Galileo är ett europeiskt system med global täckning som idag utgörs av ca tio operativa satelliter. Systemet utökas successivt och beräknas vara fullt operativt runt år 2020. Fyra nya satelliter är planerade att aktiveras under 2017 och ytterligare fyra satelliter kommer att skjutas upp under 2017.  Syftet med studien har varit att testa tillgängligheten och osäkerheten i Galileo mot SWEPOS i en multi-GNSS-konstellation. Där målet har varit att visa vilka fördelar Galileo kan bidra med vid satellitpositionering i Network Real Time Kinematic (Nätverks-RTK) under tuffare mätförhållanden.   Nätverks-RTK mätningar har genomförts för att studera förbättringar Galileosignaler kan bidra till i olika utmanande miljöer. Mätningar har utförts i två typer av miljöer, skogsmiljö där träd stör och blockerar satellitsignaler och även i urban miljö där höga byggnader och fordon kan störa signaler och orsaka fel. Mätningarna har utförts över punkter med kända koordinater i Gävle stad och Mårtsbo. Flera mätningar har gjorts över varje punkt, en mätning varje sekund i 60 sek, vilket möjliggör 60 observationer. Denna procedur har gjorts flera gånger med elevationsvinklarna 15, 25 och 35°. SWEPOS, det permanenta GNSS-nätverket i Sverige har använts vid genomförandet av nätverks-RTK-mätningarna. SWEPOS är ännu inte kompatibelt med Galileo, därför har tillfälliga SWEPOS-referensstationer som stöder Galileo använts. Mottagaren och den handhållna enheten som används under mätningarna har varit från tillverkaren Trimble. GNSS-planering har använts för att se till att det alltid funnits Galileo-satelliter tillgängliga under mätningarna. Studien visade att för att kunna se fördelarna med Galileo under nätverksRTK måste elevationsvinkeln sättas högre än 15°. Detta begränsar antalet satelliter som tillhör Globalnaya Navigatsionnaya Sputnikovaya Sistema (Glonass) och Global Positioning System (GPS), vilket kan visa fördelarna med Galileo. På vissa punkter som använts för mätningarna var det inte möjligt att få fixlösning utan Galileosignaler.  Slutsatsen av studien är att Galileo med få satelliter kan bidra till en högre satellittillgänglighet, en högre chans till att uppnå fixlösning och minimera tiden för att uppnå fixlösning vid användning av en hög elevationsvinkel eller i tuffa miljöer.

Realtidsuppdaterad fri stationsetablering (RUFRIS) är en metod för att utföra geodetiska mätningar med totalstation. Metodiken bygger på fri station som använder bakåtobjekt skapade i realtid med Nätverks - Real Time Kinematic (N-RTK). Den praktiska användningen är gynnsam i olika verksamhetsområden och nödvändigheten att ajourhålla passiva stomnät och fixpunkter upphört. Syftet med denna studie är att utforska vad den förväntade mätosäkerheten är vid RUFRIS-etablering och detaljmätning med mätningsinstrument av fabrikaten Leica, Trimble och Topcon. Andra studier visar att ökat antal bakåtobjekt vid RUFRIS ger en minskad mätosäkerhet, vilket också testas i denna studie.Olika tidsintervall vid kontinuerlig datalagring för positionsbestämning av bakåtobjekt med N-RTK har använts, tidsintervallerna är 10, 60 och 180 sekunder. I kombination med olika antal bakåtobjekt har stationsetableringar och detaljmätning utförts. Antalet bakåtobjekt använda är 3, 5, 10/15 och 25. Koordinaterna från RUFRIS har kontrollerats mot referenspunkter skapade med långa GNSS-mätningar så kallad. statisk mätning med 4 timmar och 30 minuter lång observationstid. Rådata skickades in till SWEPOS-efterberäkningstjänst, för att få noggrant positionsbestämda referenspunkter i SWEREF 99 16 30 och RH 2000 referenssystem. I sin tur användes referenspunkterna för att avgöra hur stora avvikelser som erhålls vid RUFRIS.Mätosäkerheten vid stationsetablering är upp till cirka 40 mm i plan och höjd, beroende på längd av tidsintervall och antal bakåtobjekt, och god geometrisk spridning av bakåtobjekt upprätthålls. Mätosäkerheten i plan vid detaljmätning är ca 25 mm och ca 30 mm i höjd. Vid positionsbestämning i höjd gav 180 sekunder med få bakåtobjekt (3-5 st) en mindre avvikelse på ca 10 mm.Den största felkällan som påträffades är grova fel, dessa kan minimeras gengenom att kontrollera hur väl bestämda bakåtobjekten är skapade med N-RTK. Systematiska fel påträffades också och kan undvikas genom att hålla instrumenten servade och kalibrerade med jämna mellanrum.

Fri stationsetablering med nätverks-RTK är en metod för att etablera en totalstation över en okänd punkt utan att ha tillgång till några kända punkter. Detta möjliggör för noggranna mätningar där stompunkter saknas. Det finns olika sätt att genomföra fri stationsetablering med n-RTK, och i denna studie utvärderades fyra olika sådana, där skillnaden mellan dem handlar om hur bakåtobjekten bestäms. De metoder som studerades var RUFRIS med 15 respektive 3 bakåtobjekt, Dubbelmätning och 180-sekundersmetoden. Vid RUFRIS mättes varje bakåtobjekt in med en observationstid på 5 s. Vid Dubbelmätning användes tre bakåtobjekt som var medeltal från två inmätningar vardera i 5 s med en tidsseparation på 30 min. Bakåtobjekten vid 180-sekundersmetoden var tre till antalet som mättes in med en observationstid på 180 s. Metoderna beskrivs bl.a. kortfattat i HMK – GNSS-baserad detaljmätning 2017 och ytterligare ett syfte med studien var att utvärdera beskrivningen utav dem däri. Med varje metod genomfördes tio etablering och efter varje sådan mättes en detaljpunkt in för att även undersöka hur noggranna inmätta detaljpunkter blev med de olika metoderna. Metoderna utvärderades genom att jämföra osäkerheter, RMS och användarvänlighet för etablerings- respektive detaljpunkter. Osäkerheterna var dels baserade på spridningen av tio etableringar/inmätningar per metod över en och samma punkt och dels sådana som presenterades i instrumentet vid varje etablering. För beräkning av RMS användes referenspunkter som mätts in genom statisk GNSS-mätning som efterberäknats i SWEPOS Beräkningstjänst. Förutom jämförelser mellan metoderna kontrollerades även om metoderna gav tillräckligt låga osäkerheter för att klara de rekommenderade toleranser för fri stationsetablering som anges i HMK – Terrester detaljmätning 2017. Beräknade osäkerheter i plan, alla metoder inräknat, varierade från 3 till 6 mm sett till både etablerings- och detaljpunkten vilket innebär att samtliga metoder klarar de högre toleranserna i HMK. Den metod som fick både lägst osäkerhet och RMS var RUFRIS med 15 bakåtobjekt, vilken dessutom var ensam om att vara tillräckligt noggrann för att klara de lägre toleranserna. Motsvarande osäkerheter i höjd varierade mellan 3 och 8 mm. Vad gäller toleranserna, visade sig endast RUFRIS med 15 bakåtobjekt vara lämplig, vid lägre krav. Vid högre krav fordras noggrannare metoder. Referenspunkterna hade för höga osäkerheter i förhållande till osäkerheterna hos de studerade metoderna, för att kunna utvärdera metoderna baserat på RMS, i den omfattning det var tänkt. / Free station set up with network-RTK (n-RTK) is a method of establishing a total station over an unknown point without having access to any known points. This allows for accurate surveying even though control points are missing. There are different ways to perform free station set up with n-RTK, and in this study, four different methods were evaluated. The difference between the methods is how the target points are determined. The methods evaluated were RUFRIS (real time updated free station) with 15 and 3 target points, double measurement and the 180seconds method. With RUFRIS, each target point was measured with a 5 s observation time. In double measurement, three target points were used, where each target point was the average of two measurements. Each of these measurements used a 5 s observation time, and a 30 minute separation between the measurements. The number of target points in the 180-seconds method were also three, measured with an observation time of 180 s. The methods are briefly mentioned in HMK – GNSS-baserad detaljmätning 2017 and another purpose of the study was to evaluate the description of them in that document. With each method, ten establishments were performed and after each of them a detail point was surveyed to also analyze how accurate the different methods were in surveying. The methods were evaluated by comparing uncertainties, RMS and user-friendliness for establishments and detail points, between the respective methods. The uncertainties were on one hand based on the deviation of the ten establishments/detail points per method, each one made over the same point, and on the other hand based on the uncertainties presented by the instrument after each establishment. For calculation of RMS, reference points were used, which were measured by static GNSS, and then postprocessed in SWEPOS Beräkningstjänst. In addition to comparisons between the methods, they were also tested to see if they reached sufficiently low uncertainties to meet the recommended tolerances for free stationing, stated in HMK – Terrester detaljmätning 2017. Calculated planar uncertainties, all methods included, ranged from 3 to 6 mm for both the total station and the detail point, which means that all methods can handle the higher tolerances in HMK. The method with the lowest uncertainty and RMS was RUFRIS with 15 target points, which was also low enough to be able to cope with the lower tolerances. The uncertainties of the heights varied from 3 to 8 mm, in which RUFRIS with 15 target points was the only method precise enough to pass the higher tolerances. Another method with lower uncertainty is required when the higher tolerances for heights is specified. The chosen method for determining the reference points turned out to be too uncertain relative to the evaluated methods. Therefore RMS were not as appropriate for comparisons as planned.

Today, GNSS measurements play an important role in the surveying industry, and their use is ever increasing. Many different GNSS receivers and antenna manufacturers are on the market with new ones appearing. The purpose of this study is to investigate the level of measurement uncertainty of three different GNSS receivers: Leica GS15, Sokkia GCX2 and Satlab SL300. The method in this study is based mainly on the method proposed by HMK - Geodatakvalitet 2015 (Manual in measurement and map issues – Geographic data quality 2015 [author’s translation]) by Swedish Lantmäteriet for "Evaluation of measurement uncertainty in Network RTK [author’s translation]”. Some corrections and additions are made to this method but the basis of the method is retrieved from there. Formulas are used to calculate radial deviation and limit requirements for these. Even standard deviations and radial mean deviations as well as tolerances for these are calculated. The field measurements are made on two RIX 95-points. This is done repeatedly to get up to 20 measurements. The GNSS receivers are mounted on a tripod with a tribrach that is centered over the known points. The main finding from this study is that all investigated receivers, apart from four overriding values ​​for the Leica GS15, perform better than specified by their manufacturers. However, Sokkia GCX2 and Satlab SL300 are approved with uncertainties within the calculated tolerances. The Leica GS15 instrument is very close to meeting the demands but does not reach all the way. A committed error during the performed measurements with the Satlab SL300 makes its evaluation based on 19 instead of 20 measurements. Still, calculations are performed on the collected data that resulted in low measurement uncertainties well below the manufacturer's specified uncertainty. The study was conducted during five weeks in May and June 2017.

Flygfotografering med Unmanned Aircraft System (UAS) är i jämförelse med traditionell fotogrammetri effektivare, billigare och säkrare vilket har medfört att denna teknik föredras av många aktörer. Ett tidskrävande arbete som varit svårt att kringgå är att etablera flygsignaler på marken som används för att georeferera och kontrollera flygbilderna med. Under 2018 presenterade UAS-tillverkaren DJI sin nya quadcopter med integrerad Real-Time Kinematic (RTK)-modul. I samband med detta kan kontinuerliga och noggranna positioner levereras via Nätverks-RTK (NRTK) och behovet av markstödpunkter reduceras. I denna studie undersöktes lägesosäkerheterna i plan för ortofoton som framställdes med hjälp av en DJI Phantom 4 RTK där flygbilderna georefererades med begränsat antal eller utan markstödpunkter. Lägesosäkerheterna beräknades och kontrollerades enligt Handbok i mät- och kartfrågor (HMK) – Ortofoto, vilket är ett stöddokument inom ämnet. Vid framställning av ett ortofoto krävs även en digital terrängmodell (DTM) eller en digital ytmodell (Digital Surface Model, DSM) och kvaliteten av denna har stor inverkan på ortofotots kvalitet. I denna studie kontrollerades och utvärderades därför en del av den DSM som användes vid ortofotoframställning för respektive uppsättning enligt den tekniska specifikationen SIS-TS 21144:2016. Resultatet från studien visar att ett ortofoto går att framställas utan markstödpunkter och samtidigt klara kraven på specificerad lägesosäkerhet enligt HMK-standardnivå 3. Den sammanlagda lägesosäkerheten beräknades till 0,029 m vilket är 5 mm högre i jämförelse med ett ortofoto som baserats på traditionell georefereringsmetod, dvs. med markstödpunkter. Kravet på kvalitet i höjddata uppfylldes också för ortofotoframställning trots att en systematisk effekt i höjd uppkom. Denna effekt påverkade inte ortofotots koordinater i plan då standardosäkerheterna i höjd var låga. Resultatet visade att om två markstödpunkter adderades i vardera änden av området, kunde de systematiska effekterna i höjd minimeras och det var då möjligt att skapa en DSM som uppfyller kraven för detaljprojektering (noggrannhetsklass 1–3) enligt SIS-TS 21144:2016. / Aerial photography with UAS is in comparison with traditional photogrammetry more efficient, cheaper and safer which has led to this technology being preferred by many performers. A time-consuming job that has been difficult to avoid is to establish signals at the ground that are used for georeferencing and evaluate the results. In 2018, the UAS manufacturer DJI presented its new quadcopter with integrated Real-Time Kinematic (RTK) module. This allows continuous and accurate positions delivered via Network RTK (NRTK) and the need of ground control points can be reduced. In this study, investigations of the position uncertainties in orthophotos produced using a DJI Phantom 4 RTK carried out where the aerial images were georeferenced with limited numbers or without ground control points. The position uncertainties were calculated and controlled according to the Swedish HMK – Ortofoto (Orthophoto) which is a document within the subject. When producing an orthophoto, a digital terrain model (DTM) or a digital surface model (DSM) is also required and the quality of this has a great impact on the result. Therefore, a part of the DSM used for orthophoto production for each set was checked and evaluated according to the Swedish technical specification, SIS-TS 21144:2016. The result of the study shows that an orthophoto can be produced without ground control points and at the same time meet the requirements for specified position uncertainty according to HMK standard level 3. The total position uncertainty was calculated to be 0,029 m, which is 5 mm higher compared to the orthophoto based on the traditional georeferencing method, i.e. with ground control points. The requirement for quality in height data was also met for orthophoto production even though a systematic effect in height occurred. This effect did not affect the plane coordinates in the orthophoto because of the low standard uncertainties in height. The result showed that if two ground control points were added at each end of the area, the systematic effects were minimized, and it was possible to produce a DSM that fulfils the requirements for accuracy class 1-3 according to SIS-TS 21144:2016.

Le cancer du sein triple négatif (CSTN) représente 10-15% des cancers du sein. Son pronostic est sombre en particulier face à la rareté des thérapies ciblées adaptées à ce sous type. Sa complexité de prise en charge est directement liée à sa grande hétérogénéité tant au niveau moléculaire que morphologique.Dans ce contexte, nous avons développés des modèles de Patient Derived Xenograft (PDX) issus de CSTN. Ce modèle, robuste, a la particularité de retenir les caractéristiques (histologiques, génotypiques mais aussi phénotypiques) des tumeurs observées chez les patients.Dans notre cohorte de 61 PDX de CSTN, nous avons confirmé l’hétérogénéité anatomopathologique et génomique de ce sous type. Les différentes anomalies moléculaires mises en évidence sont de faible fréquence (<10%) mais 88% de nos modèles ont une altération potentiellement ciblables et plus de la moitié ont au moins 2 altérations ciblables. Nous nous sommes particulièrement intéressés à 2 sous types de CSTN : (i) le sous -type LAR (Luminal Androgen Receptor) dont nous avons décrit les premiers modèles de PDX : ces modèles présentent des altérations fréquentes de la voie PI3K ainsi que des réponses majeures aux inhibiteurs de cette voie ; (ii) le sous type métaplasique, dont 4 de nos 9 modèles présentent une double altération genomique dans les voies PI3K et RTK-MAPK ainsi que des réponses complètes et durables à la combinaison d’inhibiteurs de PI3K et de MAPK.Dans les autres sous-types de CSTN, nous avons également mis en évidence des taux de réponse importants aux inhibiteurs de la voie PI3K et MAPK. Les biomarqueurs de réponse à ces différentes thérapies ciblées testées sont en cours d’étude en particulier par intégration des données génomique et protéique de nos modèles. / Triple negative breast cancer (TNBC) accounts for 10-15% of breast cancers. Its prognosis is worse, particularly due to the rarity of targeted therapies adapted to this subtype. Its complexity of management is directly related to its high heterogeneity, both at the morphological and genomical levels.In this context, we developed Patient Derived Xenograft (PDX) models from TNBC. This robust model has the specificity of retaining the characteristics (histological, genotypic but also phenotypic) of the tumors observed in patients.In our cohort of 61 PDXs of TNBC, we confirmed the anatomopathological and genomical heterogeneity of this subtype. Majority of targeted alterations are of low frequency (<10%) but 88% of our models harbour a potential targetable alteration and more than half have at least 2 targetable alterations. We were particularly interested in 2 subtypes of TNBC: (i) the LAR subtype for which we have described the first PDX models: these models present frequent alterations of the PI3K pathway as well as major responses to PI3K inhibitors; (ii) the metaplastic subtype, of which 4 of our 9 models show double alterations in the PI3K and RTK-MAPK pathways and complete and durable responses to the combination of PI3K-MAPK inhibitors.In the other CSTN subtypes, we have also demonstrated significant response rates to PI3K and MAPK inhibitors. Biomarkers of response to these various targeted therapies tested are being studied, in particular by integrating the genomic and protein data from a higher number of PDX models.

<p>Multiple myeloma (MM) is an incurable B-cell malignancy mainly localized to the bone marrow. Our aim was to examine the growth- and survival-promoting role of the IGF-IR and its downstream signaling components in MM cells to identify potential targets for therapy. </p><p>Octreotide, a somatostatin analog that has been demonstrated to interfere with the actions of IGF-I, induced growth inhibition in both IL-6-dependent and IL-6-independent MM cell lines expressing the somatostatin receptors sst2, sst3 and sst5. Additionally, a slight pro-apoptotic effect could be observed in a few cell lines. In primary MM cells octreotide induced apoptosis, an effect that was abrogated by exogenously added IGF-I, but not by IL-6.</p><p>Inhibition of IGF-I signaling in Karpas 707 cells, using either the anti-IGF-IR antibody αIR3 or the PI 3-K inhibitors LY294002 and wortmannin, increased sensitivity to apoptosis induced by dexamethasone. Exogenously added IGF-I prevented dexamethasone-induced apoptosis, an effect that could partly be mimicked by the pharmacological GSK-3β inhibitors LiCl and SB415286. Thus, we suggest the GSK-3β as an important mediator of the anti-apoptotic effects of IGF-IR signaling in MM.</p><p>Using rapamycin we selectively inhibited mTOR, a phosphoprotein downstream of the IGF-IR. In MM cell lines rapamycin induced G0/G1-arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of the cyclins D2, D3 and E. Interestingly, in primary MM cells rapamycin induced apoptosis. Moreover, rapamycin potentiated dexamethasone-induced apoptosis, an effect that was associated with a downregulation of the anti-apoptotic protein survivin. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the anti-apoptotic effects of exogenously added IGF-I and IL-6, thus suggesting this drug-combination to be active also in vivo. </p><p>Two newly developed, selective IGF-I RTK inhibitors proved to be very effective in MM cell lines and in primary MM cells providing 50-90% growth inhibition within 48 h of incubation. The inhibitors induced massive apoptosis together with a prominent cell cycle arrest in the G2/M-phase. Importantly, the IGF-I RTK inhibitors downregulated the tyrosine phosphorylation of the IGF-IR β-chain but not of the insulin receptor β-chain. </p><p>In conclusion, the IGF-IR potently promotes growth and survival of MM cells. Therefore, interfering with the IGF-IR signaling pathway might be a suitable strategy to improve MM treatment.</p>

<p>Multiple myeloma (MM) is a virtually incurable B cell malignancy of the bone marrow. One important part of tumor progression and an obstacle for successful therapy is resistance to apoptosis. To combat this resistance, the mechanisms of apoptosis and survival in MM must be better defined. </p><p>In this thesis, we identified Fas up-regulation as a mechanism underlying interferon (IFN)-mediated sensitization to Fas-induced apoptosis in the MM cell line U-266-1970. IFN treatment induced activation of signal transducer and activator of transcription (Stat)1 but, intriguingly, also attenuated activation of MM survival factor Stat3. </p><p>Exploring the role of Stat1 further, we established sub-lines of U-266-1970 with a stable over-expression of Stat1 and of its active mutant Stat1C. These sub-lines displayed a decreased expression and activation of Stat3, and an altered expression of apoptosis-related genes Harakiri, Bcl-2 and Mcl-1. In a drug library screening, Stat1 over-expression was associated with an increased sensitivity to Fas-induced apoptosis and, conversely, an increased resistance to several drugs, including the cyclin dependent kinase (cdk)1 inhibitor CGP74514A. We conclude that Stat1 over-expression does not confer a general resistance or sensitivity to apoptosis in MM, but may strongly affect the response to some specific drugs.</p><p>We also explored the effects of picropodophyllin (PPP), an inhibitor of the insulin-like growth factor I (IGF-I) receptor tyrosine kinase (RTK), in MM. PPP selectively inhibited the IGF-I RTK activity without inhibiting the insulin RTK activity. Furthermore, PPP potently induced cell cycle arrest and apoptosis in all MM cell lines and patient samples tested, also in the presence of survival factors IGF-I and IL-6. We conclude that PPP has great therapeutic potential in MM </p><p>Finally, we examined the expression and regulation of the inhibitors of apoptosis proteins (IAPs) in a panel of MM cell lines and patient samples. The glucocorticoid dexamethasone, which is used in MM therapy, induced a transient up-regulation and a subsequent down-regulation of c-IAP2, as well as a down-regulation of XIAP, possibly influencing the sensitivity to apoptosis induced by this drug. Supporting this notion, abrogation of IGF-IR signaling by PPP, which sensitizes MM cells to dexamethasone-induced apoptosis, enhanced the down-regulation of c-IAP2 and XIAP.</p>

Multiple myeloma (MM) is an incurable B-cell malignancy mainly localized to the bone marrow. Our aim was to examine the growth- and survival-promoting role of the IGF-IR and its downstream signaling components in MM cells to identify potential targets for therapy. Octreotide, a somatostatin analog that has been demonstrated to interfere with the actions of IGF-I, induced growth inhibition in both IL-6-dependent and IL-6-independent MM cell lines expressing the somatostatin receptors sst2, sst3 and sst5. Additionally, a slight pro-apoptotic effect could be observed in a few cell lines. In primary MM cells octreotide induced apoptosis, an effect that was abrogated by exogenously added IGF-I, but not by IL-6. Inhibition of IGF-I signaling in Karpas 707 cells, using either the anti-IGF-IR antibody αIR3 or the PI 3-K inhibitors LY294002 and wortmannin, increased sensitivity to apoptosis induced by dexamethasone. Exogenously added IGF-I prevented dexamethasone-induced apoptosis, an effect that could partly be mimicked by the pharmacological GSK-3β inhibitors LiCl and SB415286. Thus, we suggest the GSK-3β as an important mediator of the anti-apoptotic effects of IGF-IR signaling in MM. Using rapamycin we selectively inhibited mTOR, a phosphoprotein downstream of the IGF-IR. In MM cell lines rapamycin induced G0/G1-arrest, an effect being associated with an increase of the cyclin-dependent kinase inhibitor p27 and a decrease of the cyclins D2, D3 and E. Interestingly, in primary MM cells rapamycin induced apoptosis. Moreover, rapamycin potentiated dexamethasone-induced apoptosis, an effect that was associated with a downregulation of the anti-apoptotic protein survivin. Strikingly, the combinatorial treatment with rapamycin and dexamethasone suppressed the anti-apoptotic effects of exogenously added IGF-I and IL-6, thus suggesting this drug-combination to be active also in vivo. Two newly developed, selective IGF-I RTK inhibitors proved to be very effective in MM cell lines and in primary MM cells providing 50-90% growth inhibition within 48 h of incubation. The inhibitors induced massive apoptosis together with a prominent cell cycle arrest in the G2/M-phase. Importantly, the IGF-I RTK inhibitors downregulated the tyrosine phosphorylation of the IGF-IR β-chain but not of the insulin receptor β-chain. In conclusion, the IGF-IR potently promotes growth and survival of MM cells. Therefore, interfering with the IGF-IR signaling pathway might be a suitable strategy to improve MM treatment.

Multiple myeloma (MM) is a virtually incurable B cell malignancy of the bone marrow. One important part of tumor progression and an obstacle for successful therapy is resistance to apoptosis. To combat this resistance, the mechanisms of apoptosis and survival in MM must be better defined. In this thesis, we identified Fas up-regulation as a mechanism underlying interferon (IFN)-mediated sensitization to Fas-induced apoptosis in the MM cell line U-266-1970. IFN treatment induced activation of signal transducer and activator of transcription (Stat)1 but, intriguingly, also attenuated activation of MM survival factor Stat3. Exploring the role of Stat1 further, we established sub-lines of U-266-1970 with a stable over-expression of Stat1 and of its active mutant Stat1C. These sub-lines displayed a decreased expression and activation of Stat3, and an altered expression of apoptosis-related genes Harakiri, Bcl-2 and Mcl-1. In a drug library screening, Stat1 over-expression was associated with an increased sensitivity to Fas-induced apoptosis and, conversely, an increased resistance to several drugs, including the cyclin dependent kinase (cdk)1 inhibitor CGP74514A. We conclude that Stat1 over-expression does not confer a general resistance or sensitivity to apoptosis in MM, but may strongly affect the response to some specific drugs. We also explored the effects of picropodophyllin (PPP), an inhibitor of the insulin-like growth factor I (IGF-I) receptor tyrosine kinase (RTK), in MM. PPP selectively inhibited the IGF-I RTK activity without inhibiting the insulin RTK activity. Furthermore, PPP potently induced cell cycle arrest and apoptosis in all MM cell lines and patient samples tested, also in the presence of survival factors IGF-I and IL-6. We conclude that PPP has great therapeutic potential in MM Finally, we examined the expression and regulation of the inhibitors of apoptosis proteins (IAPs) in a panel of MM cell lines and patient samples. The glucocorticoid dexamethasone, which is used in MM therapy, induced a transient up-regulation and a subsequent down-regulation of c-IAP2, as well as a down-regulation of XIAP, possibly influencing the sensitivity to apoptosis induced by this drug. Supporting this notion, abrogation of IGF-IR signaling by PPP, which sensitizes MM cells to dexamethasone-induced apoptosis, enhanced the down-regulation of c-IAP2 and XIAP.