140 professors~1000 scientists in 80 groups5500 university students10 Doctoral Programs100 new Doctors (PhD/MD) annually

Jan 2014

1. RESEARCH INFRASTRUCTURE AND PROGRAMMES AT BIOTURKU® 1

1.1 Research Infrastructure ..................................................................... 1

1.2 Academic Research Programmes ..................................................... 4 1.2.1 Biomaterials Research ........................................................ 4 1.2.2 Centre of Reproductive and Developmental Medicine

(CREDE) Research Programme.......................................... 5 1.2.3 Diagnostic Technologies and Applications .......................... 5 1.2.4 Program of Infection Biology and Infectious Diseases

(PIBID) ................................................................................ 6 1.2.5 Receptor Program ............................................................... 7 1.2.6 Turku Centre for Systems Biology ....................................... 7 1.2.7 Cardiometabolic Research Program .................................... 8

2. RESEARCH PROJECTS RELATED TO CANCER AND HORMONAL DISEASES ................................................................................................. 9

2.1 Signalling Mechanisms in Cancer ...................................................... 9 2.1.1 Novel Mechanism of the Ras Oncogenes – Future Drug

Targeting Opportunities ....................................................... 9 2.1.2 Receptor Tyrosine Kinases in Cancer and Development ..... 9 2.1.3 Cell Adhesion and Cancer ................................................. 10 2.1.4 Hypoxia in Cancer ............................................................. 10 2.1.5 Mitosis and Drug Discovery ............................................... 10 2.1.6 Signalling Pathways Regulated by Oncogenic Pim

Kinases ............................................................................. 11 2.1.7 Matrix Metalloproteinases in Skin Cancer .......................... 11 2.1.8 Targeting Cell Fate Decisions in Cancer ........................... 12 2.1.9 Transcriptional Regulation of the Heat Shock Response ... 12 2.1.10 Keratins as Modulators of Epithelial Health and Disease ... 13 2.1.11 Sphingolipids, Ion Channels and Cellular Signaling ........... 13 2.1.12 Cancer Cell Signalling ....................................................... 14

2.2 Endocrine Cancer and Cancer Models ............................................ 14 2.2.1 Prognostic and Predictive Cancer Biomarkers................... 14 2.2.2 Diagnostic, Prognostic and Predictive Biomarkers in

Epithelial Ovarian Cancer .................................................. 15 2.2.3 Structure and Function of Collagen Receptor Integrin ....... 15 2.2.4 Growth Mechanisms of Hormone-Regulated Cancer ......... 15 2.2.5 Organotypic Cancer Models, Extracellular Matrix, and

Tumour Microenvironment ................................................. 16 2.2.6 NF1 Tumour Suppressor / Histogenesis Factor ................. 16 2.2.7 Novel Treatment Strategies for Endocrine Tumors ............ 17 2.2.8 Genetic Predisposition to Prostate Cancer ........................ 17

2.3 Immune Cells and Cancer ............................................................... 18 2.3.1 Lymphocytes and Inflammation ........................................ 18 2.3.2 Innate Immune Cells and Antimicrobial Defence in

Autoimmune Diabetes ....................................................... 18 2.3.3 Immunogenetics of Autoimmune Diseases ....................... 18 2.3.4 Cell Trafficking .................................................................. 19 2.3.5 Molecular Systems Immunology and Stem Cell Biology .... 19 2.3.6 Stem Cells and Transcriptional Networks of B and

Plasma Cells ..................................................................... 20 2.3.7 Lymphocyte Cytoskeleton Group ...................................... 20 2.3.8 Regulation of Innate Immunity by Ubiquitin Signaling ........ 21

2.4 Metabolic Diseases and Bone ......................................................... 21 2.4.1 Exercise Physiology and Metabolic Research ................... 21 2.4.2 Bone and Energy Metabolism ........................................... 22 2.4.3 New Regulators of Thyroid Function - Genetics of

Congenital Hypothyroidism in Finland ............................... 22 2.4.4 Molecular Regulation of the Bone Marrow

Microenvironment ............................................................. 23 2.4.5 Diabetes, Obesity, Metabolic Diseases and Brown Fat ..... 23

2.5 Reproduction and Steroid Hormone Action ..................................... 23 2.5.1 Control of Gene Expression in Male Germ Cells ............... 23 2.5.2 Novel Diagnostics and Treatments in Reproductive

Health ............................................................................... 24 2.5.3 Pre-receptor Regulation of Nuclear Receptor Signaling

by Hydroxysteroid (17beta) dehydrogenases (HSD17Bs): Novel Targets for Hormonal Therapies ............................. 25

2.5.4 Dietary Modulation of Sex Steroid Action .......................... 25 2.5.5 Male Reproductive Health, Developmental Disorders and

Spermatogenesis .............................................................. 25

2.6 Cancer Imaging and Diagnostics ..................................................... 26 2.6.1 Laboratory of Biophysics ................................................... 26 2.6.2 Environmental and Food Diagnostics ................................ 26 2.6.3 Cancer Imaging in the Era of Molecular Diagnosis and

Therapy ............................................................................ 27 2.6.4 Novel Biomarkers and Test Platforms for Diagnostic

Applications ...................................................................... 27 2.6.5 BioNanoMaterials group ................................................... 28 2.6.6 Chemi- and Biosensors for Bioanalytical Applications ....... 28 2.6.7 Bioanalytical Assay Concepts and Technologies .............. 29

2.7 Data Mining and Bioinformatics ....................................................... 29 2.7.1 Computational Biomedicine .............................................. 29 2.7.2 Structural Bioinformatics Laboratory and Core Facility

(SBL) ................................................................................ 30 2.7.3 Binder Molecule and Biomarker Discovery ........................ 30

2.8 Clinical Research ............................................................................ 30 2.8.1 Health and Quality of Life After Early Onset Cancer.......... 30

2.8.2 Human and Animal Pharmacokinetics, Biomarker Analysis, Early-phase Clinical Trials .................................. 31

3. BIOTURKU® COMPANIES AND THE PRODUCT AND PROJECT PORTFOLIOS .......................................................................................... 31

Bayer in Finland (www.bayer.fi) ....................................................... 31 BioCis Pharma Ltd (www.biocis.com) .............................................. 32 Bioxid Ltd ......................................................................................... 32 DelSiTech Ltd (www.delsitech.com) ................................................ 32 Faron Pharmaceuticals Ltd (www.faronpharmaceuticals.com) ......... 32 Forendo Pharma Ltd (www.forendo.com) ........................................ 33 Hormos Medical Ltd (www.hormos.com) ......................................... 33 Hycail Oy (www.hycail.fi) ................................................................. 33 Labmaster Ltd (www.labmaster.fi) ................................................... 33 Laurantis Pharma Ltd (www.laurantis.com) ..................................... 34 Montisera Ltd (www.montisera.com) ................................................ 34 Orion Corporation, Orion Pharma (www.orion.fi) .............................. 34 Orion Diagnostica Oy (www.oriondiagnostica.com) ......................... 35 PerkinElmer Human Health / Wallac Oy (www.perkinelmer.com) .... 35 Pharmatest Services Ltd (www.pharmatest.com) ............................ 35 Skulle Implants Corporation (www.skulleimplants.com) ................... 36 SYRINX Bioanalytics Ltd (www.syrinxbioanalytics.com) .................. 36

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1. RESEARCH INFRASTRUCTURE AND PROGRAMMES AT BIOTURKU®

The BioTurku cluster builds on a strong scientific basis - the largest single-location Biocampus in Finland is located in Turku, with internationally recognised academic research and education.

The two universities, University of Turku (www.utu.fi) and Åbo Akademi University (www.abo.fi), as well as Finland’s largest polytechnic University of Applied Sciences (www.turkuamk.fi) form the main educational structure for the biotechnology research.

In addition to the university faculties and polytechnic, biotechnology research is carried out in a number of research units, institutes and other organisations, e.g.

1.1 Research Infrastructure

Auria Biobank (www.auriabiopankki.fi/en/) Auria Biobank is the first hospital integrated biobank established in Finland by University of Turku and the hospital districts of Southwest Finland, Satakunta and Vaasa. After starting by the end 2013, it serves as an infrastructure for medical research. Auria Biobank currently holds over 100000 paraffin embedded tissue samples from a range of tumors from various organs. The tissue of origin and tumor type are recorded by SNOMED nomenclature. Routine clinical and tissue-based prognostic and predictive markers (e.g. tumor size and grade, TNM classification, hormone receptor expression etc.) and a basic set of clinical data are available for selected tumor types and collection periods. The data from hospital and certain national health registries can be combined and released to researchers in a decoded fashion to protect the identity of the sample donors. Specimens will be available for research purposes based on applications and approval of the scientific board as specified on the Auria Biobank www-pages. Clinical Research Services Turku (CRST) (www.crst.fi) CRST is a university-based contract research organization (CRO) that conducts clinical, preclinical and bioanalytical studies for the pharmaceutical industry and for other customers. CRST is run by experienced specialists with in-depth understanding of basic and clinical pharmacology and analytical chemistry, especially in therapeutic areas such as disorders of the central nervous system, metabolic diseases and cancer. The services cover clinical drug development from Phase I to Phase IV and bioanalytical and pharmacokinetic services related to clinical and preclinical trials of new pharmaceuticals. Early-phase clinical trials employing imaging (PET and other modalities) and other efficacy biomarkers form the core competence area of CRST.

Functional Foods Forum (http://fff.utu.fi) Functional Foods Forum (FFF) brings together the multidisciplinary expertise for the research and development of high-quality and healthy foods of the future. FFF has a long-standing expertise in preclinical dietary intervention studies and in vivo cancer models. In close collaboration with TCDM Nutrition and Metabolism Unit, FFF offers

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multidisciplinary know-how and research services in investigating the role of dietary factors in cancer development and growth.

National Institute for Health and Welfare (THL) (www.thl.fi) The National Institute for Health and Welfare (THL) is a research and development institute under the Finnish Ministry of Social Affairs and Health. THL works to promote the well-being and health of the population, prevent diseases and social problems, and develop social and health services. THL is the statutory statistical authority in health and welfare and maintains a strong knowledge base within its own field of operations.

Turku BioImaging (www.bioimaging.fi) Turku has genuine traditions in imaging research. The Turku BioImaging initiative represents state-of-the-art technologies in the bioscience community in Turku and is highly interdisciplinary, encompassing all areas of imaging, ranging from molecular to cellular, from single molecule to whole animal imaging, and from single cell analysis of sub-cellular events to high-throughput screening (HTS). The initiative also includes proteomics, systems biology, and computational modelling of cellular processes as their own specific modalities of bioimaging.

Turku Brain and Mind Center (TBMC) (www.tbmc.fi) The center was created in 2011 and gathers twenty research groups from various fields of neuroscience in Turku. TBMC groups are from the University of Turku and Åbo Akademi University. We are pioneers in systemic neuroscience, molecular neuroscience and brain imaging. TBMC researchers work in multi-disciplinary teams to explore the mechanisms underlying brain function in health and disease. In addition to scientific research, we provide high-level specialized education (PhD and postdoctoral level) to young scientists with a keen interest to excel in the field of neuroscience. Our teams carry out internationally competitive research and aim to break new horizons in neuroscience. World class academics from the University of Turku, Åbo Akademi University together with our collaborators will help in achieving this goal. A key endeavour of TBMC is to facilitate collaboration with commercial enterprises and pharmaceutical companies, thereby helping to bridge the gap between academic neuroscience research and drug development.

Turku Center for Disease Modeling (TCDM) (www.tcdm.fi) TCDM is a research infrastructure at the Faculty of Medicine, University of Turku, providing state-of-the-art facilities and expertise for experimental in vivo studies. TCDM carries out both academic and industry associated non-clinical research, and its facilities are also available for contract research. TCDM Tumor Biology Unit provides expertise in performing tumor xenocraft studies, including treatment trials with drug candidates, and the Mouse Genetics and Biology Unit generates genetically modified mice tailored for cancer research.

Turku Centre for Biotechnology (www.btk.fi) CBT is a joint independent department of the University of Turku and Åbo Akademi University. The Centre provides technical expertise and coordinating services for academic and industrial projects in several central areas of biotechnology. The centre also provides a forum for active interactions between academia and industry. The central areas of research are cell signalling, regulation of gene and protein expression and systems biology focusing on neuroscience, oncology, stem cell research and immunology. CBT has strategically invested in the development of

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state-of-the-art platforms in areas such as genomics, functional genomics, proteomics, cell imaging and bioinformatics supporting -omics technologies. In addition to serving local needs, based on national profiling of infrastructures, CBT further develops and provides national services in these key areas as well as some other areas (viral vectors, x-ray crystallography) within national infrastructure networks. As a part of CBT’s infrastructure, the Central Animal Laboratory serves researchers campus-wide, enabling other functions such as disease modelling.

Turku Clinical Biomaterials Centre (TCBC) (www.biomaterials.utu.fi) TCBC has special expertise in non-metallic biomaterials in medicine and dentistry. The centre has a core- facility laboratory with a comprehensive range of up-to-date equipment to meet the challenges of research and development of novel biomaterials and implant designs for clinical applications in head and neck surgery, cranio-maxillofacial surgery and orthopedics as well as in dentistry. Non-metallic bioactive implants have found to be beneficial in reconstructive surgery of cancer patients. TCBC offers custom-made bioactive composite implants for clinical research purposes. Several facilities are dedicated to particular tasks in the manufacturing, characterization and biomechanical testing of materials.

Turku Clinical Research Centre (Turku CRC) (www.turkucrc.fi) Turku Clinical Research Centre consists of units of its background organizations, the Hospital District of Southwest Finland and the University of Turku. The work of Turku CRC is aimed at enhancing the prerequisites for investigator initiated clinical research, ensuring a high quality of research, easing the investigators’ workload of research administration, and intensifying research collaboration with external partners.

Turku PET Centre (www.pet.fi) Turku PET Centre is a Finnish National Research Institute for the use of short-lived positron emitting isotopes in the field of medical research, with focus on high quality scientific research and diagnostic service for the whole country. The centre has 150 staff members and is equipped with e.g. 3 cyclotrons, 19 hot cells for GMP level tracer production, 6 PET or PET/CT scanners, 1.5 T MRI, PET/MRI (3.0T). The centre is ranked among the top 5 in the world. The scientific research strategy of the centre involves five major topics: Molecular imaging in cardiovascular and metabolic research, neurotransmission in health and disease, oncology research, preclinical and translational research and PET radiochemistry research.

Turku University Hospital (www.tyks.fi) The catchment area of highly specialised medical care in western Finland includes Turku University Hospital in the Hospital District of South-West Finland, Satakunta Hospital District and Vaasa Hospital District. The area has some 862 000 inhabitants. In every hospital district, there is treatment on cancer, as well as cancer research. University Hospital's role is to coordinate both the medical care and the research and development of new diagnostic and therapeutic methods with other hospital districts and the PET Centre, University of Turku, and the biotech companies in the area. The new challenge is to create a unit of Comprehensive Cancer Centre in Turku as part of the CCC-Fin project, and thereby more clearly be connected, also nationally, into the therapeutic and research areas of expertise.

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VTT–Technical Research Centre of Finland (www.vtt.fi) VTT is a multidisciplinary expert organisation on technology development and business. VTT's special strength is its ability to create new, globally competitive technologies and innovations by combining knowledge and expertise in different fields. In VTT Turku, new high-throughput cell based screening methods and biochip technologies are developed and applied in drug development and diagnostics. The new technologies, such as organotypic 3D cell cultures, speed up the existing processes and also open up new therapeutic opportunities. Systems biology techniques are used to identify biomarkers for future diagnostic applications. Such biomarkers enable more precise diagnostics, and can be included in the new generation of diagnostic systems, combining biosciences with microelectronics and information technology.

1.2 Academic Research Programmes

BioCity Turku (www.biocity.turku.fi) is an umbrella organization supporting and coordinating life science and molecular medicine related research in the University of Turku and Åbo Akademi University. It is a multi-disciplinary research community consisting of over 100 research groups with some 1000 people: researchers, graduate students and assisting personnel.

Research at the Faculty of Medicine of the University of Turku is active, multidisciplinary, innovative and internationally recognized. Based on an international evaluation, the Faculty of Medicine together with the BioCity Turku have nominated thematic research programmes to profile the research activities: The research groups in BioTurku are organized under research programmes:

■ Biomaterials Research ■ Centre for Reproductive and Developmental Medicine ■ Diagnostic Technologies and Applications ■ Program for Infection Biology and Infectious Diseases ■ Receptor Program ■ Turku Centre for Systems Biology ■ Cardiometabolic Research Program

Biomaterials Research

Director: Professor Pekka Vallittu, Department of Dentistry, University of Turku Email: pekka.vallittu@utu.fi www.biomaterials.utu.fi Research program has seven active research groups covering modern fields of biomaterial science in medicine and dentistry with strong basis of natural and engineering sciences. Main focus of the program is in non-metallic and bioactive materials in replacement of hard tissues of bone and tooth. Emphasis has been put on biomimetics, where naturally fibrous materials are simulated with synthetic materials. Example of these are fiber-reinforced composites which utilize the structure of collagen and cellulose based composites of bone and wood.

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Combination of fibre-reinforced materials with bioactive components and printed biologically active substances are basis for next generation biomaterial devices. Program has core-facility research laboratory TCBC and locally clinical research collaboration with Turku University Hospital and Turku Municipal Health Center.Highlights:

■ Non-metallic medical and dental biomaterials ■ Biocompatible and biologically active medical devices of reconstructive and

regenerative medicine and dentistry ■ Hospitals and industry utilize the results for the benefit of patients ■ Biomaterials Research

Centre of Reproductive and Developmental Medicine (CREDE) Research Programme

Director: Juha Peltonen, MD, PhD, Professor, Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku Email: juha.peltonen@utu.fi http://crede.utu.fi

The CREDE Programme aims at problem-oriented and penetrative research from basic molecular and cellular mechanisms to clinical and industrial applications in three major categories:

■ Reproductive health and the mechanisms of hormone action ■ Developmental mechanisms ■ Skeletal research

The basic science projects under the different research topics are highly overlapping in themes such as the mechanisms of cell division, development, differentiation and hormone action. This is exemplified in studies elucidating e.g. steroid hormone action, or hormonally active dietary factors in breast and prostate cancer in animal models, control population and patients with the NF1 cancer syndrome.

Diagnostic Technologies and Applications

Directors: Kim Pettersson, PhD, Professor, Department of Biochemistry, University of Turku, and Pekka Hänninen, PhD, Professor, Institute of Biomedicine, University of Turku Email: kim.pettersson@utu.fi http://www.biocity.turku.fi/research-programs/diagnostic-technologies-and-applications/ The Turku area is a nationally and internationally recognised stronghold of research on in vitro diagnostic technologies both from a scientific and commercial point of

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view. A central task for the Research Programme is the further development and coordination of the basic and higher education of researchers to promote the interactions within the research community and to the innovative segments of Finnish biotechnological industry. To cope with an ever increasing number of new and/or clinically improved analytes (nucleic acids for gene detection, gene expression and infectious diseases, growth factors, tumor markers, markers of degeneration etc.) new approaches and test principles are needed. Solutions to these challenges are sought from

■ Advanced reporter technologies ■ New assay formats ■ Improved bioaffinity reagents ■ Creative instrumental solutions and platforms

Program of Infection Biology and Infectious Diseases (PIBID)

Director: Pentti Huovinen, PhD, Professor, Department of Medical Microbiology and Immunology, University of Turku Email: pentti.huovinen@utu.fi http://www.med.utu.fi/mikrobiologia/pibid/ PIBID covers research of basic and clinical science in the field of bacteriology, virology, immunology, clinical diagnostics and clinical infectious diseases research. This research field has long traditions in Turku. Several hundreds of thesis works have been published from 1940’ies. The program has collected together 17 study groups from basic research to clinical research together The research groups of PIBID can be positioned under five umbrellas:

■ Clinical and diagnostic research ■ Virology research ■ Bacteriology research ■ Immunogenetics and host defence ■ Oral microbiology and general health

Our research goals are 1) to understand action of microbes and microbiota and their interaction with human host, 2) to develop and apply diagnostic tools for diagnosis of infectious diseases, 3) to improve targeted treatment of infectious diseases and 4) to develop prevention of infectious diseases. PIBID is organizing two meeting series, monthly Infection meeting and weekly Micromedicum-meeting but also special research and further education courses. In addition, we enhance education of young scientist by tailored courses on various topics and deal travel grants. BioCity Turku facilities and activities are important connections for PIBID to biomedicine and biotechnology.

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Receptor Program

Directors: Sirpa Jalkanen, MD, PhD, Professor, MediCity Research Laboratory and Department of Medical Microbiology, University of Turku and John Eriksson, PhD, Professor, Department of Biosciences, Åbo Akademi University and Turku Centre for Biotechnology Email: sirpa.jalkanen@utu.fi http://www.biocity.turku.fi/research-programs/receptor-program/

The receptor research programme is focused on how cells receive and process signals. The research projects have a long record of high quality basic research on receptors to cell adhesion molecules, hormones, cytokines, death ligands, and growth factors, as well as cellular receptors for microbes. There is also a strong emphasis on the molecular mechanisms of signal transduction and transcriptional regulation, structure-activity relationships of ligand-receptor interactions, regulation of receptor expression, and on molecular pharmacology.

■ Control of cell growth and differentiation ■ Imaging of cell behaviour, inflammation and cancer growth ■ Identification of targets for drug development

Turku Centre for Systems Biology

Director: Riitta Lahesmaa, MD, PhD, Professor, University of Turku and Åbo Akademi University Email: riitta.lahesmaa@btk.fi http://sbrp.btk.fi/ The research programme aims for a system-level understanding of specific biological processes to better comprehend cell signalling and metabolism, and to define the molecular basis of specific biological processes and diseases. Several collaborative research projects are already ongoing. Common to all the groups focusing on research projects in biology, cell biology, biomedical research or molecular genetics is a devotion to an integrative and holistic approach exploiting and further developing and combining modern technologies in novel ways. The programme has a strong emphasis on

■ Data integration ■ Bioinformatics ■ Biomathematics and computational biology ■ Structural biology and molecular modelling

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Cardiometabolic Research Program

The Cardiometabolic Research Program covers epidemiologic, clinical, interventional, and basic research imaging studies exploring the risk factors and early development of cardiovascular diseases and diabetes. Included are the major research projects/study groups within the Medical Faculty in the fields of cardiovascular and metabolic research. The Cardiovascular Risk in Young Finns Study (YFS) is a long-lasting cohort study into cardiovascular risk that is collecting comprehensive data on biological and lifestyle factors spanning the period of childhood to adulthood. The ongoing projects examine how exposure to a large range of biomarkers, including dietary factors, life-style, behavioral characteristics and genetic variants in early in life contribute to the development of cardiovascular disease risk. Email: olli.raitakari@utu.fi The STRIP Project is a prospective randomized intervention trial to prevent atherosclerosis by a life-style intervention, which began in infancy and has continued until early adulthood. The prevention has included dietary modification, primary prevention of smoking, and promotion of physical activity in sedentary children. The results contribute to the knowledge on the effects of modifiable early life-style habits for a variety of key carrdio-metabolic risk factors in childhood and adolescence. Email: olli.raitakari@utu.fi Centre of Excellence in Cardiovascular and Metabolic Disease (2014-2019, joint program with University of Eastern Finland) The main objectives are to investigate the molecular mechanisms, genetic and environmental factors, pathogenesis, and new diagnostic and therapeutic approaches for cardiovascular disease, obesity and diabetes. The CoE consists of four integrated and complementary research lines. Metabolic research is focusing on tissue specific insulin resistance and impaired insulin secretion utilizing novel genetic studies and advanced molecular imaging methodology. Cardiovascular research is focusing on molecular mechanisms and new diagnostic and treatment approaches for vulnerable plaques and angiogenesis that has a major role in ischemic heart disease, heart failure and myocardial remodeling, and is significantly impaired in T2DM. The ultimate aim is to develop novel diagnostic tools and therapies for these disorders. Email: juhani.knuuti@utu.fi DIPP and TEDDY projects - Diabetes Prediction and Prevention Study & The Environmental Determinants of Diabetes in the Young The objectives of the DIPP study are the discovery and analysis of genetic and environmental factors that trigger diabetes-related autoimmunity and development of clinical T1D in children, and prevention of the disease. The aim of TEDDY study is to investigate the role of infectious agents, dietary and other environmental factors in the development of T1D. Email: jorma.toppari@utu.fi

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2. RESEARCH PROJECTS RELATED TO CANCER AND HORMONAL DISEASES

2.1 Signalling Mechanisms in Cancer

Novel Mechanism of the Ras Oncogenes – Future Drug Targeting Opportunities

Daniel Abankwa, PhD, Docent (Adjunct Professor), Academy of Finland Research Fellow, Turku Centre for Biotechnology Email: daniel.abankwa@btk.fi Despite 30 years of intensive research, it is still not possible to specifically inhibit oncogenic Ras, which accounts for one of the hallmarks of cancer. We have recently described a novel mechanism of how Ras operates in the plasma membrane. A new switch III region guides the reorientation of Ras proteins paralog-specifically and this translates into its organisation into signalling packages. These so called Ras nanoclusters are absolutely required for Ras signalling. Our current data suggest that several cancer associated Ras mutations in the switch III region exhibit nanoclustering defects, as an unrecognized mechanistic cause. Thus both the novel orientation-switch III mechanism, as well as nanoclustering, represent new drug targets. In addition, we have developed and applied a unique, high-throughput amenable FRET-assay to screen for modulators of nanoclustering, as well as classical inhibitors of Ras membrane anchorage, such as statins and lipid transferase inhibitors. We foresee a particular relevance for Ras nanoclustering in (cancer) stem cell biology. Ras; inhibitors; nanoclusters; FRET; stem cell

Receptor Tyrosine Kinases in Cancer and Development

Klaus Elenius, MD, Professor, Department of Medical Biochemistry and Genetics, and MediCity Research Laboratories, University of Turku Email: klaus.elenius@utu.fi Our goal is to understand how receptor tyrosine kinases (RTK) regulate the pathogenesis of human diseases, such as cancer. This information is needed for the development of molecularly targeted therapies. To recognize aberrations of RTK signaling in diseased tissue, our laboratory also works on the molecular mechanism by which RTKs control normal processes, such as embryonic development. The work mainly focuses on the ErbB family of RTKs. Our laboratory has contributed to the field by e.g. by characterizing novel RTK signaling mechanisms, by identifying novel ErbB4 isoforms, and by determining the role of ErbBs and their ligands in angiogenesis. EGFR; ErbB; cancer; targeted drug; receptor tyrosine kinases

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Cell Adhesion and Cancer

Johanna Ivaska, PhD, Professor of Molecular Cell Biology, Turku Centre for Biotechnology, University of Turku and VTT Email: johanna.ivaska@vtt.fi Our laboratory is interested in how cell adhesion receptors and the cytoskeleton regulate cell migration and metastasis. Invasive and metastatic behaviour of malignant cells is the major cause of mortality in all cancer patients. Migration of cancer cells is critically regulated by physical adhesion of cells to each other and to their non-cellular surroundings (i.e. extracellular matrix). Cell-matrix interactions are mediated by a class of proteins called the integrins. Adhesion dependent migration in tissue is a prerequisite for lymphatic or hematogenous cancer cell dissemination. Epithelial tissue is the source of more than 80% of human cancers and epithelial-to-mesenchymal transition (EMT), where epithelial cells loose polarization is an important event during tumor progression and metastasis. Integrin mediated adhesion regulates in part epithelial cell polarity. The endo-exocytic traffic of integrins is important for directional cell motility of transformed cells. However, the molecular mechanisms regulating this process are still poorly characterized. In addition, it is unknown whether integrin traffic plays a role in the homeostasis of epithelial cells and if alterations in integrin traffic are necessary for cell transformation to occur. Metastasis; migration; invasion; adhesion; integrin

Hypoxia in Cancer

Panu Jaakkola, MD, PhD, Docent (Adjunct Professor), Turku Centre for Biotechnology, University of Turku and Department of Oncology, Turku University Hospital Email: panu.jaakkola@utu.fi Hypoxia (reduced O2 tension) is the main tissue damaging factor in normal tissues but tumors use hypoxia as a growth-promoting factor. During cancer progression hypoxia causes inhibition of apoptosis and enhances tumor aggressiveness and metastasis. In keeping with this, hypoxia causes resistance to cancer treatments -both to chemotherapy and radiotherapy - and leads to poor prognosis. The aim of the research group is to reveal mechanisms by which hypoxia regulates survival decisions in ischemic diseases and cancer progression. The reduced oxygen is sensed by a family of enzymes called the HIF prolyl hydroxylases (PHD1-3). Our studies have revealed functions for PHDs in regulating cell growth, survival and apoptosis. The ultimate aim is to understand how the manipulation of PHDs could be used to enhance clinical cancer treatments, both chemotherapy and radiotherapy. Angiogenesis; head and neck cancer; hypoxia; kidney cancer

Mitosis and Drug Discovery

Marko Kallio, PhD, Docent (Adjunct Professor), VTT Biotechnology for Health and Wellbeing, and Turku Centre for Biotechnology, University of Turku Email: marko.kallio@btk.fi

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The Mitosis and Drug Discovery Team investigates mechanisms of cell division in somatic cells and in meiotic systems. Study of cell division errors may help to explain origin of genomic instability and can lead to discovery of novel therapeutic possibilities and diagnostics opportunities in the fight against cancer. We are especially interested of conditions that suppress cancer cell's viability as a consequence of premature inactivation of the spindle assembly checkpoint (SAC), a conserved signalling pathway which monitors the fidelity of mitosis. In our main projects, we are working to validate the mechanism of action of our putative anti-Hec1 compounds and SAC targeting miRNAs that effectively perturb normal mitosis and trigger cancer cell killing in cell-based assays. Cell division; cancer; checkpoint; miRNA; anti-cancer therapeutics

Signalling Pathways Regulated by Oncogenic Pim Kinases

Päivi J. Koskinen, PhD, Docent (Adjunct Professor), Department of Biology, University of Turku Email: paivi.koskinen@utu.fi Our studies focus on oncogenic Pim family of serine/threonine-specific protein kinases and their substrates. We and others have observed that in human cancer patients, elevated levels of pim mRNA and protein can be found in hematological malignancies like lymphomas and in solid cancers like prostate cancer. Moreover, we have shown that pim overexpression confers radioresistance to cells derived from squamous cell carcinomas. To learn more about the functional roles of Pim kinases in cancer, we have searched for Pim substrates by several approaches, including the yeast two-hybrid system and phosphoproteomics. These studies have shown that Pim kinases promote cell survival e.g. by stimulating activities of several transcription factors that are important for production of survival cytokines. Together with chemists, we have identified and validated Pim-selective small molecule inhibitors, which have provided great tools for our research, but may also have therapeutic value. Using these inhibitors, we have recently revealed a novel role for Pim kinases in stimulation of cancer cell motility. Experiments are ongoing to elucidate the critical downstream effectors for Pim kinases in cancer cell migration and metastatic growth. Pim kinases; kinase inhibitors; prostate cancer; migration; metastases

Matrix Metalloproteinases in Skin Cancer

Veli-Matti Kähäri, MD, PhD, Professor of Dermatology, Department of Dermatology, University of Turku and Turku University Hospital Email: veli-matti.kahari@utu.fi The aim of the project is to elucidate the molecular mechanisms of skin cancer progression. The incidence of skin cancer is increasing globally. This project focuses on the role and regulation of metalloproteinases, e.g. matrix metalloproteinases (MMPs), proteinases with a disintegrated and a metalloproteinase domain (ADAMs), and ADAMs with thrombospodin domain (ADAM-TSs) in skin cancer (squamous cell carcinoma and melanoma) growth and invasion, as well as in tissue repair and fibrosis. Elucidation of the role of metalloproteinases in the progression of skin cancer is likely to be feasible in identification of novel biomarkers for growth and metastasis capacity of highly invasive primary tumors. Furthermore, understanding the roles of specific signaling

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pathways in the regulation of proteolytic capacity of normal and malignant cells will help in developing specific therapeutic modalities for skin cancer. Cancer; skin; proteinase; wound; metastasis

Targeting Cell Fate Decisions in Cancer

Cecilia Sahlgren, PhD, Docent (Adjunct Professor), Academy of Finland Researcher, Turku Centre for Biotechnology, University of Turku and Abo Akademi University Email: cecilia.sahlgren@btk.fi Our laboratory is interested in the basic molecular principles of signaling mechanisms regulating cell fate choices during stem cell differentiation, and how disturbances in these mechanisms link to cancer. Another important goal is to develop technology to specifically monitor and tune these signals at will in specific cell populations to to steer stem cell fate and curtail oncogenic activities. We are particularly interested in the role and regulation of the evolutionary conserved Notch signaling pathway, a key regulator of stem cell function and tumorigenesis. The main objectives of our research are to understand i) how the cellular microenvironment influences Notch signaling activities and how this impinges on cell identity, function and tumor progression, ii) how Notch signaling interlinks with other signaling and cellular mechanisms to fine tune and modulate the cellular response, iii) how intracellular temporal and spatial control of Notch signaling activities are achieved and to iv) develope technology platforms to regulate Notch signaling in targeted cell populations and for bioimaging of cellular functions in vivo. Cell fate decisions; Stem cells; Tumor microenvironment, Functional biomaterials and nanotechnology;Notch signaling

Transcriptional Regulation of the Heat Shock Response

Lea Sistonen, PhD, Professor of Cell and Molecular Biology, Professor of the Academy of Finland, Department of Biology and Turku Centre for Biotechnology, Åbo Akademi University Email: lea.sistonen@abo.fi The research project aims at understanding the molecular mechanisms by which cells and whole organisms respond to heat stress and other protein-damaging insults, leading to a dramatic reprogramming of gene expression patterns essential for the maintenance of protein homeostasis or proteostasis. The main goal is to elucidate the expression and activity of two heat shock transcription factors, HSF1 and HSF2, which belong to the HSF family consisting of four members (HSF1-4) in mammals and other vertebrates. The research group has also undertaken a number of unbiased strategies to search for novel target genes for HSF1 and HSF2, especially in the context of development and differentiation (e.g. corticogenesis and spermatogenesis). Using high-resolution chromatin immunoprecipitation on promoter microarray (ChIP-chip) on mouse testis, which to the research group’s knowledge was the first attempt to apply this method to a mammalian tissue instead of cells grown in culture, the research group identified a multitude of HSF2 target genes. Analysis of the chromosomal distribution of HSF2 occupancy led to a surprising discovery that HSF2 regulates the Y-chromosomal genes critical for male germ cell differentiation and sperm quality Recently, our ChIP-seq analysis revealed the importance of the cell cycle phase in

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provoking cellular responses and identify molecular mechanisms that direct transcription during the progression of the cell cycle. Cell cycle; cell stress; chaperone; heat shock factor; spermatogenesis

Keratins as Modulators of Epithelial Health and Disease

Diana M. Toivola, PhD, Docent (Adjunct Professor), Academy of Finland Researcher, Lecturer in Cell Biology, Åbo Akademi University Email: dtoivola@abo.fi Cytoskeletal keratin intermediate filaments are emerging as important stress protectors in many epithelial tissues. This is evidence by keratin mutations predisposing to multiple human diseases. Aims of these studies are to understand the roles of keratins on physiological and molecular levels in the health of the intestine and endocrine pancreas, with focus on colorectal cancer (CRC) and inflammatory bowel disease (colitis) and diabetes. Common murine models and related expertise used to study these diseases are available through our Intestinal diseases unit at the Turku Center for Disease Modeling (TCDM). Intestinal research is focused on the role of keratins in colonic epithelia using keratin 8 knockout mice which develop early colonocyte hyperproliferation, ion transport abnormalities and are highly susceptible to carcinogen-induced CRC. For the endocrine pancreas, the modulation by keratins of hormonal blood glucose regulation in relationship to diabetes is investigated. Thus far these studies show that keratins are important in beta-cell intracellular organization basally and in diabetic stress. Since keratins also participate in systemic blood glucose regulation, these studies may help unravel novel aspects in regulation of insulin secretion and islet regeneration. Under development are also modalities for in vivo imaging of colitis and primary culture system for colonic crypts and pancreatic islets. Colorectal cancer; colitis; diabetes; intestine; keratin; cell stress; beta-cells

Sphingolipids, Ion Channels and Cellular Signaling

Kid Törnquist, PhD, Professor of Biology (Physiology), Department of Biosciences, Åbo Akademi University Email: ktornqvi@abo.fi We are interested in understanding the mechanisms regulating calcium entry, the modulation of intracellular calcium stores and the processes regulating proliferation and migration of endocrine cells. One topic of interest is how different members of the transient receptor potential cation channels (e.g. the TRPC-family of calcium channels) are regulated, and their physiological importance. We also aim at understanding the importance of calcium in regulating signal-transduction pathways, and the importance of sphingomyelin derivatives as modulators of endocrine cells, especially thyroid cells. Furthermore, among the endocrine cancers, thyroid cancer is rapidly increasing in prevalence, and several forms of thyroid cancers lack effective treatments. Thus, the regulation and importance of plasma membrane receptors for sphingosine 1-phosphate (S1P) for the regulation of thyroid cancer cell invasion and migration is one important topic of interest. Furthermore, cross-communication between S1P receptors, tyrosine kinase receptors (especially receptors for VEGF) and ion channels is also a topic that seems to be of great significance in understanding invasion, migration and the proliferation of thyroid cancer cells.

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Thyroid; cancer; calcium; sphingolipids; signaling

Cancer Cell Signalling

Jukka Westermarck, MD, PhD, Docent (Adjunct Professor), Research Professor of the Finnish Cancer Institute, Turku Centre for Biotechnology, University of Turku Email: jukka.westermarck@utu.fi The overall goal of our research group is to understand how activity of human tumor suppressor Protein Phosphatase 2A (PP2A) is inhibited in human cancer and to identify novel therapeutic strategies for PP2A re-activation. As PP2A inhibition has been recognized as a prerequisite for human cell transformation, it is plausible that further understanding of the function of PP2A inhibitors will reveal fundamental novel information about the basic mechanisms of cancer progression. Most of our work is focused on understanding the function of two PP2A interaction partners CIP2A and PME-1, which we have demonstrated to inhibit PP2A in human malignancies. Function and importance of CIP2A and PME-1 in cancer progression is studied by using combination of molecular biology, cell biology and functional genetics methods. In addition, we are especially focusing in generating new genetic mouse models to model the function and therapeutic role of CIP2A and PME-1. As our current results suggest that targeting of CIP2A and PME-1 could be beneficial in the treatment of cancer, our goal is also to develop approaches to target their function for cancer therapies Protein phosphatase 2A (PP2A); CIP2A; PME-1; genetic mouse cancer models; targeted therapies

2.2 Endocrine Cancer and Cancer Models

Prognostic and Predictive Cancer Biomarkers

Olli Carpén, MD, PhD, Professor of Pathology, Department of Pathology, University of Turku Email: olli.carpen@utu.fi The main goals of the research group are (1) to identify novel biomarkers that would predict outcome or treatment response in cancer, and (2) to understand the role of actin cytoskeleton in cancer dissemination. Goal (1) focuses on ovarian and colorectal cancer. We use primary cell lines, prospectively collected tissue and serum cohorts and various mouse xenograft models to identify drug-resistance mechanisms and to develop methods for predicting the drug response of individual ovarian cancer patients. In colorectal cancer, we are especially interested in biomarkers that predict response to anti-EGFR antibody treatment. Goal (2) focuses on two actin-organizing protein families, the ERM proteins and the formin proteins. We wish to understand the mechanism, by which the ERM protein family member ezrin associates with aggressive cancer behavior. In addition, we are systematically analyzing the expression of various formins in human cancers and studying the association of formins with invasive features, epithelial-mesenchymal transition and clinical parameters including disease outcome. Biomarker; EGFR signaling; actin cytoskeleton; ovarian cancer; colorectal cancer

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Diagnostic, Prognostic and Predictive Biomarkers in Epithelial Ovarian Cancer

Seija Grénman, MD, PhD, Professor, Department of Obstetrics and Gynecology, Turku University Hospital and Olli Carpén, MD, PhD, Professor, Department of Pathology, University of Turku Email: seija.grenman@tyks.fi, olli.carpen@utu.fi The objective of this study is to evaluate novel imaging techniques (PET-CT) in EOC staging and follow-up and to identify and characterize prognostic and predictive markers in epithelial ovarian cancer. Specifically, we aim to: 1) investigate the value of PET-CT in EOC staging, 2) evaluate the role of PET-CT in predicting early response to chemotherapy, 3) compare the response as evaluated with PET-CT, conventional imaging and serum biomarkers (CA-125, HE4 and other novel biomarkers), 4) generate ovarian cancer stem cell lines and analyze their DNA alterations, and 4) identify and validate predictive markers for early responding and refractory disease. PET-CT; biomarkers; stem cell lines

Structure and Function of Collagen Receptor Integrin

Jyrki Heino, MD, PhD, Professor of Biochemistry, Department of Biochemistry and Food Chemistry, University of Turku and Scientific Director, BioCity Turku Email: jyrki.heino@utu.fi The research group is specialized in the structure–function relationship of the collagen receptor integrins. These receptors are involved in cancer cell – stroma interaction, as well as in the regulation of cancer stem cells and cancer associated fibroblasts. We are studying these functions in prostate cancer. The most important methods used include the production of recombinant protein domains, functional assays and mutations of the domains, bioinformatics as well as the expression and analysis of the full-length receptor proteins on cell surface. In addition to the structural work, the research group is studying integrin function during signal transduction, lateral movement on cell surface and internalisation. In these experiments the group uses the general methods of molecular cell biology, imaging by confocal microscopy and proteomics. A separate project is aimed at the development of new computer programmes for the analysis of data from confocal microscopy (www.bioimagexid.org). Integrin; collagen; cell adhesion; prostate cancer; cancer associated fibroblasts

Growth Mechanisms of Hormone-Regulated Cancer

Pirkko Härkönen, MD, PhD, Professor, Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku Email: pirkko.harkonen@utu.fi

The aim is to study the mechanisms of steroid hormone action in regulation of breast and prostate cancer growth, progression and metastasis. We use explant cultures to study hormone regulation, hormone treatment responsiveness and cancer susceptibility of normal human breast tissue. To study growth regulation of breast and prostate cancer we use in vitro models of parental and genetically modulated tumour cell lines and in vivo models including orthotopic and metastatic

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tumours in syngenic or immune deficient mice. In collaboration with clinical researchers we analyse prostate cancer specimens obtained from prostate cancer surgery. A special focus is on the role of autocrine/paracrine mechanisms of fibroblast growth factor (FGF) /FGF receptor signaling in progression of hormone-sensitive to hormone resistant tumours and in bone metastasis, which forms a major clinical problem in advanced breast and prostate cancer. Currently, we focus on studying the interactions of breast and prostate cancer cells with bone marrow stromal cells to evaluate the mechanisms of bone metastasis. We also establish methods of using patient-derived specimens of prostate cancer as experimental xenografts that would enable characterisation of tumour specific properties and testing drug responses with the aim of development of personalised cancer treatment. Breast cancer; prostate cancer; metastasis; steroid hormones; fibroblast growth factor signalling

Organotypic Cancer Models, Extracellular Matrix, and Tumour Microenvironment

Matthias Nees, PhD, Docent (Adjunct Professor), VTT Technical Research Centre of Finland, University of Turku Email: matthias.nees@vtt.fi The aim of our groups’ activities is to more faithfully recapitulate the growth conditions of tumor cells in their natural “habitat”. For this purpose, we have developed organotypic cell culture models that allow us to faithfully mimic the tumour microenvironment (TME) and extracellular matrix (ECM) in which normal and malignant carcinoma cells (epithelial tumours) interact with each other and stromal counterparts (normal- and cancer-associated fibroblasts, immune- and endothelial cells etc.). Using confocal microscopy and live cell imaging methods, assisted by automated image analysis software and statistical tools, we have developed miniaturized and standardized platforms that allow us to monitor the dynamics, growth and homeostasis of tumour microtissues. These experimental platforms can be utilized to systematically test the impact of altered growth conditions, gene expression patterns, biomarkers, or small molecule inhibitors on the morphology and histology of cancer tissues in vitro. A particular focus is on monitoring the intrinsic heterogeneity and invasive properties of tumour cells in response to their microenvironment. Tumor microenvironment; extracellular matrix; threedimensional tissue culture; organotypic models; tumor cell invasion

NF1 Tumour Suppressor / Histogenesis Factor

Juha Peltonen, MD, PhD, Professor of Anatomy, Department of Cell Biology and Anatomy, University of Turku Email: juha.peltonen@utu.fi Neurofibromatosis 1 (NF1) is a neurocutaneous-skeletal Rasopathy that affects about 1 in ~3000 persons worldwide. NF1 is also the most common cancer predisposition syndrome. The general scientific aim is to increase understanding of NF1 gene in cellular differentiation and the effect of inactivation of one, or two, NF1 alleles on the reading of the whole genome. The cancer-related aims are as follows: To identify all neurofibromatosis type 1 patients in Finland and search for cancers

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diagnosed in these patients, and to compare the frequencies of these malignancies in general population and in NF1. Breast cancer and malignant peripheral nerve sheath tumors are targets of in depth biomarker and transcriptome analyses. Neurofibromatosis; cancer; malignant peripheral nerve sheath tumor; Ras; epidemiology

Novel Treatment Strategies for Endocrine Tumors

Nafis Rahman, MD, PhD, Docent (Adjunct Professor), Department of Physiology, Institute of Biomedicine, University of Turku Email: nafis.rahman@utu.fi The goal of our research is to study the pathomechanisms of several endocrine cancers/tumors and to search for their novel treatment strategies, as well as novel biomarkers for them. We are interested in the molecular mechanisms of prostate, ovarian, testicular and adrenocortical cancer in principal. Among others, gonadotropin effects on the ontogeny and tumor progression of these hormonally regulated cancers, belongs to our major research interest. We work on novel cancer vaccines, such as the therapeutic potential of tumor specific zona pellucida antigen 3 (ZP3) to enhance therapeutic effects in several hormonally regulated cancers and their underlying molecular mechanisms. We are also studying the molecular mechanisms underlying the zinc finger transcription factor GATA-4, luteinizing hormone receptor and several other novel gene interactions on the adrenocortical tumor ontogeny and progression, or issues like adrenal progenitor cell formation towards malignant cells. We also used successfully conjugated lytic peptides to eradicate cancer cells through their specific hormonal receptors (such as lhcgr), but sparing the normal healthy cells. We utilize transgenic (TG) murine endocrine cancer metastatic disease models along with our own immortalized murine cell lines to test the feasibility of such novel treatments strategies starting at cellular levels, then in vivo in TG mice and finally aim for further human clinical trials. Hormonally regulated cancers; prostate, ovarian, gonadal and adrenocortical cancers; immunotherapy; receptor-targeted lytic peptide; transgenic murine models for human diseases; novel biomarkers

Genetic Predisposition to Prostate Cancer

Johanna Schleutker, PhD, Professor of Medical Genetics, Department of Medical Biochemistry and Genetics, Institute of Biomedicine, University of Turku Email: johanna.schleutker@utu.fi The project is addressing the need to identify causative genetic events leading to prostate cancer (PCa). The group is doing genomic research, which is based on nation-wide genetic epidemiological studies and unique material collected from the entirety of Finland. Together with the special advantages of the Finnish population, existing data and novel methods, such as NSG-based technologies, the group improves understanding of prostate cancer biology. The goal is to identify and characterize predisposing genes and variants, especially those affecting aggressive disease outcome, and castration resistant disease, including treatment response to therapies. The aim is to identify novel risk factors/markers and ultimately explain their functionality in prostate carcinogenesis and therapy response. This data will have diagnostic utility, especially for more aggressive disease at an early, curable

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stage of the disease. Further, the aim is to develop tools for prognostic purposes, i.e. prognostic biomarkers, which are urgently needed in PCa screening and clinical practice. Prostate cancer; genetic susceptibility; prognostic biomarker; gene variant

2.3 Immune Cells and Cancer

Lymphocytes and Inflammation

Zhi Jane Chen, MD, PhD, Academy of Finland Research Fellow, Turku Centre for Biotechnology, University of Turku Email: zchen@btk.fi

Inflammation and cancer underlie a vast variety of human diseases. The immune system is often involved in these disorders. We are investigating the role of the relatively newly identified subsets of CD4+ T cells, Th17 and iTreg in inflammatory diseases. We study Th17 and iTreg differentiation at multiple levels from mouse and human and integrate the results to build a comprehensive view of the processes. We are particularly interested in understanding the regulation and interactions between the immune and hormonal responses and how the interactions contribute to pathogenesis of immune-mediated diseases. T cells; Th17; iTreg; inflammation; hormones

Innate Immune Cells and Antimicrobial Defence in Autoimmune Diabetes

Arno Hänninen, MD, PhD, Docent (Adjunct Professor), Department of Medical Microbiology, University of Turku Email: arno.hanninen@utu.fi

The current aims are to investigate in the effects of orally ingested microbes on antigen-specific regulatory T cells and on dendritic cell traffic and antigen presentation in gut-associated lymphoid tissues. The research group is also studying T cell trafficking and the role of memory T cells in protective immunity in a tumour model. The aim is that the results can be directly applied in the design of clinical trials where such protocols would be tested among subjects with increased genetic risk for these diseases. Gut immune system; type 1 diabetes; nonobese diabetic (NOD) mice; host-microbe interactions; lymphocyte traffic

Immunogenetics of Autoimmune Diseases

Jorma Ilonen, MD, PhD, Professor of Immunogenetics, MediCity Research Laboratory, Faculty of Medicine, University of Turku Email: jorma.ilonen@utu.fi Several autoimmune diseases are a result of interaction between genetic susceptibility and environmental influences including microbes and nutritional factors. These diseases include type 1 diabetes, rheumatoid arthritis, celiac disease

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and multiple sclerosis, which all are strongly associated with specific alleles in the HLA gene complex, although polymorphisms in several other gene regions also modify disease susceptibility. The research project aims to identify genes important in disease susceptibility and to understand their interaction with environmental factors in the disease pathogenesis. Emphasis in the project has been in studies of Type 1 diabetes where the current and obtained knowledge has been applied for prediction and prevention of the disease in the framework of on-going clinical studies including national and international projects like TRIGR, DIPP, FINDIA, PRODIA, and TEDDY projects. Autoimmunity; diabetes; prediction; prevention; immunogenetics

Cell Trafficking

Sirpa Jalkanen, MD, PhD, Professor of Immunology, and Marko Salmi, MD, PhD, Professor of Molecular Medicine, MediCity Research Laboratory, University of Turku and the National Institute of Health and Welfare, Turku Email: sirpa.jalkanen@utu.fi, marko.salmi@utu.fi Various numbers of host immune cells enter the tumors from the blood circulation. They may be cells capable of preventing tumor growth and they can even kill the tumor cells. On the other hand, tumor infiltrating immune cells can be tumor promoting ones leading to enhanced growth of the tumor. Eventually the activity of the immune system determines the outcome of the patient. Metastasising malignant cells often use the same mechanisms as the lmmune cells when extravasating from the blood to different organs. The main goal of the project is to identify molecules, which mediate harmful immune cell trafficking to tumors and the spread of cancer to distant organs in the body. These molecules are potential targets for developing new anti-cancer drugs. Immunity; cell migration; cancer; metastasis; lymphatics

Molecular Systems Immunology and Stem Cell Biology

Riitta Lahesmaa, MD, PhD, Professor, Director of Turku Centre for Biotechnology, University of Turku and Åbo Akademi University Email: riitta.lahesmaa@btk.fi Regulation of the immune response is central for human health. In healthy individuals there is an appropriate balance of the immune response. T cells in particular orchestrate the adaptive arm of the immune system and are required for key immune functions. Selective activation of lymphocyte subsets plays an important role in the pathogenesis of human allergy and chronic inflammatory and autoimmune diseases. Immune response is also crucial in host defense against cancer. We use genome wide methods and holistic approaches complemented by detailed molecular mechanistic studies to identify key regulators and pathways leading to human T helper cell differentiation to functionally distinct subsets. Understanding the gene regulatory pathways controlling these processes is crucial to understand the pathogenesis of immune-mediated diseases and to develop better therapies. We also elucidate the molecular mechanisms regulating self-renewal and pluripotency to understand the link between stem cells and cancer. In these studies we exploit human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC), that have a unique capacity to differentiate to any type of cell or tissue providing an enormous potential for therapeutic applications. Our research group

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belongs to the "Centre of Excellence on Molecular Systems Immunology and Physiology" Academy of Finland selected for years 2012-17. Molecular systems immunology, stem cell biology, T cell differentiation, human immune mediated diseases, cancer, therapeutic applications

Stem Cells and Transcriptional Networks of B and Plasma Cells

Olli Lassila, MD, PhD, Director of Turku Doctoral Programme of Biomedical Sciences (TuBS), Professor of Immunobiology, Department of Medical Microbiology and Immunology, University of Turku Email: olli.lassila@utu.fi As several genome projects have been completed the next challenge in biomedical research is to increase the understanding of how the genomic sequences are used. A key issue in understanding haematopoietic stem cells and B cell biology is to define the function of transcription factors. The aim of the research project is to increase the understanding of the molecular and cellular mechanisms that regulate stem cell differentiation into B cells and further B cell development and function in germinal centers into memory B and antibody producing plasma cells. The ease of gene targeting and compactness of avian light chain loci also, makes DT40 an ideal model to investigate the molecular mechanisms of immunoglobulin gene conversion and somatic hypermutation. Currently the research group studies the regulation and function of activation induced cytidine deaminase (AID) that is needed for somatic hypermutation, class switch recombination and gene conversion. The research group studies gene regulatory pathways and networks including Pax5, Bcl6, IRF4, IRF8, Ikaros, Aiolos, Helios, Bach2 genes. Many of these genes are either activated or inactivated, deleted, mutated in human B cell lymphomas, leukemias and myelomas. Stem cells; B cells; plasma cells; transcription factors; cancer (lymphoma, leukemia, myeloma)

Lymphocyte Cytoskeleton Group

Pieta Mattila, PhD, Turku Collegium for Science and Medicine Researcher, Institute of Biomedicine, BioCity, University of Turku Email: pieta.mattila@utu.fi B cells constitute an essential part of the adaptive immune system by producing antibodies, which neutralize toxins and infected or malignant cells. Our projects deal with understanding the molecular regulation of B cell activation and, specifically, unveiling the role of the actin cytoskeleton in this process. Tightly regulated, yet robust triggering of B cells is critical for mounting of humoral immune response upon infection or vaccination. Diminished B cell activation leads to a variety of immune deficiencies and, on the other hand, lowered activation threshold leads to autoimmune disorders. Furthermore, transformations in the B cell signaling pathways may lead to malignant growth and development of lymphoma. Thus, understanding the mechanisms of B cell activation contributes to better appreciation of the immune system both in health and disease. We are particularly interested in the role of the actin cytoskeleton in different stages of B cell activation. How the remodeling of the cytoskeleton is orchestrated in response to the antigen receptor signaling? How specific features of this multifaceted structure, such as the submembranous actin cortex, can directly

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influence the receptor signaling and activation potential of the cell? To answer these questions, we take advantage of advanced microscopic methods, such as super-resolution microscopy, in combination with cell biological and biochemical methods. B cells; antigen receptor signaling; actin cytoskeleton; advanced microscopy

Regulation of Innate Immunity by Ubiquitin Signaling

Annika Meinander, PhD, University research fellow, Department of Biosciences, Åbo Akademi University E-mail: annika.meinander@abo.fi A proper innate immune response is essential for an organism to survive in an environment where it is exposed to hostile microbes. The innate immune system is not only important for protection against foreign pathogens, but also plays a major role in immunological disorders as well as in cancer. The NF-kappaB signalling pathway is a major regulator of innate immune responses. To understand how the innate immune transcriptional program is activated, the signalling cascades regulating NF-kappaB needs to be characterised. We study how signalling mediated via ubiquitylation regulates NF-kappaB signalling, aiming at elucidating common principles for ubiquitin-mediated regulation of innate immune responses. For this purpose, we use Drosophila as a model organism. Because of the ease with which Drosophila can be manipulated genetically and the broad range of biochemical methods suitable for research on innate immune responses in flies, Drosophila is a powerful model for our research. However, as we are also interested in understanding human biology in health and disease, we aim at translating the results gained in the fly model into mammalian systems. Taken together, innate immunity is an evolutionarily conserved defence mechanism, making Drosophila suitable to investigate the common principles of regulation of NF-kappaB signaling. Drosophila, inflammation, innate immunity, ubiquitin, NF-kappaB

2.4 Metabolic Diseases and Bone

Exercise Physiology and Metabolic Research

Jarna Hannukainen, PhD, and Kari Kalliokoski, PhD, Docent (Adjunct Professor), Finnish Centre of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research, Turku PET Centre, University of Turku Email: jarna.hannukainen@tyks.fi, kari.kalliokoski@tyks.fi The research on exercise physiology has focused mainly on skeletal muscle and myocardial perfusion and metabolism over the past years. Along with continuing deeper research in these tissues we are focusing also on the effects of acute exercise and exercise training on metabolism and adiposity in internal organs and how different tissues interplay in response to exercise training. We also focus on studying the effects of different types of exercise training protocols in patients with cardiovascular and metabolic diseases, including diabetes. To understand the molecular mechanisms behind the positive effects of exercise training on tissue metabolism we are carrying out both preclinical and translational research projects. Exercise; adiposity; diabetes

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Bone and Energy Metabolism

Kaisa Ivaska, PhD, Docent (Adjunct Professor), Department of Cell Biology and Anatomy, Institute of Biomedicine, University of Turku Email: kaisa.ivaska@utu.fi Bone is a highly metabolic tissue which is continuously being remodeled by the osteoblasts and osteoclasts. Skeleton is no longer considered an isolated organ but it is increasingly recognized as an important player in the energy metabolism through its interactions with other tissues, such as adipose tissue and the pancreas. Disorders of glucose metabolism are known to be associated with adverse skeletal effects and increased fracture risk, but the mechanisms underlying glucose toxicity and glucose uptake are poorly understood. We aim to better understand the skeletal effects related to altered glucose metabolism by using in vitro bone cell cultures. We mainly use mesenchymal stem cell and osteoblast cultures and collaborate also with clinicians on selected patient materials. Bone; osteoblast; glucose; osteoporosis; diabetes

New Regulators of Thyroid Function - Genetics of Congenital Hypothyroidism in Finland

Jukka Kero, MD, PhD, Institute of Biomedicine, Department of Physiology,University of Turku, Turku, Finland Email: jukka.kero@utu.fi Congenital hypothyroidism (CH) is one of the most common preventable causes of mental retardation affecting every 1:3000 newborn worldwide. The incidence of CH has been reported to be increasing, but the etiology is largely unknown. While thyroid dyshormogenesis, mainly due to genetic defects, comprises only 10-20% of the CH cases, further reasons for CH remain to be identified. The genetics of CH has not been studied in Finland so far. In this study, we aim to find novel causes for CH using both well-documented register information and up-to-date genetic methods. In preliminary analysis we have found a novel dominantly inherited gene mutation segregating well with a pedigree of hereditary CH. The gene has not earlier been shown to play a role in the thyroid. We are at the moment evaluating the role of that mutation in thyroid function. We believe that this work can provide important information with respect to the etiology and mechanism of congenital hypothyroidism. In addition to the CH project, the group aims to provide new information about the role of different G-protein-, microRNAs, G-protein coupled receptors- and other novel signaling pathways in thyroid function using already generated, and by generating new, thyroid specific knockout models. On the basis of these in vivo and in vitro studies, it will be possible to gain more insight into thyroid function. Eventually, the elucidation of the molecular processes underlying the regulation of the thyroid gland will have considerable impact on the understanding of the pathogenesis of various thyroid disorders and may lead to new prophylactic or therapeutic approaches for thyroid gland diseases or other related endocrinological diseases. Thyroid, G-protein, microRNA, congenital hypothyroidism

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Molecular Regulation of the Bone Marrow Microenvironment

Riku Kiviranta, MD, PhD, Docent (Adjunct Professor), Department of Medical Biochemistry and Genetics, and Department of Medicine, University of Turku Email: riku.kiviranta@utu.fi The old paradigm of bone as a mere structural element has evolved dramatically in recent years. Bone tissue has emerged as a dynamic endocrine organ capable of regulating diverse physiologic functions such as hematopoiesis, calcium and phosphate homeostasis as well as energy metabolism. Bone is also a frequent target for metastasis of breast and prostate cancer, and hematological malignancies often arise in the bone marrow. Bone consists of several different cell types, the bone cells (osteoblasts, osteocytes and osteoclasts), the hematopoietic stem cells (HSCs) and their offspring as well as bone marrow adipocytes. The complex interplay between these different cell types within the bone marrow microenvironment is essential for normal bone metabolism and for the regulatory functions of bone marrow. Our research group is interested in the molecular mechanisms of these cellular interactions as well as transcriptional regulation of osteoblast and osteoclast differentiation and function. Ultimately, our goal is to identify novel therapeutic targets for metabolic and malignant bone diseases. Bone; osteoblast; osteoclast; adipocytes

Diabetes, Obesity, Metabolic Diseases and Brown Fat

Pirjo Nuutila, MD, Professor, Turku PET Centre, University of Turku and Turku University Hospital; and Kirsi Virtanen, MD, Docent (Adjunct Professor), Academy Research Fellow, Turku PET Centre, Turku University Hospital Email: pirjo.nuutila@utu.fi, kirsi.virtanen@utu.fi Currently, the research on hormonal diseases with PET focuses on understanding the development of type 2 diabetes, tissue-specific insulin resistance and neuro-metabolic regulation and brain function in obesity in type 2 diabetes. Pancreatic beta-cell dysfunction is studied via identification of new PET tracers for beta cell imaging of the pancreas. Research on brown fat is concentrating on understanding the role of brown fat in human metabolic network regulating energy balance and metabolic health. Glucose and fatty acid metabolism as well as oxygen consumption by the specific tissues are studied in conjunction with other metabolic measurements (for example indirect calorimetry) in healthy and obese subjects as well as in patients with type 2 diabetes. Combination of tracers and different modalities, such as PET/CT, PET and MRI and PET/MRI are implemented in these studies. PET; type 2 diabetes; metabolism; energy balance; oxygen consumption

2.5 Reproduction and Steroid Hormone Action

Control of Gene Expression in Male Germ Cells

Noora Kotaja, PhD, Assistant Professor in Molecular Medicine, Department of Physiology, University of Turku Email: noora.kotaja@utu.fi

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The goal of our research is to clarify the mechanisms of sperm production and male fertility by investigating the molecular factors involved in the control of male germ cell differentiation. Spermatogenesis is a complex process including dramatic changes in the morphology and biochemistry of male germ cells. All the differentiation steps in spermatogenesis are governed by a strict control of gene expression, one important mechanism being the post-transcriptional RNA regulation by non-coding RNAs. Male germ cells express outstanding amount of different non-coding RNAs, including both small RNAs (miRNAs, endo-siRNAs, piRNAs) and yet poorly characterized long non-coding RNAs. We aim to elucidate the roles of non-coding RNAs in the control of gene expression and chromatin rearrangements during spermatogenesis. Especially we are interested in characterizing the functions of cytoplasmic ribonucleoprotein (RNP) granules in male germ cell –specific RNA regulation. These studies will give novel important insight into the complex molecular network of germ cells and the factors required for successful spermatogenesis. Spermatogenesis; fertility; gene regulation; non-coding RNAs; RNP granules

Novel Diagnostics and Treatments in Reproductive Health

Antti Perheentupa, MD, PhD, Docent (Adjunct Professor) and Juha Mäkinen, MD, Professor of Gynaecology, Department of Obstetrics and Gynaecology, University of Turku and Turku University Hospital Email: antti.perheentupa@utu.fi; juha.makinen@tyks.fi Our research aims at developing novel tools for evaluating and improving reproductive health in both men and women. We have three major fields of interest: 1) Endometriosis, 2) New Biomarkers for malignant and benign gynaecological conditions and 3) Male fertility and treatment of male infertility. Endometriosis is a chronic inflammatory disease with functional endometrial glands and stroma in ectopic locations outside the uterine cavity. The aim of our research is to understand the aetiology of the disease, find new diagnostic tools and novel therapeutic targets. Through understanding of the disease, we are hoping to shorten the diagnostic delay and develop effective medical treatments with little or no side effects. We are also carrying out long term follow up, in order to evaluate the long-term effectiveness of the clinical practices at the Turku University Clinic. New biomarkers are actively being search for in order to develop the non-invasive diagnostics of endometriosis. This part of the project extends to the evaluation of a relatively new marker for ovarian cancer, HE-4, which we are evaluating both in malignant (endometrial and ovarian cancer) as well as in benign conditions (endometriosis, IVF stimulation, PID). This is done in order to evaluate the use of HE-4 in screening for ovarian cancer, the prognosis of which has improved little if any during the past decades. As well as taking part in the follow-up studies on semen quality (prof. Jorma Toppari) we have been developing the surgical treatment of the most challenging cases of male infertility, non-obstructive azoospermia. Since 2008, we have operated some 50 cases with a decent sperm recovery rate of about 40%. As the importance of the preceding hormonal treatment in different groups of patient still remains uncertain, we are planning to evaluate the benefits of hormonal treatments in these men. Endometriosis; male fertility and infertility; biomarkers; HE-4

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Pre-receptor Regulation of Nuclear Receptor Signaling by Hydroxysteroid (17beta) dehydrogenases (HSD17Bs): Novel Targets for Hormonal Therapies

Matti Poutanen, PhD, Professor of Physiology, Department of Physiology, and Director, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku Email: matti.poutanen@utu.fi In a traditional view, the action of steroid hormones is based on the concept where the hormone is synthesized in the endocrine gland and reaches the target organ via blood circulation. Our group has been actively involved in studies providing evidence for the concept of paracrine and intracrine sex steroid action where the hormone concentration available for nuclear receptor binding at the target cells is regulated by the target tissue metabolism. The studies are focused on Hydroxysteroid (17beta) dehydrogenase (HSD17B) enzymes that catalyze the activation of the low potent 17-keto steroids (e.g. androstenedione and estrone) to the highly potent 17beta hydroxysteroids (e.g. testosterone and estradiol), and vice versa, depending on the enzyme. As research models we apply genetically modified mice, tumor xenografts in immune deficient mice and clinical patient material. Inhibiting the activity of various HSD17B enzymes is considered as a novel strategy to lower the action of sex steroids, and studies by us and others have provided evidence for the putative usefulness of HSD17B1 inhibitors in diseases such as breast cancer and endometriosis. Furthermore, recent data indicate that HSD17B enzymes may have a central role in the de novo synthesis of active androgens in castration-resistant prostate cancer. Hydroxysteroid (17beta) dehydrogenase; sex steroid; endometriosis; breast cancer; prostate cancer

Dietary Modulation of Sex Steroid Action

Sari Mäkelä, MD, PhD, Professor of Biomedicine, Institute of Biomedicine, Turku Center for Disease Modeling and Functional Foods Forum, University of Turku Email: sari.makela@utu.fi The main goal is to clarify the role of dietary factors in the development of hormone-dependent cancers. The focus is on altered sex steroid action, associated with obesity-related metabolic dysregulation, and its impact on the development of breast and prostate cancer. More specifically, we explore the mechanisms by which plant-derived polyphenols (such as lignans, stilbenoids and isoflavonoids) modulate estrogen action in normal and cancerous tissues. Breast; prostate; estrogen; polyphenol; obesity

Male Reproductive Health, Developmental Disorders and Spermatogenesis

Jorma Toppari, MD, PhD, Professor of Physiology, Departments of Physiology and Pediatrics, University of Turku Email: jorma.toppari@utu.fi Our research group is studying the basis of male reproductive health by follow-up of a large cohort of boys from fetal development to adult age. Large data bases and

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biological sample collections allow the analyses of environmental and genetic determinants of reproductive health. We have focused our studies on the congenital malformations of genital organs (cryptorchidism and hypospadias), semen quality and testicular cancer that together encompass testicular dysgenesis syndrome. These studies are performed in close collaboration with the Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen. To understand the developmental mechanisms and their disruption we are studying the regulation of testicular development and function with experimental animal models and in vitro. Retinoblastoma protein family and E2F transcription factors are currently the main targets. We are also a part of the Nordic Center of Fertility Preservation of Children with Cancer that is coordinated together with the Pediatric Endocrine Unit in Karolinska Hospital, Stockholm. Testis; fertility; environment; sperm; development

2.6 Cancer Imaging and Diagnostics

Laboratory of Biophysics

Pekka Hänninen, PhD, Professor of Medical Physics, and Harri Härmä, PhD, Docent (Adjunct Professor), Laboratory of Biophysics, Institute of Biomedicine, University of Turku Email: pekka.hanninen@utu.fi; harri.harma@utu.fi The main field of research of the Laboratory of Biophysics is development of luminescence-based methods and technologies to detect interactions at molecular level. The research relies on the use of optical nanoscopy and force imaging, novel approaches for labeling of biomolecules and novel bioaffinity assay techniques basing on the utilization of non-specificity. The group is among the founding members of Turku Bioimaging, hosts STED- and AFM microscopy service and is one of the key players within the International Bioimaging Master’s Program. Luminescence; optical nanoscopy; bioaffinity assays

Environmental and Food Diagnostics

Timo Lövgren, PhD, Professor in Biotechnology, Department of Biochemistry and Food Chemistry, University of Turku Email: timo.lovgren@utu.fi

The research within the Food and Environmental focus area comprises of field-suitable diagnostic methods for food as well as water safety. Current activities focus on detection of water-borne pathogenic microbes and their toxicological products with up-to-date technologies. Methods include genetic typing of toxin producing microbes, on site detection of produced toxins as well as a number of pathogenic microbes. Similarly, toxin profiles and amount of toxin in samples are measured with immunometric assays using novel in-house available recombinant antibodies and reporter molecules. Similar technologies can and have been adapted also to food safety diagnostics, e.g. group-specific assays of antibiotics (fluoroquinolones, sulphonamides). Food safety; water safety; microbes; toxins

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Cancer Imaging in the Era of Molecular Diagnosis and Therapy

Heikki Minn, MD, Professor, Oncology and Radiotherapy, Turku University Hospital and Turku PET Centre; and Marko Seppänen, MD, PhD, Nuclear Medicine, Turku University Hospital and Turku PET Centre; and Anne Roivainen, Professor, Preclinical Imaging and Drug Development, Turku PET Centre; and Tove Grönroos, PhD, Docent (Adjunct Professor), Turku PET Centre Email: heikki.minn@utu.fi; marko.seppanen@tyks.fi; anne.roivainen@utu.fi; tovgro@utu.fi Positron emission tomography (PET) is the only noninvasive method to study metabolic pathways in human tissues in vivo. Oncologic PET research has studied the role of tumour and host metabolism in prediction of outcome with emphasis on effect of microenvironmental changes such as reduced oxygenation and perfusion. Another important field has been development of tracers for imaging of cerebral gliomas, neuroendocrine tumours and prostate cancer where glucose metabolism is either low or does not result in satisfactory signal-to-noise ratio against physiological activity. Now the field is moving towards the development of highly specific molecular probes predicting e.g. the activity of certain signaling pathways, angiogenesis or growth factor receptor expression. We aim to increase the impact of multimodality imaging in the management of common cancers and development of PET/CT and PET/MRI imaging protocols compatible with planning of biologically guided radiotherapy. The preclinical and translational research focuses on studying therapy resistance associated with oxygen status, angiogenesis and inflammatory responses in experimental cancer models in collaboration with Turku Center for Disease Modelling. Microenvironmental changes; new tracers; molecular probes; multimodality imaging; translational

Novel Biomarkers and Test Platforms for Diagnostic Applications

Kim Pettersson, PhD, Professor in Biotechnology, PhD, Department of Biochemistry and Food Chemistry, University of Turku Email:kim.pettersson@utu.fi

The group focuses on exploring new and established markers and multiplexed marker families with emphasis on degenerative diseases (cardiovascular disease, cancers, neurodegenerative diseases) primarily for early detection and preventive medicine. Furthermore, rapid test technologies and platforms in several critical care application areas (acute coronary syndromes, stroke, infectious diseases including sepsis and microbiology resistance testing) are under development. Several generic point-of-care platforms have been defined leading to start-up companies locally or to be incorporated into novel technology platforms of established diagnostic companies. The group interacts closely with several corresponding research institutes in India with the ambition to define and provide novel technical platforms for high quality and affordable diagnostics in various decentralized scenarios. An Indo-Finnish Diagnostic Research Centre with branches in Turku and Delhi is under formation. Early detection; preventive medicine; platforms

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BioNanoMaterials group

Jessica Rosenholm, DSc (Tech), Docent (Adjunct Professor), Laboratory for Physical Chemistry, Åbo Akademi University Email: jessica.rosenholm@abo.fi The first nanotechnology-based drug delivery systems are already on the market, some are in clinical trials, but the majority is still under development. About two-thirds of the current investigational applications related to nanomedical products are focused on cancer treatment. Besides drug delivery systems, another highly attractive area of nanomedicine is diagnostics at the nanoscale, which is the second out of the three interrelated nanomedical research areas that have been identified by the European Technology Platform for Nanomedicine. Furthermore, new nanoparticulate formulations can combine these two (targeted drug delivery and imaging) to allow simultaneous diagnostics and therapy, often referred to as “theranostics”, which is an important step towards personalized medicine. In this context, the main objectives of the BioNanoMaterials group are to 1) develop functional nanoparticles for detection, tracking, diagnostic and therapeutic biomedical applications by smart design and 2) synthesize composite nanostructures for improved bio-applicability and theranostic activity and 3) to apply the developed nanomaterials for in vitro and in vivo drug targeting and biomedical imaging together with our collaborators. One such collaborative effort together with Tuomas Näreoja, Department of Cell Biology and Anatomy, University of Turku, involves the development of a nanoparticle-based multimodal imaging approach. Such an integrated cancer imaging platform encompassing advanced imaging systems like in vivo two-photon microscopy of chorioallantoic membrane (CAM) model, MRI and high-content imaging in vitro, will facilitate high-resolution studies on cancer growth, vascularization, metastasis development and monitoring efficacy of treatments. These novel nanoimaging methods on CAM model provide vital information to understand cancer progression mechanisms in vivo while simultaneously providing efficient, improved diagnostic tools. Nanomedicine; biomaterials; in-vivo; in-vitro; drug deliver; theranostics

Chemi- and Biosensors for Bioanalytical Applications

Michael Schäferling, PhD, FiDiPro Fellow, Department of Biochemistry, University of Turku Email: michael.schaferling@utu.fi

The group will focus on upconversion luminescence and luminescence lifetime-based multifunctional probes and their use in diagnostic applications and luminescence imaging. The project aims to development of upconversion reporter technology to be applied in immunoassays, nucleic acid hybridization assay and other ligand binding assays, and quantitative optical biosensors for measurement of protease enzyme activity within whole blood. The objective is to combine the inorganic upconversion nanoparticles chemistry with chemical and biochemical recognition and sensor functions to be applied in biochemical sensors and luminescence imaging applications. Luminescence; nanoparticles; chemistry

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Bioanalytical Assay Concepts and Technologies

Tero Soukka, PhD, Professor in Biotechnology, Department of Biochemistry, University of Turku Email: tero.soukka@utu.fi

The research aims to respond to the modern challenges of in vitro diagnostics by supporting the development of high performance, yet relatively simple, assay technology platforms for next-generation diagnostics. The research is focused on luminescent lanthanide chelates, lanthanide chelate-dyed nanoparticles and inorganic lanthanide-doped nanocrystals applied to various diagnostic applications. It also aims at identification of novel assay concepts and formats centrally benefitting from designed molecular binders. Extensive knowledge and theoretical modeling of performance potential of different technologies provide strong background for development of new methods. High-sensitivity immunoassays; multiplexing; time-resolved fluorescence; fret-assays; lanthanide reporters

2.7 Data Mining and Bioinformatics

Computational Biomedicine

Laura Elo, PhD, Docent (Adjunct Professor), Turku Centre for Biotechnology, and Department of Mathematics and Statistics, University of Turku Email: laliel@utu.fi We develop computational data analysis tools and mathematical modelling methods for biomedical research in close collaboration with experimental and clinical groups. A specific focus is on transforming high-dimensional molecular and clinical data into biomedical knowledge. While modern high-throughput biotechnologies, such as deep sequencing and mass-spectrometry-based proteomics, enable large-scale measurements of molecular events in health and disease, the experimental data alone are not sufficient for understanding the complex disease processes. Therefore, the goal of our research is to enable robust and reproducible interpretation of the data. Building on our previous computational, statistical and network-based studies, we aim at establishing a computational framework that allows optimized integration and analysis of large-scale clinical and molecular data at multiple levels as well as heterogeneity between individuals. The ultimate goal is to improve the diagnosis, prognosis and treatment of complex diseases, such as diabetes and cancer, by combining computational, experimental and clinical expertise. Computational biomedicine; statistical data mining; predictive modelling; network-based modelling; clinical and molecular markers

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Structural Bioinformatics Laboratory and Core Facility (SBL)

Mark Johnson, PhD, Professor, Department of Biochemistry and Pharmacy, Åbo Akademi University; and Tiina Salminen, PhD, Docent (Adjunct professor), Department of Biochemistry and Pharmacy, Åbo Akademi University; and Konstantin Denessiouk, PhD, Turku Center for Biotechnology, Åbo Akademi University Email: johnson4@abo.fi; tiina.salminen@abo.fi; kdenessi@abo.fi

The Structural Bioinformatics Laboratory (SBL) has a unique combination of expertise where the independent groups have formed a tight network, sharing the research facilities and infrastructure. The unit exploits protein structures to study complex biological phenomena, primarily associated with cell function and signaling, although the approaches are extendable to any system. A large group of proteins that we study are receptors, often from humans. X-ray crystallography and computer-based bioinformatics approaches are central to the research. We design novel computational tools as they are needed for research. We participate in a very large number of collaborative research projects but always welcome new challenges. The unit is a member of the Åbo Akademi Center of Excellence in Cell Stress. The unit provides bioinformatics infrastructures to the community via Biocenter Finland. Receptor; 3D structure; ligand binding; X-ray crystallography; bioinformatics

Binder Molecule and Biomarker Discovery

Urpo Lamminmäki, PhD, and Eeva-Christine Brockmann, PhD, Biotechnology, Department of Biochemistry and Food Chemistry, University of Turku Email: urpo.lamminmaki@utu.fi; eeva-christine.brockmann@utu.fi

The primary research focus of the group is on the development and utilization of the synthetic human antibody phage libraries. Instead of taking the conventional way of constructing a single universal antibody library, the concept is to build several mutually compatible focused libraries each having a different binding site design. As demonstrated with tens of targets, a single selection experiment with these libraries generally yields a diverse set of specific antibodies targeting a large number of different epitopes in a protein target. In addition to generation of novel binders, the libraries are also utilized as a tool for biomarker discovery. We also employ the methods of protein engineering to improve the performance of the existing antibodies in immunoassays. Synthetic human antibodies; antibody phage libraries; biomarker discovery; tailor-made antibodies for immunoassays

2.8 Clinical Research

Health and Quality of Life After Early Onset Cancer

Päivi Lähteenmäki, MD, PhD, Docent (Adjunct Professor), Department of Pediatrics, University of Turku Email: paivi.maria.lahteenmaki@tyks.fi

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The Finnish nationwide healthcare registries provide a unique opportunity to study late-effects of cancer therapies. Our projects aim to recognition and alleviation of adverse effects of cancer therapies in patients still in the process of physical and psychosocial maturation. Projects studying the immune reconstitution and viral infections in children after conventional treatment, and after stem cell transplantation for acute lymphoblastic leukemia are going on. Evaluation on survival after Wilms’ tumor, and definition of the accuracy of serum markers for detection of abnormal renal function in children undergoing chemotherapy for malignancy have been started in collaboration with national data providers. GCCT-project (Genetic consequences of cancer therapies at early age) is a large collaboration study with researchers in Denmark and USA to study the effects of radiation and certain chemotherapeutic agents on the health of the offspring of cancer survivors. Bone health after early onset malignancies, Health and quality of life after early age onset brain tumors, Educational and occupational achievements after comprehensive school, and Cardiovascular morbidity and mortality following cancer treatment at early age, are nation-wide clinical and registry-based studies going on at the moment. Physical activity and metabolic changes after childhood leukemia, and active video games to promote physical activity in children with cancer, are novel multi-disciplinary project initiations to make interventions diminishing the adverse effects of cancer therapies in childhood. Cancer, child, health, late-effects, recovery

Human and Animal Pharmacokinetics, Biomarker Analysis, Early-phase Clinical Trials

Mika Scheinin, MD, PhD, Professor, Department of Pharmacology, Drug Development and Therapeutics, University of Turku, and Clinical Research Services Turku CRST Email: mika.scheinin@utu.fi Facilities are in place for the GCP-compliant conduct of early-phase clinical trials on healthy volunteers and outpatients, and in collaboration with the clinics of Turku University Hospital, also on hospitalized subjects in selected indications. Biochemical and imaging biomarkers are used for early efficacy assessment. Drug and biomarker assays are carried out with LC-MS/MS and other appropriate methods in a GLP-certified laboratory. GCP-certified; biomarkers; drug assays

3. BIOTURKU® COMPANIES AND THE PRODUCT AND PROJECT PORTFOLIOS

Bayer in Finland (www.bayer.fi) Company Profile: Bayer is a global enterprise with core competencies in the fields of health care, nutrition, and high-tech materials. Our products and materials are designed to benefit people and improve their quality of life. Our product portfolio in Finland includes Bayer HealthCare prescription medicines, over-the-counter products and tools for monitoring diabetes therapy, Bayer CropScience crop protection agents and control substances as well as industrial materials and chemicals of Bayer MaterialScience. Our international operations in Finland focus on prescription medicines: research and development, production, and export to over 100 countries

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of products manufactured in Finland. The production plant in Turku is one of the global pharmaceutical supply centers of the Bayer Group. In our research and development, the use of polymers in long-term administration of drugs represents the Finnish expertise. Bayer employs about 750 people in Finland.

Product and Project Portfolio: Products from the plant in Turku: MIRENA® - hormonal intrauterine system, JADELLE® - contraceptive implant, NOVA T® and NOVA T® 380 copper intrauterine devices, BONEFOS®, a product for supportive cancer therapy, RECOFOL®, a short-acting anaesthetic and TAMOFEN®, a product for the treatment of breast cancer.

BioCis Pharma Ltd (www.biocis.com) Company Profile: BioCis Pharma is a clinical stage drug development company with the business idea to design and develop novel anti-inflammatory and anti-cancer products based on its proprietary technology platform. Safety, tolerability and therapeutic efficacy of the company products have been demonstrated in clinical trials in patients and in preclinical studies.

Product and Project Portfolio: ProtoCureTM emulsion cream for atopic dermatitis, ProtoCureTM eye drops for dry eye syndrome, ProtoCureTM intravesical solution for bladder cancer.

Bioxid Ltd Company Profile: A biomaterial holding company specialized in patenting (in- and out-licensing), planning and starting new biomaterial based business in dentistry, orthopedics and different clinical areas like oncology, ophthalmology and in areas of drug delivery and gene delivery.

Product and Project Portfolio: Patenting/in-licensing/out-licensing. Bioactive glass/silica gel/titanium gel/reinforced glassfiber.

DelSiTech Ltd (www.delsitech.com) Company Profile: DelSiTech Ltd, founded in 2001, specialises in a silica-based controlled release techno-logy for small molecular drugs and biopharmaceuticals: viral vectors, proteins, heparins. Routes of administration: implant, sc and im. Oncology and other therapeutic areas where controlled released technology for local/systemic use is needed.

Product and Project Portfolio: Controlled drug delivery (implant, im, sc) Delivery times days-months. Systemic and local delivery. Viral vectors, proteins, small molecular drugs. Out-licensing of technology &co-development projects.

Faron Pharmaceuticals Ltd (www.faronpharmaceuticals.com) Company Profile: Faron is a clinically staged drug discovery and development company with three major drug development projects (see previously) focusing on acute trauma, incipient vasculopathies, inflammatory diseases, and cancer growth and metastasis.

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Faron’s lead product FP-1201 (Traumakine®) is entering phase III clinical trial in 2012 to treat vascular leakage in ALI/ARDS patients.

Product and Project Portfolio:Proprietary pharmaceutical targets include CD73, Clecer-1 and AOC3.

Forendo Pharma Ltd (www.forendo.com) Company Profile: Founded in 2012, Forendo is a drug discovery and development company specializing on women’s and men’s health through its 17HSD and SERM platforms acquired on 2013 from Hormos Medical Ltd. It closed the first financing round of 10M€ on 2013.

Product and Project Portfolio:

Fispemifene has demonstrated efficacy in phase II in treatment of low testosterone. A first-in-man 17HSD1 inhibitor is progressing to phase I for endometriosis with further opportunities for e.g. breast cancer.

Hormos Medical Ltd (www.hormos.com) Company Profile: Founded in 1997,Hormos Medical is since 2005 a subsidiary of QuatRx Pharmaceuticals Company (USA). Today Hormos is managing the IPR of its two proprietary commercial products marketed by its licensees.

Product and Project Portfolio: Ospemifene (Osphena™ for postmenopausal urogenital atrophy) is marketed in USA by Shionogi Inc. and approvals are pending in EU and other countries. HMRlignan™ (nutraceutical ingredient; NDI status in USA) is on the market e.g. in USA through Swiss company Linnea S.A.

Hycail Oy (www.hycail.fi) Company Profile: Hycail have since 2004 developed technologies for production of biodegradable polymers and materials combining biopolymers with other bio-based materials like natural fibres. The latest product in development is an ultrapure, bioactive cellulose based biomaterial for medical devices as well as for life science research applications. This tissue compatible ultrapure cellulose is an excellent matrix for regenerative medicine and drug research and Hycail have developed a product for studying angiogenesis in vivo.

Product and Project Portfolio: Hycail is specialized in Biopolymers and Biomaterials technologies for life science and medical applications. The company possesses a portfolio of materials and unique production technology for both biopolymer and cellulose based materials.

Labmaster Ltd (www.labmaster.fi) Company Profile: Labmaster Oy is privately owned and employs 8 professionals. The company is specialized in technology development, manufacturing and marketing of own IVD products. Over 95 % of turnover is generated from exporting products worldwide. Since 2001 the company has been investing strongly in development of novel proprietary detection technology platform combining Silicon chip technology and recent findings in Electrochemiluminescence detection technology. Commercialization of LM-CECL technology in Point of Care market applications is the most important objective at the moment and in future for the company.

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Product and Project Portfolio: Phytoestrogen kits (TR-FIA) are based on the use of microtitration plates and therefore allows screening of numerous samples simultaneously. They are used for research of functional food ingredients, specifically fiber-rich food and isoflavones and their anti-carcinogenic features. LM-CECL (Hot Electron Induced Cathodic Electrochemiluminescence), novel proprietary detection technology for use in analytical and diagnostic applications (POC). LM-CECL technology is most suitable for low cost all-in-one chip based quantitative diagnostic tests in future where very excellent analytical sensitivity and reliability of results is needed.

Laurantis Pharma Ltd (www.laurantis.com) Company Profile: Laurantis Pharma is a clinical stage drug development company focusing on inflammation and oncology. The company is developing an innovative treatment for secondary lymphedema. In addition, the subsidiary of Laurantis Pharma, BioCis Pharma Ltd, is developing novel drug therapies to skin and eye inflammation and bladder cancer.

Product and Project Portfolio: Lymfactin, a gene therapy product based on adenovirus vector.

Montisera Ltd (www.montisera.com) Company Profile: Montisera develops bioactive compounds and sells them onwards for commercialization. Mission is to make molecule development more efficient and to offer high-value, low-risk investment opportunities. Projects bring together investors, candidate molecule owners, contract research organizations and drug & biotechnology companies. Lean organization with experienced professionals. Founded in March 2012.

Product and Project Portfolio: Montisera makes molecule development more efficient and offers higher-value, lower risk investment opportunities. Our mission is to provice our customers with a fast and cost-effective way to develop lead molecules from discovery through clinical proof of concept.

Orion Corporation, Orion Pharma (www.orion.fi) Company Profile: Orion is a pharmaceuticals and diagnostics company dedicated to treating and preventing disease by discovering and developing innovative medicinal treatments and diagnostic products for global markets. Orion is engaged in human and veterinary drugs, active pharmaceutical ingredients and diagnostic tests. Orion’s corporate headquarters and most of the supply chain and R&D operations are located in Finland. The company’s own marketing organisation is almost European-wide. Partnerships and networking are one of the key elements in Orion’s business strategy. Orion is listed on the NASDAQ OMX Helsinki stock exchange. Corporate homepage www.orion.fi/en.

Product and Project Portfolio: Orion Pharma is the pharmaceuticals business division of the Orion Group. Its businesses consist of proprietary and generic medicines for humans and animal health, as well as active pharmaceutical ingredients. Orion’s pharmaceutical research operations mainly engage in the first phases of the research process, the preclinical research aiming at creating new drug molecules for the subsequent

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clinical trials in patients. The two therapeutic areas are CNS (Central Nervous System) and OCC (Oncology & Critical Care). Orion has dedicated research teams and tools to identify and characterise novel compounds. The research has yielded several novel and innovative lead candidates that deserve further characterisation to relieve their full potential. Orion’s early phase research has also yielded a number of highly potent antagonists for certain steroid-dependent pathways. Basic research over the years has confirmed that pathways inhibited by these compounds play a critical role in certain hormone-dependent and -refractory cancers (e.g. prostate cancer). Novel and innovative cancer mechanisms and models are being investigated while also performing chemistry and in vitro optimisation of the most promising compound families both in Orion and within collaboration network. In future, the platforms of nuclear receptors enzyme inhibition, G-protein coupled receptors and, ion channels, approaches will be leveraged to discover additional medically relevant druggable targets in the treatment of humans and animals.

Orion Diagnostica Oy (www.oriondiagnostica.com) Company Profile: Orion Diagnostica is part of the Orion Group, Finland’s leading healthcare company, which develops, manufactures, and markets pharmaceuticals, active pharmaceutical ingredients, and diagnostic tests for markets worldwide. Orion Diagnostica specialises in easy-to-use, cost-effective clinical diagnostic tests and hygiene monitoring solutions designed to improve healthcare effectiveness and individual well-being. The focus is on products for primary healthcare that enable consultation, testing, and treatment decisions to be completed during a single patient visit. The company also serves large clinical laboratories that carry out high-volume analyses.

Product and Project Portfolio: Tests for infectious diseases, disorders affecting bone and soft-tissue metabolism, specific protein and hormone assays as well as tests for hygiene monitoring.

PerkinElmer Human Health / Wallac Oy (www.perkinelmer.com) Company Profile: The Life & Analytical Sciences (LAS) division of PerkinElmer provides drug discovery, ge-netic screening and chemical analysis instrumentation, reagents and services for scientific research and clinical applications.

Product and Project Portfolio: Comprehensive screening systems to accurately and efficiently detect genetic deficiencies and abnormalities, application-driven solution systems for laboratory work.Kits for Newborn and Prenatal Screening. Diagnostic kits for Thyroid, Fertility, Oncology, Anemia, and Diabetes. Instruments: Gamma Counters, Quantulus, Victor, MicroBeta, En-vision, Viewlux, AutoDelfia, Delfia Xpress. Application software.

Pharmatest Services Ltd (www.pharmatest.com) Company Profile: Pharmatest Services Ltd is a Contract Research Organization offering translational research services for diseases with unmet clinical needs. We offer full-service research solutions for early drug development. Our focus is on preclinical efficacy models in the fields of cancer and skeletal diseases ranging from in vitro cell culture assays to in vivo models.

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Product and Project Portfolio: Clinically predictive preclinical research services for pharmaceutical and biotechnology industry.

Skulle Implants Corporation (www.skulleimplants.com) Company Profile: Skulle Implants Corporation has been established in 2011 for production and development of next generation bioactive implants which utilize world-leading fibre-reinforced composite technology in medical devices. Research-wise, the background is in systematic in vitro, preclinical and clinical research which have shown number of benefits of Skulle implants for surgery.

Product and Project Portfolio: Patient-specific and other types of bioactive non-metallic composite implants for cranial and maxillofacial surgery.

SYRINX Bioanalytics Ltd (www.syrinxbioanalytics.com) Company Profile: SYRINX is a privately owned company and was founded in 2007 as a spinn-off from Bayer Schering Pharma. Analytical experience of SYRINX is based on the work of bioanalytical laboratory established in Turku during 1980's. The laboratory is GLP certified since 1990 and is involved in numerous drug development projects from preclinical to globally marketed products in Europe, Nothern America and Japan. Areas of core comptetence: Immunological and cell based assays for macromolecules (biologicals) and GC-MS and RIA assays for small molecules.

Product and Project Portfolio: CRO, Bioanalytical services (bioanalysis of biologicals, biomarkers, anti-drug antibodies and small molecules).