TY  - JOUR
A1  - Oliveira-Ferrer, Leticia
A1  - Schmalfeldt, Barbara
A1  - Dietl, Johannes
A1  - Bartmann, Catharina
A1  - Schumacher, Udo
A1  - Stürken, Christine
T1  - Ovarian cancer-cell pericellular hyaluronan deposition negatively impacts prognosis of ovarian cancer patients
JF  - Biomedicines
N2  - Background: Hyaluronan (HA), a component of the extracellular matrix, is frequently increased under pathological conditions including cancer. Not only stroma cells but also cancer cells themselves synthesize HA, and the interaction of HA with its cognate receptors promotes malignant progression and metastasis. Methods: In the present study, HA deposition in tissue sections was analyzed by hyaluronan-binding protein (HABP) ligand histochemistry in 17 borderline tumors and 102 primary and 20 recurrent ovarian cancer samples. The intensity and, particularly, localization of the HA deposition were recorded: for the localization, the pericellular deposition around the ovarian cancer cells was distinguished from the deposition within the stromal compartment. These histochemical data were correlated with clinical and pathological parameters. Additionally, within a reduced subgroup of ovarian cancer samples (n = 70), the RNA levels of several HA-associated genes were correlated with the HA localization and intensity. Results: Both stroma-localized and pericellular tumor-cell-associated HA deposition were observed. Cancer-cell pericellular HA deposition, irrespective of its staining intensity, was significantly associated with malignancy, and in the primary ovarian cancer cohort, it represents an independent unfavorable prognostic marker for overall survival. Furthermore, a significant association between high CD44, HAS2 and HAS3 mRNA levels and a cancer-cell pericellular HA-deposition pattern was noted. In contrast, stromal hyaluronan deposition had no impact on ovarian cancer prognosis. Conclusions: In conclusion, the site of HA deposition is of prognostic value, but the amount deposited is not. The significant association of only peritumoral cancer-cell HA deposition with high CD44 mRNA expression levels suggests a pivotal role of the CD44–HA signaling axis for malignant progression in ovarian cancer.
KW  - ovarian cancer
KW  - stromal hyaluronan
KW  - tumor-associated hyaluronan staining pattern
KW  - hyaluronan-related enzymes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297539
SN  - 2227-9059
VL  - 10
IS  - 11
ER  - 
TY  - JOUR
A1  - Häder, Antje
A1  - Schäuble, Sascha
A1  - Gehlen, Jan
A1  - Thielemann, Nadja
A1  - Buerfent, Benedikt C.
A1  - Schüller, Vitalia
A1  - Hess, Timo
A1  - Wolf, Thomas
A1  - Schröder, Julia
A1  - Weber, Michael
A1  - Hünniger, Kerstin
A1  - Löffler, Jürgen
A1  - Vylkova, Slavena
A1  - Panagiotou, Gianni
A1  - Schumacher, Johannes
A1  - Kurzai, Oliver
T1  - Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity
JF  - Nature Communications
N2  - Innate immune responses vary by pathogen and host genetics. We analyze quantitative trait loci (eQTLs) and transcriptomes of monocytes from 215 individuals stimulated by fungal, Gram-negative or Gram-positive bacterial pathogens. We identify conserved monocyte responses to bacterial pathogens and a distinct antifungal response. These include 745 response eQTLs (reQTLs) and corresponding genes with pathogen-specific effects, which we find first in samples of male donors and subsequently confirm for selected reQTLs in females. reQTLs affect predominantly upregulated genes that regulate immune response via e.g., NOD-like, C-type lectin, Toll-like and complement receptor-signaling pathways. Hence, reQTLs provide a functional explanation for individual differences in innate response patterns. Our identified reQTLs are also associated with cancer, autoimmunity, inflammatory and infectious diseases as shown by external genome-wide association studies. Thus, reQTLs help to explain interindividual variation in immune response to infection and provide candidate genes for variants associated with a range of diseases.
KW  - antimicrobial responses
KW  - immunogenetics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357441
VL  - 14
ER  - 
TY  - JOUR
A1  - Graus, Dorothea
A1  - Konrad, Kai R.
A1  - Bemm, Felix
A1  - Nebioglu, Meliha Görkem Patir
A1  - Lorey, Christian
A1  - Duscha, Kerstin
A1  - Güthoff, Tilman
A1  - Herrmann, Johannes
A1  - Ferjani, Ali
A1  - Cuin, Tracey Ann
A1  - Roelfsema, M. Rob G.
A1  - Schumacher, Karin
A1  - Neuhaus, H. Ekkehard
A1  - Marten, Irene
A1  - Hedrich, Rainer
T1  - High V-PPase activity is beneficial under high salt loads, but detrimental without salinity
JF  - New Phytologist
N2  - The membrane-bound proton-pumping pyrophosphatase (V-PPase), together with the V-type H+-ATPase, generates the proton motive force that drives vacuolar membrane solute transport. Transgenic plants constitutively overexpressing V-PPases were shown to have improved salinity tolerance, but the relative impact of increasing PPi hydrolysis and proton-pumping functions has yet to be dissected.

For a better understanding of the molecular processes underlying V-PPase-dependent salt tolerance, we transiently overexpressed the pyrophosphate-driven proton pump (NbVHP) in Nicotiana benthamiana leaves and studied its functional properties in relation to salt treatment by primarily using patch-clamp, impalement electrodes and pH imaging.

NbVHP overexpression led to higher vacuolar proton currents and vacuolar acidification. After 3 d in salt-untreated conditions, V-PPase-overexpressing leaves showed a drop in photosynthetic capacity, plasma membrane depolarization and eventual leaf necrosis. Salt, however, rescued NbVHP-hyperactive cells from cell death. Furthermore, a salt-induced rise in V-PPase but not of V-ATPase pump currents was detected in nontransformed plants.

The results indicate that under normal growth conditions, plants need to regulate the V-PPase pump activity to avoid hyperactivity and its negative feedback on cell viability. Nonetheless, V-PPase proton pump function becomes increasingly important under salt stress for generating the pH gradient necessary for vacuolar proton-coupled Na+ sequestration.
KW  - cell death
KW  - plasma membrane voltage
KW  - proton pump currents
KW  - salt
KW  - vacuolar pH
KW  - vacuolar proton-ATPase (V-ATPase)
KW  - vacuolar proton-pyrophosphatase (V-PPase)
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227553
VL  - 219
ER  -