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Carl, Christin ; Landgraf, Dirk ; Van der Maaten-Theunissen, Marieke ; Biber, Peter ; Pretzsch, Hans
Mahajan-Thakur, Shailaja ; Bien-Möller, Sandra ; Marx, Sascha ; Schroeder, Henry ; Rauch, Bernhard H.
The multifunctional sphingosine-1-phosphate (S1P) is a lipid signaling molecule and central
regulator in the development of several cancer types. In recent years, intriguing information has
become available regarding the role of S1P in the progression of Glioblastoma multiforme (GBM),
the most aggressive and common brain tumor in adults. S1P modulates numerous cellular processes
in GBM, such as oncogenesis, proliferation and survival, invasion, migration, metastasis and stem cell
behavior. These processes are regulated via a family of five G-protein-coupled S1P receptors (S1PR1-5)
and may involve mainly unknown intracellular targets. Distinct expression patterns and multiple
intracellular signaling pathways of each S1PR subtype enable S1P to exert its pleiotropic cellular
actions. Several studies have demonstrated alterations in S1P levels, the involvement of S1PRs
and S1P metabolizing enzymes in GBM pathophysiology. While the tumorigenic actions of S1P
involve the activation of several kinases and transcription factors, the specific G-protein (Gi, Gq,
and G12/13)-coupled signaling pathways and downstream mediated effects in GBM remain to be
elucidated in detail. This review summarizes the recent findings concerning the role of S1P and its
receptors in GBM. We further highlight the current insights into the signaling pathways considered
fundamental for regulating the cellular processes in GMB and ultimately patient prognosis.
Monitoring of Calcite Precipitation in Hardwater Lakes with Multi-Spectral Remote Sensing Archives
(2017)
Heine, Iris ; Brauer, Achim ; Heim, Birgit ; Itzerott, Sibylle ; Kasprzak, Peter ; Kienel, Ulrike ; Kleinschmit, Birgit
Ungefroren, Hendrik ; Witte, David ; Fiedler, Christian ; Gädeken, Thomas ; Kaufmann, Roland ; Lehnert, Hendrik ; Gieseler, Frank ; Rauch, Bernhard
Background: Recently, the expression of proteinase-activated receptor 2 (PAR2) has been
shown to be essential for activin receptor-like kinase 5 (ALK5)/SMAD-mediated signaling and cell
migration by transforming growth factor (TGF)-β1. However, it is not known whether activation
of non-SMAD TGF-β signaling (e.g., RAS–RAF–MEK–extracellular signal-regulated kinase (ERK)
signaling) is required for cell migration and whether it is also dependent on PAR2. Methods: RNA
interference was used to deplete cells of PAR2, followed by xCELLigence technology to measure
cell migration, phospho-immunoblotting to assess ERK1/2 activation, and co-immunoprecipitation
to detect a PAR2–ALK5 physical interaction. Results: Inhibition of ERK signaling with the MEK
inhibitor U0126 blunted the ability of TGF-β1 to induce migration in pancreatic cancer Panc1 cells.
ERK activation in response to PAR2 agonistic peptide (PAR2–AP) was strong and rapid, while it was
moderate and delayed in response to TGF-β1. Basal and TGF-β1-dependent ERK, but not SMAD
activation, was blocked by U0126 in Panc1 and other cell types indicating that ERK activation is
downstream or independent of SMAD signaling. Moreover, cellular depletion of PAR2 in HaCaT
cells strongly inhibited TGF-β1-induced ERK activation, while the biased PAR2 agonist GB88 at 10
and 100 µM potentiated TGF-β1-dependent ERK activation and cell migration. Finally, we provide
evidence for a physical interaction between PAR2 and ALK5. Our data show that both PAR2–APand TGF-β1-induced cell migration depend on ERK activation, that PAR2 expression is crucial for
TGF-β1-induced ERK activation, and that the functional cooperation of PAR2 and TGF-β1 involves a
physical interaction between PAR2 and ALK5
A New Kind of Permutation Entropy Used to Classify Sleep Stages from Invisible EEG Microstructure
(2017)
Water Consumption of Agriculture and Natural Ecosystems along the Ili River in China and Kazakhstan
(2017)
Leukocyte telomere length (TL) has been suggested as a marker of biological age in healthy
individuals, but can also reflect inherited and acquired hematopoietic dysfunctions or indicate an
increased turnover of the hematopoietic stem and progenitor cell compartment. In addition, TL is able
to predict the response rate of tyrosine kinase inhibitor therapy in chronic myeloid leukemia (CML),
indicates clinical outcomes in chronic lymphocytic leukemia (CLL), and can be used as screening tool
for genetic sequencing of selected genes in patients with inherited bone marrow failure syndromes
(BMFS). In tumor cells and clonal hematopoietic disorders, telomeres are continuously stabilized by
reactivation of telomerase, which can selectively be targeted by telomerase-specific therapy. The use of
the telomerase inhibitor Imetelstat in patients with essential thrombocythmia or myelofibrosis as well
as the use of dendritic cell-based telomerase vaccination in AML patients with complete remissions are
promising examples for anti-telomerase targeted strategies in hematologic malignancies. In contrast,
the elevation in telomerase levels through treatment with androgens has become an exciting clinical
intervention for patients with BMFS. Here, we review recent developments, which highlight the
impact of telomeres and telomerase targeted therapies in hematologic dysfunctions.
Ungefroren, Hendrik ; Witte, David ; Rauch, Bernhard ; Settmacher, Utz ; Lehnert, Hendrik ; Gieseler, Frank ; Kaufmann, Roland
The G protein-coupled receptor proteinase-activated receptor 2 (PAR2) has been implicated
in various aspects of cellular physiology including inflammation, obesity and cancer. In cancer,
it usually acts as a driver of cancer progression in various tumor types by promoting invasion and
metastasis in response to activation by serine proteinases. Recently, we discovered another mode
through which PAR2 may enhance tumorigenesis: crosstalk with transforming growth factor-β
(TGF-β) signaling to promote TGF-β1-induced cell migration/invasion and invasion-associated gene
expression in ductal pancreatic adenocarcinoma (PDAC) cells. In this chapter, we review what is
known about the cellular TGF-β responses and signaling pathways affected by PAR2 expression,
the signaling activities of PAR2 required for promoting TGF-β signaling, and the potential molecular
mechanism(s) that underlie(s) the TGF-β signaling–promoting effect. Since PAR2 is activated through
various serine proteinases and biased agonists, it may couple TGF-β signaling to a diverse range of
other physiological processes that may or may not predispose cells to cancer development such as
local inflammation, systemic coagulation and pathogen infection.
Schmidt, Anke ; Woedtke, Thomas ; Stenzel, Jan ; Lindner, Tobias ; Polei, Stefan ; Vollmar, Brigitte ; Bekeschus, Sander
Multiple evidence in animal models and in humans suggest a beneficial role of cold physical
plasma in wound treatment. Yet, risk assessment studies are important to further foster therapeutic
advancement and acceptance of cold plasma in clinics. Accordingly, we investigated the long-term
side effects of repetitive plasma treatment over 14 consecutive days in a rodent full-thickness ear
wound model. Subsequently, animals were housed for 350 days and sacrificed thereafter. In blood,
systemic changes of the pro-inflammatory cytokines interleukin 1β and tumor necrosis factor α
were absent. Similarly, tumor marker levels of α-fetoprotein and calcitonin remained unchanged.
Using quantitative PCR, the expression levels of several cytokines and tumor markers in liver,
lung, and skin were found to be similar in the control and treatment group as well. Likewise,
histological and immunohistochemical analysis failed to detect abnormal morphological changes
and the presence of tumor markers such as carcinoembryonic antigen, α-fetoprotein, or the neighbor
of Punc 11. Absence of neoplastic lesions was confirmed by non-invasive imaging methods such as
anatomical magnetic resonance imaging and positron emission tomography-computed tomography.
Our results suggest that the beneficial effects of cold plasma in wound healing come without apparent
side effects including tumor formation or chronic inflammation.
Ashraf, Kerolos ; Yasrebi, Kaveh ; Hertlein, Tobias ; Ohlsen, Knut ; Lalk, Michael ; Hilgeroth, Andreas
Majumdar, Abhijit ; Drache, Steffen ; Wulff, Harm ; Mukhopadhyay, Arun ; Bhattacharyya, Satyaranjan ; Helm, Christiane ; Hippler, Rainer
Gümbel, Denis ; Bekeschus, Sander ; Gelbrich, Nadine ; Napp, Matthias ; Ekkernkamp, Axel ; Kramer, Axel ; Stope, Matthias
: Human osteosarcoma (OS) is the most common primary malignant bone tumor occurring
most commonly in adolescents and young adults. Major improvements in disease-free survival have
been achieved by implementing a combination therapy consisting of radical surgical resection of the
tumor and systemic multi-agent chemotherapy. However, long-term survival remains poor, so novel
targeted therapies to improve outcomes for patients with osteosarcoma remains an area of active
research. This includes immunotherapy, photodynamic therapy, or treatment with nanoparticles.
Cold atmospheric plasma (CAP), a highly reactive (partially) ionized physical state, has been shown
to inherit a significant anticancer capacity, leading to a new field in medicine called “plasma oncology.”
The current article summarizes the potential of CAP in the treatment of human OS and reviews the
underlying molecular mode of action.
Climate Change-Induced Shift of Tree Growth Sensitivity at a Central Himalayan Treeline Ecotone
(2018)
Schwab, Niels ; Kaczka, Ryszard J. ; Janecka, Karolina ; Böhner, Jürgen ; Chaudhary, Ram P. ; Scholten, Thomas ; Schickhoff, Udo
Planning Modes for Major Transportation Infrastructure Projects (MTIPs): Comparing China and Germany
(2018)
Pueppke, Steven G. ; Iklasov, Margulan K. ; Beckmann, Volker ; Nurtazin, Sabir T. ; Thevs, Niels ; Sharakhmetov, Sayat ; Hoshino, Buho
Production-Integrated Compensation in Environmental Offsets—A Review of a German Offset Practice
(2018)
Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species
(2018)
Ungefroren, Hendrik ; Gieseler, Frank ; Kaufmann, Roland ; Settmacher, Utz ; Lehnert, Hendrik ; Rauch, Bernhard H.
For the last two decades, heparins have been widely used as anticoagulants. Besides
numerous advantages, up to 5% patients with heparin administration suffer from a major adverse
drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep
vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and
a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using
single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding
mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in
typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT
caused by a subset of human-derived antibodies in patients without heparin exposure. The findings
proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review,
the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms
inducing thrombocytopenia by both heparins and antibodies will be discussed.
Sphingosine-1-phosphate (S1P) regulates the migration of follicular B cells
(B2 cells) and directs the positioning of Marginal zone B cells (MZ B cells) within the spleen. The
function of S1P signalling in the third B cell lineage, B1 B cells, mainly present in the pleural and
peritoneal cavity, has not yet been determined. Methods: S1P receptor expression was analysed
in peritoneal B cells by real-time polymerase chain reaction (qPCR). The chemotactic response to
S1P was studied in vitro. The role of S1P signalling was further explored in a s1p4
−/− mouse
strain. Results: Peritoneal B cells expressed considerable amounts of the S1P receptors 1 and 4
(S1P1 and S1P4, respectively). S1P1 showed differential expression between the distinct peritoneal B
cell lineages. While B2 cells showed no chemotactic response to S1P, B1 B cells showed a migration
response to S1P. s1p4
−/− mice displayed significant alterations in the composition of peritoneal
B cell populations, as well as a significant reduction of mucosal immunoglobulin A (IgA) in the
gut. Discussion: S1P signalling influences peritoneal B1 B cell migration. S1P4 deficiency alters the
composition of peritoneal B cell populations and reduces secretory IgA levels. These findings suggest
that S1P signalling may be a target to modulate B cell function in inflammatory intestinal pathologies.
Steinmetz, Ivo ; Wagner, Gabriel ; Kanyala, Estelle ; Sawadogo, Mamadou ; Soumeya, Hema ; Teferi, Mekonnen ; Andargie, Emawayish ; Yeshitela, Biruk ; Yaba Atsé-Achi, Louise ; Sanogo, Moussa ; Bonfoh, Bassirou ; Rakotozandrindrainy, Raphael ; Pongombo Shongo, Célestin ; Shongoya Pongombo, Mick ; Kasamba Ilunga, Eric ; Lichtenegger, Sabine ; Assig, Karoline ; May, Jürgen ; Bertherat, Eric ; Owusu, Michael ; Owusu-Dabo, Ellis ; Adu-Sarkodie, Yaw
Trinh, Trung ; Nguyen, Linh ; Nguyen, Trung ; Tran, Chuong ; Le, An ; Nguyen, Hao ; Assig, Karoline ; Lichtenegger, Sabine ; Wagner, Gabriel ; Do, Cuong ; Steinmetz, Ivo
Bekeschus, Sander ; Lackmann, Jan-Wilm ; Gümbel, Denis ; Napp, Matthias ; Schmidt, Anke ; Wende, Kristian
on-healing wounds continue to be a clinical challenge for patients and medical staff.
These wounds have a heterogeneous etiology, including diabetes and surgical trauma wounds. It is
therefore important to decipher molecular signatures that reflect the macroscopic process of wound
healing. To this end, we collected wound sponge dressings routinely used in vacuum assisted therapy
after surgical trauma to generate wound-derived protein profiles via global mass spectrometry.
We confidently identified 311 proteins in exudates. Among them were expected targets belonging to
the immunoglobulin superfamily, complement, and skin-derived proteins, such as keratins. Next to
several S100 proteins, chaperones, heat shock proteins, and immune modulators, the exudates
presented a number of redox proteins as well as a discrete neutrophil proteomic signature, including
for example cathepsin G, elastase, myeloperoxidase, CD66c, and lipocalin 2. We mapped over 200
post-translational modifications (PTMs; cysteine/methionine oxidation, tyrosine nitration, cysteine
trioxidation) to the proteomic profile, for example, in peroxiredoxin 1. Investigating manually
collected exudates, we confirmed presence of neutrophils and their products, such as microparticles
and fragments containing myeloperoxidase and DNA. These data confirmed known and identified
less known wound proteins and their PTMs, which may serve as resource for future studies on
human wound healing
Wirthgen, Elisa ; Otten, Winfried ; Tuchscherer, Margret ; Tuchscherer, Armin ; Domanska, Grazyna ; Brenmoehl, Julia ; Günther, Juliane ; Ohde, Daniela ; Weitschies, Werner ; Seidlitz, Anne ; Scheuch, Eberhard ; Kanitz, Ellen
: An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased
mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be
a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT)
is currently in the interest of research due to its potential inhibitory effects on IDO1 and
immunomodulatory properties. The present study aims to investigate the protective and
immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine
in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan
(TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite
kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils
and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP
to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that
degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide
no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven
interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be
considered for therapeutic applications of 1-MT.
Maaß, Sandra ; Otto, Andreas ; Albrecht, Dirk ; Riedel, Katharina ; Trautwein-Schult, Anke ; Becher, Dörte
Maaß, Sandra ; Otto, Andreas ; Albrecht, Dirk ; Riedel, Katharina ; Trautwein-Schult, Anke ; Becher, Dörte
β-Phenylalanine Ester Synthesis from Stable β-Keto Ester Substrate Using Engineered ω-Transaminases
(2018)
Buß, Oliver ; Voss, Moritz ; Delavault, André ; Gorenflo, Pascal ; Syldatk, Christoph ; Bornscheuer, Uwe ; Rudat, Jens
Rotter, Markus ; Brandmaier, Stefan ; Covic, Marcela ; Burek, Katarzyna ; Hertel, Johannes ; Troll, Martina ; Bader, Erik ; Adam, Jonathan ; Prehn, Cornelia ; Rathkolb, Birgit ; Hrabe de Angelis, Martin ; Grabe, Hans Jörgen ; Daniel, Hannelore ; Kantermann, Thomas ; Harth, Volker ; Illig, Thomas ; Pallapies, Dirk ; Behrens, Thomas ; Brüning, Thomas ; Adamski, Jerzy ; Lickert, Heiko ; Rabstein, Sylvia ; Wang-Sattler, Rui
Kaul, Anne ; Masuch, Annette ; Budde, Kathrin ; Kastenmüller, Gabi ; Artati, Anna ; Adamski, Jerzy ; Völzke, Henry ; Nauck, Matthias ; Friedrich, Nele ; Pietzner, Maik
Siebert, Nikolai ; Troschke-Meurer, Sascha ; Marx, Madlen ; Zumpe, Maxi ; Ehlert, Karoline ; Gray, Juliet ; Garaventa, Alberto ; Manzitti, Carla ; Ash, Shifra ; Klingebiel, Thomas ; Beck, James ; Castel, Victoria ; Valteau-Couanet, Dominique ; Loibner, Hans ; Ladenstein, Ruth ; Lode, Holger N.
Trouillier, Mario ; Van der Maaten-Theunissen, Marieke ; Harvey, Jill E. ; Würth, David ; Schnittler, Martin ; Wilmking, Martin
Bahls, Martin ; Atzler, Dorothee ; Markus, Marcello R.P. ; Friedrich, Nele ; Böger, Rainer H. ; Völzke, Henry ; Felix, Stephan B. ; Schwedhelm, Edzard ; Dörr, Marcus
The platinum(II) complexes carboplatin (CBDCA), cisplatin (CDDP) and oxaliplatin
(1-OHP) are used as anticancer drugs in a large number of tumour chemotherapy regimens.
Many attempts have been made to combine Pt(II)-based chemotherapy with alternative treatment
strategies. One such alternative anticancer approach is known as photodynamic therapy (PDT),
where a non-toxic photosensitizer (PS) produces oxidative stress via the formation of reactive
oxygen species (ROS) after local illumination of the affected tissue. A very promising PS is
5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC, Temoporfin), which is approved for the treatment
of head and neck cancer in Europe. In the present study, a combination of mTHPC-mediated PDT
and either CBDCA, CDDP, or 1-OHP was applied to five human cancer cell lines from different
tumour origins. Cytotoxicity was determined by the MTT assay and synergistic effects on cytotoxicity
were evaluated by calculation of Combination Indices (CI). Synergy was identified in some of the
combinations, for example, with 1-OHP in three of the tested cell lines but antagonism was also
observed for a number of combinations in certain cell lines. In cases of synergy, elevated ROS levels
were observed after combination but apoptosis induction was not necessarily increased compared
to a treatment with a single compound. Cell cycle analysis revealed a formation of apoptotic
subG1 populations and S phase as well as G2/M phase arrests after combination. In conclusion,
pre-treatment with mTHPC-PDT has the potential to sensitize some types of tumour cells towards
Pt(II) complexes, in particular 1-OHP but synergy is highly dependent on the type of cancer.