TY  - THES
A1  - Schäfer, Florian
T1  - Kontraktionsverhalten neonataler Rattenkardiomyozyten bei Überexpression phosphorylierungsdefizienter RKIP Mutanten S51/S52
T1  - Contractility of neonatal rat cardiomyocytes after overexpression of phosphorylation-deficient RKIP mutants S51 /S52
N2  - Durch Phosphorylierung inaktiviert GRK2 kardiale ß-Adrenorezeptoren und vermindert dadurch die Kontraktilität von neonatalen Rattenkardiomyozyten. Als natürlicher Inhibitor der GRK2 beeinflusst RKIP die Signalweiterleitung bei Stimulation von ß-Adrenorezeptoren. In dieser Arbeit konnte gezeigt werden, dass eine Überexpression von RKIP die Kontraktilität von neonatalen Rattenkardiomyozyten erhöht. Es wurde die Anzahl auftretender Spontankontraktionen vor und nach Stimulation mit Isoproterenol erfasst sowie eine zeitliche Analyse der Calciumfreisetzung und –aufnahme nach elektrischer Stimulation durchgeführt. Im unstimulierten Zustand zeigten neonatale Rattenkardiomyozyten, die Wildtyp-RKIP überexprimierten, verglichen mit der Kontrollgruppe, keine signifikanten Unterschiede hinsichtlich auftretender Spontankontraktionen. Nach Stimulation mit Isoproterenol zeigten neonatale Rattenkardiomyozyten, in denen Wildtyp-RKIP überexprimiert wurde, eine signifikant höhere Anzahl auftretender Spontankontraktionen. Eine Analyse der Calciumtransienten zeigte bei RKIP-Wildtyp überexprimierenden neonatalen Rattenkardiomyozyten eine erhöhte Calciumfreisetzung während der Systole sowie eine beschleunigte Calciumwiederaufnahme während der Diastole. Zudem wurden die RKIP-Mutanten RKIPS51V und RKIPS52V im Hinblick auf ihre Kontraktilität untersucht. Neonatale Rattenkardiomyozyten welche RKIPS51V und RKIPS52V überexprimierten zeigten weder im Hinblick auf auftretende Spontankontraktionen noch bei der Analyse der Calciumtransienten signifikante Unterschiede zur Kontrollgruppe. Da auch eine Phosphorylierung an Aminosäureposition 51 bzw. Aminosäureposition 52 ohne direkte Auswirkung auf die Kontraktilität möglich ist, wurde in einem in vitro Kinase Assay analysiert, ob neben der bekannten Phosphorylierungsstelle S153 eine weitere Phosphorylierung von RKIP durch PKA oder PKC erfolgt. Bei Einsatz der an Aminosäureposition 153 phosphorylierungsdefizienten RKIP Mutante RKIPS153A konnte keine Phosphorylierung beobachtet werden. In der vorliegenden Arbeit konnte neben einer Phosphorylierung an S153 keine weitere Phosphorylierung von RKIP durch PKC oder PKA beobachtet werden.
N2  - By phosphorylation, GRK2 inactivates cardiac ß-adrenoreceptors and thereby reduces the contractility of neonatal rat cardiomyocytes. As a natural inhibitor of GRK2, RKIP influences cell signaling when ß-adrenoreceptors are stimulated. The presented research shows that an overexpression of RKIP increases the contractility of neonatal rat cardiomyocytes. The number of spontaneous contractions occurring before and after stimulation with isoproterenol was recorded and a temporal analysis of calcium release and uptake after electrical stimulation was performed. In the unstimulated state, neonatal rat cardiomyocytes which overexpressed wild-type RKIP showed no significant differences in terms of spontaneous contractions compared with the control group. After stimulation with isoproterenol, neonatal rat cardiomyocytes in which wild-type RKIP was overexpressed showed a significantly higher number of occurring spontaneous contractions. 
Neonatal rat cardiomyocytes overexpressing wild-type RKIP showed an increased calcium release during systole and an accelerated calcium reuptake during diastole.
The RKIP mutants RKIPS51V and RKIPS52V were examined regarding their contractility. Neonatal rat cardiomyocytes which overexpressed RKIPS51V and RKIPS52V showed no significant differences compared to the control group in terms of spontaneous contractions or calcium cycling. Since phosphorylation at amino acid position 51 or amino acid position 52 could also be possible without direct effect on contractility, an in vitro kinase assay focusing on PKA and PKC was performed.
In the presented work, apart from phosphorylation at S153, no further phosphorylation of RKIP by PKC or PKA could be observed.
KW  - Herzinsuffizienz
KW  - Raf-Kinasen
KW  - Inhibition
KW  - Beta-Rezeptor
KW  - beta-adrenerge Signalwege
KW  - phopohrylierungsdefizient
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213747
ER  - 
TY  - JOUR
A1  - Bachmann, Friederike
A1  - Schreder, Martin
A1  - Engelhardt, Monika
A1  - Langer, Christian
A1  - Wolleschak, Denise
A1  - Mügge, Lars Olof
A1  - Dürk, Heinz
A1  - Schäfer-Eckart, Kerstin
A1  - Blau, Igor Wolfgang
A1  - Gramatzki, Martin
A1  - Liebisch, Peter
A1  - Grube, Matthias
A1  - Metzler, Ivana v.
A1  - Bassermann, Florian
A1  - Metzner, Bernd
A1  - Röllig, Christoph
A1  - Hertenstein, Bernd
A1  - Khandanpour, Cyrus
A1  - Dechow, Tobias
A1  - Hebart, Holger
A1  - Jung, Wolfram
A1  - Theurich, Sebastian
A1  - Maschmeyer, Georg
A1  - Salwender, Hans
A1  - Hess, Georg
A1  - Bittrich, Max
A1  - Rasche, Leo
A1  - Brioli, Annamaria
A1  - Eckardt, Kai-Uwe
A1  - Straka, Christian
A1  - Held, Swantje
A1  - Einsele, Hermann
A1  - Knop, Stefan
T1  - Kinetics of renal function during induction in newly diagnosed multiple myeloma: results of two prospective studies by the German Myeloma Study Group DSMM
JF  - Cancers
N2  - Background: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. Results: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined “renal complete response (CRrenal)” was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). Conclusions: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment “renal fitness” in the latter group.
KW  - multiple myeloma
KW  - renal failure
KW  - kidney
KW  - bortezomib
KW  - lenalidomide
KW  - induction regimen
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234139
SN  - 2072-6694
VL  - 13
IS  - 6
ER  - 
TY  - JOUR
A1  - Burns, Alan J.
A1  - Goldstein, Allan M.
A1  - Newgreen, Donald F.
A1  - Stamp, Lincon
A1  - Schäfer, Karl-Herbert
A1  - Metzger, Marco
A1  - Hotta, Ryo
A1  - Young, Heather M.
A1  - Andrews, Peter W.
A1  - Thapar, Nikhil
A1  - Belkind-Gerson, Jaime
A1  - Bondurand, Nadege
A1  - Bornstein, Joel C.
A1  - Chan, Wood Yee
A1  - Cheah, Kathryn
A1  - Gershon, Michael D.
A1  - Heuckeroth, Robert O.
A1  - Hofstra, Robert M.W.
A1  - Just, Lothar
A1  - Kapur, Raj P.
A1  - King, Sebastian K.
A1  - McCann, Conor J.
A1  - Nagy, Nandor
A1  - Ngan, Elly
A1  - Obermayr, Florian
A1  - Pachnis, Vassilis
A1  - Pasricha, Pankaj J.
A1  - Sham, Mai Har
A1  - Tam, Paul
A1  - Vanden Berghe, Pieter
T1  - White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies
JF  - Developmental Biology
N2  - Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.
KW  - Neural crest cells
KW  - Rat mynteric plexus
KW  - Intestinal pseudoobstruction
KW  - Hypertrophic pyloric-stenosis
KW  - Hirschsprung disease liability
KW  - Slow-transit constipation
KW  - Oxide synthase gene
KW  - Term follow-up
KW  - Nitric-oxide
KW  - In-vivo
KW  - Enteric nervous system
KW  - Enteric neuropathies
KW  - Stem cells
KW  - Cell replacement therapy
KW  - Hirschsprung disease
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-187415
VL  - 417
IS  - 2
ER  - 
TY  - JOUR
A1  - Schäfer, Natalie
A1  - Bühler, Michael
A1  - Heyer, Lisa
A1  - Röhr, Merle I. S.
A1  - Beuerle, Florian
T1  - Endohedral Hydrogen Bonding Templates the Formation of a Highly Strained Covalent Organic Cage Compound
JF  - Chemistry—A European Journal
N2  - A highly strained covalent organic cage compound was synthesized from hexahydroxy tribenzotriquinacene (TBTQ) and a meta-terphenyl-based diboronic acid with an additional benzoic acid substituent in 2’-position. Usually, a 120° bite angle in the unsubstituted ditopic linker favors the formation of a [4+6] cage assembly. Here, the introduction of the benzoic acid group is shown to lead to a perfectly preorganized circular hydrogen-bonding array in the cavity of a trigonal-bipyramidal [2+3] cage, which energetically overcompensates the additional strain energy caused by the larger mismatch in bite angles for the smaller assembly. The strained cage compound was analyzed by mass spectrometry and \(^{1}\)H, \(^{13}\)C and DOSY NMR spectroscopy. DFT calculations revealed the energetic contribution of the hydrogen-bonding template to the cage stability. Furthermore, molecular dynamics simulations on early intermediates indicate an additional kinetic effect, as hydrogen bonding also preorganizes and rigidifies small oligomers to facilitate the exclusive formation of smaller and more strained macrocycles and cages.
KW  - boronate esters
KW  - hydrogen bonding
KW  - dynamic covalent chemistry
KW  - density functional calculations
KW  - cage compounds
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256762
VL  - 27
IS  - 19
ER  - 
TY  - JOUR
A1  - Haake, Markus
A1  - Haack, Beatrice
A1  - Schäfer, Tina
A1  - Harter, Patrick N.
A1  - Mattavelli, Greta
A1  - Eiring, Patrick
A1  - Vashist, Neha
A1  - Wedekink, Florian
A1  - Genssler, Sabrina
A1  - Fischer, Birgitt
A1  - Dahlhoff, Julia
A1  - Mokhtari, Fatemeh
A1  - Kuzkina, Anastasia
A1  - Welters, Marij J. P.
A1  - Benz, Tamara M.
A1  - Sorger, Lena
A1  - Thiemann, Vincent
A1  - Almanzar, Giovanni
A1  - Selle, Martina
A1  - Thein, Klara
A1  - Späth, Jacob
A1  - Gonzalez, Maria Cecilia
A1  - Reitinger, Carmen
A1  - Ipsen-Escobedo, Andrea
A1  - Wistuba-Hamprecht, Kilian
A1  - Eichler, Kristin
A1  - Filipski, Katharina
A1  - Zeiner, Pia S.
A1  - Beschorner, Rudi
A1  - Goedemans, Renske
A1  - Gogolla, Falk Hagen
A1  - Hackl, Hubert
A1  - Rooswinkel, Rogier W.
A1  - Thiem, Alexander
A1  - Romer Roche, Paula
A1  - Joshi, Hemant
A1  - Pühringer, Dirk
A1  - Wöckel, Achim
A1  - Diessner, Joachim E.
A1  - Rüdiger, Manfred
A1  - Leo, Eugen
A1  - Cheng, Phil F.
A1  - Levesque, Mitchell P.
A1  - Goebeler, Matthias
A1  - Sauer, Markus
A1  - Nimmerjahn, Falk
A1  - Schuberth-Wagner, Christine
A1  - Felten, Stefanie von
A1  - Mittelbronn, Michel
A1  - Mehling, Matthias
A1  - Beilhack, Andreas
A1  - van der Burg, Sjoerd H.
A1  - Riedel, Angela
A1  - Weide, Benjamin
A1  - Dummer, Reinhard
A1  - Wischhusen, Jörg
T1  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
JF  - Nature Communications
N2  - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
KW  - cancer microenvironment
KW  - immunotherapy
KW  - T cells
KW  - tumour immunology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333
VL  - 14
ER  -