Scientific Papers - Life Sciences and Medical Imaging
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2007
Ainscow E, Pilling J, Brown N, Sullivan E, Sullivan M, Arini N, Linssen B, Zenger-Landolt B, Korn R, Harberichter T, Cholewinski A, Blackmore C: 
Automated Multivariate Analysis of Phospholipidosis in primary Hepatocytes Poster presented by AstraZeneca and Definiens at SBS 13th Annual Conference and Exhibition, April 15 - 19, 2007, Montreal, Canada
Athelogou M, Schmidt G, Feehan O, Binnig G: Definiens Cognition Network Technology for Analysis of Experimental and Simulated Images of Liver and Endocytosis Detailed knowledge about the morphology and changes of biological systems give valuable and precious information about their function. Developments in imaging technologies enable users to acquire thousands of images of different modalities and at different levels of resolution of biological systems such as the human liver. Sub cellular structures, cells, cell groups, tissue and the whole organ can be automatically analyzed, measured and quantified using image analysis software. On the other hand, modelling and simulations of processes within cells give better understanding of biological processes like endocytosis. Simulated images help, for example, to gain a better understanding and to create valuable knowledge about the endocytotic transport in hepatocytes. Furthermore, this knowledge is valuable for the improvement of related experimental design. Therefore, the combination of knowledge extracted from both experimental and simulated images can improve experimental design, modelling and simulations for the endocytotic transport in the hepatocytes. Definiens enables the analysis and multiresolution quantification of both experimental and simulated images. Therefore it is possible to maximize knowledge exploitation for the endocytotic transport in the hepatocytes. (Poster presented at the HEPATOSYS Program Status Seminar 2007, Oct 15, Communication Centre DKFZ, Heidelberg)
Athelogou M, Schmidt G, Schäpe A, Baatz M, Binnig G: Definiens Cognition Network Technology – A Novel Multimodal Image Analysis Technique for Automatic Identification and Quantification of Biological Image Contents Detailed knowledge about the morphology of a biological system gives valuable and precious information about its functions and dynamics. Improvements in imaging technologies enable users to acquire thousands of images of different modalities with different resolutions from biological systems. Such images show subcellular structures, cells, cell groups, tissue, organs and organisms. On the other hand, image data are of high value only if they can be transformed into valuable knowledge. Therefore, the problem of automatic information extraction from such images has become a prime priority in academic and industrial biomedical research and development. The Definiens Cognition Network Technology solves that problem by simulating human cognition processes using knowledge-based and context-dependent processing. It is represented in its entirety by the image data, image processing methods, image derived layers, and image objects and their definitions in a unified model. The Definiens Cognition Network Technology incorporates elements from semantic networks, description logics and functional programming. We applied this technology to imagery of different magnification, resolution and different modalities such as electron micrographs, optical microscopy and modalities in the area of radiology. Using a unified approach with a scale- and problem-invariant processing and knowledge model is a prerequisite for studying complex hierarchical systems such as biological systems. (In: Imaging Cellular and Molecular Biological Functions, by Spencer L. Shorte and Friedrich Frischknecht, ISBN-13: 978-3-540-71330-2, Springer-Verlag Berlin Heidelberg, 2007, pp 407-421)
Athelogou M, Schmidt G, Schönmeyer R, Binnig (GERMAN version only): Kontextbasierte Bildanalyse mit Cognition Networks Basierend auf der Idee, elementare Mechanismen der menschlichen Wahrnehmung in einem Bildanalyseverfahren natürlich und einfach abzubilden, entwickelten Nobelpreisträger Gerd Binnig und sein Team die Definiens Cognition Network Technology. (In: BIOspektrum, Spektrum Akademischer Verlag, Heidelberg, 13. Jahrgang, Ausgabe 0607, pp 657 - 659)
Danckaert A, Machu C, Marchand M, Nguyen M, Nicola M-A, Perret E, Renaud O, Rogers K, Roux P, Shorte S (FRENCH version only): Plate-Forme d’Imagerie Dynamique Poster presented by Institute Pasteur et al., June 2007, Grenoble, France
Fromaget M, Cook PR: Photobleaching reveals complex effects of inhibitors on transcribing RNA polymerase II in living cells RNA polymerase II transcribes most eukaryotic genes. Photobleaching studies have revealed that living Chinese hamster ovary cells expressing the catalytic subunit of the polymerase tagged with the green fluorescent protein contain a large rapidly exchanging pool of enzyme, plus a smaller engaged fraction; genetic complementation shows this tagged polymerase to be fully functional. We investigated how transcriptional inhibitors – some of which are used therapeutically – affect the engaged fraction in living cells using fluorescence loss in photobleaching; all were used at concentrations that have reversible effects. Various kinase inhibitors (roscovitine, DRB, KM05283, alsterpaullone, isoquinolinesulfonamide derivatives H-7, H-8, H-89, H-9), proteasomal inhibitors (lactacystin, MG132), and an anti-tumour agent (cisplatin) all reduced the engaged fraction; an intercalator (actinomycin D), two histone deacetylase inhibitors (trichostatin A, sodium butyrate), and irradiation with ultra-violet light all increased it. The polymerase proves to be both a sensitive sensor and effector of the response to these inhibitors. (In:Exp. Cell Res. (2007), doi:10.1016/j.yexcr.2007.04.036)
Fromaget MGM , Blackmore CG, Cook PR: Automated Analysis of RNA Polymerase II Activity in Cells treated with Inhibitors of Transcription
Poster presented by Sir William Dunn School of Pathology, University of Oxford and Definiens at the European Light Microscopy Initiative (ELMI) meeting at the University of York, April 2007
Okamoto Y, Higashiyama H, Inoue H, Kanematsu M, Kinoshita M, Asano S: Quantitative image analysis in adipose tissue using an automated image analysis system: Differential effects of peroxisome proliferator-activated receptor-a and -g agonist on white and brown adipose tissue morphology in AKR obese and db/db diabetic mice Morphometric analysis of adipocytes is widely used to demonstrate the effects of antiobesity drugs or anti-diabetic drugs on adipose tissues. However, adipocyte morphometry has been quantitatively performed by manual object extraction using conventional image analysis systems. The authors have developed an automated quantitative image analysis method for adipose tissues using an innovative object-based quantitative image analysis system (Definiens Enterprise Image Intelligence Suite). Using this system, it has been shown quantitatively that morphological features of adipose tissues of mice treated with peroxisome proliferator-activated receptor (PPAR) agonists differ dramatically depending on the type of PPAR agonist. Marked alteration of morphological characteristics of brown adipose tissue (BAT) treated with GI259578A, a PPAR-a agonist, was observed in AKR/J (AKR) obese mice. Furthermore, there was a 22.8% decrease in the mean size of adipocytes in white adipose tissue (WAT) compared with vehicle. In diabetic db/db mice, the PPAR-g agonist GW347845X decreased the mean size of adipocytes in WAT by 15.4% compared with vehicle. In contrast to changes in WAT, GW347845X increased the mean size of adipocytes in BAT greatly by 96.1% compared with vehicle. These findings suggest that GI259578A may activate fatty acid oxidation in BAT and that GW347845X may cause adipocyte differentiation in WAT and enhancement of lipid storage in BAT. (In: Pathology International 2007; 57: 369–377 doi:10.1111/j.1440-1827.2007.02109.x)
Okamoto Y, Higashiyama H, Rong JX, McVey MJ,Kinoshita M, Asano S, Hansen MK: Comparison of mitochondrial and macrophage content between subcutaneous and visceral fat in db/db mice Central (visceral) obesity is more closely associated with insulin resistance, type 2 diabetes, and cardiovascular disease than peripheral (subcutaneous) obesity, however the underlying differences in morphology and pathophysiology between subcutaneous and visceral adipose arelargely unknown. To evaluate the effects of diabetes and rosiglitazone (RSG) treatment, the expression of mitochondrial Hsp60, UCP-1 and F4/80 in inguinal subcutaneous (SC) fat, composed of white and brown adipose tissues, and epididymal (EP) fat, mainly white adipose tissue, were evaluated. In diabetic db/db mice, there was significant increased number of aggregated macrophage foci compared to db/+ mice, especially in EP fat. On the other hand, the expression of mitochondrial Hsp60 protein was suppressed in both SC and EP fat of db/db mice compared to db/+ mice, and the expression level of mitochondrial Hsp60 in db/+ mice was lower in EP fat compared with SC. In db/db mice, RSG suppressed the number of aggregated macrophage foci in EP fat, but not in SC fat. RSG ameliorated the mitochondrial Hsp60 expression and induced the expression of UCP-1 in both SC and EP fat. Taken together, these data suggest that differences exist in mitochondrial and macrophage content, and in the response to RSG between visceral and subcutaneous adipose tissue, and adipose type and distribution may be important for obesitylinked insulin resistance. (In: Exp. Mol. Pathol (2007), doi:10.1016/j.yexmp.2007.02.007)
Persohn E, Seewald W, Bauer J, Schreiber J: Cell proliferation measurement in cecum and colon of rats using scanned images and fully automated image analysis: Validation of method The purpose of this study was to establish and validate fully automatic measurement of cell proliferation on scanned images of rat cecum and colon. Tissue slides were taken from a 4-week mechanistic study and processed for BrdU immunohistochemistry. Four sections of the cecum and colon per slide were scanned with the Zeiss MIRAX SCAN and transferred to the Definiens eCognition Analyst LS5.0 system for evaluation. Two rule sets for automatic counting of BrdU-positive and negative nuclei from mucosal cells on the image tiles were created by Definiens, one for cecum, one for colon. For validation, manual counting of 16 randomly selected tiles from five different slides of colon and cecum was performed. Negative and positive cell nuclei were counted in each image tile by four different people. Comparison of results from manual counting with the automatic counting showed that the sum as well as single tile data and labeling index (LI) from automatic counting were within the range of manual counting results 710%. Automatic counting included only cell nuclei within the mucosa whereas muscularis and lymphoid tissue as well as wrinkles from tissue preparation were excluded. In addition, two data sets from automatic counting of the same image tile were compared: (1) data where image tiles with incorrect detection of mucosa were excluded from further calculation of LI and area, and (2) data where no visual check was performed and all measurements were included. Results were very similar for both data sets. The necessity of the manual correction may therefore be doubted. (In: Exp Toxicol Pathol (2007), doi:10.1016/j.etp.2007.01.005; 2007 Elsevier GmbH. All rights reserved.)
Persohn E, Schreiber J, Zimmermann J: Automated Analysis of Cell Proliferation in images of BrdU stained Rat Cecum and Colon
Poster presented by Novartis and Definiens at the Tucson Symposium 2007, Ventana Medical Systems , March 6 -7, 2007, Tucson, Arizona, US
Rong JX, Qiu Y, Hansen MK, Zhu L, Zhang V, Xie M, Okamoto Y, Mattie MD, Higashiyama H, Asano S, Strum JC, Ryan TE: Adipose Mitochondrial Biogenesis is suppressed in db/db & high-fat diet-fed Mice and improved by Rosiglitazone The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a PPARγ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type II diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD), and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. (In: Diabetes In Press, published online April 24, 2007; Copyright American Diabetes Association, Inc., 2007)
Schönmeyer R, Rotarska-Jagiela A, Prvulovic D, Haenschel C, Linden DEJ (GERMAN version only): Automatische Segmentierung des
Corpus Callosum aus sagittalen Schichten
von kernspintomographischen Datensätzen In dieser Arbeit stellen wir einen voll-automatisierten Algorithmus vor, der in der Lage ist, die Struktur des Corpus Callosum aus sagittalen Schichten von T1-gewichteten kernspintomographischen Datensätzen des menschlichen Gehirns zu segmentieren. Die Segmentierungsergebnisse werden dabei für die Untersuchung morphometrischer Merkmale in einer Studie zur Schizophrenie in definierte Abschnitte unterteilt, um sie im weiteren Verlauf statistisch auswerten zu können. Der Algorithmus wurde unter Zuhilfenahme der Definiens Cognition Network Technology implementiert, die eine regelbasierte und kontextsensitive Handhabung der Bilddaten erlaubt, und dabei nur wenige Voraussetzungen über die Beschaffenheit und Qualität der zu verarbeitenden Datensätze macht. Das Verfahren scheitert im Rahmen einer Testreihe bei einem von 50 Datensätzen und erzielt ansonsten einen Dice-Koeffizienten von 0,97 im Vergleich zu manuell segmentierten Ergebnissen. (In: Horsch A, Deserno TM, Handels H, Meinzer H-P, Tolxdorff T, ed. Bildverarbeitung für die Medizin (BVM); 25.-27.03.2007; München, Germany: Springer-Verlag, Berlin Heidelberg, 2007: 389-393)
Schmidt G, Horsch A, Schulz-Wendtland R, Kaur S, Elter M, Sittek H, Wittenberg T, Athelogou M, Binnig G: Definiens Cognition Network Technology for Automated Holistic Analysis in Mammography
Digital mammography and comprehensive breast cancer screening approaches have led to the generation of a vast amount of image data. Since the visual inspection of a large set of images is expensive and to some extend also subjective, new methods for fully automated mammography image analysis are needed. The Definiens Cognition Network Technology solves the image analysis problem by simulating human cognition processes using knowledge based and context dependent processing. It represents processed image data, image processing methods, and image objects and their definitions in a unified model which incorporates elements from semantic networks, description logics and functional programming. We present first steps towards a successful application of this technology on automated detection of masses and calcifications according to the ACR BI-RADS™ standard. (in: Horsch A, Deserno TM, Handels H, Meinzer H-P, Tolxdorff T, ed. Bildverarbeitung für die Medizin (BVM); 2007 25.-27.03.2007; München, Germany: Springer-Verlag, Berlin Heidelberg, 2007: 282-287)
Strömberg S, Björklund MG, Asplund C, Sköllermo A, Persson A, Wester K, Kampf C, Nilsson P, Andersson A, Uhlen M, Kononen J, Ponten F, Asplund A: A high-throughput strategy for protein profiling in cell microarrays using automated image analysis Advances in antibody production render a growing supply of affinity reagents for immunohistochemistry (IHC), and tissue microarray (TMA) technologies facilitate simultaneous analysis of protein expression in a multitude of tissues. However, collecting validated IHC data remains a bottleneck problem, as the standard method is manual microscopical analysis. Here we present a high-throughput strategy combining IHC on a recently developed cell microarray with a novel, automated image-analysis application (TMAx). The software was evaluated on 200 digital images of IHC-stained cell spots, by comparing TMAx annotation with manual annotation performed by seven human experts. A high concordance between automated and manual annotation of staining intensity and fraction of IHC-positive cells was found. In a limited study, we also investigated the possibility to assess the correlation between mRNA and protein levels, by using TMAx output results for relative protein quantification and quantitative real-time PCR for the quantification of corresponding transcript levels. In conclusion, automated analysis of immunohistochemically stained in vitro-cultured cells in a microarray format can be used for high-throughput protein profiling, and extraction of RNA from the same cell lines provides a basis for comparing transcription and protein expression on a global scale. (In: Proteomics 2007, 7, 2142–2150; DOI 10.1002/pmic.200700199)
Verma A, Kriete A: Robust Object-Oriented Segmentation for
High-Content Screening Fluorescent based functional assays often rely on counterstains to derive locational information, such as cell position, cytoplasm, nucleus or organelles. While a range of solutions exists to segment nuclei, the detection of cytoplasmic boundaries is by far more challenging. In high-content screening applications the detection of the cytosol, prior to the measurement of concentrations of specific markers within, requires a stable segmentation process. Watershed algorithms, using nuclei as seeds, are limited by noise and intensity variations, which typically results in over-segmentation. In contrast to pixel-oriented segmentation methods, we incorporate the definition of homogeneous objects and geometric constraints into the segmentation process. Objects are defined in a multi-scale fashion by homogeneity criteria using region growing. Subsequent application of watershed segmentation to cytoplasmic areas largely reduces over-segmentation. We further compare this method with a local segmentation approach which defines homogenous areas using quadtrees. We demonstrate that this method, if combined with geometric constraints, is handling the difficult detection of cytoplasmic boundaries of weakly stained and touching cells most efficiently. (Paper presented at the second international workshop on Microscopic Image Analysis with Applications in Biology, MIAAB 2007, Piscataway, NJ, USA, Sept 21 2007).
Wijsman JA, Obert LA, Piccotti JR, Guzman RE, Dunstan RW: Evaluation of Drug-Induced Alterations in Lymphoid Tissues by Object Oriented Image Analysis using Virtual Imaging Poster presented by Pfizer at the Society of Toxicology’s 46th Annual Meeting, March 25–29, 2007, Charlotte, North Carolina, US
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