenyl) at the phosphorus are accessible using Si/B exchange, but the oligomer with Mes* (2,4,6-tri-tert-butylphenyl) as substituent needed a salt elimination pathway to give the desired product. Experimental data and theoretical investigations indicate, that the P-substituent has a high influence on the geometry of the phosphorus center and therefore on the possible conjugation over the BP units.
N2 - In den letzten Jahren haben PI-konjugierte Organoborpolymere und BN-dotierte polyzyklische aromatische Kohlenwasserstoffe aufgrund ihres großen Potenzials in organischer Elektronik großes Interesse auf sich gezogen. In der Literatur sind jedoch nur wenige Beispiele für konjugierte Polymere mit BN-Einheiten in ihrer Hauptkette bekannt. In dieser Arbeit wird die Silazanspaltung mit Silizium-Bor (Si/B)-Austausch zur Synthese einer neuen Klasse von anorganisch-organischen Hybridpolymeren vorgestellt. Diese Polymere bestehen aus alternierenden NBN- und para-Phenylen-Einheiten in der Hauptkette. Es wurden photophysikalische Untersuchungen und TD-DFT-Berechnungen für das Polymer und molekulare Modellsysteme durchgeführt, welche auf ein geringes Ausmaß an PI-Konjugation über die NBN-Einheiten deuten. Durch eine Vernetzungsreaktion über ZrIV-Verbindungen besteht die Möglichkeit diese neuen Polymere als makromolekulare Polyliganden einzusetzen. Im nächsten Kapitel wird die Synthese und Charakterisierung des ersten Poly(p-phenyleniminoborans) vorgestellt. Dieses neue anorganisch-organische Hybridpolymer kann als ein BN-Analogon des bekannten Poly(p-phenylenvinylen) (PPV) beschrieben werden und ist auch über den zuvor beschriebenen Si/B-Austausch als Synthesestrategie zugänglich. Photophysikalische Untersuchungen und TD-DFT-Berechnungen an dem Polymer und an entsprechenden Oligomeren als Modellsystem liefern deutliche Hinweise auf eine PI-Konjugation über die B=N-Einheiten und eine Erweiterung der Konjugationslänge mit wachsender Kettenlänge. Weiterhin wurde die Anwendungsmöglichkeit des Si/B-Austausches für die Synthese von Polysulfoximinen untersucht. Dabei dienen Diarylsulfoximine und p-Phenylenbisboran als Bausteine für neue BN- und BO-dotierte alternierende anorganisch-organische Hybridkopolymere. Während die BN-verknüpften Polymere über den Silizium/Bor-Austausch als Synthesestrategie zugänglich waren, wird die Synthese der Polymere mit B-O-Bindungen in der Hauptkette durch eine Salzeliminierung erreicht. Im letzten Kapitel wurde das Konzept des Si/B-Austausches für die Synthese von BP-verknüpften Oligomeren untersucht. Dabei sind Oligomere mit sterisch weniger anspruchsvollen Substituenten (Substituenten: 2,4,6-trimethylphenyl oder 2,4,6-tri-iso-propylphenyl) am Phosphor mittels Si/B-Austausch zugänglich, während für die Synthese des Oligomers mit Mes* (2,4,6-tri-tert-Butylphenyl) als Substituent eine Salzeliminierung notwendig war um das gewünschte Produkt zu erhalten. Experimentelle Daten und theoretische Untersuchungen deuten darauf hin, dass der P-Substituent einen großen Einfluss auf die Geometrie des Phosphorzentrums und damit auf die mögliche Konjugation über die BP-Einheit hat.
KW - Polyphenylenvinylenanaloga
KW - Iminoborane
KW - Sulfoximin
KW - Konjugierte Polymere
KW - Silizium-Boraustausch
KW - silicon-boron exchange
KW - diimidoborane
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219230
ER -
TY - JOUR
A1 - Tolstik, Elen
A1 - Ali, Nairveen
A1 - Guo, Shuxia
A1 - Ebersbach, Paul
A1 - Möllmann, Dorothe
A1 - Arias-Loza, Paula
A1 - Dierks, Johann
A1 - Schuler, Irina
A1 - Freier, Erik
A1 - Debus, Jörg
A1 - Baba, Hideo A.
A1 - Nordbeck, Peter
A1 - Bocklitz, Thomas
A1 - Lorenz, Kristina
T1 - CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease
JF - International Journal of Molecular Sciences
N2 - Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient’s prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90–96%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.
KW - coherent anti-Stokes Raman scattering (CARS) microscopy
KW - Raman micro-spectroscopy
KW - cardiovascular diseases
KW - Fabry Disease (FD)
KW - Gb3 and lyso-Gb3 biomarkers
KW - multivariate data analysis
KW - immunohistochemistry
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284427
SN - 1422-0067
VL - 23
IS - 10
ER -
TY - JOUR
A1 - Geyer, Johannes
A1 - Haan, Peter
A1 - Lorenz, Svenja
A1 - Zwick, Thomas
A1 - Bruns, Mona
T1 - Role of labor demand in the labor market effects of a pension reform
JF - Industrial Relations
N2 - This paper shows that labor demand plays an important role in the labor market reactions to a pension reform in Germany. Employers with a high share of older worker inflow compared with their younger worker inflow, employers in sectors with few investments in research and development, and employers in sectors with a high share of collective bargaining agreements allow their employees to stay employed longer after the reform. These employers offer their older employees partial retirement instead of forcing them into unemployment before early retirement because the older employees incur low substitution costs and high dismissal costs.
KW - pension reform
KW - labor demand
KW - labor market
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259446
VL - 61
IS - 2
ER -
TY - JOUR
A1 - Walther, Kay-Arne
A1 - Gonzales, José Roberto
A1 - Gröger, Sabine
A1 - Ehmke, Benjamin
A1 - Kaner, Dogan
A1 - Lorenz, Katrin
A1 - Eickholz, Peter
A1 - Kocher, Thomas
A1 - Kim, Ti-Sun
A1 - Schlagenhauf, Ulrich
A1 - Koch, Raphael
A1 - Meyle, Jörg
T1 - The role of polymorphisms at the Interleukin-1, Interleukin-4, GATA-3 and Cyclooxygenase-2 genes in non-surgical periodontal therapy
JF - International Journal of Molecular Sciences
N2 - Periodontitis is a multifactorial disease. The aim of this explorative study was to investigate the role of Interleukin-(IL)-1, IL-4, GATA-3 and Cyclooxygenase-(COX)-2 polymorphisms after non-surgical periodontal therapy with adjunctive systemic antibiotics (amoxicillin/metronidazole) and subsequent maintenance in a Caucasian population. Analyses were performed using blood samples from periodontitis patients of a multi-center trial (ClinicalTrials.gov NCT00707369=ABPARO-study). Polymorphisms were analyzed using quantitative real-time PCR. Clinical attachment levels (CAL), percentage of sites showing further attachment loss (PSAL) ≥1.3 mm, bleeding on probing (BOP) and plaque score were assessed. Exploratory statistical analysis was performed. A total of 209 samples were genotyped. Patients carrying heterozygous genotypes and single-nucleotide-polymorphisms (SNP) on the GATA-3-IVS4 +1468 gene locus showed less CAL loss than patients carrying wild type. Heterozygous genotypes and SNPs on the IL-1A-889, IL-1B +3954, IL-4-34, IL-4-590, GATA-3-IVS4 +1468 and COX-2-1195 gene loci did not influence CAL. In multivariate analysis, CAL was lower in patients carrying GATA-3 heterozygous genotypes and SNPs than those carrying wild-types. For the first time, effects of different genotypes were analyzed in periodontitis progression after periodontal therapy and during supportive treatment using systemic antibiotics demonstrating a slight association of GATA-3 gene locus with CAL. This result suggests that GATA-3 genotypes are a contributory but non-essential risk factor for periodontal disease progression.
KW - periodontitis
KW - polymorphisms
KW - risk factor
KW - periodontal therapy
KW - antibiotics
KW - GATA-3
KW - Interleukin-1
KW - Interleukin-4
KW - Cyclooxygenase-2
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284386
SN - 1422-0067
VL - 23
IS - 13
ER -
TY - JOUR
A1 - Nemes, Karolina
A1 - Johann, Pascal D.
A1 - Steinbügl, Mona
A1 - Gruhle, Miriam
A1 - Bens, Susanne
A1 - Kachanov, Denis
A1 - Teleshova, Margarita
A1 - Hauser, Peter
A1 - Simon, Thorsten
A1 - Tippelt, Stephan
A1 - Eberl, Wolfgang
A1 - Chada, Martin
A1 - Lopez, Vicente Santa-Maria
A1 - Grigull, Lorenz
A1 - Hernáiz-Driever, Pablo
A1 - Eyrich, Matthias
A1 - Pears, Jane
A1 - Milde, Till
A1 - Reinhard, Harald
A1 - Leipold, Alfred
A1 - van de Wetering, Marianne
A1 - Gil-da-Costa, Maria João
A1 - Ebetsberger-Dachs, Georg
A1 - Kerl, Kornelius
A1 - Lemmer, Andreas
A1 - Boztug, Heidrun
A1 - Furtwängler, Rhoikos
A1 - Kordes, Uwe
A1 - Vokuhl, Christian
A1 - Hasselblatt, Martin
A1 - Bison, Brigitte
A1 - Kröncke, Thomas
A1 - Melchior, Patrick
A1 - Timmermann, Beate
A1 - Gerss, Joachim
A1 - Siebert, Reiner
A1 - Frühwald, Michael C.
T1 - Infants and newborns with atypical teratoid rhabdoid tumors (ATRT) and extracranial malignant rhabdoid tumors (eMRT) in the EU-RHAB registry: a unique and challenging population
JF - Cancers
N2 - Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.
KW - atypical teratoid rhabdoid tumors
KW - extracranial malignant rhabdoid tumor
KW - RTPS1
KW - RTPS2
KW - germline mutation
KW - EU-RHAB registry
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270730
SN - 2072-6694
VL - 14
IS - 9
ER -
TY - JOUR
A1 - Matern, Johannes
A1 - Koch, Raphael
A1 - Petersmann, Astrid
A1 - Kocher, Thomas
A1 - Eickholz, Peter
A1 - Lorenz, Katrin
A1 - Kim, Ti‐Sun
A1 - Meyle, Jörg
A1 - Kaner, Doğan
A1 - Schlagenhauf, Ulrich
A1 - Gravemeier, Martina
A1 - Harks, Inga
A1 - Ehmke, Benjamin
T1 - Effect of periodontal therapy on adipokine biomarkers in overweight
JF - Journal of Clinical Periodontology
N2 - Aim
The aim of this study was to evaluate the effect of non‐surgical periodontal therapy on circulating levels of the systemic inflammation‐associated biomarkers orosomucoid (ORM), high‐sensitivity C‐reactive protein (hsCRP), chemerin, and retinol‐binding protein 4 (RBP4) in overweight or normal‐weight patients with periodontitis at 27.5 months after therapy.
Materials and methods
This exploratory subanalysis includes patients from the ABPARO‐trial (ClinicalTrials.gov NCT00707369). The per‐protocol collective provided untreated periodontitis patients with high (≥28 kg/m\(^{2}\)) or moderate (21–24 kg/m\(^{2}\)) BMI. Out of the per‐protocol collective, 80 patients were randomly selected and stratified for BMI group, sex, and treatment group (antibiotics/placebo), resulting in 40 overweight and normal‐weight patients. Patients received non‐surgical periodontal therapy and maintenance at 3‐month intervals. Plasma samples from baseline and 27.5 months following initial treatment were used to measure the concentrations of ORM, hsCRP, chemerin, and RBP4.
Results
At the 27.5‐month examination, ORM and hsCRP decreased noticeably in the overweight group (ORM: p = .001, hsCRP: p = .004) and normal‐weight patients (ORM: p = .007, hsCRP: p < .001). Chemerin decreased in the overweight group (p = .048), and RBP4 concentrations remained stable.
Conclusion
Non‐surgical periodontal therapy reduced systemically elevated inflammation‐associated biomarkers in periodontitis patients. These improvements were more pronounced in overweight patients than in normal‐weight patients.
KW - chemerin
KW - orosomucoid
KW - overweight
KW - periodontitis
KW - retinol‐binding protein 4
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215546
VL - 47
IS - 7
SP - 842
EP - 850
ER -
TY - JOUR
A1 - Beierle, Felix
A1 - Schobel, Johannes
A1 - Vogel, Carsten
A1 - Allgaier, Johannes
A1 - Mulansky, Lena
A1 - Haug, Fabian
A1 - Haug, Julian
A1 - Schlee, Winfried
A1 - Holfelder, Marc
A1 - Stach, Michael
A1 - Schickler, Marc
A1 - Baumeister, Harald
A1 - Cohrdes, Caroline
A1 - Deckert, Jürgen
A1 - Deserno, Lorenz
A1 - Edler, Johanna-Sophie
A1 - Eichner, Felizitas A.
A1 - Greger, Helmut
A1 - Hein, Grit
A1 - Heuschmann, Peter
A1 - John, Dennis
A1 - Kestler, Hans A.
A1 - Krefting, Dagmar
A1 - Langguth, Berthold
A1 - Meybohm, Patrick
A1 - Probst, Thomas
A1 - Reichert, Manfred
A1 - Romanos, Marcel
A1 - Störk, Stefan
A1 - Terhorst, Yannik
A1 - Weiß, Martin
A1 - Pryss, Rüdiger
T1 - Corona Health — A Study- and Sensor-Based Mobile App Platform Exploring Aspects of the COVID-19 Pandemic
JF - International Journal of Environmental Research and Public Health
N2 - Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July 2020) in eight languages and attracted 7290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures.
KW - mobile health
KW - ecological momentary assessment
KW - digital phenotyping
KW - longitudinal studies
KW - mobile crowdsensing
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242658
SN - 1660-4601
VL - 18
IS - 14
ER -
TY - JOUR
A1 - Dammert, Marcel A.
A1 - Brägelmann, Johannes
A1 - Olsen, Rachelle R.
A1 - Böhm, Stefanie
A1 - Monhasery, Niloufar
A1 - Whitney, Christopher P.
A1 - Chalishazar, Milind D.
A1 - Tumbrink, Hannah L.
A1 - Guthrie, Matthew R.
A1 - Klein, Sebastian
A1 - Ireland, Abbie S.
A1 - Ryan, Jeremy
A1 - Schmitt, Anna
A1 - Marx, Annika
A1 - Ozretić, Luka
A1 - Castiglione, Roberta
A1 - Lorenz, Carina
A1 - Jachimowicz, Ron D.
A1 - Wolf, Elmar
A1 - Thomas, Roman K.
A1 - Poirier, John T.
A1 - Büttner, Reinhard
A1 - Sen, Triparna
A1 - Byers, Lauren A.
A1 - Reinhardt, H. Christian
A1 - Letai, Anthony
A1 - Oliver, Trudy G.
A1 - Sos, Martin L.
T1 - MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer
JF - Nature Communications
N2 - MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC-paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC-paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.
KW - genetic engineering
KW - oncogenes
KW - small-cell lung cancer
KW - targeted therapies
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223569
VL - 10
ER -