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Implications of digital transformation for migrant labour

Accelerated by the Covid-19 pandemic, rapid digitalisation has fundamentally transformed European working conditions. While its positive consequences are well recognised, digital transformation also puts a sorely needed part of the European workforce at risk of unemployment, poverty and social exclusion. IDILAB (Implications of digital transformation for migrant labour) investigates the impacts that technological progress and subsequent structural changes have on the labour market integration of migrant workers. By developing a new methodological approach, IDILAB shall provide novel evidence on migrants’ exposure to the process of digitalisation, and formulate evidence-based and innovative policy options for the EU and national governments to improve on the scope and adequacy of national and European policy directed at encouraging a fair digital transition for all, including migrants. The proposed project will contribute with new knowledge on migrants’ own perspectives on barriers and enablers for a sustainable integration in a fast-changing labour market. I, the experienced researcher (Dr Olga Gheorghiev, the Czech Republic), will work with a European centre of excellence (the Research Centre for Digitalisation of Public Services and Citizenship (CEDIC, OsloMet, Norway), and the European Trade Union Institute (ETUI, Belgium) for intersectoral knowledge transfer, career development, and European added value.

Locating Intergenerational Ties, rematriating late-19th-century unpublished photographs of Sámi Women and Children

Employing a decolonial approach inspired by critical museology and Indigenous studies, LIT aims to initiate a visual restitution/rematriation process fostering attention to Sámi people’s experiences during colonial encounters, and to illuminate individual life-stories of women and children photographed by Italian anthropologists Mantegazza and Sommier between 1879 and 1886. It wishes to generate dialogical knowledge of unpublished visual/written materials, enabling Sámi communities of interest to gain access to these scholars’ photographs. In complex socio-historical Indigenous/settler contexts such as Sápmi (the Sámi homeland), Sámi people’s control over their own heritage has proved essential to processes of cultural and ethnopolitical self-determination. Part of the Sámi visual heritage consists of photographs taken - often through mild violence and coercion - by academics engaged in physical anthropological practices involving Sámi individuals of all ages and genders. The resulting academic and divulgative publications circulated in Europe for decades, shaping and reinforcing stereotypes of Sámi peoples and cultures. Photos taken in colonial encounters by late-19th/early-20th century scholars to visualize Sámi people’s supposed biological-cultural inferiority (until a few decades ago inaccessible to the Sámi) have become important means of decolonization and empowerment through art and activism. The visual restitution of such photographs is of the utmost importance not only from a cultural heritage perspective but is also considered by Sámi institutions and individuals as an urgent necessity. LIT proposes an innovative approach based on the co-construction of knowledge and with a gender dimension. I shall reconstruct life stories of women and children photographed by Italian ethnologists, locating their descendants and returning their photographs to their communities. LIT would benefit my career, making me a leading researcher in Sami Studies and museology.

CULTUral heritage in RurAL remote areas for creative tourism and sustainabilITY

The main objective of the project is to contribute to the promotion of cultural and creative tourism activities, considering the different capacities, resources, and specificities (material, creative, human...) of the territories, as a mean to help with the sustainable development of peripheral rural areas, favoring job creation and population settlement. For this, the potential of its cultural heritage will be researched, taking into account both the artisan material culture (techniques, materials, patterns and decorative elements), as well as the intangible culture (music, oral knowledge and culinary traditions) as a resource.
 
To promote non-seasonal tourism as a form of sustainable development with a stable population settlement we are going to research the crafts linked to the territory and their implications, but we will also carry out a documentation of the productive processes. First and foremost, we are going to cater to the necessities of the local communities and pay attention to aspects related to societal groups at risk of exclusion, such as women, the elderly and the youth.

All this will be developed from a multidisciplinary perspective, for which we will count on the various teams —most of them linked to different countries— that will be part of the consortium. Each of these partners will contribute to the development, as well as to the final result of the project through input directly related to their area of ??expertise: for example, among the collaborators we have intellectual teams specialized in the digitalization of heritage, research, or communication and dissemination, as well as as various institutions that will act as a testing ground for the more practical parts of the proposal. However, if something will characterize our work, it will be the constant collaboration between all parties, as well as the exchange of advice and experiences that will help to enrich collective knowledge and guarantee optimal results.

POWERING ARTISTIC AND CULTURAL ENTREPRENEURSHIP TO DRIVE THE CLIMATE TRANSITION

PACESETTERS responds to the abstract challenge of the climate transitions by shifting from a model of entrepreneurship based on individual, short-term incentives to one that is driven by co-agency and new capacities to act together in sustainable ways. It does so by examining the concrete circumstances, investigating possible support mechanisms and stress-testing instruments that enable art and culture, creativity and heritage to drive the climate transition.
Therefore, PACESETTERS will set out to:
-Create knowledge from collaborative research to keep pace with the transition
-Propose and test creative business models to set the pace of the transition
-Assess strategies of valorisation to push the pace of the transition
 
This approach will identify and analyse advanced practices that run transversally across the cultural and creative sectors; contextualise the outcomes of co-research in real-world laboratories for social imagination; further develop and promote the preliminary results of experiments in iterative support and evaluation frames. The PACESETTERS approach centres on inclusion, participation and iteration in order ensure that gender equity and diversity inform it at every step and on every level.

The result will be a critical evaluation and all-encompassing demonstration of the actual potentials of the CCIs to drive the climate transition while systematically analysing their impact on micro-, meso- and macro-level:
-Understanding the climate transition as a triple transition: green, digital and inclusive
-Innovating aPACESETTERS responds to the abstract challenge of the climate transitions by shifting from a model of entrepreneurship based on individual, short-term incentives to one that is driven by co-agency and new capacities to act together. It does so by examining the concrete circumstances, investigating possible support mechanisms and stress-testing instruments that enable art and culture, creativity and heritage to drive the climate transition.

Smart and Sustainable Host UniverCities: leveraging city-university interactions to further the twin green and digital transition

SUNSET aims to develop innovative research and training capacity around city-university interactions driving the EU’s green and digital transition. This twin transition is a defining element of the current EU policy agenda towards achieving climate neutrality and sustainable growth. The European Commission considers cities to be frontrunners in this transition agenda, but their transformational capacity and resilience crucially depends on the presence of agile and high-performing urban innovation ecosystems. SUNSET brings together (1) prominent researchers working in diverse geographical and disciplinary settings at leading universities (N=6) with (2) partners (N=16) from city governments (often participating in the Cities Mission to achieve climate neutrality by 2030), innovation companies, research institutes and civil society organizations to analyze and foster the performance of these urban innovation ecosystems: drawing on a purposeful range of interdisciplinary, international, and intersectoral exchanges, the Doctoral Network will investigate whether and how universities can successfully become key drivers of the twin transition in cities via their role as innovation partners, the implementation of campus living labs, and as architects of decision-making in governance ecosystems. Through a tailored combination of network-wide training events and academic and non-academic secondments, the SUNSET Doctoral Network will train a new generation of researchers to become future urban innovation ecosystem leaders in the pursuit of the twin green and digital transition. The findings will lead to practical guidelines regarding the design and implementation of living labs for university and city management, tailored strategies to foster more inclusive and diverse urban ecosystems, and diverse forms of scientific outreach and dissemination.

Providing research infrastructure services to support Next Generation EU

This four-year project will harness outputs from key social science RIs in Europe and other reliable sources to support the aims of the ‘Next Generation EU’ programme and to inform EU youth policy. Virtual access will be provided to the outputs through special installations (portals) developed during the project. The core of the proposal is a set of existing research ‘services’, which will be re-purposed and customised to focus directly on the five themes: Make it Green; Make it Digital; Make it Healthy; Make it Strong; and Make it Equal. 

For each area, the consortium will work collaboratively to produce seven sets of resources:

i)	A searchable inventory of relevant variables drawn from multiple cross-national datasets; 

ii)	Analytical summaries, suitable for policy makers and analysts new to the field, as well as interactive resources available through the project portal;

iii)	Harmonised and merged extracts from these datasets that reduce the burden on analysts and increase sample sizes;

iv)	New data collected through the ESS’s established CRONOS web panel infrastructure. Eleven countries will field five waves of the panel, each one dedicated to a NextGenEU theme. Free and rapid access to the data will be available through the CRONOS portal alongside analytical summaries;

v)	In-person and virtual deliberative forums with young people (aged 18-34) in four countries covering the five Next Generation EU’ themes;

vi)	An educational tool (E-NextGen) channelling our data for use in classrooms and by the general public;

vii)	Comprehensive training materials related to all project outputs.


EXPRESS 2 SPECIFY AND PROTECT THE EU SOCIAL CONTRACT (EXPRESS2)

EXPRESS2 is a project that addresses from a multidisciplinary, interdisciplinary and cross-sectional perspective, the growing demand for a new, more democratic, inclusive, and sustainable social contract in the EU. To achieve this, the project will work to create a more appealing and legitimate EU social contract draft that will be submitted to inhabitants, Member States and EU institutions that will have the possibility to participate and decide upon the conditions, rights, and obligations to be binding. The goal is to strengthen the EU agreement of association by promoting social dialogue, civic engagement, and integration. An express draft shall be achieved by means of policy dialogue, campaign implementation, collaborative workshops, advocacy planning, and innovative offline and online formats and tools to create spaces for dialogue. To this end, EXPRESS2 will involve EU policymakers and institutions throughout the project to obtain a more appealing and legitimate EU social contract draft. 
The project will also focus on identifying and analyzing disruptive elements of the social contract, such as insecurity, populism, climate change, mistrust in institutions, gender discrimination, digitalisation and pandemics. The analysis of these stressors includes both individualised and cross-sectional approaches to cover the plausible relation of multiple disruptors, their concatenation or the “trigger” effect of a disruptive phenomenon to another. By understanding these disruptive elements and their effects on the social contract, the project will propose concrete measures to ironclad the social contract and it will provide relevant information to protect it from actual and potential disruptions thus we conceive social contracts as incomplete theorised agreements and living documents. In addition to academic, policy, and socio-economic outcomes, EXPRESS2 will propose recommendations to strengthen the social contract's resilience and capacity for further development.


Mapping of Longitudinal data of Inequalities in Education

The MapIE project aims to identify mechanisms causing educational inequalities and policies or interventions compensating for them. We do a systematic review of how these have been studied internationally using longitudinal designs. We map existing longitudinal data that we describe in a public metadata database, and we analyse them to describe the mechanisms of inequalities and to identify effective policies and interventions in different local contexts. We focus on the contextual differences between the Nordic and Central European countries that have structurally different education systems. Within national contexts and using comparative research designs, we look at system-, regional- and school-level policies and practices and individual-level factors (e.g. socioeconomic status, immigrant background, gender, special educational needs) that are associated with the development of educational inequalities and the successful prevention of achievement gaps. We publish and disseminate the empirical results of the project through multiple channels to scientific audiences, policy makers and the wider public. At the end, we create a public framework for studying educational inequalities longitudinally in future studies, acknowledging the role of local contexts but aiming for comparability at the European level. 

We implement the project in seven work packages. Our consortium consists of internationally acknowledged experts in large-scale educational assessment research from Finland, Sweden, Norway, Hungary and Luxembourg/Germany. The partners have a long-standing history of collaboration with each other, European researchers, and national and international education policy makers, and they bring extensive longitudinal datasets to the project. The project will considerably strengthen the knowledge base of what shapes educational outcomes over time, how to best support the learning of all students and how to reduce education inequalities in the short, medium and long term.

Contextualized pathways to reduce housing inequalities in the green and digital transition.

The project Reducing housing inequalities in the green and digital transition (ReHousIn) is committed to better understand the impacts of recent crises on housing inequalities across different European regions, especially with regard to the implementation of the green transition launched by the EU. The overall aim is to explore the mechanisms affecting the (re)production of housing inequalities under recent crisis conditions, and the impacts of the EU induced green transition in different national contexts and along different degrees of urbanisation. Based on a contextualized and comparative understanding of the mechanisms (re)producing housing inequalities, ReHousIn inquiries into multi-level pathways and inclusive local housing initiatives to spark innovative EU, national and local policy solutions towards inclusionary and quality housing, mitigating the possible negative impacts of the EU induced green transition. It conducts a comparative, multi-level analysis in 9 European countries – Austria, France, Hungary, Italy, Norway, Poland, Spain, Switzerland, United Kingdom – focusing on attractive metropolitan regions, middle-sized cities and rural areas by means of a mixed-method project design. A quantitative data analysis on recent trends in housing inequalities and their relation to crises across different levels of urbanization will provide the framework for 27 local cases studies in which the impact of multi-level trajectories of housing-system, welfare regimes and environmental policy instrumentations on the (re)production of local housing inequalities and the emergence of inclusive housing initiatives are analyzed. Based on this, ReHousIn compares mechanisms of differentiation feeding into policy labs, aiming to formulate recommendations on how to tackle negative social externalities related the EU green transition at EU, national and local levels.

Strengthening resilience and mental wellbeing through the Support4Resilience toolbox for leaders in elderly care

European elderly care experiences labor shortages, lack of qualified workers and a mismatch between capacity and demands, causing stress, burnout, and reduced mental wellbeing among healthcare workers and informal caregivers. Leaders are crucial in promoting supportive working conditions but lack research-based measures to act upon these challenges.

Support4Resilience (S4R) will develop, implement, and evaluate a research-based Toolbox to support healthcare leaders in improving healthcare workers’ and informal caregivers’ resilience and mental wellbeing in elderly care. S4R will identify resilience and mental wellbeing factors among healthcare workers and informal caregivers; explore their perspectives and needs; develop new theory on the relationship between individual and organizational resilience, and mental wellbeing; and develop recommendations and cost-effective interventions. The Toolbox with tailormade resources for policy and practical use will be available through an open access S4R Resource Bank.

The S4R Toolbox includes three main tools: 1) Mapping and identification, 2) Reflection and education, and 3) Reorganization. Measures are initiated at the organizational level and effects on mental wellbeing and resilience transpire at the frontline of elderly care. The Toolbox covers different situational contexts, types of healthcare providers and health system levels. Elderly care settings in six European countries will implement and evaluate the Toolbox through a process evaluation, effectiveness evaluation, and cost-effectiveness evaluation. 

S4R provides policymakers, decisions-makers and leaders with solutions for taking action to solve specific risks for healthcare workers’ and informal caregivers’ resilience and mental wellbeing. Thus, pertinent to the work programme, S4R will support the development of resilient health systems in European elderly care through improved leadership capabilities, governance structures, and adaptive capacities.

Midlene fra ERC-European Research Council (ERC) fordelt på år

Midlene fra ERC-European Research Council (ERC) fordelt på fylker

Midlene fra ERC-European Research Council (ERC) fordelt på fagområde

Antiviral Proteins Applied as Therapeutics in Aquaculture

In the last decades aquaculture seems to be the only real alternative for global fish food supply. At present, the aquaculture world production has reached 82.1 million tons worldwide representing the fastest growing animal production sector in the world. Among aquaculture species, salmonid aquaculture, trout and salmon species, are the highest-value species for global and European aquaculture. The biggest global constraint to aquaculture production is disease with an estimate of a 10% of all cultured aquatic animals lost because of infectious diseases, amounting to >10 billion USD in losses annually on a global scale. Among infectious diseases, viral outbreaks are a serious concern, since they are an impediment to the development, productivity, and profitability of fish farms. Intensive fish farming amplifies diseases caused by bacteria, viruses, and parasites, resulting in severe losses. Few vaccines are available for viral diseases in aquaculture and they are not completely effective. Moreover, up to date there are not antiviral therapeutic treatments to mitigate the outbreaks in unvaccinated fish or to diminish the percentage of losses do not covered by prophylactics vaccines. During my ERC Starting Grant our group identified a number of antiviral proteins in rainbow trout nucleated red blood cells (RBCs) implicated in halting viral infections. The OBJECTIVE of this project is to perform a Proof of Concept of the antiviral molecules previosuly identified. We will evaluate the new business opportunity of introducing a new antiviral therapeutic that decreases viral infection and related economic loss in aquaculture.

T-cellereseptorer kan sammenlignes med målstyrte raketter, og utgjør den delen av T-cellene som gjør dem i stand til å gjenkjenne og drepe virusinfiserte celler med stor effektivitet og spesifisitet. Derfor kan T-celler effektivt kurere influensa uten bivirkninger. Prosjektet utnytter disse egenskapene ved T-celler til å drepe kreftceller. Siden kreftcellene, til forskjell fra virus, ofte ignoreres av T-cellene, benytter vi forskjeller i vevstype-molekyler for å få T-cellene til å respondere effektivt mot egne proteiner. Dermed kan vi få T celler til å angripe normale proteiner som er selektivt uttrykt på celletypen som kreften utgår fra. Dette utgjør et nytt immunologisk konsept som har vist seg svært effektivt i våre studier. Ved hjelp av denne strategien har vi generert en rekke T-cellereseptorer som gjenkjenner det B-cellespesifikke proteinet CD20, som er uttrykt i lymfekreft og leukemi. Vi vil overføre genene for slike T-cellereseptorer til pasientens T celler. Dette kan gjøre dem om til celler som effektivt kan gjenkjenne og drepe  lymfekreftceller etter re-infusjon til pasienten. I prosjektet har vi: 1) klonet en rekke CD20-spesifikke T-cellereseptorer inn i vektorer som tillater genmodifikasjon av T celler, 2) testet og identifisert hvilken metode og hvilken vektor som gir mest effektiv genoverføring til T cellene (modifisert med musekonstante deler, ekstra cysteinbroer og codon optimisering), 3) etablert ekspansjonsprotokoller for T cellene, 4) testet og sammenlignet en rekke CD20-spesifikke reseptorer etter at de er satt inn i T celler fra perifert blod. Dette har resultert i at vi har identifisert  to kandidatreseptorer som begge medierer effektivt drap av leukemi- og lymfekreftceller (cellelinjer og pasientceller) samtidig som de sparer celler med opprinnelse fra en lang rekke organer i kroppen, 5) etablert en musemodell for testing av efficacy av humane genmodifiserte T celler som uttrykker CD20 spesifikke T cellereseptorer, og startet etablering av en musemodell for safety.

The main objective of the project is to treat leukemia and lymphoma patients with gene therapy. We will conduct a clinical trial using a T cell receptor (TcR) targeted at CD20 that mediates highly efficient killing of primary human leukemia cells. T cell- mediated killing is independent of p53, as opposed to chemotherapy or monoclonal antibodies. Rather than seeking a cancer-specific response, we have developed an innovative approach to generate T cells that recognize peptides from cell type-restricted pro teins. To overcome tolerance to wild-type human proteins, T cells are exposed to peptides in the context of a foreign HLA-molecule. We have established that this is a highly efficient method to generate T cells that specifically recognize the B cell-restr icted antigen CD20 and that kill primary chronic lymphocytic leukemia cells with unprecedented efficiencies. From these cells we have now cloned a number of TcRs. The present application seeks funding for a phase I/II clinical trial that will include pati ents with small lymphocytic lymphoma or follicular lymphoma. The TcRs can be used to treat HLA-A*0201+ patients (50% of Caucasians). The primary end point is safety/tumor response rate. The preclinical phase involves optimization of the protocols for T ce ll expansion and large-scale gene transfer of CD20-specific TcRs to T cells. We will transfect the cells by electroporation with mRNA encoding the TcR. This method has been used in many clinical protocols at Radiumhospitalet, is documented to be safe and  leads to transient expression. Research will be performed to maximize TcR expression, and to investigate if expression of molecules that direct T cell migration will improve homing to tumor areas. An innovative, stepwise trial design will ensure that info rmation is gathered along the way and that each patient will serve as his/her own control.

CD20-specific T cell receptors in gene therapy of leukemia and lymphoma

Multiple myeloma is due to clonal expansion of malignant plasma cells. The incidence in the Nordic countries is approximately 6 new cases per 100,000 per year, which corresponds to nearly 20% of all haematological cancers.  Approximately 300 people are gi ven this diagnosis each year in Norway. In most patients the neoplastic clones induce osteoclast activity as well as impaired osteoblast activity, resulting in osteoporosis, osteolytic lesions and pathological fractures that are characteristic for the dis ease. The bone disease of multiple myeloma represents a serious complication that generally is associated with pain and severely reduced quality of life. Multiple myeloma is still an incurable disease, it is likely that new and better treatments of multip le myeloma will emerge from a better understanding of the underlying biology of the disease.  WE found Hepatocyte growth factor (HGF) at elevated levels in sera from myeloma patients, and that high serum levels of HGF were associated with  apoor prognosis . This project aims, by clinical and pre-clinical studies, to estabish HGF-signaling as a treatment target in multiple myeloma. Furthermore, the project aims at studying the role of Bone Morphogenetic Proteins (BMPs) in multiple myeloma, - in particular t he potential tumor supressor function of BMPs as well as the interplay between BMP - and HGF-signaling in the maintenance of bone homeostasis.

Integration of clinical and basic research to improve treatment of multiple myeloma

Purpose:
Metastasis is the principal cause of cancer death, and for most tumor types staging, prognostication and therapy is inadequate. Hence, new knowledge on how to prevent metastasis and identification of predictive markers is among the most important  challenges in cancer research. Our strategy is to investigate biological mechanisms involved in the metastatic process and thereby identify target molecules to be utilized in early detection, prognosis prediction and development of improved anti-metastat ic therapy.
Challenges:
Metastastatic spread is a complex process involving factors inherent to the cancer cells and to the surrounding normal cells. Tumor heterogeneity and differences between tumors of individual patients with the same diagnosis contrib ute to the difficulty in developing anti-metastatic therapy. Hence, in the search for more personalized treatment a prerequisite is to identify new predictive markers and therapeutic targets. A small population of cancer cells is hypothesized to initiate  and sustain tumor growth, implying also that metastases originate from such stem cells and that disseminated tumor cells (DTC) express stem cell related markers. It is a major challenge to characterize such rare cells in a large population of other cells,  but we have developed means to isolate rare cells from body fluids and solid tumors that will be utilized in the project.
Applications:
Detection and characterization of DTC in bone marrow or in sentinel lymph nodes may be used as surrogate marker for th erapy response, for selecting patients for targeted and neo-adjuvant therapy, and possibly for intra-operative sentinel node evaluation in breast cancer patients.
By utilizing cell lines, in vivo models and clinical material in comprehensive molecular stu dies of biological mechanisms involved in the metastatic process, the project has a unique possibility to identify new molecules for translation into diagnostic and prognostic markers and therapeutic targets.

Molecular and biological characterization of cancer metastases

Endometrial carcinoma is the most common pelvic gynecologic malignancy. Methods for effective selection of patient at risk for metastasis, improved treatment for metastatic endometrial carcinoma and reliable predictive markers for response to new targeted  therapeutics are urgently needed. This project is an international prospective multicenter study of tumor tissue aiming to facilitate implementation of molecularly based targeted therapy amongst women with endometrial carcinoma. The focus on methods to d etect lymph node metastases and aggressive disease trough studies of molecular markers in curettage specimens and functional imaging by MRI and FDG-PET, will potentially reduce side effects from extensive lymph node removal among low-risk patients. Furthe r, we focus on molecular alterations in endometrial cancer that can potentially be targeted. We have recently sequenced 129 tumor related genes in primary endometrial cancers, 90 of which are in the receptor tyrosine kinase pathway, with several mutations  identified. Amongst these, we have further studied novel FGFR2 mutations in endometrial carcinomas and found them to be oncogenic and drug-sensitive. (Dutt,Salvesen et al. Proc Natl Acad Sci 2008). We have also found that gene expression profiles identif y an aggressive subtype of endometrial carcinoma associated with amplification of PIK3CA and PI3 kinase signature overexpression (AACR, late breaking news, 2008, Salvesen et al. revised manuscript submitted PNAS 2008). We want to expand these studies to s equence 2000 genes in collaboration with Broad Institute/Harvard and to validate the clinical significance of these findings in the prospective clinical trial we have initiated. Effects of new molecular targeted treatment in endometrial cancer cell lines  based on their molecular profile will be studied. Finally we plan to design and initiate prospective treatment trials for new targeted therapy based on the results.

Molecular alterations and targeted therapy in Endometrial Cancer

We seek to reach a more fundamental understanding of the biological dynamics of breast cancer. High-throughput molecular data at multiple levels (eg DNA, mRNA, miRNA and protein level) have become available on increasing numbers of patients, and various m olecular profiles have been associated with tumor aggressiveness, response to therapy and patient outcome. Still, it is very rare that all or most analyses are performed on the same patient material. In this project we will use 4 sample sets (Oslo I,II,II I, MDG/NOWAC) and obtain molecular profiles at all levels. This will facilitate identification of risk factors, search for novel diagnostic markers, prediction of therapeutic effects and prognosis  as well as identification of new targets for therapy. Thi s is a very ambitious project, but with the existing and ongoing collection of high quality patient materials in Norway with a genetically homogeneous population, the very high participation rate of Norwegian women, the high quality clinical data and the  expertise in molecular and statistical analyses combined in this project, we are confident that we will be able to advance and translate our knowledge into improvement of patient care. The project is part of a larger collaborative BC program between Radiu mhospitalet, Ulleval and Akershus University Hospitals, as well the MR-center at NTNU/Trondheim University Hospital. Systematic studies performed at the cellular, genomic, and population levels, will be analyzed in an integrative manner in conjunction wit h epidemiological and clinical data. By bringing together several strong research teams that jointly cover a broad area of expertise; we have created an interdisciplinary BC research unit of high worldwide reputation. Only with joint forces will we be abl e to achieve sample numbers which eventually will lead to universally valid markers that can be used for the benefit of the patient.

Understanding  Breast Cancer Genomics; Towards combined  molecular profiles for better diagnosis and treatment

Det er kjent at brystkreftsykdommen kan inndeles i ulike undergrupper eller subtyper, men det er ikke kjent om "tradisjonelle" risikofaktorer har ulik sammenheng med ulike subtyper. Derfor har vi undersøkt sammenhengen mellom kjente risikofaktorer og seks  ulike subtyper av brystkreft, identifisert med såkalt "tissue micro array" (TMA)-metodikk. 

I tillegg er det ikke klart om prognosen (overlevelsen) etter diagnose er vesensforskjellig for de ulike subtypene av brystkreft. Derfor har vi også undersøkt  overlevelsen blant kvinner med brystkreft som ble diagnostisert for mange år siden, og deretter fulgt dem så lenge som mulig.

I forhold til risiko for å få sykdommen, har vi funnet at kjente risikofaktorer har særlig sammenheng med såkalte luminale svu lster, og med såkalte HR2 positive svulster, men vi fant lite eller ingen sammenheng med såkalte basal-like svulster og med andre ikke-luminale svulster uten spesielle kjennetegn.

I forhold til prognose har vi funnet at luminale svulster har en langt b edre overlevelse enn ikke-luminale svulster de første årene (5-10 år) etter diagnose, men luminale svulster fortsetter å ta liv lenge etter 10 års oppføging. De ikke-luminale svulstene har en dårlig prognose de første 5 år etter diagnose, men fra 5-10 år  etter diagnosen er det slik at overlevelsen for kvinner med ikke-luminale og luminale svulster konvergerer, og på meget lang sikt ser det ut som prognosen ikke er vesentlig forskjellig mellom subtypene. Det betyr også at for en viss andel kvinner med brys tkreft, uansett hvilken subtype de har, så er lang tids prognosen god. Hvorvidt det skyldes at disse kvinnene har hatt meget god nytte av behandlingen som de fikk, eller om de har hatt en relativt lite aggressiv sykdom, kan vi ikke vite, men dette er et m eget viktig forskningsspørsmål for framtidige studier.

This proposal describes 3 specific studies, each with several specific aims. 
The first is a case-control study nested within a cohort of 30,000 pregnant women who have been followed for 10 years after pregnancy. Blood was collected three times during pre gnancy, and we will compare pro- and anti-angiogenic factors in pregnancy and subsequent risk of breast cancer in 152 women who were diagnosed during follow-up and 300 age-matched controls. 

The second study is a cohort of 20,000 women who participated i n a breast cancer screening more than 45 years ago. Only a fraction of these women are alive, and more than 1500 have developed breast cancer. We want to use tissue micro array technology and determine three subtypes of breast cancer in these women. We wi ll assess the association of conventional (especially reproductive factors) risk factors with each subtype to find out if all subtypes of breast cancer are similarly associated with the established risk factors for this disease. In this study, we will als o investigate the prognosis of each subtype of breast cancer.

In the third study, we have followed approximately 35,000 women for 9 years, and 460 have developed breast cancer. These women have participated in an international consortium on genetic facto rs and breast cancer risk, and the association of 90 genetic variants with breast cancer risk have been determined. We want to use these genetic variants and study their interaction with conventional risk factors (reproductive factors, height, weight etc)  in relation to breast cancer risk. 
We also want to explore the possible gene-environment interactions in relation to breast cancer subtypes determined with tissue micro array. For this part of the proposal, we will attempt to analyse the data in collabo ration with other cohort studies, preferably the Nurses' Health Study, to increase the statistical power of the study.

Aspects of breast cancer risk: subtypes of breast cancer, relation to angiogenic factors and gene-environment interactions

Background: The number of long-term cancer survivors (LTCSs) (>5 years after primary treatment) is rapidly increasing and currently concerns >100,000 patients in Norway. Although frequently cured by their disease, the treatments and the cancers have late  effects that impair the physical and mental health and reduce quality of life of LTCSs.The Norwegian government has established The National Resource Centre for Long-Term Studies after Cancer (The Centre) which got the task of doing research and spread in formation concerning LTCSs to the health care system. The Centre has to get grants in order to fulfil these tasks. Objectives: The Centre shall do research concerning LTCSs, and this application concerns five projects: one epidemiological/registry (income  and health insurance issues), two clinical (arm/shoulder morbidity and association between radiotherapy and later heart disease) and two translational 
(genetic variation in second cancers and in breast cancer patients with fatigue and hypothyroidism as  late effects). Methods: The  following methods are used: merging of register data, comparison of self-report and objective measurements, detailed data collection of clinical and radiotherapy issues, and analysis of genetic variants on the molecular level.  The research is mostly part of international collaboration with leading centres in Europe and the United States. With these contacts the Centre has the competence to carry out the research objectives. Relevance and dissemination: The projects will contri bute to the prevention of late effect development, and to the diagnosis and treatment of such effects in LTCSs thereby reducing premature death, functional impairment and reduced quality of life. The results will be presented at international meeting and  be published in international journals and also include 2 PhD theses. Nationally the results will be disseminated to the oncological community and to the patients through the Norwegian Cancer Association.

Somatic, translational and psychosocial research in long-term cancer survivors

Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer mortality in men in western countries, including Norway. Prostate cancer encompasses a biological continuum from a slow-growing indolent tumour to a highly a ggressive and potentially fatal form. A major challenge in the clinic is to identify men with localized prostate cancer who are at high risk of dying from the disease, in order to maximize disease control and survival, without overtreating men who are lik ely to die from comorbidities. Despite ongoing research and active education, the need for novel biomarkers for predicting the biologic behaviour of individual tumors remains a major issue. It is now well established that Prostate Specific Antigen (PSA),  the most widely used marker in the clinic, although useful, is far from an ideal marker with both high false positive and false negative rates. It is argued that PSA screening allows for the excessive detection of insignificant cancer, which is invariably  overtreated in most western countries, while a substantial number of cancer diagnoses may be missed. Moreover, no single marker has been identified which indicates disease outcome. Therefore, there is an urgent need and intense focus on the development o f additional markers for prostate cancer. 
The goal of this project is to assess the possible use of three genes and the proteins that they encode, as well as their interacting partners, as biomarkers for prostate cancer. All these genes have either been  first cloned in our laboratory or have been implicated for prostate carcinogenesis during our studies of molecular and cell biological aspects of prostate cancer cells. Through extensive immunohistochemical analysis of human prostate cancer specimens, as  well as work using mouse models of prostate cancer, we will now conclusively assess the possible utility of these genes and the proteins that they encode as biomarkers/therapeutic targets for prostate cancer.

Development of biomarkers and identification of therapeutic targets for prostate carcinogenesis

Our group conducts translational research with the primary aim of identifying the mechanisms of resistance to chemotherapy in breast cancer. We have concentrated our work on alterations in genes participating in the p53 and retinoblastoma protein pathway  as cause of anthracycline resistance. In 1996, in collaboration with Dr. Børresen-Dales group at the Norwegian Radiumhospital we were the first to report mutations affecting the TP53 gene to predict resistance to anthracyline therapy. Now, we have identif ied also mutations affecting the p53 protein upstream gene CHEK2 (coding the chk2 protein) to be associated with anthracycline resistance, providing evidence activation by chk2 is critical to p53 activation in response to genotoxic stress in vivo. Current ly, we are exploring the effect of dominant negative chk2 splice variants in this respect. Considering the retinoblastoma pathway, we have identified epigenetic and genetic changes in multiple genes involved in this pathway with a significant correlation  to lack of responsiveness to anthracycline chemotherapy. Currently, we are exploring several of these alterations with respect to functional status by in vitro assays. Following finding of correlation between BRCA1 mutations and lack of responsiveness to  paclitaxel therapy, we are currently exploring alterations in other genes involved in the BRCA1 DNA-repair pathway as potential causative agents of resistance to taxane therapy. Finally, following discovery of hypermethylation of the BRCA1 promoter in som e breast tumours to be accompanied by promoter hypermethylation also in the white blood cells, in a collaborative project with Professor Gareth Evans (Manchester), we are exploring epigenetic alterations in the BRCA1 promoter as a potential non-medallion  inherited trait for breast cancer.

Translational research directed toward identification of the mechanisms of chemoresistance in breast cancer.

EURAMOS- KREFT

Metastasis, cancer spread to other organs, is the principle cause of death of cancer patients. Early detection of metastatic tumor cells, development of new treatment strategies and knowledge about how to prevent cancer metastasis are some of the most cha llenging tasks in cancer research. Our project is addressing aspects of these problems, spanning from studies on biological and molecular aspects of metastatic proscess, development of methods for detection and characterization of circulating, micrometast atic tumor cells, and evaluation of new methods for treatment.
To study the interplay between malignant and normal cells that characterize metastasis formation we have established several animal models mimicking human cancer, and in the proposed project w e will use these models and clinical material for in vivo imaging of secondary tumor formation, for expression profiling aimed at identifying molecular signatures predicting organ-preferred metastasis, and for evaluating principles of targeted therapy.
Us ing immunomagnetic and fluorescent beads combined with a semi-automatic capillary system we can prepare pure tumor cell fractions from bone marrow samples, and use the selected cells in high throughput analyses (RNA or protein) for molecular comparison of  primary, metastatic or micrometastatic cells, making it possible to identify novel genes involved in the metastatic process or of importance for predicting prognosis or therapeutic effects. Functional studies on interesting protein candidates will be per formed. 
We have developed an immunotoxin which is now in clinical phase I trial, and in parallel we study its effects with emphasis on induction of apoptosis. In this and other trials, we also monitor the effect by using micrometastasis in bone marrow as  a surrogate marker

MOLECULAR AND BIOLOGICAL STUDIES OF CANCER METASTASIS

More than 20% of the human genome encodes proteins that are devoted to cellular signalling. Signal networks that involve the signal molecule cyclic AMP (cAMP) are involved in diseases such as cancer, cardiovascular disease, type II diabetes, obesity, HIV and asthma. Cyclic AMP acts as an acute inhibitor of T cell activation that prevents T cell proliferation and cytokine production. We have previously mapped a novel regulatory pathway in T cell lipid rafts involving cAMP- PKA type I and C-terminal Src kin ase (Csk) that modulate immune function in T effector cells.  One of the main objectives of the present proposal is to investigate whether cAMP signalling is involved in the Treg induced immune suppression of T effector cells during anti-neoplastic immune  responses.
By combining complementary expertise held by our group and collaborators both nationally and internationally, we will co-ordinate an effort to understand a key question in clinical immunology and cancer research. Based upon proven expertise, a  particular approach will be to understand how regulatory T cells suppress anti-tumor immune function. Our unpublished preliminary data suggest that the Treg-mediated immune suppression of anti-tumor activity involves activation of the cAMP signalling pat hway in engaged T cells and through this mechansim inhibits the immune response. Specific objectives include: 1) Identification of the molecular mechanism employed by adaptive regulatory T cells in inhibition of surrounding T effector cells. 2) Identifica tion and characterization of regulatory T cells in relation to colon cancer and other neoplasms. 3) In vitro evaluation of the suppressive function of regulatory T cells on specific anti-tumor immune activity. 4) Target the molecular inhibitory function e mployed by regulatory T cells in order to enhance the anti-neoplastic immune function in vitro. 5) Develop clinically useful strategies for improving the immune function against malignant tumors.

Novel therapeutic strategies for stimulation of anti-neoplastic immune activity

DNA repair genes represent a class of tumor suppressor genest hat have proven increasingly important in preventing cancer development in humans. This is not unexpected as DNA repair has been demonstrated to have a crucial role in maintaining genome stabil ity. DNA damage induced by cellular exposure |to environmental chemical and physical agents as well as those induced by endogenous metabolites, e.g. oxygen radical species, are rapidly and faithfully removed by efficient repair mechanisms. At present, mor e than 150 h\genes have been recognized in human cells, constituting at least six different pathways. Normally, it is only a small fraction of the damages formed that will remain to induce mutations and other detrimental effects on living cells. However, defects in DNA repair will greatly sensitize cells to exposure to mutagenic and carcinogenic agents and the rate of mutations increases radically by inactivation of repair genes. The classical example is natural mutations occurring in xeroderma pigmentosu m genes in man that imposes extreme sensitivity to sunlight and will induce skin cancer in all affected individuals within the age 10-20 years. The overall aim of the proposed project is to improve our understanding of the relationship between deficiencie s, mutations and polymorphisms in DNA repair genes and the development of cancer. The work involves mechanistic and functional analysis of different DNA repair pathways in cancer as well as in normal cells to determine more precisely their role in prevent ing genome instability and cancer susceptibility. It also includes searches for new polymorphisms and mutations in repair genes associated with cancer development. Special emphasis will be put on the role of base excision repair since this pathway is esse ntial for removing endogenous as well as exogenous DNA damage and will also protect from detrimental effects of chronic inflammation often associated with common types of cancer.

GENOME MAINTENANCE MECHANISMS AND THEIR ROLE IN PREVENTING CANCER DEVELOPMENT

Aim: The goal is to improve the prognosis of patients with multiple myeloma and B cell lymphoma by vaccination with a recombinant antibody-like vaccine (Vaccibodies). Background: B cell tumors produce a highly tumor-specific antigen, monoclonal immunoglob ulin with unique variable(V) regions, that may be used for vaccination purposes. Vaccibodies: We have developed a novel vaccination strategy based on recombinant Ig-like molecules (Vaccibodies). Vaccibodies are dimeric molecules that express V regions fro m monoclonal Ig of a tumor, connected through a dimerization motif to another set of V regions that target antigen presenting cells (APC) for induction of powerful immune responses. Unpublished results: Vaccibodies have been genetically constructed. Vacci body proteins have a correct structure. Vaccibodies induce strong tumor-protective immune responses in mice, especially as a naked DNA vaccine. Experiments of the proposal: 1) Vaccibodies will be constructed and tested for a number of different mouse myel omas and B cell lymphomas. 2) The cellular mechanism of action of Vaccibodies will be investigated. 3) Vaccibodies will be constructed for human multiple myeloma and B cell lymphoma patients. 4) Vaccibodies of 3) (above) will be hybrid human/mouse molecul es that target mouse APC, and will be tested in mice. 5) We will construct hybrid Vaccibodies specific for targets on human APC (HLA-DP, CD14). 6) Fully human Vaccibodies will be produced and tested in HLA transgenic mice. 8) Fully human Vaccibodies will be used to vaccinate conventionally treated multiple myeloma and B cell lymphoma patients with minimal residual disease in clinical trials. Budget: Salaries for 2 researchers and expenditures total 1.25 million NOK/year. Project management: The project le ader, professor Bjarne Bogen MD, runs a 16-member lab at RH University Hospital. The translation to the clinic is performed in collaboration with Dr. Gedde-Dahl and Dr. Lauritzsen at RH and DNR University Hospitals.

Vaccination against B cell cancers: from experimental immunology to patients

Retinol and its metabolites (vitamin A, retinoids) orchestrates proliferation and differentiation through its nuclear retinoic acid receptors. Antioxidants have also recently been implied in regulation of cell signalling and gene transcription. There exis t convincing evidence that diets high in vegetables and fruit decrease the risk of cancer in a number of organs. Provitamin A carotenoids and antioxidants in fruits and vegetables are strong candidates for explaining this anti-cancer effect. 

Retinoids a nd antioxidants efficiently regulates gene expression in cell cultures, but much less is known about their role in living organism. We have therefore develop techniques for assessing  their roles in intact experimental animals. These transgenic reporter m ice allows non-invasive imaging of gene expression in living mice. We will now develop these reporter mice further and study role of retinoic acid and antioxidants  on gene expression during tumor development. We will also develop caspase reportermice sin ce retinoids and antioxidants modulate these important activators of apoptosis in vitro. 

In collaboration with scientists at the Norwegian Radium Hospital we study gene profiling of oxidative stress-related genes in patients with head and neck squamous cell carcinoma (HNSCC) and the association between plasma redox status and survival in patients with HNSCC since a pilot study suggested a strong association between HNSCC survival and plasma total glutathione and carotenoids. We will also test the abilit y of dietary antioxidants to improve oxidatice stress in a group of smoking middle-aged men.

We have performed total antioxidant analysis of several thousand foods. By using this antioxidannt table we are now testing association between dietary antioxida nts and cancer risk in three large epidemiological studies (Nurses' Health Study, Health Professionals' Follow-up Study, Iowa Women Health Study) in collaboration with Walter Willett and David Jacobs.

Retinoids, antioxidants and cancer

We study three human cancer diseases, colorectal cancer (CRC), testicular germ cell tumour (TGCT), and malignant peripheral nerve sheath tumour (MPNST), originating from different types of stem cells. All three diseases develop through morphologically def ined stages, and the stepwise molecular biology of these diseases are being studied. Common changes or disruptions of the same cellular pathways will provide new insights to tumourigenesis in general and have impact on the molecular understanding of embry ogenesis. The identified sets of molecular discriminators will be clinically validated in large patient cohorts. A molecular stratification of each cancer type both for complex datasets and for individual markers will be performed in order to predict pati ent treatment and disease outcome. We have access to the necessary human material ensuring the biological premises of the outlined project. The technological availability and know-how are presented in the application. Interaction with the dept. Pathology ensures the contribution from national reference pathologists and joint facilities for molecular pathology technologies. Our group has long term connections to relevant clinical milieus, and to explore diagnostic and clinical relevant questions. One of th e most challenging clinical questions and one of the main issues of the present project, is how to use the available new technology to identify CRC patients in need for aggressive treatment and those who are better off not receiving it. The letters of sup port from our two co-applicants confirms the close interaction with the Pathology dept. and clinic. Finally, national ethical demands are taken care of.

Developmental biology of solid tumours may pave the way for advanced medicine

In this proposal, we describe three separate studies. 
First, in a cohort study of more than 35,000 men and women born between 1920 and 1958, we propose to use historical data from birth records to study the association between perinatal factors (primaril y birth weight and birth length) and risk for several specified cancers (e.g. breast, cervix, prostate, colorectum). 

Second, in another cohort study of nearly 30,000 pregnant women, we will explore how pregnancy factors measured in maternal blood during  pregnancy may predict the occurrence of preeclampsia in the mother. Thereby, we hope to advance our understanding of how preeclampsia is related to reduced risk for breast cancer both in the mother, and in her female offspring. 

Third, using linked data  between women who have been recorded at delivery to the Medical Birth Registry and data on cancer incidence recorded by the Norwegian Cancer Registry, we propose to study the association between perinatal factors of the offspring (birth weight, birth len gth) and other pregnancy factors (length of gestation, pregnancy complications, e.g. preeclampsia) and subsequent risk for hormone related cancer (breast, ovary, endometrium, cervix) and colorectal cancer in the mother.

Early life factors and adult cancer risk

The NOWAC post-genome study is an integrated collaboration between epidemiologists, clinicians and basic genetic scientists. The cohort is an extension of the existing nationwide NOWAC prospective study with 130,000 participants. 
1. During the years 2003 -6 we will build a "core cohort" of 50,000 women born 1943-57 with questionnaire informations and specific blood samples for extraction of RNA in addition to DNA and plasma, partly by inviting women already recruited and partly by inviting 70,000 more. Sa mpling is based on a response rate for participation of 55% and a willingness to give a blood sample of 60%. Follow-up for cancer, mammographic screening and mortality will be based on linkage to national registers based on the unique birth number.
2. In a 5 years follow-up period we will collect tumor tissue from 500 breast cancer cases emerging among cohort participants, through a collaboration with the Norwegian Breast Cancer Group who has members at all major Norwegian hospitals. Breast cancer patient s born 1943-57 will be asked about previously participation in NOWAC before they give informed consent for a core biopsy and another blood sample. More than one third of all women born 1943-57 will be a participant of NOWAC.
3. The genetic analysis will b e done partly at the Departement of genetics at the Norwegian Radium Hospital and partly in collaboration with different FUGE platforms and Stanford university, USA. 
4. Statistical analysis will be performed in close collaboration with statisticians at S tanford and Department of biostatistics, University of Oslo.

The Norwegian Women and Cancer post genome cohort study - NOWAC

Angiogenesis and tumor-vascular interactions are essential for tumor spread. We focus on this aspect since anti-angiogenic therapy avoid treatment resistance. Adhesion molecules are important for the ability of tumor cells to invade surrounding tumor stro ma and to enter the vascular systems (blood vessels, lymphatics), a prerequisite for distant metastatic spread and reduced survival. We have shown that deregulated expression of selected surface molecules (cadherins and catenins) are significant for clini cal progress of endometrial carcinomas,  and angiogenesis is important for metastases in tumors (endometrial,prostate, breast, melanoma). Today there is a gap in our understanding of these processes, and how to predict treatment response.
    The goal of this project is to further explore the molecular determinants of tumor vascular interaction and vascular spread, by integrated DNA microarray (DMA), tissue microarray (TMA) and clinical validation studies. Microarray methods ensure the simultaneous examin ation of multiple markers and regulatory networks associated with predefined molecular pathways, such as cadherin-families, catenins, and the wnt-system. These studies are supported by advanced bioinformatics (CBU, FUGE platform). Invasion of tumor cells into vascular units, which has been documented in our previous studies, will be focused. Its detailed regulation remains to be established. Co-existence of reduced cell-cell adhesion (dysregulated surface molecules) and vascular invasion is of special int erest. Further, the relationship between tumor angiogenesis (microvessel density), vascular proliferation, vascular maturation and vascular invasion by tumor cells, will be studied, and we have preliminary data on the relative importance of these characte ristics. 
    APPLICATION: This application focus on the regulation of tumor-vascular interaction and activated angiogenesis and the ability of related markers to predict  therapy response and patient prognosis.

Critical regulatory networks for tumor-vascular interactions and activated angiogenesis in urogenital cancers

Mammographic density represents a strong and independent breast cancer risk factor, and possibly a useful surrogate endpoint for breast cancer risk. Mammographic density decreases when women undergo menopause or start tamoxifen therapy, but increases in w omen starting postmenopausal hormone therapy with combined estrogen and progestin. There is, however, substantial variation in how mammographic density changes when hormone exposure changes, but the genetic predictors of this change is unknown. Because of  the role of hormones in breast cell proliferation, genetic predictors involved in hormone metabolism or action seem plausible candidates in explaining ‘endogenous’ mammographic density. Identifying these genes is important as they may provide important c lues to hormonal carcinogenesis of the breast.
We are proposing to identify genetic predictors of mammographic density in women on and in women not on hormone therapy among women in the Norwegian Breast Cancer Screening Program (NBCSP), a national mammogr aphic screening program. We will also provide pilot data as to whether genetic predictors for mammographic density explain breast cancer risk.

Genetic predictors of mammographic density

Molecular mechanisms of androgen action and prostate carcinogenesis

The group was formally established in 2002 thanks to a research grant from Norwegian 
Research Council (NFR) (2001-2003). The group consist of core personnel in permanent positions at The Faculty of Medicine, 
NTNU and personnel supported by the above NFR  grants and other grants including NFR. The research groups comprise a broad 
spectrum of competence within clinical medicine, molecular biology, pharmacology and psychiatry/social sciences, as well as 
competent persons founding a good infrastructure for  the research. The group has conducted original research with opioid 
pharmacology and pharmacogenetics as well as subjective symptom assessment and control of symptoms. Clinical trials in 
palliative care and follow-up of cancer survivors have been a bas ic approach together with establishment of biobanks. We will 
now expand into non-malignant pain (which include post cancer morbidity), establish more specific (to understand pain 
mechanisms) or larger biobank samples, and also expand the laboratory acti vities. We have engaged our activity to also 
involve the planned, large population sutdy HUNT-3 with its biobank for pain research.

ERC-European Research Council (ERC)

Antiviral Proteins Applied as Therapeutics in Aquaculture

Awarded: NOK 0.10 mill.

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ERC-European Research Council (ERC)

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