Scientific Papers - Life Sciences and Medical Imaging

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2010

Athelogou M, Feehan O, Schönmeyer R, Schmidt G, Binnig G: Image Analysis and Quantification in Systems Biology using Definiens Cognition Network Technology Multidimensional image data arises frequently as an output of experimental processes in contemporary biology. Extracting knowledge from these images through image analysis can lead to the discovery of new information either directly or by providing parameters for further experiments or simulations. The presented work focuses on the analysis of experimental and simulation results involving the process of endocytosis in the hepatocytes. (Poster presented at The 3rd Conference on Systems Biology of Mammalian Cells (SBMC), Freiburg, Germany, Jun 03 - 05, 2010)

Athelogou M, Feehan O, Schmidt G, Binnig G: Aus Bilddaten vernetztes Wissen gewinnnen Die Quantifizierung von Strukturen in biologischen Systemen anhand von Bilddaten liefert wertvolle Informationen über deren Funktion und Dynamik. Dabei erzeugen neue und leistungsfähigere bildgebende Verfahren immer größere Mengen von Bilddaten. Die Bildmotive sind subzelluläre Strukturen, Zellen, Zellgruppen, Gewebe, Organe und Organismen. Solche Bilddaten sind jedoch nur dann von Wert, wenn sich daraus Wissen gewinnen lässt. Deshalb kommt der automatischen Analyse von Bilddaten und der anschließenden Extraktion von Informationen eine Schlüsselrolle für die Biologie, die Medizin und die Medikamentenentwicklung zu. (Article published in Systembiologie, Issue June 2010, pp 43 - 46)

Athelogou M, Schmidt G, Feehan O: High Tech for Liver Cells - Automated image analysis of endocytosis As part of the HepatoSys initiative, the Endocytosis Network (EndoSys) focuses upon analysis of endocytosis and its influence on signal transduction using systems biology. The members of the consortium, for instance, investigate the formation of vesicles (cell compartments enclosed by the cytoplasmic membrane with which membrane proteins or nutrients are ingested into the cell), and how the vesicles are transported within the cell. These investigations produce large quantities of very heterogeneous image data, such as two- or threedimensional microscopic images of hepatocytes and their components, as well as simulated image data of different biological processes. Relevant parameters for investigation are simultaneously determined using both experiments and simulations. As the technology partner of the HepatoSys network, Definiens AG Munich has the task of generating automated image analysis so as: to enable these heterogeneous datasets to be combined; to generate parameters from the experimental image files; and, conversely, to produce simulated images from the experimental measurements. (published in Systems Biology - Results, Progress and Innovations from BMBF Funding, by the Federal Ministry of Education and Research, pp 16ff.)

Chen R, Nishimura M C, Bumbaca S M, Kharbanda S, Forrest W F, Kasman I M, Greve J M, Soriano R H, Gilmour L L, Sanchez Rivers C, Modrusan Z, Nacu S, Guerrero S, Edgar K A, Wallin6 J J, Lamszus K, Westphal M, Heim S, James CD, VandenBerg S R, Costello J F: A Hierarchy of Self-Renewing Tumor-Initiating Cell Types in Glioblastoma The neural stem cell marker CD133 is reported to identify cells within glioblastoma (GBM) that can initiate neurosphere growth and tumor formation; however, instances of CD133− cells exhibiting similar properties have also been reported. Here, we show that some PTEN-deficient GBM tumors produce a series of CD133+ and CD133− self-renewing tumor-initiating cell types and provide evidence that these cell types constitute a lineage hierarchy. Our results show that the capacities for self-renewal and tumor initiation in GBM need not be restricted to a uniform population of stemlike cells, but can be shared by a lineage of self-renewing cell types expressing a range of markers of forebrain lineage. (Published in: Cancer Cell,Volume 17, Issue 4, pp 311-414)

Heidari P, Prasad V, Korn R, Binnig G, Alavi A, Baum R P: Quantification in molecular PET/CT using cognition network technology: A novel concept PET/CT has a well established role in the assessment of response to therapy in oncology. For a precise evaluation of therapy response, the visual interpretation of PET/CT DICOM images as well as the measurement of quantitative parameters are necessary (reference 1). However, the visual identification and subsequent measurement of the standardized uptake value (SUV) for every single lesion on PET images are very time-consuming, especially in patients with multiple metastases. In addition, new parameters like molecular tumor volume (MTV) and molecular tumor index (MTI), which can be used for the assessment of response to therapy and for molecular radiation therapy planning (MRTP) (reference 2), cannot be consistently measured using current commercially available software. The purpose of this study was to develop a software routine which can automatically define and separate organs and tumoral tissue in PET images, calculate parameters like SUVmax and SUVmean and give an approximate measurement of MTV and MTI which can be used for the more accurate evaluation of molecular therapy response. (ePoster C-2141 presented at ECR 2010, Vienna, March 4-8)

Heidari P, Prasad V, Korn R, Binnig G, Alavi A, Baum R P: Assessment of Response to Therapy in Molecular PET/CT Using Cognition Network Technology: A Preliminary Study We developed Quantitative Molecular Imaging Tool ("BBQ-MIT”) as an automatic solution for segregation and quantification of hot spots in oncologic molecular PET/CT. The aim of this study is to compare the results from BBQ-MIT, with those from commercially available standard PET/CT software for the assessment of response to therapy. Methods: BBQ-MIT has been developed in the Cognition Network Language (CNL) (1) generating a semantic object network of context objects (spleen, kidneys, liver, tumoural foci, etc) using a suitable development environment. The Ga-68-DOTA-TOC PET/CT DICOM sets of 4 patients (2 male) with neuroendocrine tumours before and after one session of peptide receptor radiation therapy (PRRT) were processed using BBQ-MIT on an Intel 2 GHz client (2GB RAM). Consecutively the results were compared to reports of a nuclear medicine specialist who used Siemens E.soft for analysis of the images. BBQ-MIT calculated the SUVmax, SUVmean, molecular tumour volume (MTV) and molecular tumour index (MTI) while the three latter parameters were not measured by specialist as it was either not possible by E.soft or very time consuming. Results: Using BBQ-MIT a total of 101 / 100 lesions were detected pre/post PRRT, while the specialist reported 65/50 lesions, respectively. Overall 21 target lesions were included for assessment of response in these patients. According to EORTC criteria both the results from E.soft and BBQ-MIT showed 2 progressive diseases, 1 stable disease and 1 partial metabolic response. There was a very high correlation between the ΔSUVmax measured by E.soft and both ΔSUVmax (r=0.996, p<0.001) and ΔSUVmean (r=0.943, p<0.001) calculated by BBQ-MIT. The median time for detection and quantitative assessment of the lesions was 32 minutes for the specialist while it was 4:37 minutes. Conclusions: The results of this preliminary study provide a convincing proof of applicability of the concept enabling automatic analysis of lesions for assessment of response to therapy in molecular imaging. This technology seems extremely promising for significantly improving the time required for analysis, precision, and reproducibility by specialists as well as increasing sensitivity over "traditional”, subject-dependent measurements. (Poster presented at the 48th Annual Meeting of the DGN (Deutsche Gesellschaft für Nuklearmedizin e.V.), March 21 - 24, 2010)

Herrmann A, Tozzo E, Funk J: Semi-automated quantitative image analysis of podocytedesmin immunoreactivity as a sensitive marker for acute glomerular damage in the rat puromycin aminonucleoside nephrosis(PAN)model Glomerular visceral epithelial cells or podocytes are crucial for glomerular function and podocyte damage has been shown to be inevitably involved in glomerulopathies. Podocytes react to injury in a stereotypic manner. Accompanying morphologic changes is altered expression of intermediate filaments. Desmin is strongly upregulated in injured podocytes. Here we show, that semi-automated quantitative image analysis of desmin immunoreactivity in glomerula is a valid and sensitive marker for acute podocyte and thus glomerular damage in the puromycin aminonucleoside nephrosis (PAN) model in the rat with the potential of an efficacy marker in animal disease models as well as a toxicity marker for podocyte injury. Additionally, a panel of acknowledged urinary kidney biomarkers was evaluated for utility in the PAN model (published in Experimental and Toxicologic Pathology 2010 )

Patel K: Imaging-Based Assays for Neuroscience Drug Discovery Microscope-based methods constitute a key experimental platform in advancing basic neuroscience research. In the last several years, technological and scientific advances have led to an explosive growth in our understanding of how cell physiology and neural circuitry underpin the functioning of the brain. These advances are accessible and applicable to neuroscience drug discovery and, as a consequence, there is a growing shift from a target-based to pathway- or mechanism-based approaches in new medicine development for both psychiatric diseases and neurodegenerative disorders. The development of practical imagingbased assays to study mechanism-based biology in a neuroscience drug discovery environment is an important aspect of this new paradigm. (Published in International Drug Discovery, Issue April/May 2010, Volume 5, Issue 2, pp. 64-66.)

Pospisilik J A, Schramek D, Schnidar H, Cronin S., Nehme N T, Zhang X, Knauf C, Cani P D, Aumayr K, Todoric J, Bayer M, Haschemi A, Puviindran V, Tar K, Orthofer M, Neely G G, Dietzl G, Manoukian A, Funovics M, Prager G, Wagner O, Ferrandon D, Aberger F: Drosophila Genome-wide Obesity Screen Reveals Hedgehog as a Determinant of Brown versus White Adipose Cell Fate Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals... Definiens' software suite was used for the automated determination of adipocyte size and number from multiple intervalled histological sections. (Published in Cell, Volume 140, Issue 1, 148-160, 8 January 2010)

Schönmeyer R, Athelogou M, Sittek H, Ellenberg P, Feehan O, Schmidt G, Binnig G: Prototyp eines Mammographie-CAD-Systems auf Basis der Cognition Network Technology In dieser Arbeit wird ein neues Assistenzsystem für die computerunterstützte Detektion und Diagnose von Herdbefunden in der Mammographie vorgestellt, das mit Hilfe der Cognition Network Technology eine bildbasierte Ähnlichkeitssuche in einer Referenzdatenbank ermöglicht. Dabei wird vorverarbeitend vollautomatisch eine mehrskalige Segmentierung und Klassifikation auffälliger Objekte durchgeführt, deren Ergebnisse zusammengefasst in der Datenbank zur Verfügung stehen. Die Ähnlichkeitssuche lässt sich interaktiv konfigurieren und der Prototyp ist offen für Erweiterungen und die Einbindung von Daten weiterer Modalitäten. (Presented at "Bildverarbeitung für die Medizin", March 15 - 16, Aachen, Germany)

Schönmeyer R, Athelogou M, Sittek H, Ellenberg P, Feehan O, Schmidt G, Binnig G: Definiens Cognition Network Technology prototype of a CAD system for mammography to assist radiologists by finding similar cases in a reference database We present a new approach for computer-aided detection and diagnosis in mammography based on Cognition Network Technology (CNT). Originally designed for image processing, CNT has been extended to also perform context- and knowledge-driven analysis of tabular data. For the first time using this technology, an application was created and evaluated for fully automatic searching of patient cases from a reference database of verified findings. The application aims to support radiologists in providing cases of similarity and relevance to a given query case. It adopts an extensible and knowledge-driven concept as a similarity measure. Methods: As a preprocessing step, all input images from more than 400 patients were fully automatically segmented and the resulting objects classified—this includes the complete breast shape, the position of the mammilla, the pectoral muscle, and various potential candidate objects for suspicious mass lesions. For the similarity search, collections of object properties and metadata from many patients were combined into a single table analysis project. Extended CNT allows for a convenient implementation of knowledge-based structures, for example, by meaningfully linking detected objects in different breast views that might represent identical lesions. Objects from alternative segmentation methods are also be considered, so as to collectively become a sufficient set of base-objects for identifying suspicious mass lesions. Results: For 80% of 112 patient cases with suspicious lesions, the system correctly identified at least one corresponding mass lesion as an object of interest. In this database, consisting of 1,024 images from a total of 303 patients, an average of 0.66 false-positive objects per image were detected. An additional testing database contained 480 images from 120 patients, 15 of whom were annotated with suspicious mass lesions. Here, 47% (7 out of 15) of these were detected automatically with 1.13 false-positive objects per image. A diagnosis is predicted for each patient case by applying a majority vote from the reference findings of the ten most similar cases. Two separate evaluation scenarios suggest a fraction of correct predictions of respectively 79 and 76%. (published in: International Journal of Computer Assisted Radiology and Surgery, May 26, 2010)

Wilbertz T, Wagner P, Stied A-C, Reisch M, Petersen K, Scheble V J, Altorki N K, Storz M, Moch H, Weder W, Fend F, Alex Soltermann A, Perne S: SOX2 amplification is a frequent event in squamous cell lung cancer Transcription factor SOX2 (3q26.3-q27) is a key regulator of pluripotency in embryonic stem cells and cooperates in the generation of induced pluripotent stem cells. In foregut development, SOX2 plays a critical role by maintaining cells in a pluripotent state. Recently, we found that SOX2 is amplified in about 30% of squamous cell lung and esophageal cancers (Bass et al. Nat Genet. 2009). These findings suggest that SOX2 is activated by amplification as a lineage-survival oncogene. Activated SOX2 might return adult cells into a stemness state and thus participate in the carcinogenesis and progression of squamous cell lung carcinomas. Aim of our study was to verify SOX2 amplification and protein overexpression in non-small cell lung cancers (NSCLC) and to compare these results with patient and tumor characteristics. (Poster presented at USCAP, March 2010, Washington).

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