Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics

Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (225Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods: Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [177Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results: Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [177Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions: This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225Ac labeled hu11B6, however emerging at a later timepoint

Comparative energy analysis and performance estimation of decentralized ventilation control strategies in local Norway climate

The present work evaluates different decentralized ventilation control strategy and supply temperature regulation strategy combinations in local Norway climate and is the main focus. Field measurements on decentralized ventilation systems are utilized, which is further applied to mold a representative decentralized ventilation unit for evaluation of energy performance in a single-person reference zone. Evaluation is performed using a monthly time-step energy analysis, and the IDA ICE simulation tool for a comparative primary energy analysis on the strategy combinations, while simultaneously agreements of the national requirements are upheld. Primary energy comparison is conducted with respect to a centralized constant air volume (CAV) system, which is compared with all decentralized ventilation strategy combinations for a full comprehensive comparative analysis. The strategy combinations are assessed with respect to comfort criteria for a better understanding of the strategy potential. Assessment of the decentralized ventilation heat recovery unit applicability in local Norway climate is conducted based on seasonal energy analysis. Furthermore, the strategy combinations are tested with respect to higher occupancy zones, and also by using commercially available decentralized ventilation unit specifications for a wider understanding of the decentralized ventilation potential in local Norway climate. The results of the evaluation show that the representative decentralized ventilation system has the greatest energy performance under demand controlled ventilation control strategies, as the lower heat recovery efficiency is less utilized in the cold climate, and the low specific fan power can efficiently be used for zone cooling in summer. If the commercially available decentralized ventilation system does not exaggerate the given specifications, the decentralized ventilation technology has great potential in Norway climate due to the high heat recovery unit efficiency and low specific fan power, and supply air strategies such as natural fan-assisted ventilation and temperature regulation, in combination with the superior room-by-room/personalized ventilation control strategy possibilities.publishedVersio

Wellhead platform subjected to accidental loads

Cost reduction in the oil and gas industry forces new and innovative solutions. Unmanned wellhead platforms are alternative solutions for developing small fields which would normally be developed with subsea wellheads. For an installation to be approved to operate on the Norwegian Continental Shelf, it must be designed against accidental actions such as fire. Current rules regarding design against fire loads has been reviewed, showing examples of heat transfer hand calculations, as well as material's strength degradation as function of temperature. A generic wellhead platform has been designed, based on comparable structures, and simple hand calculations to have a reasonable model to work with. Conservativeness has been applied to end up with a tough structure and reduce the need for passive fire protection. The structure was tested against normal operational loads and were proven to have more than sufficient resistance. Operational-, variable maintenance- and accidental loads has been established with help from Trond Granli in Kværner. Characteristic fire scenarios were provided and cases set up. A shell script has been adapted for use on the heat transfer and response simulations. Trouble with multi- threading simulations prevented it from functioning perfectly, but it worked for single- threading. A large amount of simulations has been run, resulting in the conclusion that loads relating to wireline well intervention operations in combination with moderate jet fires is survived by the structure. Reserve strength ratios in the range above 4.5 were exhibited. The case of accidental jack- up rig cantilever collapse was shown to be tolerated, and the case involving a large jet fire inside the platform also survived the duration of the characteristic fire scenario. But further simulations are recommended to confirm. Temperature- domain simulations has been run to validate a few of the pushdown simulations, with promising results. A good pool fire model was not established, but was simulated with the standard hydrocarbon temperature curve. The results showed adequately strength after the duration of the fire

Assistert fjernkontroll av innendørs UAV

Denne oppgaven presenterer konseptsystem for assisteert fjernkontroll av innendørs UAV. Systemet skal håndtere de mest aktive og krevende oppgaver knyttet til flyging av innendør UAV, hvilket er posisjonsregulering. Det skal ha et brukergrensesnitt som er lett å bruke, slik at flyging blir en enkel affære for "piloten". Den implementerte løsningen er basert på avstandsmålinger i seks retning ved bruk av sonarer, samt et kamera for overføring av bilde. Løsningen er implementert på en kombinasjon av en minidatamaskin med Linux og en mikrokontroller. Systemet er montert på et firerotors helikopter (quadcopter). Løsningen er bygget og testet. Testene viste at systemet ikke kan levere en posisjonskontroll som er nøyaktig nok for innendørs flygning. Systemet vil passe best som et anti-kollisjonssystem for en UAV, hvor posisjonkontroll er håndtert av andre systemer

Hybrid Method for Numerical Implementation of Segmented Power Cable Conductors in Finite-element Based Ampacity Calculation

This paper addresses challenges with modelling of segmented power cable conductors using finite element analysis (FEA) for ampacity calculation. Segmented conductors improve current distribution by minimizing skin and proximity effects, thus reducing conductor losses. 2D FEA simulation offers high flexibility and accuracy beyond IEC 60287 for complex laying geometries, but the modelling of losses in segmented constructions using FEA has proven difficult due to the big difference in wire size and twisting pitch, requiring great amounts of computational power. In this paper a hybrid method is proposed, in which the IEC 60287 empirical formulae for segmented conductors are included in a 2D FEA model. The proposed method shows a good correspondence to IEC standard calculations, with deviations in conductor AC resistance of less than 1 %.Hybrid Method for Numerical Implementation of Segmented Power Cable Conductors in Finite-element Based Ampacity CalculationpublishedVersio

Erfaringer med boligkjøpsmodeller i Norge

De siste årene har nye boligkjøpsformer fått økt oppmerksomhet og salg i Norge. Slike modeller er en mellomting mellom leie og eie, og målet er at kjøperen kan bli full boligeier på sikt. I den samme perioden har også renten økt kraftig, samtidig har leieprisene økt og realprisen på boliger har falt. Denne masteroppgaven undersøker hvilke erfaringer vi har med boligkjøpsmodellene i denne perioden. Oppgavene diskuterer også om det er nødvendig eller fornuftig med endringer basert på erfaringene. Erfaringene er kartlagt gjennom intervjuer med relevante personer hos en utbygger og tilbyder av boligkjøpsmodeller, forbrukermyndigheten og eiendomsmeglerne. Intervjuene var semistrukturerte og foregikk enten fysisk eller på telefon. Svarene ble kodet i relevante kategorier og er i oppgaven gjengitt etter kategori og ikke etter intervjuobjekt. Et av grunnlagene for intervjuspørsmålene var en kvantitativ bakgrunnsanalyse som tar utgangspunkt i teori og litteratur om boligmarkedet og boligkjøpsmodeller. De viktigste funnene er: •Erfaringene er i hovedsak positive. Sammenlignet med vanlige kjøp og salg av boliger kan det ved boligkjøpsmodeller være vanskeligere for kjøperen å forstå alle detaljene ved avtalen. Det har likevel ikke vært betydelige klager fra kjøpere. •Det at boligkjøpsmodellene er regulert i flere forskjellige lover er en ulempe sammenlignet med leie og eie som har mer enhetlig lovregulering. •Boligkjøpsmodellene har vist seg å være attraktiv også for andre enn førstegangsetablerere. Særlig trekkes det frem eldre kjøpergrupper. •Renteøkningen i etterkant av pandemien innebærer at de første kjøperne av boligkjøpsmodeller har fått en vesentlig annen økonomisk situasjon å forholde seg til enn da de inngikk kontrakten. •Inntektskravet i utlånsforskriften har blitt vanskeligere å oppfylle når husholdningene skal øke eierandel. Det kan se ut som inntektskravet har vært noe i bakgrunnen av egenkapitalkravet i omtalen og markedsføringen av boligkjøpsmodellene. •Kapitalbindingsproblemet til utbyggerne har økt med økende rente. Kapitalbindingen kan være et vesentlig hinder for videre utrulling av boligkjøpsmodeller, særlig for mindre solide tilbydere. Situasjonen kan også føre til prosjekter med høyere fellesgjeld. Enklere og mer enhetlig lovregulering av boligkjøpsmodeller vil være positivt. Samtidig er det viktig med god opplæring av selgersiden. Opplæring og informasjon må også vise konsekvensen av en situasjon der boligprisene faller. Regulering av tilbydere er et vanskelig spørsmål. Trolig er det fornuftig å være føre-var og stille krav til tilbyderne for å unngå fremtidige problematiske situasjoner. I oppgaven er det Forbrukerrådet som kan sies å representere kjøpernes side. Til videre forskning vil det være interesant å gjøre kvalitative og kvantitative studier av kjøperne direkte. Dette krever et visst antall av kjøpere for å få et repesentativt utvalg fordelt på ulike boligkjøpsmodeller. En slik tilnærming vil gi et bredere grunnlag for å svare på forskningsspørsmålene.In recent years, alternative homeownership models have gained increased attention and sales in Norway. The models are a hybrid between renting and owning, with the goal being that the buyer may eventually become a full homeowner. In the same period, interest rates have risen sharply, as have rental prices, while real housing prices have decreased. This master’s thesis investigates the experiences we have had with these alternative homeownership models during this time. The thesis also discusses whether it is necessary or sensible to make changes based on these experiences. The experiences were mapped through interviews with relevant individuals from a developer and seller of alternative homeownership models, the Norwegian Consumer Council, and real estate agents. The interviews were semi-structured and conducted either in person or by phone. The responses were coded into relevant categories and are presented in the thesis by category, not by informants. One of the bases for the interview questions was a quantitative background analysis based on theory and literature on the housing market and alternative homeownership models. The main findings are: •The experiences are mainly positive. Compared to regular buying and selling of homes, it can be more challenging for buyers to understand all the contractual details of alternative homeownership models. However, there have been no significant complaints from buyers. •The fact that alternative homeownership models, are regulated by several laws is a disadvantage compared to renting and owning, with more uniform legislation. •Alternative homeownership models have also proven to be attractive to groups other than first-time homebuyers, particularly older buyer groups. •The increase in interest rates following the pandemic means that the initial buyers of alternative homeownership models, have faced a significantly different financial situation than when they signed the contract. •The income requirement in the Norwegian lending regulations has become more difficult to meet when households wish to increase their ownership share. It appears that the income requirement has been somewhat overshadowed by the equity requirement in the discussion and marketing of alternative homeownership models. •The problem with capital tie-up for developers has increased with rising interest rates and can be a significant barrier to the further rollout of alternative homeownership models, especially for less solid providers. This situation could lead to cooperative housing projects with higher joint debt. Simpler and more uniform legislation of alternative homeownership models would be positive. At the same time, it is important to provide good education for the seller’s side. Education and information must also demonstrate the consequences of a situation where housing prices fall. Regulating sellers is a difficult question. It is probably wise to be cautious and set requirements for providers to avoid future problematic situations. In the thesis, the Norwegian Consumer Council is said to represent the buyer’s perspective. For further research, it would be interesting to conduct qualitative and quantitative studies of the buyers directly. This requires a certain number of buyers to obtain a representative sample distributed across different home buying models. Such an approach would provide a broader basis for answering the research questions