| 1. |
- Harbst, Katja, et al.
(författare)
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Molecular and genetic diversity in the metastatic process of melanoma.
- 2014
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 233:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Diversity between metastatic melanoma tumours in individual patients is known; however, the molecular and genetic differences remain unclear. To examine the molecular and genetic differences between metastatic tumours, we performed gene-expression profiling of 63 melanoma tumours obtained from 28 patients (two or three tumours/patient), followed by analysis of their mutational landscape, using targeted deep sequencing of 1697 cancer genes and DNA copy number analysis. Gene-expression signatures revealed discordant phenotypes between tumour lesions within a patient in 50% of the cases. In 18 of 22 patients (where matched normal tissue was available), we found that the multiple lesions within a patient were genetically divergent, with one or more melanoma tumours harbouring 'private' somatic mutations. In one case, the distant subcutaneous metastasis of one patient occurring 3 months after an earlier regional lymph node metastasis had acquired 37 new coding sequence mutations, including mutations in PTEN and CDH1. However, BRAF and NRAS mutations, when present in the first metastasis, were always preserved in subsequent metastases. The patterns of nucleotide substitutions found in this study indicate an influence of UV radiation but possibly also DNA alkylating agents. Our results clearly demonstrate that metastatic melanoma is a molecularly highly heterogeneous disease that continues to progress throughout its clinical course. The private aberrations observed on a background of shared aberrations within a patient provide evidence of continued evolution of individual tumours following divergence from a common parental clone, and might have implications for personalized medicine strategies in melanoma treatment. Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk.
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| 2. |
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| 3. |
- Augsten, Martin, et al.
(författare)
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Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties
- 2014
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Ingår i: Cancer Research. - 1538-7445. ; 74:11, s. 2999-3010
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Tidskriftsartikel (refereegranskat)abstract
- Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1 alpha signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. (C) 2014 AACR.
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| 4. |
- Augsten, Martin, et al.
(författare)
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CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:9, s. 3414-3419
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Tidskriftsartikel (refereegranskat)abstract
- This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
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| 5. |
- Bergerson, Emma, et al.
(författare)
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Superior Outcome of Early ACL Reconstruction versus Initial Non-reconstructive Treatment With Late Crossover to Surgery A Study From the Swedish National Knee Ligament Registry
- 2022
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Ingår i: American Journal of Sports Medicine. - : SAGE Publications. - 0363-5465 .- 1552-3365. ; 50:4, s. 896-903
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Tidskriftsartikel (refereegranskat)abstract
- Background: Although comparable clinical and functional outcomes have been reported after nonsurgical and surgical anterior cruciate ligament (ACL) treatment, few studies have investigated the effects of early versus late ACL reconstruction with initial rehabilitation. Purpose: To determine patient-reported knee function in patients who initially undergo nonreconstructive treatment after an ACL injury but who later choose to undergo ACL reconstruction as compared with (1) patients undergoing ACL reconstruction close to the index injury and (2) patients treated nonreconstructively at 1 to 10 years of follow-up. Study Design: Cohort study; Level of evidence, 2. Methods: Results from the Knee injury and Osteoarthritis Outcome Score (KOOS) were extracted from the Swedish National Knee Ligament Registry for patients treated with nonreconstruction, early ACL reconstruction, and initial nonreconstruction but subsequent ACL reconstruction (crossover group). The KOOS4 (a mean of 4 KOOS subscales) was analyzed cross-sectionally at baseline and at the 1-, 2-, 5-, and 10-year follow-ups. Additionally, the Patient Acceptable Symptom State (PASS) was applied to all KOOS subscales from baseline to the 10-year follow-up. Results: A total of 1,074 crossover, 484 nonreconstruction, and 20,352 early ACL reconstruction cases were included. The crossover group reported lower KOOS4 values than the group undergoing early ACL reconstruction at baseline and at all follow-ups (mean difference [95% CI]): baseline, -6.5 (-8.0 to -5.0); 1 year, -9.3 (-10.9 to -7.7); 2 years, -4.8 (-6.3 to -3.2); 5 years, -6.1 (-8.8 to -3.4); and 10 years, -10.9 (-16.3 to -5.2). Additionally, a smaller proportion of the crossover cohort achieved a PASS on KOOS subscales at baseline and through the 1-, 2-, 5-, and 10-year follow-ups as compared with the early ACL reconstruction cohort. No differences were observed between crossover and nonreconstruction cases on either the KOOS4 or the PASS at any follow-up. Conclusion: A greater proportion of patients treated with early ACL reconstruction reported acceptable knee function and superior overall knee function as compared with patients who decided to cross over from nonreconstructive treatment to ACL reconstruction.
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| 6. |
- Blad, Karin, 1982-
(författare)
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Styrelseledamöters skyldigheter och ansvar vid risk för obestånd och liknande situationer
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Styrelseledamöter har ett antal skyldigheter när ett aktiebolag får ekonomiska svårigheter. Vilka regler som aktualiserar bolagsledningens ansvar beror på om ett aktiebolag har betalningsproblem eller balansproblem. Avseende balansproblemet finns regler om så kallat medansvar för styrelseledamöter och andra företrädare i 25 kap. aktiebolagslagen (2005:551). Syftet med kapitalbristreglerna är att tillse en snabb avveckling av ett kapitalsvagt aktiebolag och därvid skydda borgenärskollektivet. Utöver medansvarsreglerna finns det regler om skadeståndsansvar för bland andra styrelseledamöter för skador de åsamkar bolaget, aktieägare eller andra, exempelvis borgenärer. Vid ett aktiebolags betalningsproblem aktualiseras obeståndsrelaterade ansvarsregler i de fall betalningsoförmågan inte bedöms vara endast tillfällig. Härvid kan särskilt nämnas borgenärsbrotten i 11 kap. brottsbalken (1962:700), vilka förutsätter gäldenärens obestånd eller att påtaglig fara för obestånd föreligger. Därtill aktualiserar den särskilda oförmågan att betala förfallna skatteskulder det skatterättsliga företrädaransvaret i 59 kap. skatteförfarandelagen (2011:1244) (SFL) och för det räcker att betalningsoförmågan är endast tillfällig. Avhandlingen syftet är att systematisera och utvärdera reglerna om skyldigheter och personligt ansvar för styrelseledamöter när bolaget befinner sig i insolvenszonen, det vill säga när det är risk för obestånd eller obestånd är ett faktum. I syftet ingår att undersöka regleringens ändamålsenlighet.
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| 7. |
- Blad, Karin, 1982-, et al.
(författare)
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Sweden
- 2018
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Ingår i: Corporate Tax Residence and Mobility. - Amsterdam, Netherlands : International Bureau of Fiscal Documentation (IBFD). - 9789087224516 - 9789087224400 ; , s. 573-590
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Bokkapitel (refereegranskat)
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| 8. |
- Chen, Yilun, et al.
(författare)
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Identification and use of personalized genomic markers for monitoring circulating tumor DNA
- 2018
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Ingår i: Methods in Molecular Biology. - New York, NY : Springer New York. - 1064-3745. ; 1768, s. 303-322
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Bokkapitel (refereegranskat)abstract
- Digital PCR techniques are ideally suited for accurately quantifying trace amounts of target DNA sequences, such as tumor-derived mutant DNA that is present in the blood circulation of patients with cancer. Here, we describe an approach marrying low-coverage whole-genome sequencing of tumor tissues, to enumerate chromosomal rearrangement breakpoints, together with droplet digital PCR (ddPCR)-based personalized rearrangement assays to cost-effectively monitor circulating tumor DNA levels at multiple time-points during the clinical course. The method is generally applicable to essentially any cancer patient, as all cancers harbor unstable genomes, and may have uses for measuring minimal residual disease, response to therapy, and early detection of metastasis.
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| 9. |
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| 10. |
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| 11. |
- Frings, Oliver, et al.
(författare)
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Prognostic Significance in Breast Cancer of a Gene Signature Capturing Stromal PDGF Signaling
- 2013
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:6, s. 2037-2047
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we describe a novel gene expression signature of platelet-derived growth factor (PDGF) activated fibroblasts, which is able to identify breast cancers with a PDGF-stimulated fibroblast stroma and displays an independent and strong prognostic significance. Global gene expression was compared between PDGF-stimulated human fibroblasts and cultured resting fibroblasts. The most differentially expressed genes were reduced to a gene expression signature of 113 genes. The biological significance and prognostic capacity of this signature were investigated using four independent clinical breast cancer data sets. Concomitant high expression of PDGF beta receptor and its cognate Ligands is associated with a high PDGF signature score. This supports the notion that the signature detects tumors with PDGF-activated stroma. Subsequent analyses indicated significant associations between high PDGF signature score and clinical characteristics, including human epidermal growth factor receptor 2 positivity, estrogen receptor negativity, high tumor grade, and large tumor size. A high PDGF signature score is associated with shorter survival in univariate analysis. Furthermore, the high PDGF signature score acts as a significant marker of poor prognosis in multivariate survival analyses, including classic prognostic markers, Ki-67 status, a proliferation gene signature, or other recently described stroma-derived gene expression signatures.
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| 12. |
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| 13. |
- Jönsson, Göran B, et al.
(författare)
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High-resolution genomic profiles of breast cancer cell lines assessed by tiling BAC array comparative genomic hybridization.
- 2007
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 46:6, s. 543-558
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Tidskriftsartikel (refereegranskat)abstract
- A BAC-array platform for comparative genomic hybridization was constructed from a library of 32,433 clones providing complete genome coverage, and evaluated by screening for DNA copy number changes in 10 breast cancer cell lines (BT474, MCF7, HCC1937, SK-BR-3, L56Br-C1, ZR-75-1, JIMTI, MDA-MB-231, MDA-MB-361, and HCC2218) and one cell line derived from fibrocystic disease of the breast (MCF10A). These were also characterized by gene expression analysis and found to represent all five recently described breast cancer subtypes using the '' intrinsic gene set '' and centroid correlation. Three cell lines, HCC 1937 and L56BrC1 derived from BRCA I mutation carriers and MDA-MB-23 1, were of basal-like subtype and characterized by a high frequency of low-level gains and losses of typical pattern, including limited deletions on Sq. Four estrogen receptor positive cell lines were of luminal A subtype and characterized by a different pattern of aberrations and high-level amplifications, including ERBB2 and other 17q amplicons in BT474 and MDA-MB-361. SK-BR-3 cells, characterized by a complex genome including ERBB2 amplification, massive high-level amplifications on 8q and a homozygous deletion of CDH1 at 16q22, had an expression signature closest to luminal B subtype. The effects of gene amplifications were verified by gene expression analysis to distinguish targeted genes from silent amplicon passengers. JIMT1, derived from an ERBB2 amplified trastuzumab resistant tumor, was of the ERBB2 subtype. Homozygous deletions included other known targets such as PTEN (HCC1937) and CDKN2A (MDA-MB-231, MCF10A), but also new candidate suppressor genes such as FUSSEL18 (HCC1937) and WDR11 (L56Br-C1) as well as regions without known genes. The tiling BAC-arrays constitute a powerful tool for high-resolution genomic profiling suitable for cancer research and clinical diagnostics.
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| 14. |
- Kulin Olsson, Karin, 1951-
(författare)
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Arvsrätt eller rätt till arv : en studie om arvsberättigande och kvarlåtenskapens fördelning
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The present Swedish law of inheritance has developed slowly and is based on ideas stemming from an earlier social structure than that of today. When reforms have been made, modern regulations have been added to a very old structure. The rules on inheritance are still based on the nuclear family, though changes in society and the family forms that people choose have impacted on the notion of family, a notion which can no longer be seen as homogenous and clear. With changing living conditions and new forms of family, the present regulation has resulted in uncertainties and unpredictable consequences for the affected parties, such as when the wish of the deceased are restricted, equal heirs are treated differently, new forms of inheritance occur or when established protective mechanisms are sidelined. In an age when each person’s right to decide over their own interests enjoys central importance, it can be questioned whether a traditional law of inheritance is effective in contemporary society.The purpose of this dissertation is to examine from a historical perspective to what extent the law of inheritance is adapted to contemporary society, considering changing living conditions, forms of family and societal values. The dissertation’s point of departure is the law of inheritance of 1928 and the law of wills of 1930, and the question of who has the right to inherit and how the estate is distributed. Within this purpose the conditions for inheriting, principles regarding the distribution of the estate and the motives behind these are examined.The research has been conducted through an analysis of the development of the existing inheritance law's design and function in relation to the living conditions, family relationships and social values at different times in history. The approach has required that a wider perspective been applied to the design of the regulations on the right of inheritance and the distribution of the estate, which goes beyond law. The purpose and effect of the mentioned regulations have been identified and analysed on the basis of this background. The approach has meant that the current regulations have been examined both from an internal and an external perspective. The research has resulted in a proposal of change to the present principles of distribution and restrictions in order to accommodate present- day society’s living conditions and forms of family by extending the freedom of the decedent to dispose over the distribution of it’s estate after death.
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| 15. |
- Lindow, Helma, et al.
(författare)
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Integrerat kustzonsystem för Bohusläns skärgård
- 2004
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- SMHI har i samarbete med Länsstyrelsen i västra Götaland implementerat Kustzonssystemet i Bohusläns skärgård. Arbetet har pga. av sin omfattning indelats i två etapper. Kustzonssystemet är ett integrerat modellsystem där belastningen på kusten från land och atmosfär fastställs m.h.a. modeller. Syftet med kustzonssystemet är att modellerna skall vara så enkla som möjligt, för att kunna skapa långa tidsserier, och samtidigt kunna beskriva miljötillståndet i skärgården tillräckligt väl så att modellsystemet kan användas för exempelvis scenarioberäkningar. Bohuskusten kännetecknas av ett, på sina håll, komplicerat fjordsystem. Kustzonsmodellen är en s.k. en-dimensionell modell, som löser upp modellvariablerna i djupled, men beräknar ett horisontellt medelvärde i sitt område. För att kunna lösa upp de horisontella gradienterna i området måste modellområdet delas in i flertalet delbassänger. Indelningen av Kustzonsmodellens delbassänger följer i stort sett SVAR-indelningen. Detta innebär att för den norra delen av skärgården består modellen av 30 delbassänger. I den södra delen har vissa förenklingar kunnat göras, och några havsområden har kunnat slås samman i modellen och behandlats som en delbassäng. Genom dessa sammanslagningar har den södra skärgården delats in i 27 delbassänger. Modellen har simulerat en längre tidsserie i båda områdena. Observationer i Skagerack och Kattegatt driver modellen från öppna havet. En omfattande validering av modellen har genomförts m.h.a. observationer från Bohuskustens kontrollprogram. Därefter har in- och utflöden beräknats i varje bassäng för såväl total-kväve som total-fosfor.
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| 16. |
- Lindroos-Moll, Sebastian, 1985-
(författare)
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Värdering vid upprättande av kontrollbalansräkning : En aktiebolagsrättslig och redovisningsrättslig studie
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of the study is to investigate how valuation shall be carried out in drawing up balance sheet for liquidation purposes and whether valuation rules, in particular, and rules on involuntary liquidation due to capital deficiency, in general, need to be changed.It is stated in Ch. 25, sect. 13, Swedish Companies Act (SCA), that the board is under the obligation to draw up a balance sheet for liquidation purposes without delay when there is reason to expect that the company's own capital is less than half of the registered shareholder equity. Balance sheet for liquidation purposes shall be drawn up pursuant to applicable law on annual reports, but in calculating its own assets a number of adjustments may be made. The study focuses on the meaning of valuation consistent with the generally accepted accounting principles (Swedish GAAP), and reporting assets at net realisable value.In the 1970s, it was stated that the Swedish GAAP was an actual existing praxis in a qualitatively representative circle of parties under duty to keep accounts, an identified praxis among the actors. This description is far from the present situation as it is specifically stated in the general guidelines issued by the Swedish Accounting Standards Board (BFN) that private companies must comply with their guidelines.Among other things in this study, the role of the guidelines issued by the BFN are investigated and analysed in terms of their constitutional status regarding norm setting. The study includes a comparison of the Danish, Norwegian and Finnish rules on “serious loss” of the subscribed capital.One conclusion is that, under the current Swedish regulations regarding obligation to liquidate due to capital deficiency, there is room for changes which would reduce the distance between intended functions and the wording of the law. A more long-term solution, however, would require a total review of capital protection rules.
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| 17. |
- Marmefelt, Eleonor, et al.
(författare)
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Integrerat kustzonsystem för Hallandskusten
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- SMHI har i samarbete med Länsstyrelsen i Hallands län implementerat SMHIs Kustzonssystem längs Hallandskusten från Onsala kustvatten i norr till Skälderviken i söder. Kustzonssystemet är ett integrerat modellsystem där såväl belastningen på kusten från land och atmosfär som tillståndet i kustzonen beräknas med hjälp av modeller. Tillrinningen från land har beräknats med hjälp av den hydrologiska modellen HBV och koncentrationerna har fastställts med hjälp av observerade data. Atmosfärsdepositionen både på land och i kustområdet beräknas av den atmosfärskemiska MATCH-modellen. Kustzonsmodellen (PROBE-SCOBI), som är en biogeokemisk modell, beräknar tillståndet i kustvattnen. Syftet med Kustzonssystemet är att modellerna skall vara så beskaffade att det är möjligt att skapa långa tidsserier främst av näringsämnen och syrgashalt, samtidigt som miljötillståndet i kustzonen genom modellerna beskrivs med så hög kvalité att modellsystemet kan användas i analyssyfte, exempelvis vid scenariostudier. Kustzonsmodellen är en s.k. en-dimensionell modell, som löser upp modellvariablerna i djupled med hög noggrannhet, men beräknar ett horisontellt medelvärde i sitt område. För att kunna lösa upp de horisontella gradienterna i området måste modellområdet delas in i flertalet delbassänger. Beräkningar görs i alla bassänger, vilka är kopplade med varandra och utbyter egenskaper mellan varandra. Indelningen av Kustzonsmodellens delbassänger längs Hallandskusten följer SVAR-indelningen. Detta innebär att Kustzonsmodellen längs Hallandskusten består av 20 delbassänger.
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| 18. |
- Nilsson, Lars, et al.
(författare)
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The molecular signature of MDS stem cells supports a stem-cell origin of 5q-myelodysplastic syndromes
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:8, s. 3005-3014
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Tidskriftsartikel (refereegranskat)abstract
- Global gene expression profiling of highly purified 5q-deleted CD34+CD38–Thy1+ cells in 5q– myelodysplastic syndromes (MDSs) supported that they might originate from and outcompete normal CD34+CD38–Thy1+ hematopoietic stem cells. Few but distinct differences in gene expression distinguished MDS and normal stem cells. Expression of BMI1, encoding a critical regulator of self-renewal, was up-regulated in 5q– stem cells. Whereas multiple previous MDS genetic screens failed to identify altered expression of the gene encoding the myeloid transcription factor CEBPA, stage-specific and extensive down-regulation of CEBPA was specifically observed in MDS progenitors. These studies establish the importance of molecular characterization of distinct stages of cancer stem and progenitor cells to enhance the resolution of stage-specific dysregulated gene expression.
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| 19. |
- Olsson, Eleonor, et al.
(författare)
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CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers.
- 2011
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The CD44 cell adhesion molecule is aberrantly expressed in many breast tumors and has been implicated in the metastatic process as well as in the putative cancer stem cell (CSC) compartment. We aimed to investigate potential associations between alternatively spliced isoforms of CD44 and CSCs as well as to various breast cancer biomarkers and molecular subtypes. METHODS: We used q-RT-PCR and exon-exon spanning assays to analyze the expression of four alternatively spliced CD44 isoforms as well as the total expression of CD44 in 187 breast tumors and 13 cell lines. ALDH1 protein expression was determined by IHC on TMA. RESULTS: Breast cancer cell lines showed a heterogeneous expression pattern of the CD44 isoforms, which shifted considerably when cells were grown as mammospheres. Tumors characterized as positive for the CD44+/CD24- phenotype by immunohistochemistry were associated to all isoforms except the CD44 standard (CD44S) isoform, which lacks all variant exons. Conversely, tumors with strong expression of the CSC marker ALDH1 had elevated expression of CD44S. A high expression of the CD44v2-v10 isoform, which retain all variant exons, was correlated to positive steroid receptor status, low proliferation and luminal A subtype. The CD44v3-v10 isoform showed similar correlations, while high expression of CD44v8-v10 was correlated to positive EGFR, negative/low HER2 status and basal-like subtype. High expression of CD44S was associated with strong HER2 staining and also a subgroup of basal-like tumors. Unsupervised hierarchical cluster analysis of CD44 isoform expression data divided tumors into four main clusters, which showed significant correlations to molecular subtypes and differences in 10-year overall survival. CONCLUSIONS: We demonstrate that individual CD44 isoforms can be associated to different breast cancer subtypes and clinical markers such as HER2, ER and PgR, which suggests involvement of CD44 splice variants in specific oncogenic signaling pathways. Efforts to link CD44 to CSCs and tumor progression should consider the expression of various CD44 isoforms.
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| 20. |
- Olsson, Eleonor
(författare)
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Molecular Analysis of Breast Cancer Transcriptomes, Genomes, and Circulating Tumor DNA
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is a very heterogeneous disease in terms of clinical characteristics, genetic aberrations and prognosis. In Paper I, we focused on the CD44 molecule that often is aberrantly expressed in breast cancer and is widely used as a marker for cancer stem cells. Several isoforms of the CD44 molecule were analyzed at the transcriptome level across breast tumors and the expression of individual isoforms was correlated to molecular subtypes, protein expression of clinical markers, and cancer stem cell (CSC) phenotypes in breast tumors and cell lines. The CD44S isoform was associated with expression of the CSC marker ALDH1 and the CSC phenotype CD44+/CD24- was correlated to alternatively spliced isoforms in tumors. The isoforms were differentially expressed in molecular subtypes and HER2 and EGFR positive tumors were associated to CD44S and CD44v8-10, respectively. In Paper II, by using targeted genomic re-sequencing we screened for somatic mutations in 1237 genes in a panel of basal-like breast cancer cell lines, both in coding and surrounding non-coding regions. In total, 658 high confidence SNVs and indels were detected and 315 of these were novel (not in COSMIC). A selection of the variants were validated with Sanger sequencing and, 123 of 130 high confidence variants were confirmed including 111 novel variants. The mutation frequency was higher in coding (CDS) compared to non-coding (non- CDS) regions and in particular G or C base replacements were higher in the CDS compared to non-CDS. The SNVs within the context of T[C]A/T[G]A and T[C]T/A[G]A were significantly more common in the CDS than in the non-CDS regions. Re-sequenced data was used to derive copy number estimations, which correlated well to SNP array data. In Paper III, the potential in using tumor-specific rearrangements present in circulating tumor DNA (ctDNA) to detect occult metastatic breast cancer was evaluated. In total, 14 eventual metastatic (EM) patients and 6 long-term disease free (DF) patients were investigated. We used whole-genome sequencing on the primary tumors to derive patient-specific rearrangements that were confirmed by PCR. Circulating tumor DNA levels across multiple plasma samples during the clinical course were analyzed by quantitative droplet digital PCR. Accurate post-surgical discrimination of EM patients (93%) from DM (100%) was achieved by ctDNA monitoring. The average lead-time to clinical detection of metastatic disease was 11 months (range 0-37 months). Moreover, the ctDNA level was a quantitative predictor for both recurrence (P=0.02) and death (P=0.04). We demonstrated that monitoring of ctDNA can be used for early detection of metastatic breast cancer and is a potential tool for optimization of adjuvant therapy and should be evaluated further in clinical studies.
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| 21. |
- Olsson, Eleonor, et al.
(författare)
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Mutation Screening of 1,237 Cancer Genes across Six Model Cell Lines of Basal-Like Breast Cancer.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Basal-like breast cancer is an aggressive subtype generally characterized as poor prognosis and lacking the expression of the three most important clinical biomarkers, estrogen receptor, progesterone receptor, and HER2. Cell lines serve as useful model systems to study cancer biology in vitro and in vivo. We performed mutational profiling of six basal-like breast cancer cell lines (HCC38, HCC1143, HCC1187, HCC1395, HCC1954, and HCC1937) and their matched normal lymphocyte DNA using targeted capture and next-generation sequencing of 1,237 cancer-associated genes, including all exons, UTRs and upstream flanking regions. In total, 658 somatic variants were identified, of which 378 were non-silent (average 63 per cell line, range 37-146) and 315 were novel (not present in the Catalogue of Somatic Mutations in Cancer database; COSMIC). 125 novel mutations were confirmed by Sanger sequencing (59 exonic, 48 3'UTR and 10 5'UTR, 1 splicing), with a validation rate of 94% of high confidence variants. Of 36 mutations previously reported for these cell lines but not detected in our exome data, 36% could not be detected by Sanger sequencing. The base replacements C/G>A/T, C/G>G/C, C/G>T/A and A/T>G/C were significantly more frequent in the coding regions compared to the non-coding regions (OR 3.2, 95% CI 2.0-5.3, P<0.0001; OR 4.3, 95% CI 2.9-6.6, P<0.0001; OR 2.4, 95% CI 1.8-3.1, P<0.0001; OR 1.8, 95% CI 1.2-2.7, P = 0.024, respectively). The single nucleotide variants within the context of T[C]T/A[G]A and T[C]A/T[G]A were more frequent in the coding than in the non-coding regions (OR 3.7, 95% CI 2.2-6.1, P<0.0001; OR 3.8, 95% CI 2.0-7.2, P = 0.001, respectively). Copy number estimations were derived from the targeted regions and correlated well to Affymetrix SNP array copy number data (Pearson correlation 0.82 to 0.96 for all compared cell lines; P<0.0001). These mutation calls across 1,237 cancer-associated genes and identification of novel variants will aid in the design and interpretation of biological experiments using these six basal-like breast cancer cell lines.
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| 22. |
- Olsson, Eleonor, et al.
(författare)
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Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
- 2015
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 7:8, s. 1034-1047
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Tidskriftsartikel (refereegranskat)abstract
- Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.
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| 23. |
- Olsson, Stefan, 1965-, et al.
(författare)
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Sweden
- 2018. - 1
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Ingår i: Corporate Tax Residence and Mobility. - Amsterdam : International Bureau of Fiscal Documentation (IBFD). - 9789087224516 ; , s. 573-590
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 24. |
- Olsson, Stefan, 1965-, et al.
(författare)
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Sweden
- 2018. - 1
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Ingår i: Corporate Tax Residence and Mobility. - Amsterdam : International Bureau of Fiscal Documentation (IBFD). - 9789087224516 ; , s. 573-590
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 25. |
- Olsson, Stefan, 1965-, et al.
(författare)
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Sweden
- 2018. - 1
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Ingår i: Corporate Tax Residence and Mobility. - Amsterdam : International Bureau of Fiscal Documentation (IBFD). - 9789087224516 ; , s. 573-590
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Bokkapitel (övrigt vetenskapligt/konstnärligt)
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| 26. |
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| 27. |
- Pena, Cristina, et al.
(författare)
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STC1 Expression By Cancer-Associated Fibroblasts Drives Metastasis of Colorectal Cancer
- 2013
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Ingår i: Cancer Research. - : American Association for Cancer Research. - 0008-5472 .- 1538-7445. ; 74:4, s. 1287-1297
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factor (PDGF) receptor signaling is a major functional determinant of cancer-associated fibroblasts (CAF). Elevated expression of PDGF receptors on stromal CAFs is associated with metastasis and poor prognosis, but mechanism(s) that underlie these connections are not understood. Here, we report the identification of the secreted glycoprotein stanniocalcin-1 (STC1) as a mediator of metastasis by PDGF receptor function in the setting of colorectal cancer. PDGF-stimulated fibroblasts increased migration and invasion of cocultured colorectal cancer cells in an STC1-dependent manner. Analyses of human colorectal cancers revealed significant associations between stromal PDGF receptor and STC1 expression. In an orthotopic mouse model of colorectal cancer, tumors formed in the presence of STC1-deficient fibroblasts displayed reduced intravasation of tumor cells along with fewer and smaller distant metastases formed. Our results reveal a mechanistic basis for understanding the contribution of PDGF-activated CAFs to cancer metastasis. Cancer Res; 73(4); 1287-97.
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| 28. |
- Sundström, Johan, Professor, 1971-, et al.
(författare)
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Risk factors for subarachnoid haemorrhage : a nationwide cohort of 950 000 adults
- 2019
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Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 48:6, s. 2018-2025
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Subarachnoid haemorrhage (SAH) is a devastating disease, with high mortality rate and substantial disability among survivors. Its causes are poorly understood. We aimed to investigate risk factors for SAH using a novel nationwide cohort consortium.METHODS: We obtained individual participant data of 949 683 persons (330 334 women) between 25 and 90 years old, with no history of SAH at baseline, from 21 population-based cohorts. Outcomes were obtained from the Swedish Patient and Causes of Death Registries.RESULTS: During 13 704 959 person-years of follow-up, 2659 cases of first-ever fatal or non-fatal SAH occurred, with an age-standardized incidence rate of 9.0 [95% confidence interval (CI) (7.4-10.6)/100 000 person-years] in men and 13.8 [(11.4-16.2)/100 000 person-years] in women. The incidence rate increased exponentially with higher age. In multivariable-adjusted Poisson models, marked sex interactions for current smoking and body mass index (BMI) were observed. Current smoking conferred a rate ratio (RR) of 2.24 (95% CI 1.95-2.57) in women and 1.62 (1.47-1.79) in men. One standard deviation higher BMI was associated with an RR of 0.86 (0.81-0.92) in women and 1.02 (0.96-1.08) in men. Higher blood pressure and lower education level were also associated with higher risk of SAH.CONCLUSIONS: The risk of SAH is 45% higher in women than in men, with substantial sex differences in risk factor strengths. In particular, a markedly stronger adverse effect of smoking in women may motivate targeted public health initiatives.
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| 29. |
- Tang, Man-Hung Eric, et al.
(författare)
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Remarkable similarities of chromosomal rearrangements between primary human breast cancers and matched distant metastases as revealed by whole-genome sequencing.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:35, s. 37169-37184
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Tidskriftsartikel (refereegranskat)abstract
- To better understand and characterize chromosomal structural variation during breast cancer progression, we enumerated chromosomal rearrangements for 11 patients by performing low-coverage whole-genome sequencing of 11 primary breast tumors and their 13 matched distant metastases. The tumor genomes harbored a median of 85 (range 18-404) rearrangements per tumor, with a median of 82 (26-310) in primaries compared to 87 (18-404) in distant metastases. Concordance between paired tumors from the same patient was high with a median of 89% of rearrangements shared (range 61-100%), whereas little overlap was found when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited diverse genomic patterns of rearrangements: some carried events distributed throughout the genome while others had events mostly within densely clustered chromothripsis-like foci at a few chromosomal locations. Irrespectively, the patterns were highly conserved between the primary tumor and metastases from the same patient. Rearrangements occurred more frequently in genic areas than expected by chance and among the genes affected there was significant enrichment for cancer-associated genes including disruption of TP53, RB1, PTEN, and ESR1, likely contributing to tumor development. Our findings are most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from primary tumor to distant metastasis.
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| 30. |
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| 31. |
- Tormin, Ariane, et al.
(författare)
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Characterization of bone marrow-derived mesenchymal stromal cells (MSC) based on gene expression profiling of functionally defined MSC subsets.
- 2009
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Ingår i: Cytotherapy. - : Elsevier BV. - 1477-2566 .- 1465-3249. ; 11, s. 114-128
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Tidskriftsartikel (refereegranskat)abstract
- Background aims Human mesenchymal stromal cells (MSC) are promising candidates for cell therapy because of their intriguing properties (high proliferation and differentiation capacity, microenvironmental function and immune modulation). However, MSC are heterogeneous and a better understanding of the heterogeneity of the cells that form the MSC cultures is critical. Methods Human MSC were generated in standard cultures and stained with carboxyfluorescein succinimidyl ester (CFSE) for cell division tracking. Gene expression profiling of MSC that were sorted based on functional parameters (i.e. proliferation characteristics) was utilized to characterize potential MSC subpopulations (progenitor content and differentiation capacity) and identify potential MSC subpopulation markers. Results The majority of MSC had undergone more than two cell divisions (79.7+/-2.0%) after 10 days of culture, whereas 3.5+/-0.9% of MSC had not divided. MSC were then sorted into rapidly dividing cells (RDC) and slowly/non-dividing cells (SDC/NDC). Colony-forming unit-fibroblast (CFU-F) frequencies were lowest in NDC and highest in RDC with low forward-/side-scatter properties (RDC(lolo)). Comparative microarray analysis of NDC versus RDC identified 102 differentially expressed genes. Two of these genes (FMOD and VCAM1) corresponded to cell-surface molecules that enabled the prospective identification of a VCAM1(+)/FMOD(+) MSC subpopulation, which increased with passage and showed very low progenitor activity and limited differentiation potential. Conclusions These data clearly demonstrate functional differences within MSC cultures. Furthermore, this study shows that cell sorting based on proliferation characteristics and gene expression profiling can be utilized to identify surface markers for the characterization of MSC subpopulations.
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| 32. |
- Wiklander, Per-Ola, 1984-
(författare)
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Kommunal redovisning : En rättsvetenskaplig studie
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Swedish municipalities are obliged to continually and annually account and disclose information in certain accounting reports. The accounting obligation for municipalities is set forth in the Swedish Local Government Act. Since the year 1998 there is also a Local Government Accounting Act (LGAA) in place. In accordance with LGAA a requirement on all accounting is that it needs to be established in line with Swedish General Accepted Accounting Principles (GAAP).At the same time as LGAA came into effect, the state and the municipal federations established a new standard-setting body. It had, and still has, the task to publish recommendations with the body’s view on how municipalities should account in accordance with Swedish GAAP. The body received the name The Council for Municipal Accounting, CMA. In this study the complex of norms that is of certain importance for Swedish municipalities when they account are analysed. Questions that are analysed are e.g. what position and function the standard-setting body CMA and the body’s recommendations have in a legal context. Another question that is analysed is how the regulation for municipalities should be understood in relation to the regulation for private sector.Some of the conclusions in the study are that there is a possibility to identify a Swedish GAAP for Municipalities which has its own systematic. The legal control of whether municipalities account in accordance to Swedish GAAP is weak though. When evaluating what should be seen as Swedish GAAP for municipalities, there is a presumption that the recommendations from CMA are the correct interpretations, even though the recommendations in line with the constitution can not be seen as any form of binding law. In light of this, the strength of the presumption is somewhat unclear, but should not be seen as strong as the equivalent presumption that recommendations from standard-setting bodies in private sector are the correct interpretation of Swedish GAAP.
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| 33. |
- Wikman, Agneta Taune, et al.
(författare)
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Noninvasive Single-Exon Fetal RHD Determination in a Routine Screening Program in Early Pregnancy.
- 2012
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Ingår i: Obstetrics and Gynecology. - 1873-233X. ; 120:2, s. 227-234
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To develop a simple and robust assay suitable for fetal RHD screening in first-trimester pregnancy and to estimate the sensitivity and specificity of the test after its implementation in an unselected pregnant population. METHODS: Pregnant women attending their first antenatal visit were included, and fetal RHD determination was performed for all women who typed RhD-negative by routine serology. DNA was extracted by an automated system and quantitative polymerase chain reaction was done by an assay based on exon 4. Reporting criteria were simple and strict. RESULTS: Four thousand one hundred eighteen pregnancies, with a median gestational age of 10 weeks, were included. After 211 (5.1%) reanalyses, fetal RHD was reported positive in 2,401 (58.3%), negative in 1,552 (37.7%), and inconclusive in 165 (4.0%) based on the first sample. After a second sample in 147 of 165, only 14 remained inconclusive, all resulting from a weak or silent maternal RHD gene. Using blood group serology of the newborns as the gold standard, the false-negative rate was 55 of 2,297 (2.4%) and the false-positive rate was 15 of 1,355 (1.1%). After exclusion of samples obtained before gestational week 8, the false-negative rate was 23 of 2,073 (1.1%) and the false-positive rate was 14 of 1,218 (1.1%). Both sensitivity and specificity were close to 99% provided samples were not collected before gestational week 8. From gestational week 22, sensitivity was 100%. CONCLUSION: : Fetal RHD detection in early pregnancy using a single-exon assay in a routine clinical setting is feasible and accurate. LEVEL OF EVIDENCE: : I.
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