Marinen – En lærende organisasjon? En studie av fokusområder for lærende organisasjoner blant Marinens ansatte

Hensikten med studien er å undersøke i hvilken grad Marinen kan sies å være en lærende organisasjon. Studien stiller to forskningsspørsmål hvor det ene tar for seg Marinen som helhet, mens det andre ser på relative forskjeller mellom avdelinger i organisasjonen. Studien er basert på resultater fra en spørreundersøkelse gjennomført julen 2020, blant Marinens ansatte. Denne var basert på “The Learning Organization Survey”, beskrevet i den vitenskapelige artikkelen “Is Yours A Learning Organization”. I alt var det 455 respondenter som utgjorde datagrunnlaget for studien. Gjennom vår analyse vurderte vi grunnlaget for å være representativt for populasjonen, og at studiens totale gyldighet var å anse som tilfredsstillende. Funn i studien indikerer at Marinen har et generelt støttende læringsmiljø, som vil si at psykologisk trygghet, åpenhet for nye ideer, verdsettelse av forskjeller og tid til refleksjon er til stede på gruppenivå i organisasjonen. Videre viser studien at Marinen har et forbedringspotensial innen konkrete læringsprosesser og praksiser, noe som innbefatter områder som eksperimentering, innsamling, analyse og deling av informasjon, samt utdanning og trening. Funn indikerer også at Marinen har et forbedringspotensial innen ledelse som forsterker læring. Til slutt viser studien at enkelte avdelinger i Marinen, likevel kan sies å inneha stor grad av karakteristikker tilknyttet lærende organisasjoner. Studien konkluderer med at Marinen i noe mindre grad kan sies å være en lærende organisasjon

Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines

Background Most in vitro cancer cell experiments have been performed using 2D models. However, 3D spheroid cultures are increasingly favored for being more representative of in vivo tumor conditions. To overcome the translational challenges with 2D cell cultures, 3D systems better model more complex cell-to-cell contact and nutrient levels present in a tumor, improving our understanding of cancer complexity. Despite this need, there are few reports on how 3D cultures differ metabolically from 2D cultures. Methods Well-described cell lines from colorectal cancer (HCT116 and SW948) and pancreatic ductal adenocarcinoma (Panc-1 and MIA-Pa-Ca-2) were used to investigate metabolism in 3D spheroid models. The metabolic variation under normal glucose conditions were investigated comparing 2D and 3D cultures by metabolic flux analysis and expression of key metabolic proteins. Results We find significant differences in glucose metabolism of 3D cultures compared to 2D cultures, both related to glycolysis and oxidative phosphorylation. Spheroids have higher ATP-linked respiration in standard nutrient conditions and higher non-aerobic ATP production in the absence of supplemented glucose. In addition, ATP-linked respiration is significantly inversely correlated with OCR/ECAR (p = 0.0096). Mitochondrial transport protein, TOMM20, expression decreases in all spheroid models compared to 2D, and monocarboxylate transporter (MCT) expression increases in 3 of the 4 spheroid models. Conclusions In this study of CRC and PDAC cell lines, we demonstrate that glucose metabolism in 3D spheroids differs significantly from 2D cultures, both in terms of glycolytic and oxidative phosphorylation metrics. The metabolic phenotype shift from 2D to 3D culture in one cell line is greater than the phenotypic differences between each cell line and tumor source. The results herein emphasize the need to use 3D cell models for investigating nutrient utilization and metabolic flux for a better understanding of tumor metabolism and potential metabolic therapeutic targets.publishedVersio

Lessons Learnt in Implementation of Coordinated Voltage Control Demonstration

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Punktlighet i jernbanen - hvert sekund teller

Denne boken gir en innføring i punktlighetsarbeid for jernbane, og er ment som et supplement til annen litteratur som finnes på området. Boken er basert på forsknings‐ og utviklingsarbeid utført ved SINTEF, Norges teknisk‐naturvitenskapelige universitet (NTNU) og Transportøkonomisk institutt (TØI) i samarbeid med de største aktørene i norsk jernbanesektor. Jernbanen er et komplekst og sammensatt trafikksystem der kravene til kvalitet og presisjon er stadig økende. En av de mest sentrale kvalitetsindikatorene ved transport er punktlighet. Gjennom en serie større forskningsprosjekter de siste 10–15 årene har aktører i norsk jernbanesektor i fellesskap utviklet kunnskap og løsninger for å nå målet om god punktlighet og forutsigbarhet i togtrafikken. Jernbaneverket har vært prosjekteier for disse prosjektene, SINTEF, TØI og NTNU har vært utøvende forskningspartnere, mens CargoNet, NSB og Flytoget har deltatt i arbeidet. Prosjektene ble finansiert av Norges forskningsråd og de deltakende organisasjonene. Denne boken bygger på resultatene fra forskningsprosjektene og fokuserer på analyser av punktlighetsdata. Vi vil takke alle som har bidratt til å realisere denne boken; både i utarbeidelsen av boken og gjennom finansiering og gjennomføring av de forutgående forskningsprosjektene. Framtiden er spennende – framtiden går på skinner!publishedVersio

Intrinsic Differences in Spatiotemporal Organization and Stromal Cell Interactions Between Isogenic Lung Cancer Cells of Epithelial and Mesenchymal Phenotypes Revealed by High-Dimensional Single-Cell Analysis of Heterotypic 3D Spheroid Models

The lack of inadequate preclinical models remains a limitation for cancer drug development and is a primary contributor to anti-cancer drug failures in clinical trials. Heterotypic multicellular spheroids are three-dimensional (3D) spherical structures generated by self-assembly from aggregates of two or more cell types. Compared to traditional monolayer cell culture models, the organization of cells into a 3D tissue-like structure favors relevant physiological conditions with chemical and physical gradients as well as cell-cell and cell-extracellular matrix (ECM) interactions that recapitulate many of the hallmarks of cancer in situ. Epidermal growth factor receptor (EGFR) mutations are prevalent in non-small cell lung cancer (NSCLC), yet various mechanisms of acquired resistance, including epithelial-to-mesenchymal transition (EMT), limit the clinical benefit of EGFR tyrosine kinase inhibitors (EGFRi). Improved preclinical models that incorporate the complexity induced by epithelial-to-mesenchymal plasticity (EMP) are urgently needed to advance new therapeutics for clinical NSCLC management. This study was designed to provide a thorough characterization of multicellular spheroids of isogenic cancer cells of various phenotypes and demonstrate proof-of-principle for the applicability of the presented spheroid model to evaluate the impact of cancer cell phenotype in drug screening experiments through high-dimensional and spatially resolved imaging mass cytometry (IMC) analyses. First, we developed and characterized 3D homotypic and heterotypic spheroid models comprising EGFRi-sensitive or EGFRi-resistant NSCLC cells. We observed that the degree of EMT correlated with the spheroid generation efficiency in monocultures. In-depth characterization of the multicellular heterotypic spheroids using immunohistochemistry and high-dimensional single-cell analyses by IMC revealed intrinsic differences between epithelial and mesenchymal-like cancer cells with respect to self-sorting, spatiotemporal organization, and stromal cell interactions when co-cultured with fibroblasts. While the carcinoma cells harboring an epithelial phenotype self-organized into a barrier sheet surrounding the fibroblasts, mesenchymal-like carcinoma cells localized to the central hypoxic and collagen-rich areas of the compact heterotypic spheroids. Further, deep-learning-based single-cell segmentation of IMC images and application of dimensionality reduction algorithms allowed a detailed visualization and multiparametric analysis of marker expression across the different cell subsets. We observed a high level of heterogeneity in the expression of EMT markers in both the carcinoma cell populations and the fibroblasts. Our study supports further application of these models in pre-clinical drug testing combined with complementary high-dimensional single-cell analyses, which in turn can advance our understanding of the impact of cancer-stroma interactions and epithelial phenotypic plasticity on innate and acquired therapy resistance in NSCLC.publishedVersio

Human organotypic airway and lung organoid cells of bronchiolar and alveolar differentiation are permissive to infection by influenza and SARS-CoV-2 respiratory virus

The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.publishedVersio

Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis

Melanoma patients carry a high risk of developing brain metastases, and improvements in survival are still measured in weeks or months. Durable disease control within the brain is impeded by poor drug penetration across the blood-brain barrier, as well as intrinsic and acquired drug resistance. Augmented mitochondrial respiration is a key resistance mechanism in BRAF-mutant melanomas but, as we show in this study, this dependence on mitochondrial respiration may also be exploited therapeutically. We first used high-throughput pharmacogenomic profiling to identify potentially repurposable compounds against BRAF-mutant melanoma brain metastases. One of the compounds identified was β-sitosterol, a well-tolerated and brain-penetrable phytosterol. Here we show that β-sitosterol attenuates melanoma cell growth in vitro and also inhibits brain metastasis formation in vivo. Functional analyses indicated that the therapeutic potential of β-sitosterol was linked to mitochondrial interference. Mechanistically, β-sitosterol effectively reduced mitochondrial respiratory capacity, mediated by an inhibition of mitochondrial complex I. The net result of this action was increased oxidative stress that led to apoptosis. This effect was only seen in tumor cells, and not in normal cells. Large-scale analyses of human melanoma brain metastases indicated a significant role of mitochondrial complex I compared to brain metastases from other cancers. Finally, we observed completely abrogated BRAF inhibitor resistance when vemurafenib was combined with either β-sitosterol or a functional knockdown of mitochondrial complex I. In conclusion, based on its favorable tolerability, excellent brain bioavailability, and capacity to inhibit mitochondrial respiration, β-sitosterol represents a promising adjuvant to BRAF inhibitor therapy in patients with, or at risk for, melanoma brain metastases.publishedVersio

Punktlighet i jernbanen - hvert sekund teller

Denne boken gir en innføring i punktlighetsarbeid for jernbane, og er ment som et supplement til annen litteratur som finnes på området. Boken er basert på forsknings‐ og utviklingsarbeid utført ved SINTEF, Norges teknisk‐naturvitenskapelige universitet (NTNU) og Transportøkonomisk institutt (TØI) i samarbeid med de største aktørene i norsk jernbanesektor. Jernbanen er et komplekst og sammensatt trafikksystem der kravene til kvalitet og presisjon er stadig økende. En av de mest sentrale kvalitetsindikatorene ved transport er punktlighet. Gjennom en serie større forskningsprosjekter de siste 10–15 årene har aktører i norsk jernbanesektor i fellesskap utviklet kunnskap og løsninger for å nå målet om god punktlighet og forutsigbarhet i togtrafikken. Jernbaneverket har vært prosjekteier for disse prosjektene, SINTEF, TØI og NTNU har vært utøvende forskningspartnere, mens CargoNet, NSB og Flytoget har deltatt i arbeidet. Prosjektene ble finansiert av Norges forskningsråd og de deltakende organisasjonene. Denne boken bygger på resultatene fra forskningsprosjektene og fokuserer på analyser av punktlighetsdata. Vi vil takke alle som har bidratt til å realisere denne boken; både i utarbeidelsen av boken og gjennom finansiering og gjennomføring av de forutgående forskningsprosjektene. Framtiden er spennende – framtiden går på skinner!publishedVersio

The Significance of Cell-related Challenges in the Clinical Application of Tissue Engineering.

Tissue engineering is increasingly being recognized as a new approach that could alleviate the burden of tissue damage currently managed with transplants or synthetic devices. Making this novel approach available in the future for patients who would potentially benefit is largely dependent on understanding and addressing all those factors that impede the translation of this technology to the clinic. Cell-associated factors in particular raise many challenges, including those related to cell sources, up- and downstream techniques, preservation, and the creation of in vitro microenvironments that enable cells to grow and function as far as possible as they would in vivo. This paper highlights the main confounding issues associated with cells in tissue engineering and how these issues may hinder the advancement of therapeutic tissue engineering. This article is protected by copyright. All rights reserved