German Cancer Research Center | Date: 2012-09-26
Described is an adenovirus derived helper virus which may comprise the adenoviral DNA sequences for E2a, S4 (orf6), the VA1 RNA gene, and the parvovirus VP capsid gene unit. Also described is a method of efficiently preparing a recombinant parvovirus (particle) which is based on the use of various adenoviral derived helper viruses/vectors.
German Cancer Research Center | Date: 2017-04-12
A fluorescence microscope instrument (1) includes a light source (2) providing light (3) to be directed to a sample (4); a detector (5) detecting fluorescence light (5) emitted out of the sample (4); an objective (7) focusing the light (3) from the light source (2) into a focal area within the sample (4) and collecting the fluorescence light (6) emitted out of the focal area to be detected by the detector (5); and a beam path separator (9) arranged in a beam path of the light (3) from the light source (2) between the light source (2) and the objective (7) and in a beam path of the fluorescence light (6) between the objective (7) and the detector (5). Wavelengths of the light (3) to be directed to the sample (4) and of the light (6) to be detected by the detector fall into a range of wavelengths extending from a low end wavelength over at least 20 % of the low end wavelength. The beam path separator (9) separates the beam path of the fluorescence light (6) from the beam path of the light (3) from the light source (2) in that it is transferable between a first state in which it is transparent for light of any wavelength falling in the range of wavelengths and coming along the beam path of the light (3) from the light source (2), and a second state in which it is transparent for light of any wavelength falling in the range of wavelengths and coming along the beam path of the fluorescence light (6) from the sample (4).
Agency: Cordis | Branch: H2020 | Program: RIA | Phase: PHC-03-2015 | Award Amount: 5.70M | Year: 2016
Hepatocellular carcinoma (HCC) is the most common liver malignancy, with an estimated 750,000 new cases and 695,000 deaths per year, rating third in incidence and mortality in the world. Whilst incidence and mortality for other cancers are declining, HCC represents an increasing public health problem in Europe with men having a higher incidence than women. Several liver diseases lead to HCC and become per definition co-morbidities, such as nonalcoholic steatohepatitis (NASH) or hepatitis B and C virus infection. Most patients die within one year of diagnosis and treatment failure reflects the heterogeneous nature of this tumour, highlighting the need to identify common and co-morbidity specific disease pathways for individualized therapy. HEP-CAR will focus on three leading HCC associated co-morbidities, specifically NASH and hepatitis B and C infection. Non-biased genetic and lipidomic screens will define cellular pathways that are deregulated in HCC and the impact of co-morbidities and gender. Next to established patient cohorts, several in vitro and in vivo models are available to evaluate the role of co-morbidities as drivers of host oncogenic pathways and to provide much needed pre-clinical models for mechanistic studies and future drug screening. We will develop new approaches to study the impact of co-morbidities on HCC immunobiology, ranging from state-of-art tissue explant models to novel humanized mouse models. The aim of HEP-CAR is to define host pathways that impact HCC pathogenesis and to assess their role in different co-morbidities and treatment responses. The research and clinical excellence will be combined with the knowledge transfer and communication competence of leading organizations such as the European Association for the Study of the Liver (EASL) and the European Liver Patients Association (ELPA). Thus, HEP-CAR will generate tangible and sustained improvements in the understanding, prevention and management of HCC for all European citizens.
Niehrs C.,German Cancer Research Center |
Niehrs C.,Institute of Molecular Biology
Nature Reviews Molecular Cell Biology | Year: 2012
30 years after the identification of WNTs, their signal transduction has become increasingly complex, with the discovery of more than 15 receptors and co-receptors in seven protein families. The recent discovery of three receptor classes for the R-spondin family of WNT agonists further adds to this complexity. What emerges is an intricate network of receptors that form higher-order ligand-receptor complexes routing downstream signalling. These are regulated both extracellularly by agonists such as R-spondin and intracellularly by post-translational modifications such as phosphorylation, proteolytic processing and endocytosis. © 2012 Macmillan Publishers Limited. All rights reserved.
Fiegler N.,German Cancer Research Center
Blood | Year: 2013
Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7 family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6, we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and messenger RNA (mRNA) expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after small interfering RNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells that has implications for potential cancer treatments combining immunotherapy with HDACi.
Niehrs C.,German Cancer Research Center
Development | Year: 2010
The regulation of body axis specification in the common ancestor of bilaterians remains controversial. BMP signaling appears to be an ancient program for patterning the secondary, or dorsoventral, body axis, but any such program for the primary, or anteroposterior, body axis is debated. Recent work in invertebrates indicates that posterior Wnt/β-catenin signaling is such a mechanism and that it evolutionarily predates the cnidarian-bilaterian split. Here, I argue that a Cartesian coordinate system of positional information set up by gradients of perpendicular Wnt and BMP signaling is conserved in bilaterians, orchestrates body axis patterning and contributes to both the relative invariance and diversity of body forms.
Gerhauser C.,German Cancer Research Center
Topics in Current Chemistry | Year: 2013
The term "epigenetics" refers to modifications in gene expression caused by heritable, but potentially reversible, changes in DNA methylation and chromatin structure. Epigenetic alterations have been identified as promising new targets for cancer prevention strategies as they occur early during carcinogenesis and represent potentially initiating events for cancer development. Over the past few years, nutri-epigenetics-the influence of dietary components on mechanisms influencing the epigenome-has emerged as an exciting new field in current epigenetic research. During carcinogenesis, major cellular functions and pathways, including drug metabolism, cell cycle regulation, potential to repair DNA damage or to induce apoptosis, response to inflammatory stimuli, cell signalling, and cell growth control and differentiation become deregulated. Recent evidence now indicates that epigenetic alterations contribute to these cellular defects, for example epigenetic silencing of detoxifying enzymes, tumor suppressor genes, cell cycle regulators, apoptosis-inducing and DNA repair genes, nuclear receptors, signal transducers and transcription factors by promoter methylation, and modifications of histones and non-histone proteins such as p53, NF-κB, and the chaperone HSP90 by acetylation or methylation. The present review will summarize the potential of natural chemopreventive agents to counteract these cancer-related epigenetic alterations by influencing the activity or expression of DNA methyltransferases and histone modifying enzymes. Chemopreventive agents that target the epigenome include micronutrients (folate, retinoic acid, and selenium compounds), butyrate, polyphenols from green tea, apples, coffee, black raspberries, and other dietary sources, genistein and soy isoflavones, curcumin, resveratrol, dihydrocoumarin, nordihydroguaiaretic acid (NDGA), lycopene, anacardic acid, garcinol, constituents of Allium species and cruciferous vegetables, including indol-3-carbinol (I3C), diindolylmethane (DIM), sulforaphane, phenylethyl isothiocyanate (PEITC), phenylhexyl isothiocyanate (PHI), diallyldisulfide (DADS) and its metabolite allyl mercaptan (AM), cambinol, and relatively unexplored modulators of histone lysine methylation (chaetocin, polyamine analogs). So far, data are still mainly derived from in vitro investigations, and results of animal models or human intervention studies are limited that demonstrate the functional relevance of epigenetic mechanisms for health promoting or cancer preventive efficacy of natural products. Also, most studies have focused on single candidate genes or mechanisms. With the emergence of novel technologies such as next-generation sequencing, future research has the potential to explore nutri-epigenomics at a genome-wide level to understand better the importance of epigenetic mechanisms for gene regulation in cancer chemoprevention. © 2013 Springer-Verlag Berlin Heidelberg.
Schulz A.,German Cancer Research Center
Blood | Year: 2013
Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental stimuli for their survival, provided for example by monocyte-derived nurse-like cells (NLCs). The immunomodulatory drug lenalidomide shows therapeutic effects in subgroups of CLL patients, and is believed to act via the microenvironment. To investigate the effects of lenalidomide on the survival support of NLCs, cocultures of monocytes and CLL cells were treated for 14 days with lenalidomide, which resulted in significantly decreased viability of CLL cells. Among the changes induced by this drug, we observed reduced expression of HLA-DR in NLCs as well as increased secretion of interleukin-10 (IL-10), indicating an altered inflammatory milieu in the cocultures. The increase in IL-10 levels lead to an induction of STAT1 phosphorylation in CLL cells and to enhanced cell-surface expression of intercellular adhesion molecule 1 and altered expression of cytoskeletal and migration-related genes. Chemotaxis assays with lenalidomide-treated CLL cells revealed an impaired migration capability. Our data show that lenalidomide reduces the survival support of NLCs for CLL cells in vitro, suggesting that this drug affects the myeloid microenvironment in CLL in vivo. Furthermore, lenalidomide acts on the migratory potential of CLL cells, which may affect circulation and homing of CLL cells in vivo.
Li-Weber M.,German Cancer Research Center
Cancer Letters | Year: 2013
The traditional Chinese medicine (TCM) uses a combination of different natural products based on practical experiences. To better understand the therapeutic functions of TCM, large efforts have been made to identify the principle constituents of TCM and to unravel the molecular mechanisms behind the efficacy observed. This review aims to summarize research results obtained from the most intensively studied TCM phytochemical compounds namely the alkaloids Berberine, Evodiamine; anthraquinones Emodin, Aloe-emodin, Rhein; the terpenoids Artemisinin, Celastrol, Triptolide; the flavones Apigenin, Chrysin, Wogonin, Baicalein; and the cyclopenta[b]benzofuran derivatives Rocaglamide. Most of them have been originally identified as anti-inflammatory and anti-viral reagents and are now known to also possess anti-tumor activities by targeting the apoptosis pathways in cancer. This review also intends to give an overview of the mechanisms of action identified so far. These breakthrough findings may have important implications for targeted-cancer therapy and for modernization of TCM. © 2010 Elsevier Ireland Ltd.
von Deimling A.,German Cancer Research Center
Acta neuropathologica communications | Year: 2014
BACKGROUND: IDH mutations frequently occur in diffuse gliomas and result in a neo-enzymatic activity that results in reduction of α-ketoglutarate to D-2-hydroxyglutarate. In gliomas, the frequency of IDH1 mutations in codon 132 increases in the order R132L-R132S-R132G-R132C-R132H with R132H constituting more than 90% of all IDH1 mutations.RESULTS: We determined the levels of D-2-hydroxyglutarate in glioma tissues with IDH1 mutations. D-2-hydroxyglutarate levels increased in the order of R132H-R132C-R132S/R132G/R132L. We expressed and purified IDH1 wild type and mutant protein for biochemical characterization. Enzyme kinetics of mutant IDH protein correlated well with D-2-hydroxyglutarate production in cells with R132H exhibiting the highest and R132L the lowest KM for α-ketoglutarate. Addition of D-2-hydroxyglutarate to the medium of cell lines revealed an inhibitory effect at higher concentrations. Migration of LN229 increased at lower D-2-hydroxyglutarate concentrations while higher concentrations showed no effect.CONCLUSION: These findings may suggest natural selection against the rare IDH1R132 mutations in human glioma due to toxicity caused by high levels of D-2-hydroxyglutarate.