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BBMRI - Biobanking and Biomedical Resources Research Infrastructure

Human biological samples including associated medical data, and biomolecular research tools are key resources in unravelling the interplay of genetic and environmental factors causing diseases and impact on their outcome, identification of new targets for therapy and reduction of attrition in drug discovery and development. Furthermore these resources are required for identification of new targets for therapy and may help to reduce attrition in drug discovery and development. The European Strategy Forum on Research Infrastructures (ESFRI) foresees in its roadmap the pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) to further develop these resources and to provide access to academia and industry. The preparatory phase of BBMRI will be funded within FP7. BBMRI will build on existing sample collections, resources, technologies, and expertise, which will be specifically complemented with innovative components and will be properly embedded into European scientific, ethical, legal and societal frameworks. Sustainability will be achieved by appropriate funding and financing solutions. BBMRI will increase the scientific excellence and efficacy of European research in the biomedical sciences as well as expand and secure competitiveness of European research and industry in a global context and attract back (investments in) pharmaceutical and biomedical research facilities (from outside Europe).



In vitro diagnostics have allowed a great deal of progress in medicine but are limited by two factors: (a) the lack of guidelines in collection, handling, stabilisation and storage of biosamples which limits the reproducibility of subsequent diagnoses, and (b) its scale is restrained to the cellular level. To address this first point, SPIDIA, built of clinicians, academics, tool and assay developers, aims at developing quality guidelines for molecular in vitro diagnostics and to standardise the pre-analytical workflow in related procedures. Regarding the second point, SPIDIA aims at developing modern pre-analytical tools for diagnostics improving the stabilisation, handling and study of free biomolecules within blood, plasma, serum, tissues and tumours. Recent discoveries have revealed that RNA, DNA or proteins, released from pathological sites, like tumour cells or Alzheimer's disease (AD) brain lesions, into the blood or as a secondary blood based response to the disease can serve as biomarkers for early and reliable molecular diagnosis of such debilitating diseases. Further discoveries have shown that the cellular profiles of these molecules and structures in clinical samples can change during transport and storage thus making clinical assay results and pharmaceutical research unreliable or even impossible. It will therefore be a decisive prerequisite for future and current diagnostic assays to develop standards and new technologies, tools and devices that eliminate the human error in the pre-analytical steps of in vitro diagnostics.

At this crucial moment in the development of molecular diagnostics, SPIDIA proposes an integrated consortium that reunites 7 private research companies (Qiagen, PreAnalytiX, Tataa, Diagenic, Aros, Dako, and ImmunID Technologies), 1 private research institute (the Biotechnology Institute of the Czech Academy of Science) and 6 public research organisms (Medical University of Graz, Consorzio Interuniversitario Risonanze Magnetiche di Metalloproteine Paramagnetiche, International Agency for Research on Cancer, University of Florence, Erasmus Medical Center and Technical University of Munich), one management SME (ACIES) and an official European Standards Organisation (Centre Européen de Normalisation), a consortium balanced and empowered to maximise the impacts of in vitro diagnostics on human health'.



Steatohepatitis (SH) is a multifactorial disease of the liver which is caused by complex genetic and environmental factors. The genetic determinants of SH will be investigated by studying several established mouse models for SH, in which a variety of  key features of the disease are represented. The relevance of the findings in these models for human SH will be demonstrated by correlating them with data obtained from human liver and blood samples. The importance of the genetic background in the development of the disease has been corroborated by investigating the susceptibility of various mouse strains to develop SH. The identification of the respective genetic modifiers will be pursued by using consomic mice which represent both susceptible (A/J) and non-susceptible (PWD) strains. After localization of putative modifiers to certain chromosomal regions more precise analysis will be performed by high-throughput whole-genome sequencing. To characterize the functional impact of the putative modifiers found in this way RNA expression profiling, proteomic analysis of related pathways, and metabolomic analyses will be performed.


Research Institute of Molecular Biotechnology, IMBA, Vienna: Cooperation with Prof. Dr. Josef Penninger  

Tamara Zoranovic, a PhD student in the goup of Josef Penninger at the Research Institute of Molecular Biotechnology, IMBA, Vienna, has identified 48 tumor suppressor genes in a fruitfly (drosophila melanogaster) screen. In this collaboration we are testing if the human homologues of these genes play a role in human cancer by screening a large number of human tumor samples from the Tissue Bank at the Institute of Pathology for significant deregulation of these genes. If these genes are found to be important for the formation of tumors in cancer patients they could possibly represent new markers for tumor diagnosis or even potential targets for tumor therapy.


CRIP - the annotation project

CRIP (Central research infrastructure for molecular pathology) of the Fraunhofer Institute is a central infrastructure for biomedical research involving human tissue repositories. This platform for molecular life sciences supports scientists in their search for particular tissues available in different biobanks. CRIP provides anonymized data on and from human biospecimen available for basic, preclinical and clinical research projects. As a database partner we annotate biospecimens in our repository with clinical and further data and transfer the anonymized data to the CRIP database.

The existing data of the pathological findings are converted into a searchable form, because the information stored in some clinical databases is very complex and often not well structured, so that it is difficult to search in such data. In this case medical studies are difficult to produce. Several information are necessary to easily find the needed requirements for research questions, for example the ICD-10 and ICD-O codes, tumor status T, N, M, R, L, V, the grading and the receptor status for the different organs. In the past the information has been searched in the full text diagnose fields, but the better way to deal with such data, is to store them structured in a relational database.

Our text mining tools are a bundle of programs for structuring and clean up clinical data in a database system. We use a dictionary based text mining approach, with special negation

rules. A regular expression based system is used to extract the tumor status and the receptors. The first step in the system is to correct misspellings and abbreviations to get a clean diagnosis field. This text cleanup tool is a Java application which is only necessary to run the first time the diagnoses comes into the system. The next step is to pool the different diagnoses together, because in some clinical cases there are several extractions from the same case and for studies only the whole case is important. The last step than is the daily schedule task for coding and extraction of the information from the diagnosis.

For managing the dictionary is a web based TreeView provided, which shows the rule set in the correct handling order. In this TreeView it is possible to change all existing rules and also add new rules, including the resulting codes (ICD-10, ICD-O, SCG).

Special for research projects there is a tool to find misspellings in the name and the birthday, to get the complete follow-up for patients in a study. To calculate the junction for the names there are statistic and word similarity algorithms used in the program.

An additional tool is implemented for windows systems, to export selected codes and organs into an access database, or to count the patients und diseases for different codes and organs.

Breast Cancer

An international research project on breast cancer was initiated in 2004 as collaboration between the German Genome Program NGFN2 (project leaders, A. Poustka and H. Sültmann at the German Cancer Research Center, Heidelberg) and the Austrian Genome Program GEN-AU. The major goals of this joint research project is the generation of the largest and best standardized whole genome gene expression data set from at least 500 breast cancers, and the generation of a tissue microarray platform representing up to 2000 highly annotated breast cancers. These data are available to the public domain and should enable the discovery of novel cancer-related genes, the identification of molecular alterations associated with specific tumor subtypes and the discovery of novel prognostic markers, thus providing the basis for new targeted therapies.

Liver cancer

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide affecting approximately 500.000 people every year. BioResource-Med allowed a genome-wide search for HCC-associated genes, thus leading to the identification of a novel gene designated HULC (highly upregulated in liver cancer). HULC is a non coding RNA, which exceeded several well established cancer-related genes in its expression level and extent of deregulation. HULC is present in the cytoplasm of HCC cells and co-purifies with polysomes. siRNA-mediated knock down of HULC resulted in the upregulation of more than 30 genes, most of which are known to be affected in HCC, such as albumin and retinoblastoma1. Thus, HULC may act as a post transcriptional regulator of gene expression. As the most deregulated gene in HCC it has furthermore potential to become a novel diagnostic marker.

Metabolic diseases

Metabolic diseases, particularly diabetes and obesity, are major risk factors for cardio-vascular disease, the greatest health problem and most common cause of death in industrialized countries. Recently, chronic liver disease has been recognized as a major consequence of diabetes and obesity. Almost half of the patients with type 2 diabetes and a Body-Mass-Index (BMI) of more than 30 develop chronic liver disease, which resembles alcoholic liver disease and is designated non-alcoholic steatohepatitis (NASH). It is expected that within the next 20 years, progressive liver disease will generate a health burden in patients with diabetes and obesity similar to that of cardio-vascular diseases (Angulo, 2002; Tolman et al., 2004). Metabolic diseases are a priority research topic at the Medical University Graz and were selected as one disease focus for BioResource-Med. Consequently, the biobank generates an essential research infrastructure for an interdisciplinary approach in metabolic diseases by containing various organs of metabolic disease manifestation (i.e. blood and tissues from organs centrally involved in diabetes and obesity like liver, fatty tissue, pancreas, and blood vessels).


 Major causes of chronic liver diseases
Liver alterations in steatohepatitis. Chromotrope aniline blue-stained (CAB) human liver with steatohepatitis showing ballooned hepatocytes containing cytoplasmic protein inclusions (Mallory bodies), steatosis, fibrosis, and inflammation. Double-label immunofluorescence (IF) microscopy of human liver with steatohepatitis using antibodies to keratin (green) and antibodies to the stress protein p62 (red). IF demonstrates severe alterations of the hepatocytic keratin cytoskeleton with accumulation of keratin-containing protein aggregates (Mallory bodies) in steatohepatitis (Zatloukal et al., 2004). 

Clusterin Expression in Cholestasis and Liver Fibrosis

Project participants

Aigelsreiter A.  1
Janig E.
Sostaric J.
Pichler M.
Unterthor D.
Halasz J.
Lackner C.
Zatloukal K.
Denk H.

1 Institute of Pathology, Medical University of Graz, Austria
2 Department of Dermatology and Venerology, Medical University of Graz, Austria
3 Department of Internal Medicine, Division of Oncology, Medical University of Graz, Austria
4 2nd Department of Pathology, Semmelweis University Budapest, Hungary

Background: Clusterin is a chaperone which shares functional properties with small heat shock proteins (sHSPs). Deregulation of clusterin expression has been described in various diseases. In hepatocellular carcinomas (HCCs) cytoplasmic clusterin overexpression in tumor cells was found to be associated with poorer prognosis. The aim of our study was to evaluate the presence and distribution of clusterin in various forms of cholestatic liver diseases as well as in liver fibrosis, cirrhosis and HCCs.
Methods: Tissue microarrays were used to evaluate the expression of clusterin in 116 HCCs and 103 matched non-neoplastic livers (including fibrosis and cirrhosis) by immunhistochemistry (IHC) using 3 different antibodies. Additionally, in several cholestatic liver diseases, including primary sclerosing cholangitis (10 samples), primary biliary cirrhosis (18 samples), mechanical cholestasis (9 samples) and drug-induced cholestasis (12 samples) the presence and distribution of clusterin was explored. The distribution pattern of clusterin in portal tracts was correlated with staining of elastic fibers (Elastica - Van Gieson stain). To examine the presence of clusterin in human bile western blotting was performed in three bile samples derived from autopsy cases. To further study whether clusterin was produced by hepatocytes and its expression enhanced in cholestatic conditions Real-time RT-PCR was performed in 10 normal liver samples and in 10 samples with mechanical cholestasis.
Results: Clusterin was found to be associated with fibrotic areas of the liver, showing a colocalization with elastic fibers. Clusterin was also detected in bile plugs in all cholestatic liver diseases investigated. Moreover, in 44 of 116 cases of HCC showing pseudoglandular features, clusterin was detected within the lumina. Clusterin was also demonstrated in bile by western blotting. Clusterin mRNA expression was found in normal liver samples as well as in samples with mechanical cholestasis without significant difference between the two groups.
Conclusion: In liver fibrosis and cirrhosis clusterin was associated with elastic fibers but not with collagen, hepatocytes or bile duct epithelia. Moreover, clusterin was present in bile as revealed by western blotting and IHC. The biologic significance of the presence of clusterin in bile is as yet unclear. As it is produced by hepatocytes as shown by Real-time RT-PCR it may act as chaperone by protecting bile duct epithelium against aggressive bile components or inhibiting precipitation of biliary proteins. The association of clusterin with elastic fibers could be another extracellular chaperone function of clusterin by either protecting and stabilizing elastic tissue or shielding abnormal elastic material.