TY  - JOUR
A1  - Freimann, A.
A1  - Dierkes, M.
A1  - Petermann, T.
A1  - Liman, C.
A1  - Kempf, F.
A1  - Schilling, K.
T1  - ESTNeT: a discrete event simulator for space-terrestrial networks
JF  - CEAS Space Journal
N2  - The capabilities of small satellites have improved significantly in recent years. Specifically multi-satellite systems become increasingly popular, since they allow the support of new applications. The development and testing of these multi-satellite systems is a new challenge for engineers and requires the implementation of appropriate development and testing environments. In this paper, a modular network simulation framework for space–terrestrial systems is presented. It enables discrete event simulations for the development and testing of communication protocols, as well as mission-based analysis of other satellite system aspects, such as power supply and attitude control. ESTNeT is based on the discrete event simulator OMNeT++ and will be released under an open source license.
KW  - space–terrestrial networks
KW  - wireless communication
KW  - system simulation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235835
SN  - 1868-2502
VL  - 13
ER  - 
TY  - JOUR
A1  - Jessen, Christina
A1  - Kreß, Julia K. C.
A1  - Baluapuri, Apoorva
A1  - Hufnagel, Anita
A1  - Schmitz, Werner
A1  - Kneitz, Susanne
A1  - Roth, Sabine
A1  - Marquardt, André
A1  - Appenzeller, Silke
A1  - Ade, Casten P.
A1  - Glutsch, Valerie
A1  - Wobser, Marion
A1  - Friedmann-Angeli, José Pedro
A1  - Mosteo, Laura
A1  - Goding, Colin R.
A1  - Schilling, Bastian
A1  - Geissinger, Eva
A1  - Wolf, Elmar
A1  - Meierjohann, Svenja
T1  - The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression
JF  - Oncogene
N2  - The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H\(_2\)O\(_2\) or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.
KW  - NRF2
KW  - melanoma malignancy
KW  - COX2 expression
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235064
SN  - 0950-9232
VL  - 39
ER  - 
TY  - JOUR
A1  - Maurus, K.
A1  - Kosnopfel, C.
A1  - Kneitz, H.
A1  - Appenzeller, S.
A1  - Schrama, D.
A1  - Glutsch, V.
A1  - Roth, S.
A1  - Gerhard-Hartmann, E.
A1  - Rosenfeldt, M.
A1  - Möhrmann, L.
A1  - Fröhlich, M.
A1  - Hübschmann, D.
A1  - Stenzinger, A.
A1  - Glimm, H.
A1  - Fröhling, S.
A1  - Goebeler, M.
A1  - Rosenwald, A.
A1  - Kutzner, H.
A1  - Schilling, B.
T1  - Cutaneous epithelioid haemangiomas show somatic mutations in the mitogen-activated protein kinase pathway
JF  - British Journal of Dermatology
N2  - Background
Epithelioid haemangioma (EH) arising from the skin is a benign vascular tumour with marked inflammatory cell infiltration, which exhibits a high tendency to persist and frequently recurs after resection. So far, the underlying pathogenesis is largely elusive.

Objectives
To identify genetic alterations by next-generation sequencing and/or droplet digital polymerase chain reaction (ddPCR) in cutaneous EH.

Methods
DNA and RNA from an EH lesion of an index patient were subjected to whole-genome and RNA sequencing. Multiplex PCR-based panel sequencing of genomic DNA isolated from archival formalin-fixed paraffin-embedded tissue of 18 patients with cutaneous EH was performed. ddPCR was used to confirm mutations.

Results
We identified somatic mutations in genes of the mitogen-activated protein kinase (MAPK) pathway (MAP2K1 and KRAS) in cutaneous EH biopsies. By ddPCR we could confirm the recurrent presence of activating, low-frequency mutations affecting MAP2K1. In total, nine out of 18 patients analysed showed activating MAPK pathway mutations, which were mutually exclusive. Comparative analysis of tissue areas enriched for lymphatic infiltrate or aberrant endothelial cells, respectively, revealed an association of these mutations with the presence of endothelial cells.

Conclusions
Taken together, our data suggest that EH shows somatic mutations in genes of the MAPK pathway which might contribute to the formation of this benign tumour.
KW  - protein kinase pathway
KW  - Background Epithelioid haemangioma
KW  - somatic mutations
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258333
VL  - 186
IS  - 3
ER  - 
TY  - JOUR
A1  - Livingstone, E.
A1  - Zaremba, A.
A1  - Horn, S.
A1  - Ugurel, S.
A1  - Casalini, B.
A1  - Schlaak, M.
A1  - Hassel, J.C.
A1  - Herbst, R.
A1  - Utikal, J.S.
A1  - Weide, B.
A1  - Gutzmer, R.
A1  - Meier, F.
A1  - Koelsche, C.
A1  - Hadaschik, E.
A1  - Sucker, A.
A1  - Reis, H.
A1  - Merkelbach‐Bruse, S.
A1  - Siewert, M.
A1  - Sahm, F.
A1  - von Deimling, A.
A1  - Cosgarea, I.
A1  - Zimmer, L.
A1  - Schadendorf, D.
A1  - Schilling, B.
A1  - Griewank, K.G.
T1  - GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma
JF  - British Journal of Dermatology
N2  - Background
GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.

Objectives
To characterize these tumours in terms of clinical behaviour and genetic characteristics.

Methods
Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death‐ligand 1 and BRCA1‐associated protein (BAP)1. Existing whole‐exome cutaneous and uveal melanoma data were analysed for mutation type and burden.

Results
We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X‐linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%).

Conclusions
Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed.

What is already known about this topic?
The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented.
GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma.

What does this study add?
GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma.
GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma.

What is the translational message?
Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.
As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed.
KW  - melanoma
KW  - GNAQ
KW  - GNA11
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215434
VL  - 183
IS  - 5
SP  - 928
EP  - 939
ER  -