TY  - JOUR
A1  - Schilbach, Karin
A1  - Alkhaled, Mohammed
A1  - Welker, Christian
A1  - Eckert, Franziska
A1  - Blank, Gregor
A1  - Ziegler, Hendrik
A1  - Sterk, Marco
A1  - Müller, Friederike
A1  - Sonntag, Katja
A1  - Wieder, Thomas
A1  - Braumüller, Heidi
A1  - Schmitt, Julia
A1  - Eyrich, Matthias
A1  - Schleicher, Sabine
A1  - Seitz, Christian
A1  - Erbacher, Annika
A1  - Pichler, Bernd J.
A1  - Müller, Hartmut
A1  - Tighe, Robert
A1  - Lim, Annick
A1  - Gillies, Stephen D.
A1  - Strittmatter, Wolfgang
A1  - Röcken, Martin
A1  - Handgretinger, Rupert
T1  - Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation
JF  - OncoImmunology
N2  - Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16\(^{INK4a}\) and nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer control in vivo.
KW  - TH17 cells
KW  - cancer-targeted IL-12
KW  - differentiation
KW  - humanized mice
KW  - immunocytokine
KW  - immunotherapy
KW  - M1/M2 macrophages
KW  - rhabdomyosarcoma
KW  - TH1-induced senescence
KW  - tumor-infiltrating lymphocytes
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154579
VL  - 4
IS  - 7
ER  - 
TY  - JOUR
A1  - Föcker, Manuel
A1  - Timmesfeld, Nina
A1  - Bühlmeier, Judith
A1  - Zwanziger, Denise
A1  - Führer, Dagmar
A1  - Grasemann, Corinna
A1  - Ehrlich, Stefan
A1  - Egberts, Karin
A1  - Fleischhaker, Christian
A1  - Wewetzer, Christoph
A1  - Wessing, Ida
A1  - Seitz, Jochen
A1  - Herpertz-Dahlmann, Beate
A1  - Hebebrand, Johannes
A1  - Libuda, Lars
T1  - Vitamin D level trajectories of adolescent patients with anorexia nervosa at inpatient admission, during treatment, and at one year follow up: association with depressive symptoms
JF  - Nutrients
N2  - (1) Background: Evidence has accumulated that patients with anorexia nervosa (AN) are at higher risk for vitamin D deficiency than healthy controls. In epidemiologic studies, low 25(OH) vitamin D (25(OH)D) levels were associated with depression. This study analyzed the relationship between 25(OH)D serum levels in adolescent patients and AN and depressive symptoms over the course of treatment. (2) Methods: 25(OH)D levels and depressive symptoms were analyzed in 93 adolescent (in-)patients with AN from the Anorexia Nervosa Day patient versus Inpatient (ANDI) multicenter trial at clinic admission, discharge, and 1 year follow up. Mixed regression models were used to analyze the relationship between 25(OH)D levels and depressive symptoms assessed by the Beck Depression Inventory (BDI-II). (3) Results: Although mean 25(OH)D levels constantly remained in recommended ranges (≥50 nmol/L) during AN treatment, levels decreased from (in)patient admission to 1 year follow up. Levels of 25(OH)D were neither cross-sectionally, prospectively, nor longitudinally associated with the BDI-II score. (4) Conclusions: This study did not confirm that 25(OH)D levels are associated with depressive symptoms in patients with AN. However, increasing risks of vitamin D deficiency over the course of AN treatment indicate that clinicians should monitor 25(OH)D levels.
KW  - vitamin D
KW  - supplements
KW  - anorexia nervosa
KW  - depressive symptoms
KW  - adolescents
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242662
SN  - 2072-6643
VL  - 13
IS  - 7
ER  - 
TY  - JOUR
A1  - Kokic, Goran
A1  - Hillen, Hauke S.
A1  - Tegunov, Dimitry
A1  - Dienermann, Christian
A1  - Seitz, Florian
A1  - Schmitzova, Jana
A1  - Farnung, Lucas
A1  - Siewert, Aaron
A1  - Höbartner, Claudia
A1  - Cramer, Patrick
T1  - Mechanism of SARS-CoV-2 polymerase stalling by remdesivir
JF  - Nature Communications
N2  - Remdesivir is the only FDA-approved drug for the treatment of COVID-19 patients. The active form of remdesivir acts as a nucleoside analog and inhibits the RNA-dependent RNA polymerase (RdRp) of coronaviruses including SARS-CoV-2. Remdesivir is incorporated by the RdRp into the growing RNA product and allows for addition of three more nucleotides before RNA synthesis stalls. Here we use synthetic RNA chemistry, biochemistry and cryoelectron microscopy to establish the molecular mechanism of remdesivir-induced RdRp stalling. We show that addition of the fourth nucleotide following remdesivir incorporation into the RNA product is impaired by a barrier to further RNA translocation. This translocation barrier causes retention of the RNA 3ʹ-nucleotide in the substrate-binding site of the RdRp and interferes with entry of the next nucleoside triphosphate, thereby stalling RdRp. In the structure of the remdesivir-stalled state, the 3ʹ-nucleotide of the RNA product is matched and located with the template base in the active center, and this may impair proofreading by the viral 3ʹ-exonuclease. These mechanistic insights should facilitate the quest for improved antivirals that target coronavirus replication.
KW  - SARS-CoV-2 polymerase
KW  - Remdesivir
KW  - RNA-dependent RNA polymerase
KW  - Molecular mechanism
KW  - Biochemistry
KW  - Cryoelectron microscopy
KW  - RNA
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220979
VL  - 12
ER  -