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Tørkeperioder kan gjøre bakken hardere og frastøte seg vann, dette fører til økt fare for flom og jorderosjon hvis det skulle komme styrtregn. Sammenfallende hendelser hvor en tørkeperiode ender i styrtregn kan derfor forårsake større skader på infrastruktur og avlinger enn enkelthendelser med kun tørke eller styrtregn. Global oppvarming har forårsaket at både tørkeperioder og styrtregn intensiveres og skjer oftere, som også kan føre til at sammenfallende hendelser med tørke etterfulgt av styrtregn også kan intensiveres og skje oftere. 
Selv om det er funnet en økning i tørkeperioder og ekstremnedbør med global oppvarming også i klimamodellene, er det også en stor spredning mellom modellene på hvor mye og i hvilke områder som opplever mer tørke og nedbør. Prosjektet vil undersøke faktiske historiske hendelser hvor tørkeperioder endte i styrtregn i værobservasjoner og værmodelldata for å finne passende indekser som kan brukes til å analysere hvordan de forekommer i klimamodellene. Modeller på finere skala gjør en bedre jobb med å modellere nedbør, prosjektet vil derfor bruke finskala høytoppløselige klimamodeller og globale klimamodeller for å se hvordan tørkeperioder avsluttet med styrtregn forekommer i disse. De modellene som gjør det godt opp mot observasjoner vil bli identifisert.  Videre vil prosjektet studere endringene i hyppighet og intensitet av sammenfallende hendelser med tørke og styrtregn med global oppvarming.
En av grunnene man vet til hvorfor det er stor usikkerhet knyttet til hvordan klimamodellene gjenskaper nedbørsmønstre er hvordan fordamping varierer over skog- og andre arealer. I prosjektet vil vi se på effekten av avskoging og økt skogbruk i globale modeller, og gjøre egne beregninger over mindre areal på finskala for å for å se hvordan fordamping blir påvirket. Resultatene av prosjektet er viktig får å unngå eller minimere skadene slike sammenfallende med tørke etterfulgt av styrtregn kan forårsake.

Global warming intensifies drought and extreme precipitation. Compound events with droughts ending in intensified precipitation - DRIP can cause large damages but are extremely understudied. This project aims to estimate the change in frequency and intensity of DRIP events with global warming due to changes in the water-cycle. We will identify actual historical compound DRIP events and find indices that are suitable to identify these events in model data. As global climate models show a large spread in precipitation for both historical and the different future climate projections, there is expected to be a spread in model projections of DRIP events as well. We will constrain this spread by identifying global climate models that do a good statistical representation of historical DRIP events and by analyzing large ensembles to evaluate the natural variability. As higher resolution modelling shows a better representation of the water cycle, the project will analyze regional downscaled global models in identified regions of interest.  We will also perform in-house regional simulations of identified global models down to convection permitting scale to study the change in DRIP events with model resolution. The project will also target a highlighted uncertainty connected to the water-cycle by exploring how evapotranspiration and the occurrence of DRIP events found in climate models respond to land use change. For this analysis we will extend the regional downscaling to include sensitivity studies which contain deforestation and forestation. Results gained from DRIP will make a large contribution to the knowledge needed on future mitigation measures due to the increase in compound events.

DRIP - DRought ending in Intensified Precipitation

Renewable energy on the high seas – science-informed and indigenous knowledge-based recommendations for regulatory and governance challenges

The high seas are those marine areas under no State's jurisdiction. So far, all marine renewable energy (RE) activity is being conducted under State's jurisdiction. However, recent advances in technology are raising the prospect of carrying out RE activity on the high seas. Currently, only seabed mining activities in the Area have been regulated. The Area is the seabed and ocean floor beyond the limits of State's jurisdiction. From the legal viewpoint, the main gap is a lack of an international regulatory framework, informed by participatory mechanisms and supported by scientific evidence, for RE activities on the high seas, especially regarding their environmental and social impacts. 
The primary project objective (O) is to provide the scientific community and policymakers with science-informed and indigenous knowledge-based recommendations in support of the development of  RE regulation on the high seas. 
Two specific Os are set to complement the primary O, namely:
O1 To advance the use of systematic consultation processes that facilitates research at the crossroads of marine sciences and law. 
O2 To advance critical knowledge and understanding of environmental pressing issues comparable to the regulation of RE on the high seas, such as deep-sea mining in the Area.
A multistep innovative methodology will be adopted, by integrating marine scientific knowledge, consultative processes, and advanced critical research in the subject matter. A case study (interdisciplinary and participatory) involving marine scientists, indigenous and coastal communities and policy makers will be conducted onboard the Research Vessel KronPrins Haakon at the beginning of the project. The case study outcomes will be analysed through critical legal analysis to build a knowledge base for policy recommendations. 
The project will advance the PI’s career in an international research environment, allowing her to generate independent, high-quality, and reproducible results.




Prosjektet går ut på å invitere forskere fra norske eller utenlandske universiteter til å presentere sin forskning om økonomi og klima ved Handelshøyskolen ved Universitetet i Stavanger (HHUiS).

Dette skjer i form av et seminar som vanligvis finner sted en gang i uken. En kjent forsker fra et annet universitet kommer til Stavanger og holder et 60-minutters seminar og har en rekke møter med forskere i Stavanger. Vi prøver å ha minst 6-8 møter per gjest. I tillegg spiser gjesten lunsj og middag med UiS-ansatte.

Disse seminarene er en del av en eksisterende seminarserie som også tar for seg andre klimaspørsmål. En stor del av seminarene er imidlertid fokusert på klimaendringer og økonomi, og det er kun til disse seminarene vi søker midler.

En aktiv seminarrekke er hjertet i et forskningsuniversitet, og svært viktig for at forskerne ved universitetet skal kunne utvikle seg og være en aktiv del av det globale forskningsmiljøet. Dessverre må vi av budsjettmessige årsaker kutte ned på denne aktiviteten i år og fremover, og derfor sender vi denne søknaden for å be om midler til denne aktiviteten.

UiS har et meget energisk forskerteam innen økonomi og klima. For eksempel ble Dora Simons forskning nylig nevnt i The Economist, Anders Åkermans forskning ble denne uken nevnt av Det hvite hus i den amerikanske presidentens årlige økonomiske rapport, og Torfinn Harding skriver jevnlig artikler i Dagens Næringsliv og opptrer på norsk TV. For at denne gruppen skal overleve, er det svært viktig å kunne arrangere seminarer om klimaendringer på høyeste internasjonale nivå.

Seminarer med internasjonale forskere om økonomi og klima ved Universitetet i Stavanger

The importance of non-timber forest products (NTFPs) for better balancing tropical forest conservation and poverty alleviation goals is increasingly recognised. Yet, in Africa, poor understanding of the impact of harvesting on species’ populations and forest carbon stocks, together with little information on the traditional institutions which have informally regulated NTFPs extraction in the past -and could continue to do so in the future-, hamper the use of NTFPs in both forest conservation and development initiatives. 
AFRI-FOR will gather the knowledge needed to determine (1) the key enablers of sustainable harvesting for groups of plant or wild meat species, (2) which types of NTFP harvesting can have synergies with carbon storage, and (3) how traditional institutions can be integrated into formal conservation. To achieve these objectives, AFRI-FOR provide new methods, including (i) a new interdisciplinary approach for investigating NTFPs harvesting impacts, combining traditional ecological knowledge (TEK, from local communities), surveys of plants and wildlife, market surveys and modelling techniques; and (ii) a novel standardised protocol for gathering information about traditional institutions and compliance towards them. AFRI-FOR will gather data and knowledge from 20 socio-ecological forest contexts in five countries (Sierra Leone, Cameroon, DR Congo, Uganda and Kenya), which will allow insights to transcend single sites and provide a much-needed general understanding. This high-risk and high-gain project will provide a step-change in our ability to inform forest conservation in Africa, by identifying synergies between biodiversity conservation, carbon storage and poverty alleviation goals.


Improving tropical forest conservation in Africa

Currently, 28.2% of the total EU-28 greenhouse gas emissions come from the power sector, a large contributor to greenhouse gas emissions. Consequently, the emphasis of the research in power generation has swung towards assessing highly efficient and greener power cycles. In this reference, the novel supercritical carbon dioxide Brayton cycle (sCO2-BC) is an ideal choice that outstrips other formally well-known power cycles (Brayton & Rankine cycles). In sCO2-BC, the role of the pre-cooler is critical. It serves as a sink to the power cycle and regulates the conditions at the compressor's inlet. The compressor's inlet temperature is intended to be maintained close to the critical temperature of carbon dioxide (CO2) to achieve greater cycle efficiencies. However, exceptionally higher values of the specific heat capacity of CO2 near its critical point (up to 40 times higher than water) require exceedingly high water flow rates on the cold side to achieve the desired exit temperatures of CO2. Consequently, the pre-cooler's pumping power requirements become high enough to deteriorate the cycle's performance. This problem can only be mitigated by exploring new channel geometries with enhanced thermohydraulic characteristics. Therefore, the proposed study plan to characterize the complex thermohydraulic characteristics in the pseudocritical region of CO2 using a multifaceted technique that includes, experimental, numerical, and machine learning techniques. The proposed work will provide a step forward to the success of sCO2-BC technologies that, in turn, will facilitate its integration with the green energy resources (generation-IV nuclear reactors and solar concentrated plants), helping to meet the EU's 2030 climate and energy framework goals of achieving at least 32% share for renewable energy.

Evaluation of thermohydraulic characteristic of printed circuit heat exchangers in pseudocritical region for supercritical CO2 cycle

AGREE tar for seg klimaendringers innvirkning på kulturarv gjennom tverrfaglige metoder og samarbeid mellom ulike samfunnsaktører. Prosjektet tar særlig for seg urbane områder som påvirkes av flom. Målet er å forstå det komplekse forholdet mellom forvaltning av kulturarv, klimatilpasning og samfunnets sårbarhet, og å se på tiltak for å minimere risiko for tap og ødeleggelse som følge av klimaendringer. Sentrale delmål inkluderer integrering av strategier for bevaring av kulturarv med strategier for klimatilpasning, spesielt gjennom konseptet Historisk Urban Landskap (HUL). 

AGREE vil utvikle en beslutningsmodell forankret i HUL-konseptet som sammenligner dagens forvaltningspraksis med historiske data for å belyse sårbarhet og klimatilpasning i en urban kontekst. AGREE vil fremme transformative strategier for klimatilpasning ved å evaluere beslutningstakernes forståelse av disse samspillene. 

Prosjektet ledes av University of Leeds (Storbritannia), og har Norsk institutt for kulturminneforskning (NIKU), Politecnico di Torino (Italia) med som partnere. ICCROM (International Centre for the Study of the Preservation and Restoration of Cultural Property), British Council (Storbritannia), UK’s Department for Culture, Media and Sport (Storbritannia), Hull City Council (Storbritannia) og Innlandet fylke (Norge) deltar som samarbeidspartnere. Gjennom dette samarbeidet skal prosjektet bidra til å forme politikk og klimastrategier, både lokalt og globalt.  AGREE vil også engasjere publikum for å øke bevisstheten om klimatilpasning og mobilisere til felles handling.  Gjennom bred involvering skal AGREE bidra til å sikre at kulturarven forblir beskyttet og motstandsdyktig i møte med klimaendringer.

Alt i alt vil AGREE utforske klimaendringers påvirkning på kulturarv med en praksisorientert tilnærming, og med fokus på samarbeid, databasert beslutningstaking og samfunnsengasjement for å sikre vår felles kulturarv for fremtidige generasjoner.

AGREE champions transformative sustainability in response, emphasizing interdisciplinary methodologies and societal shifts. It explores the intricate link between cultural heritage governance, climate adaptation, and community resilience, rooted in responses to flooding in urban contexts. AGREE promotes the Historic Urban Landscape concept for integrative decision-making in climate adaptation, considering community resilience amidst environmental changes. An interactive Geographic Information System platform will illuminate this interplay over time. An innovative AGREE's contribution is a decision-making model grounded in the HUL paradigm. This model juxtaposes current national and local policies enabling cultural heritage integration in climate adaptation with historical data sources revealing urban resilience lessons and changes in the built environment over time. AGREE employs transformative governance concepts to evaluate decision-makers comprehension of these synergies and their perspectives. It advances transformative climate adaptation by uncovering potentials and barriers within heritage governance in case studies from the UK, Norway, and Italy. Beyond research, AGREE will shape policies with multi-scalar and cross-sectorial governance, interpreting climate intricacies through cultural heritage. It will strengthen global, national, and local heritage-focused climate strategies through partnerships with the British Council, ICCROM, and the UK's Department for Culture, Media, and Sport and local stakeholders, such as Hull City Council (UK) and Innlandet Region (Norway). AGREE also engages the public, raising climate adaptation awareness and mobilizing collective action, benefiting governmental climate efforts.

Advancing Cultural Heritage Governance for Resilient Climate Adaptation

RETRACE-prosjektet, som strekker seg over tre år, tar for seg den økende trusselen fra naturkatastrofer, som har rammet over 2,3 milliarder mennesker siden 2000-tallet. RETRACE fokuserer på lokalsamfunn i Arktis og Stillehavsområdet, som marquisene i Fransk Polynesia, samene og kvenene i Norge og ahtnaene i Alaska, og har som mål å styrke motstandskraften mot klimarisiko. Disse lokalsamfunnene, som er dypt sammenvevd med omgivelsene sine, gir uvurderlig innsikt i hvordan man overlever og trives i en krevende miljøsituasjon.

RETRACE tar utgangspunkt i hypotesen om at urfolks- og lokalkunnskapssystemer, særlig fra lokalsamfunn i polar- og stillehavsområdene, er uunnværlige for å utvikle effektive strategier for motstandskraft. Prosjektets metode innebærer å samle inn et rikt datasett som omfatter vitnesbyrd, kulturelle praksiser og levde erfaringer, i tillegg til kvantitative analyser. Målet er å skape et omfattende rammeverk som tar hensyn til lokale kontekster og fremmer tilpasningsdyktige og inkluderende resilienspraksiser.

Et internasjonalt forskerteam fra Frankrike, Norge og USA samler en rekke ulike ferdigheter for å bygge bro mellom vitenskapelig forskning og virkeligheten i lokalsamfunnene. Målet er å utvikle et romlig beslutningsstøttesystem som både bidrar til å visualisere resiliensdata og fungerer som et verktøy for samfunnsbasert beslutningstaking, noe som forbedrer evnen til å håndtere risiko og utnytte tradisjonell kunnskap på en effektiv måte.

Ved å kombinere lokal innsikt med vitenskapelig innovasjon skal RETRACE bane vei for resiliensstrategier som både er bærekraftige og tar hensyn til de unike behovene til sårbare lokalsamfunn. Dette prosjektet setter ikke bare søkelyset på urfolks- og lokalkunnskapens avgjørende rolle når det gjelder å håndtere klimaendringene, men har også som mål å sette lokalsamfunn over hele verden i stand til å håndtere de utfordringene som et klima i endring fører med seg.

The three-year RETRACE project responds to the increasing impact of natural disasters on over 2.3 billion people since the beginning of the millennium. It has a particular focus on Arctic and Pacific communities vulnerable to climate risks, specifically, the Marquesan community in French Polynesia, the Sámi and Kven communities in Norway, and the Ahtna people in Alaska. The project aims to address the resilience(s) of communities, in order to develop more inclusive and equitable approaches to developing and implementing resilience strategies.

Five hypotheses guide the research, based on the assumption that indigenous communities such as the ones living in Polar zones and Pacific islands, developed resilience knowledge and strategies to cope with climate-related events. The project aims to co-develop a spatial decision-support system for producing and visualizing qualitative and quantitative data on the different forms of local, community, intrinsic and traditional resiliences in those communities.

Utilizing a narrative approach, the consortium collects testimonials, cultures, memories, experiences, sensitivities and expertise from both Arctic and Pacific communities on forms of resilience and their visions of climate risks, alongside quantitative open-source data from traditional assessments. This data will be cross-referenced to build an interdisciplinary framework for a nuanced understanding of local needs, suitable to assess resilience in local contexts. 

Comprising researchers from France, Norway and the USA with diverse expertise, the consortium aims to contribute in developing risk management and resilience strategies by integrating local and indigenous knowledge into an adaptable and sustainable spatial decision-making tool. The tool aims to bridge the gap between international scientific research and local community realities, potentially informing strategies in other vulnerable territories in the future.

ResilienceS to climate risks: lessons from Arctic and Pacific communities

Potetskrell, et biprodukt fra industriproduksjon av potet (pommes frites, flak, chips mm.) er en råstoff ressurs som kan bli bedre utnyttet til nye formål. Skrellet er nemlig en rik kilde på antioksidanter, stoffer som planter naturlig har i seg for å beskytte mot skadelige UV-stråler og reaktive forbindelser som oksygen radikaler. Antioksidanter behøver vi også å tilsette i matvarer for å beskytte og ta vare på umettet fett så det ikke blir harskt og vondt i kontakt med luft. I dag brukes flere ulike syntetiske stoffer i matvarer for å hindre oksidasjon av fett og oljer. Men det er reist bekymring rundt sikkerheten for bruken av dem. Matvareindustrien, myndigheter og forbruker ønsker derfor å fjerne flere syntetiske antioksidanter og erstatte dem med naturlig alternativer. Det er imidlertid svært få slike produkter som er godkjent og tilgjengelig på markedet. Prosjektet Peel Preserve, som har et klart bærekraft mål, skal vise om et uttrekk av antioksidanter laget på industrielt potetskrell råstoff kan fungere som konserveringsmiddel og erstatte noen av de stoffene som brukes i dag. Tre næringsmiddelbedrifter skal teste potetskrell-ekstraktet i noen av sine produkter og utføre både interne og eksterne analyser på effekten. Men en viktig forutsetning for at potetantioksidant kan tas i bruk som nytt tilsetningsstoff i mat er at det blir godkjent av den Europeiske matsikkerhets myndigheten (EFSA) og gitt et E-nummer. Prosjektet skal igangsette denne lengre flertrinns godkjennings prosessen. Parallelt skal det utvikles en forretningsmodell og nødvendig beskyttelse rundt teknologien. Dersom industrien etter testingen av potetantioksidanten, vurderer denne som er god erstatning til konkurransedyktig pris, og en EFSA-godkjenning kan oppnås på sikt, åpner det for å kommersialisere et naturlig plante-basert produkt til beste for forbruker og for miljøet. Bak prosjektet Peel Preserve står Høgskolen i Innlandet i samarbeid med Nofima og Klosser Innovasjon.

Preserving foods with potato peels: Industry-relevant validation and first regulatory assessment of a new natural antioxidant

Sjøisen i Arktis har minket drastisk de siste tiårene, og Polhavet forventes å være isfritt om sommeren mot slutten av århundret. Denne nedgangen har utsatt store havområder for vind, noe som har resultert i at det oftere dannes store bølger i Polhavet. Disse bølgene kan forplante seg over flere titalls til hundrevis av kilometer i sjøisen, knekke den og akselerere smeltingen. Disse fysiske prosessene – bølger som knekker sjøis og effekten dette har på sjøissmelting og vekst – mangler i modellene vi bruker for å forutsi klimautviklingen. Dette bidrar til store usikkerheter i klimamodeller. Effekten av bølger på sjøisen er heller ikke tatt med i prognoser for havets og sjøisens forhold, som brukes av skip som opererer i islagte farvann. I ForWArd ønsker vi å vurdere bølgenes innvirkning på sjøisens utvikling i det stadig røffere Polhavet. I dette arbeidet brukes en svært avansert modell som inkluderer sjøis, hav, bølger og deres interaksjoner. Vi skal først vurdere hvor godt den representerer forholdene i Polhavet sammenlignet med de få tilgjengelige observasjonene. Vi vil så bruke modellen til å undersøke hvordan bølgehøyden og arealet av ødelagt sjøis har utviklet seg de siste tre tiårene. Deretter vil vi kombinere modellen vår med forholdene i det fremtidige Polhavet gitt av klimafremskrivninger, for å undersøke hvordan betydningen av interaksjoner mellom bølger og is vil utvikle seg ettersom sjøis avtar i det 21. århundre. Vår modells estimering av "bølgepåvirkningen" vil tillate polarvitenskapsmiljøet å vurdere hvor usikre deres klimaspådommer uten bølger er. Til syvende og sist vil våre modellresultater og utviklinger legge grunnlaget for å legge til bølgeeffekter i hav- og sjøisvarsler i Arktis. Dette vil gjøre varslene mer nøyaktige og bidra til sikkerheten for menneskelig aktivitet i denne regionen.

Arctic sea ice decline under climate change has allowed waves to form and grow more easily in the Arctic Ocean. These waves propagate into the sea ice over tens to hundreds of kilometres, fragmenting it into small floes. This area of broken ice, known as the Marginal Ice Zone (MIZ), is a highly complex region where many interactions occur between the ocean, sea ice, and atmosphere. The action of waves strongly affects these interactions, with rapid feedbacks on the sea ice. However, climate models do not account for these wave-ice interaction processes, which likely contributes to the strong biases in their estimation of modelled sea ice extent and volume and their inability to capture short-term sea ice extent variability. Given the lack of observations available, numerical models remain the best way to estimate how wave-ice interaction processes can impact Arctic sea ice, but most wave-ice coupled models are still prototypes. In ForWArd, we will use one of the most advanced of these models to assess this impact in the context of climate change. To this aim, we will use the latest observations to calibrate the modelled wave-affected area and produce a 30-year-long hindcast of the MIZ extent evolution to analyse how it responded to larger wave height, delayed refreezing, and thinner ice. Then, we will assess the relative importance of the wave-ice interactions suspected to affect sea ice in the MIZ using well-documented events. Finally, we will estimate how waves will contribute to sea ice extent and volume variability in the coming decades, as large areas of open water will remain open until late in the autumn. The flexibility of our setup will allow us to test the sensitivity of our results to model resolution and assumptions, giving invaluable insights into the biases induced by misrepresenting wave-ice interactions. ForWArd will also pave the way for the integration of wave effects in sea ice forecasts, a requirement for safer operations in ice-infested waters.

Forecasting Wave impact as Arctic sea ice declines

SASCHA har som mål å utvikle praktiske verktøy og metoder for å vurdere og håndtere kulturminner når klimaendringer utgjør en risikofaktor. Prosjektet ledes av University College London (UCL), og har Norsk institutt for kulturminneforskning (NIKU), Arizona State University (USA), NHAZCA (Italia) og North Carolina State University (USA) med som partnere. ICCROM (International Centre for the Study of the Preservation and Restoration of Cultural Property), English Heritage Trust (Storbritannia) og Ventotene kommune (Italia) deltar i prosjektet som samarbeidspartnere. 

 Hovedmål for prosjektet:  
- Utvikling av indikatorer og målemetoder for måling av klimaendringers virkning på kulturarv. 
- Etablere metoder for å involvere relevante aktører i identifiseringen og målingen av disse virkningene. Metodene skal kunne tilpasses lokale forhold og kulturell kontekst. 
- Utvikle verktøy for å hjelpe beslutningstakere til å vurdere og anvende målinger på ulike nivåer. 
- Utforske utfordringer og muligheter knyttet til bruk av nye metoder for vurdering klimarelaterte risikofaktorer for kulturminner. 

Ved å oppnå disse målene skal SASCHA ruste lokalsamfunn og kulturminneforvaltningen til å bedre forstå og håndtere klimarisiko. I tillegg, gjennom samarbeid med organisasjoner som UNESCO og ICCROM, skal SASCHA bidra til globale diskusjoner om hvordan klimaproblematikken kan integreres i kulturminneforvaltningens praksis. Alt i alt vil SASCHA legge til rette for politikkutvikling og styrke kulturminneforvaltningen ved å tilby verktøy og metoder for å effektivt vurdere, tolke og formidle klimarisiko for kulturarvsteder over hele verden.

SASCHA proposes operationalisation for transferable risk assessment and a value-based decision support tool. Supported by this approach, the overarching aim of SASCHA is therefore to develop innovative methods for understanding risks of climate change for heritage that allow for multiscale analysis and scalable approaches, bridging the gaps between local knowledge and global data, and from local vulnerability to global risks. To this end, SASCHA will: a) develop a set of operationalised indicators/metrics for relevant determinants of climate change; b) develop a locally adaptable protocol for stakeholders' engagement in the identification of relevant determinants of climate impacts that acknowledge and celebrate diversity in cultural contexts; c) develop a climate adaptation decision support tool to evaluate relevance of assessment approaches for different spatial scales; d) explore the challenges and opportunities of an operationalisation approach to climate change--heritage risk. Addressing a complex, wide and research-intensive subject, SASCHA unfolds several organisational, scientific, technical, technological and cultural heritage-oriented elements. SASCHA includes four research partners, together bringing significant experience in climate change and heritage and requisite expertise in physical sciences (UCL), social sciences and humanities (NIKU, NCSU/ASU) and technology (NHAZCA). The consortium can significantly contribute to safeguarding and protecting their region's coastal heritage but also to the global discussion of the integration of climate impacts assessment on cultural heritage through the close collaboration with UNESCO's Advisory body, ICCROM and case study stakeholders. SASCHA will develop methods for assessing, interpreting, and communicating climate change risks for heritage, while also supporting effective policy development and heritage management.

Multiscale approaches and scalability within climate change-heritage risk assessments

Midlene fra PES-EUR-Prosjektetablererstøtte Eureka fordelt på år

Midlene fra PES-EUR-Prosjektetablererstøtte Eureka fordelt på fylker

Midlene fra PES-EUR-Prosjektetablererstøtte Eureka fordelt på fagområde

Personalised cardiovascular disease prevention program: the Berkeley Heart CVD Risk Reduction (BHRR) Program

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

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

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

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

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.

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

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

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

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

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

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

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

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

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

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.

Opioids, Symptom Management and Palliation Research Group

Androgens have a pivotal role in the development and maintenance of the male reproductive system, the normal prostate, as well as the initiation and progression of prostate cancer . Prostate cancer is the most commonly diagnosed non-cutaneous cancer and s econd
leading cause of cancer death in men. Despite this high incidence rate and mortality, there is at present very limited information on the cellular and molecular alterations in prostate cancer. Androgens are one of the major factors in prostate cance r development and
progression. Despite the recognition of the importance of androgens for normal prostate and prostate cancer for over 60 years, the molecular mechanisms by which androgens influence the prostate cancer cell is not known. The goal of this research project is to
uncover some of the molecular details of androgen action as it relates to prostate cancer. The focus is on the androgen receptor, a ligand modulated transcription factor, that transduces the effect of androgens in the cell. In addit ion to structure/function studies on
the androgen receptor and its crosstalk with other signalling pathways, a major effort in the laboratory is on the identification, cloning, and characterization of androgen regulated and/or highly prostate enriched nov el genes.

Molecular mechanisms of androgen action and prostate carcinogenesis

Formålet er økt integrasjon av forskning og behandling av kreftsykdommen myelomatose gjennom følgende delprosjekter: 
<h>1. Ødeleggelse av skjelettet ved myelomatose er et hovedproblem ved sykdommen. Prosjektet undersøker hvorledes faktorer i blod og benm arg påvirker bensykdommen. Osteoprotegerin (OPG) gir beskyttelse mot beinsykdommen, og prosjektet studerer hvorledes OPG interagerer med syndecan-1 på overflaten av myelomcellene og blir internalisert i cellene. Hemming av denne mekanismen gir mulighet fo r ny behandlingsstrategi. 
<h>2. Vekst av myelomceller er selve årsaken til sykdommen. Prosjektet undersøker hvorledes faktorene bone morphogenetic protein (BMP) reduserer og interleukin 21 (IL-21) øker kreftcelleveksten. 
<h>3. Genutrykk i myelomcellene.  Gjennom isolering av mRNA fra rensete myelomceller og DNA microarray søker en å påvise gener og proteinproduksjon som er viktige for patogenesen av myelomatose 
<h>4. <i>Biobank</i>. Biologisk materiale fra pasienter med myelomatose samles i en biobank o g er et viktig grunnlag for integrert eksperimentell og klinisk forskning. 
<h>5. Utprøving av nye medikamenter gjennom behandlingsstudier i samarbeid med Nordisk myelomatose studiegruppe. Prosjektet vil ha et særlig ansvar for undersøkelse av thalidomid  til pasienter med nyoppdaget myelomatose. Studien starter høsten 2001 og omfatter 800 pasienter i Norden rekruttert over 4 år.

PES-EUR-Prosjektetablererstøtte Eureka

Personalised cardiovascular disease prevention program: the Berkeley Heart CVD Risk Reduction (BHRR) Program

Awarded: NOK 0.10 mill.

Funding scheme:

PES-EUR-Prosjektetablererstøtte Eureka

Funding Sources

Thematic Areas and Topics