TY  - JOUR
A1  - Briest, Franziska
A1  - Grass, Irina
A1  - Sedding, Dagmar
A1  - Moebs, Markus
A1  - Christen, Friederike
A1  - Benecke, Joana
A1  - Fuchs, Karolin
A1  - Mende, Stefanie
A1  - Kaemmerer, Daniel
A1  - Sänger, Jörg
A1  - Kunze, Almut
A1  - Geisler, Christina
A1  - Freitag, Helma
A1  - Lewens, Florentine
A1  - Worpenberg, Lina
A1  - Iwaszkiewicz, Sara
A1  - Siegmund, Britta
A1  - Walther, Wolfgang
A1  - Hummel, Michael
A1  - Grabowski, Patricia
T1  - Mechanisms of Targeting the MDM2-p53-FOXM1 Axis in Well-Differentiated Intestinal Neuroendocrine Tumors
JF  - Neuroendocrinology : international journal for basic and clinical studies on neuroendocrine relationships
N2  - Background/Aims: The tumor suppressor p53 is rarely mutated in gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) but they frequently show a strong expression of negative regulators of p53, rendering these tumors excellent targets for a p53 recovery therapy. Therefore, we analyzed the mechanisms of a p53 recovery therapy on intestinal neuroendocrine tumors in vitro and in vivo. Methods: By Western blot and immunohistochemistry, we found that in GEP-NEN biopsy material overexpression of MDM2 was present in intestinal NEN. Therefore, we analyzed the effect of a small-molecule inhibitor, nutlin-3a, in p53 wild-type and mutant GEP-NEN cell lines by proliferation assay, flow cytometry, immunofluorescence, Western blot, and by multiplex gene expression analysis. Finally, we analyzed the antitumor effect of nutlin-3a in a xenograft mouse model in vivo. During the study, the tumor volume was determined. Results: The midgut wild-type cell line KRJ-I responded to the treatment with cell cycle arrest and apoptosis. By gene expression analysis, we could demonstrate that nutlins reactivated an antiproliferative p53 response. KRJ-I-derived xenograft tumors showed a significantly decreased tumor growth upon treatment with nutlin-3a in vivo. Furthermore, our data suggest that MDM2 also influences the expression of the oncogene FOXM1 in a p53-independent manner. Subsequently, a combined treatment of nutlin-3a and cisplatin (as chemoresistance model) resulted in synergistically enhanced antiproliferative effects. Conclusion: In summary, MDM2 overexpression is a frequent event in p53 wild-type intestinal neuroendocrine neoplasms and therefore recovery of a p53 response might be a novel personalized treatment approach in these tumors. (c) 2017 S. Karger AG, Basel
KW  - Neuroendocrine tumors
KW  - Signaling
KW  - MDM2
KW  - p53
KW  - FOXM1
KW  - Targeted therapy
Y1  - 2017
U6  - https://doi.org/10.1159/000481506
SN  - 0028-3835
SN  - 1423-0194
VL  - 107
IS  - 1
SP  - 1
EP  - 23
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Ewert, Christina
A1  - Gaube, Benjamin
A1  - Geisler, Fay Caroline Mary
T1  - Dispositional self-compassion impacts immediate and delayed reactions to social evaluation
JF  - Personality and individual differences : an international journal of research into the structure and development of personality, and the causation of individual differences
N2  - In the present study, we investigated the beneficial effects of trait self-compassion (SC) on perceived stress, shame, and the use of coping strategies in reaction to a socio-evaluative stressor while controlling for the effects of neuroticism (N) and conscientiousness (C). Participants (N = 105) performed a mental-arithmetic task with immediate in-person feedback. SC predicted less perceived stress and shame immediately after the stressor. Additionally, SC predicted less shame after a short recovery phase. This effect was fully mediated by less use of denial. Furthermore, SC buffered the effect of N on the use of denial, and C on shame after recovery. SC also predicted more use of positive reframing. Thus, SC may make a socio-evaluative stressor less threatening and may thwart a shame-inducing conception of the stressor by promoting clearer processing. Furthermore, SC may be especially beneficial for those vulnerable to dysfunctional coping and negative self-conscious emotions. This study contributes to the understanding of how trait self-compassion beneficially influences the processing of stressful situations.
KW  - Self-compassion
KW  - Stress
KW  - Coping
KW  - Shame
KW  - Social evaluation
KW  - Denial
KW  - Acceptance
KW  - Positive refraining
Y1  - 2018
U6  - https://doi.org/10.1016/j.paid.2017.12.037
SN  - 0191-8869
VL  - 125
SP  - 91
EP  - 96
PB  - Elsevier
CY  - Oxford
ER  -