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- Alchahin, Adele Mirna
(författare)
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Identifying and targeting vulnerabilities in cancers that metastasize to the bone and bone marrow
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Evolving technologies enable scientist to ask and seek answers to advanced questions, above and beyond. During the past decade single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of biology, in particular within cancer research. Contributing with its high-resolution has unraveled complicated biological circuits, along with a profound understanding of heterogeneity, cellular and molecular processes, including gene expression profiles and transcriptional states. Especially in the quest of understanding cancer metastasis, aggressive disease phenotype and treatment resistance. In Paper I we utilize scRNA-seq on tissue material from untreated human primary clear cell renal cell carcinoma (ccRCC) patients. We dissect the tumor microenvironment (TME) and discover a metastatic gene signature that is upregulated in bone metastatic ccRCC patients that could serve as a predictive tool. We describe an immunosuppressive microenvironment with tumor associated macrophages (TAMs) with a M2 phenotype overexpressing TREM2, further associated with low survival outcome. Computational interactive receptor-ligand analysis reveals CD70 (on tumor) and CD27 (on cytotoxic T cells and regulatory T cells) as a potential pharmaceutical target. In Paper II, a continuation of Paper I, we aimed to understand genetic alterations involved in metastatic disease from the primary site, namely bone metastatic ccRCC, including comparison of a normal bone marrow to malignant. Scrutinizing the complex TME we detect, as well here, an immunosuppressive microenvironment with transcriptionally different TAMs, exhausted T cell phenotype and a tumor associated mesenchymal stem/stromal cell (TA-MSC) population that upregulates bone remodeling genes. Concluding that the relevance of TA-MSC subset causes excessive bone resorption via RANK/RANKL/OPG signaling pathway. Finally, in Paper III, we evaluate brequinar, a DHODH inhibitor, as a therapeutic agent in high-risk neuroblastoma (NB). We find DHODH as an independent risk factor in high-risk NB demonstrating prolonged survival in preclinical models when inhibited. In combination with temozolomide, already in clinical use for these children, a synergistic effect is achieved in vivo, proposing a promising approach to validate clinically. Taken together, the presented thesis has provided comprehensive insights in the progression of ccRCC in a primary and a metastatic setting, including the identification of potential vulnerable targets. Additionally, a potential combination treatment in vitro and in vivo is presented as a promising treatment option in high-risk NB by inhibiting DHODH together with standard care of treatment agent temozolomide.
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| 6. |
- Bentzen, Marte, et al.
(författare)
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Hållbart ledarskap ur ett tränar- och coachperspektiv
- 2016
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Ingår i: Utveckla ledarskapet. - Stockholm : SISU Idrottsböcker. - 9789187745973 ; , s. 196-263
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Bokkapitel (populärvet., debatt m.m.)abstract
- Syftet med kapitlet är att presentera och diskutera teoretiska och praktiska frågor på ett sätt som främjar ett långlivat och hälsosamt ledarskap med fokus på tävlingsidrotten. Författarna utgår från det förenklade antagandet att «en coach som mår bra» sannolikt är mer framgångsrik och långlivad i jämförelse med en coach som mår dåligt.
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| 7. |
- Butun, Ismail, et al.
(författare)
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Location Privacy Assured Internet of Things
- 2019
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Ingår i: Proceedings of the 5th International Conference on Information Systems Security and Privacy. - Setúbal, Portugal : SciTePress. - 9789897583599 ; , s. 623-630
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Konferensbidrag (refereegranskat)abstract
- Internet of Things (IoT) is in the booming age of its growth, therefore a vast amount of applications, projects, hardware/software solutions, and customized concepts are being developed. The proliferation of IoT will enable location-based services to be available everywhere for everyone, and this will raise a large number of privacy issues related to the collection, usage, retention, and disclosure of the user’s location information. In order to provide a solution to this unique problem of IoT, this paper proposes Location Privacy Assured Internet of Things (LPA-IoT) scheme, which uses the concepts of Mix-Zone, location-obfuscation along with context-awareness. To the authors’ best knowledge, the proposed LPA-IoT scheme is the first location-based privacy-preserving scheme for IoT that provides flexible privacy levels associated with the present context of the user.
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| 8. |
- Caroli, Anna, et al.
(författare)
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Mild cognitive impairment with suspected nonamyloid pathology (SNAP) Prediction of progression
- 2015
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 84:5, s. 508-515
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Tidskriftsartikel (refereegranskat)abstract
- Objectives:The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non-Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI).Methods:We measured markers of amyloid pathology (CSF -amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [F-18]-fluorodeoxyglucose-PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A- and N+/N- based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A-N+ cases.Results:The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A-N-, A+N-, SNAP, and A+N+, respectively; the proportion of APOE epsilon 4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N- and A+N+ groups (p 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A-N-, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N- patients did not (hazard ratio = 1.13, p = 0.771). In A+N- and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073).Conclusions:Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.
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| 9. |
- Cholewa, W, et al.
(författare)
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Identification of loss-of-coolant accidents in LWRs by inverse models
- 2004
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Ingår i: Nuclear Technology. - 0029-5450 .- 1943-7471. ; 147:2, s. 216-226
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Tidskriftsartikel (refereegranskat)abstract
- This paper describes a novel diagnostic method based on inverse models that could be applied to identification of transients and accidents in nuclear power plants. In particular, it is shown that such models could be successfully applied to identification of loss-of-coolant accidents (LOCAs). This is demonstrated for LOCA scenarios for a boiling water reactor. Two classes of inverse models are discussed: local models valid only in a selected neighborhood of an unknown element in the data set, representing a state of a considered object, and global models, in the form of partially unilateral models, valid over the whole learning data set. An interesting and useful property of local inverse models is that they can be considered as example based models, i.e., models that are spanned on particular sets of pattern data. It is concluded that the optimal diagnostic method should combine the advantages of both models, i.e., the high quality of results obtained from a local inverse model and the information about the confidence interval for the expected output provided by a partially unilateral model.
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- Choudhury, D., et al.
(författare)
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Magnetization in electron- and Mn- doped SrTiO3
- 2013
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 3, s. 1433-
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Tidskriftsartikel (refereegranskat)abstract
- Mn- doped SrTiO3.0, when synthesized free of impurities, is a paramagnetic insulator with interesting dielectric properties. Since delocalized charge carriers are known to promote ferromagnetism in a large number of systems via diverse mechanisms, we have looked for the possibility of any intrinsic, spontaneous magnetization by simultaneous doping of Mn ions and electrons into SrTiO3 via oxygen vacancies, thereby forming SrTi1-xMnxO3-delta, to the extent of making the doped system metallic. We find an absence of any enhancement of the magnetization in the metallic sample when compared with a similarly prepared Mn doped, however, insulating sample. Our results, thus, are not in agreement with a recent observation of a weak ferromagnetism in metallic Mn doped SrTiO3 system.
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