University of Mainz

About: University of Mainz is a education organization based out in Mainz, Rheinland-Pfalz, Germany. It is known for research contribution in the topics: Population & Immune system. The organization has 37673 authors who have published 71163 publications receiving 2497880 citations. The organization is also known as: Johannes Gutenberg-Universität Mainz & Universität Mainz.

Tumor hypoxia and malignant progression.

Abstract: Publisher Summary This chapter discusses tumor hypoxia and malignant progression. Hypoxic (or anoxic) areas arise as a result of an imbalance between the supply and the consumption of oxygen. Whereas in normal tissues or organs the O2 supply matches the metabolic requirements, in locally advanced solid tumors the O2 consumption rate of neoplastic as well as stromal cells may outweigh an insufficient oxygen supply and result in the development of tissue areas with very low O2 levels. Major pathogenetic mechanisms involved in the emergence of hypoxia in solid tumors are (a) severe structural and functional abnormalities of the tumor microvessels (b) a deterioration of the diffusion geometry, and (c) tumor-associated and/or therapy-induced anemia leading to a reduced O2 transport capacity of the blood. This chapter discusses current information from experimental and clinical studies, which illustrates the interaction between tissue hypoxia and the phenomenon of malignant progression. Evidence, characterization and pathogenesis of tumor hypoxia, and the role of hypoxia in malignant progressionare discussed.

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

Abstract: Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases.

Dendritic cells as mediators of tumor‐induced tolerance in metastatic melanoma

Abstract: Escape from immune surveillance is critical for tumor progression in metastatic melanoma. We assessed the function of melanoma-derived dendritic cells (DCs) in patients presenting simultaneously with responding (rM) or progressing (pM) melanoma metastases. These rare coincidences allowed us to compare syngeneically the function of tumor DCs. CD83+ DCs were purified freshly from large responding (rDCs) or progressing (pDCs) metastases following chemo-immunotherapy. rDCs were 5 times more potent inducers of allogeneic T-cell proliferation than the pDCs that were used as control. Phenotypic analysis showed a marked depression of CD86 expression on pDCs. Culture supernatants from pM showed production of Th2-type cytokines [interleukin-10 (IL-10)], whereas a Th1 pattern [IL-2], interferon-γ (IFN-γ), IL-12) predominated in rM. The IL-10 detected in progressing metastases was directly derived from melanoma cells. Culture supernatants from metastases applied to DC-supported allo-MLR assays suppressed T-cell responses by 50–75% in the case of pM, but not rM. Finally, in a co-stimulation-dependent anti-CD3 tolerance assay, pDCs (but not rDCs) induced anergy in syngeneic CD4+ T cells. Anergy could be overcome by addition of IL-12 or IL-2. Our results show that melanoma-derived factors convert DC-antigen presenting cell function to tolerance induction against tumor tissue, changing tumor DCs to “silencers” of anti-tumoral immune responses. Int. J. Cancer 73:309–316, 1997. © 1997 Wiley-Liss, Inc.