German Cancer Research Institute

Heidelberg, Germany

German Cancer Research Institute

Heidelberg, Germany
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Marten A.,Im Neuenheimer Feld | Buchler M.W.,Im Neuenheimer Feld | Werft W.,German Cancer Research Institute | Wente M.N.,Im Neuenheimer Feld | And 2 more authors.
Journal of Immunotherapy | Year: 2010

Pancreatic adenocarcinoma as an aggressive tumor still lacks specific markers. Resection offers the only potential cure, and earlier diagnosis could benefit many patients. Here, we analyzed siC3b as a potential diagnostic marker. Soluble iC3b is generated in the fluid phase after binding of autoantibodies to tumor cells and subsequent inactivation of the complement cascade by interaction with complement regulatory proteins. Two hundred thirty-two plasma samples from patients with adjuvant treatment after resection, from healthy volunteers, and from vulnerable patients were collected prospectively and analyzed for siC3b. Every 3 months, the patients underwent imaging and the results from siC3b enzyme-linked immunosorbent assay were categorized according to radiologically defined recurrence within 4 months after blood withdrawal. Furthermore, the regulatory factors of the complement system were analyzed in tumor cells and in urine. The most important finding was that up to 4 months before radiologically defined recurrence, siC3b plasma level is increased with a sensitivity and specificity resulting in an area under the curve of 0.85, which could be further increased by combining it with CA19.9 (area under the curve=0.92). Complement regulatory proteins are highly expressed in pancreatic carcinoma cells and detectable in the patient's urine. In summary, screening for siC3b in patients with an increased risk for pancreatic ductal adenocarcinoma (patients with chronic pancreatitis, hereditary pancreatitis, after curative resection, and patients with a variety of familial cancer syndromes) allows for early detection with high sensitivity, as siC3b plasma levels are increased up to 4 months before radiologic evidence. Sensitivity could be further increased by combining this approach with CA19.9. Copyright © 2010 by Lippincott Williams & Wilkins.


Ning L.,Harvard University | Laun F.,German Cancer Research Institute | Gur Y.,IBM | DiBella E.V.R.,University of Utah | And 12 more authors.
Medical Image Analysis | Year: 2015

Diffusion magnetic resonance imaging (dMRI) is the modality of choice for investigating in-vivo white matter connectivity and neural tissue architecture of the brain. The diffusion-weighted signal in dMRI reflects the diffusivity of water molecules in brain tissue and can be utilized to produce image-based biomarkers for clinical research. Due to the constraints on scanning time, a limited number of measurements can be acquired within a clinically feasible scan time. In order to reconstruct the dMRI signal from a discrete set of measurements, a large number of algorithms have been proposed in recent years in conjunction with varying sampling schemes, i.e., with varying b-values and gradient directions. Thus, it is imperative to compare the performance of these reconstruction methods on a single data set to provide appropriate guidelines to neuroscientists on making an informed decision while designing their acquisition protocols. For this purpose, the SPArse Reconstruction Challenge (SPARC) was held along with the workshop on Computational Diffusion MRI (at MICCAI 2014) to validate the performance of multiple reconstruction methods using data acquired from a physical phantom. A total of 16 reconstruction algorithms (9 teams) participated in this community challenge. The goal was to reconstruct single b-value and/or multiple b-value data from a sparse set of measurements. In particular, the aim was to determine an appropriate acquisition protocol (in terms of the number of measurements, b-values) and the analysis method to use for a neuroimaging study. The challenge did not delve on the accuracy of these methods in estimating model specific measures such as fractional anisotropy (FA) or mean diffusivity, but on the accuracy of these methods to fit the data. This paper presents several quantitative results pertaining to each reconstruction algorithm. The conclusions in this paper provide a valuable guideline for choosing a suitable algorithm and the corresponding data-sampling scheme for clinical neuroscience applications. © 2015 Elsevier B.V.


PubMed | IBM, University of Verona, University of Science and Technology Houari Boumediene, German Cancer Research Institute and 5 more.
Type: Comparative Study | Journal: Medical image analysis | Year: 2015

Diffusion magnetic resonance imaging (dMRI) is the modality of choice for investigating in-vivo white matter connectivity and neural tissue architecture of the brain. The diffusion-weighted signal in dMRI reflects the diffusivity of water molecules in brain tissue and can be utilized to produce image-based biomarkers for clinical research. Due to the constraints on scanning time, a limited number of measurements can be acquired within a clinically feasible scan time. In order to reconstruct the dMRI signal from a discrete set of measurements, a large number of algorithms have been proposed in recent years in conjunction with varying sampling schemes, i.e., with varying b-values and gradient directions. Thus, it is imperative to compare the performance of these reconstruction methods on a single data set to provide appropriate guidelines to neuroscientists on making an informed decision while designing their acquisition protocols. For this purpose, the SPArse Reconstruction Challenge (SPARC) was held along with the workshop on Computational Diffusion MRI (at MICCAI 2014) to validate the performance of multiple reconstruction methods using data acquired from a physical phantom. A total of 16 reconstruction algorithms (9 teams) participated in this community challenge. The goal was to reconstruct single b-value and/or multiple b-value data from a sparse set of measurements. In particular, the aim was to determine an appropriate acquisition protocol (in terms of the number of measurements, b-values) and the analysis method to use for a neuroimaging study. The challenge did not delve on the accuracy of these methods in estimating model specific measures such as fractional anisotropy (FA) or mean diffusivity, but on the accuracy of these methods to fit the data. This paper presents several quantitative results pertaining to each reconstruction algorithm. The conclusions in this paper provide a valuable guideline for choosing a suitable algorithm and the corresponding data-sampling scheme for clinical neuroscience applications.


Wallbach M.,University of Gottingen | Grone H.J.,German Cancer Research Institute | Kitze B.,University of Gottingen | Muller G.A.,University of Gottingen | Koziolek M.J.,University of Gottingen
American Journal of Kidney Diseases | Year: 2013

Recombinant interferon α (IFN-α) and interferon β (IFN-β) are efficient drugs for clinical use in multiple sclerosis, hepatitis C virus infection, and malignant diseases. We report a case of a 40-year-old woman with relapsing-remitting multiple sclerosis who was treated with interferon beta-1b for several years before being admitted to our department with nephrotic-range proteinuria (protein excretion, 8.3 g/d) and serum albumin level of 2.9 g/dL without any clinical and laboratory change typical for a systemic autoimmune disease. The kidney biopsy led to the diagnosis of immune complex-mediated membranoproliferative glomerulonephritis with immunoglobulin and complement deposits visible by immunohistology, as well as subendothelial deposits and tubuloreticular inclusions evident by electron microscopy. Subsequently replacing interferon beta-1b with glatiramer acetate resulted in partial remission, with proteinuria decreasing to protein excretion of 1.0 g/d 2 months thereafter. The association of a focal mesangiocapillary glomerular change and immunoglobulin-complement deposits with tubuloreticular inclusions suggests lupus nephritis. To our knowledge, this is the first report of an interferon beta-1b-induced immune complex glomerulonephritis characterized by histologic, immunohistologic, and ultrastructural features that resembled lupus nephritis, but that occurred in a patient without evidence of systemic lupus erythematosus. Our review of experimental data and earlier case reports suggests a pathogenic role of recombinant IFN in some autoimmune diseases, especially those with the potency to induce systemic lupus erythematosus-like syndromes. © 2013 National Kidney Foundation, Inc.


Mohr K.,German Cancer Research Institute | Koegl M.,Genomics and Proteomics Core Facility German Cancer Research Institute
Methods in Molecular Biology | Year: 2012

Yeast two-hybrid screening can be used to find cDNAs encoding proteins which bind to a given bait protein in large, pooled cDNA libraries. Screening of complex, pooled libraries is slower and more laborious than screening of arrayed collections of cDNAs, but has several advantages. First, the complexity of a pooled library can be orders of magnitude larger than the size of a typical arrayed library. Second, as long as available cDNA collections are incomplete and limited to full-length cDNAs, pooled cDNA libraries offer a more complete search space and are often the only way to do screens in organisms other than human and a few model organisms. We have streamlined and optimised the screening of pooled libraries in a format which uses micro-titre plates and produces quantitative signals for the selection of hits. This format has the advantage that automation of the process is straightforward and allows a throughput of up to at least 1,000 screens per year per person. © 2012 Springer Science+Business Media, LLC.


Pozdzik A.A.,Free University of Colombia | Berton A.,Free University of Colombia | Schmeiser H.H.,German Cancer Research Institute | Missoum W.,Free University of Colombia | And 4 more authors.
Histopathology | Year: 2010

Aims: The histological features of aristolochic acid nephropathy (AAN) consist of paucicellular interstitial fibrosis, severe tubular atrophy, and almost intact glomeruli with media lesions of interlobular arteries. As an early phase of interstitial inflammation preceded peritubular fibrosis in the rat model of AAN, the aim was to investigate the presence of inflammatory cells in human AAN. Methods and results: Reports of confirmed cases and case series of AAN were reviewed in terms of interstitial inflammation and found to have very conflicting results. This prompted us to search for and characterize inflammatory cells within the native kidneys provided from four end-stage AAN patients. Prior aristolochic acid exposure was attested by the intrarenal presence of the typical aristolactam I-derived DNA adduct. Besides the tubulointerstitial lesions usually seen in the cortex, a massive infiltration of macrophages, T and B lymphocytes was detected by immunohistochemistry in the medullary rays and in the outer medullae with some extension to the upper cortical labyrinth. Conclusions: In parallel with histological findings reported in the rat model, inflammatory cells are present preferentially in the interstitium of the medullary rays and of the outer medulllae in renal interstitium from human AAN cases, even in the terminal stages. Further studies must be undertaken to determine the respective roles of innate and adaptive immunity in the progression of AAN. © 2010 Blackwell Publishing Limited.


Schirrmacher V.,Immunologisches Onkologisches Zentrum Cologne | Fournier P.,German Cancer Research Institute
Frontiers in Oncology | Year: 2014

This chapter focusses on oncolytic Newcastle disease virus (NDV). It summarizes i) the peculiarities of this virus as an anti-cancer and immune stimulatory agent and ii) approaches to further harness it as a vector to combat cancer. Special emphasis is given on combining virus therapy with cell therapy and on improving tumor targeting. The review will include some of the authors work on NDV, bispecific antibodies and cell therapy as building blocks for a new perspective of multimodal cancer therapy. The broad anti-tumor immune reactivation includes innate and adaptive, tumor antigen specific and tumor antigen independent activities. © 2014 Schirrmacher and Fournier.


Horvat E.-A.,The Interdisciplinary Center | Horvat E.-A.,University of Kaiserslautern | Da Zhang J.,Computational Biology and Bioinformatics | Uhlmann S.,German Cancer Research Institute | And 3 more authors.
PLoS ONE | Year: 2013

Recent development of high-throughput, multiplexing technology has initiated projects that systematically investigate interactions between two types of components in biological networks, for instance transcription factors and promoter sequences, or microRNAs (miRNAs) and mRNAs. In terms of network biology, such screening approaches primarily attempt to elucidate relations between biological components of two distinct types, which can be represented as edges between nodes in a bipartite graph. However, it is often desirable not only to determine regulatory relationships between nodes of different types, but also to understand the connection patterns of nodes of the same type. Especially interesting is the co-occurrence of two nodes of the same type, i.e., the number of their common neighbours, which current high-throughput screening analysis fails to address. The co-occurrence gives the number of circumstances under which both of the biological components are influenced in the same way. Here we present SICORE, a novel network-based method to detect pairs of nodes with a statistically significant co-occurrence. We first show the stability of the proposed method on artificial data sets: when randomly adding and deleting observations we obtain reliable results even with noise exceeding the expected level in large-scale experiments. Subsequently, we illustrate the viability of the method based on the analysis of a proteomic screening data set to reveal regulatory patterns of human microRNAs targeting proteins in the EGFR-driven cell cycle signalling system. Since statistically significant co-occurrence may indicate functional synergy and the mechanisms underlying canalization, and thus hold promise in drug target identification and therapeutic development, we provide a platform-independent implementation of SICORE with a graphical user interface as a novel tool in the arsenal of high-throughput screening analysis. © 2013 Horvat et al.


PubMed | German Cancer Research Institute
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2012

Yeast two-hybrid screening can be used to find cDNAs encoding proteins which bind to a given bait protein in large, pooled cDNA libraries. Screening of complex, pooled libraries is slower and more laborious than screening of arrayed collections of cDNAs, but has several advantages. First, the complexity of a pooled library can be orders of magnitude larger than the size of a typical arrayed library. Second, as long as available cDNA collections are incomplete and limited to full-length cDNAs, pooled cDNA libraries offer a more complete search space and are often the only way to do screens in organisms other than human and a few model organisms. We have streamlined and optimised the screening of pooled libraries in a format which uses micro-titre plates and produces quantitative signals for the selection of hits. This format has the advantage that automation of the process is straightforward and allows a throughput of up to at least 1,000 screens per year per person.


PubMed | German Cancer Research Institute and Immunologisches Onkologisches Zentrum Cologne
Type: | Journal: Frontiers in oncology | Year: 2014

This paper focuses on oncolytic Newcastle disease virus (NDV). This paper summarizes (i) the peculiarities of this virus as an anti-cancer and immune stimulatory agent and (ii) the approaches to further harness this virus as a vector to combat cancer. Special emphasis is given on combining virus therapy with cell therapy and on improving tumor targeting. The review will include some of the authors work on NDV, bi-specific antibodies, and cell therapy as building blocks for a new perspective of multimodal cancer therapy. The broad anti-tumor immune reactivation includes innate and adaptive, tumor antigen (TA) specific and TA independent activities.

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