| 1. |
- Kasliwal, Mansi M., et al.
(author)
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Kilonova Luminosity Function Constraints Based on Zwicky Transient Facility Searches for 13 Neutron Star Merger Triggers during O3
- 2020
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In: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 905:2
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Journal article (peer-reviewed)abstract
- We present a systematic search for optical counterparts to 13 gravitational wave (GW) triggers involving at least one neutron star during LIGO/Virgo's third observing run (O3). We searched binary neutron star (BNS) and neutron star black hole (NSBH) merger localizations with the Zwicky Transient Facility (ZTF) and undertook follow-up with the Global Relay of Observatories Watching Transients Happen (GROWTH) collaboration. The GW triggers had a median localization area of 4480 deg(2), a median distance of 267 Mpc, and false-alarm rates ranging from 1.5 to 10(-25) yr(-1). The ZTF coverage in the g and r bands had a median enclosed probability of 39%, median depth of 20.8 mag, and median time lag between merger and the start of observations of 1.5 hr. The O3 follow-up by the GROWTH team comprised 340 UltraViolet/Optical/InfraRed (UVOIR) photometric points, 64 OIR spectra, and three radio images using 17 different telescopes. We find no promising kilonovae (radioactivity-powered counterparts), and we show how to convert the upper limits to constrain the underlying kilonova luminosity function. Initially, we assume that all GW triggers are bona fide astrophysical events regardless of false-alarm rate and that kilonovae accompanying BNS and NSBH mergers are drawn from a common population; later, we relax these assumptions. Assuming that all kilonovae are at least as luminous as the discovery magnitude of GW170817 (-16.1 mag), we calculate that our joint probability of detecting zero kilonovae is only 4.2%. If we assume that all kilonovae are brighter than -16.6 mag (the extrapolated peak magnitude of GW170817) and fade at a rate of 1 mag day(-1) (similar to GW170817), the joint probability of zero detections is 7%. If we separate the NSBH and BNS populations based on the online classifications, the joint probability of zero detections, assuming all kilonovae are brighter than -16.6 mag, is 9.7% for NSBH and 7.9% for BNS mergers. Moreover, no more than <57% (<89%) of putative kilonovae could be brighter than -16.6 mag assuming flat evolution (fading by 1 mag day(-1)) at the 90% confidence level. If we further take into account the online terrestrial probability for each GW trigger, we find that no more than <68% of putative kilonovae could be brighter than -16.6 mag. Comparing to model grids, we find that some kilonovae must have M-ej M, X-lan > 10(-4), or > 30 degrees to be consistent with our limits. We look forward to searches in the fourth GW observing run; even 17 neutron star mergers with only 50% coverage to a depth of -16 mag would constrain the maximum fraction of bright kilonovae to <25%.
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| 2. |
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| 3. |
- Svedenmark, Sara, 1971-, et al.
(author)
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Old Wine in a New Bottle? – Interpreting Gender Mainstreaming in a Municipal Reorganisation
- 2022
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In: Scandinavian Journal of Public Administration. - Göteborg : University of Gothenburg. - 2001-7405 .- 2001-7413. ; :4, s. 73-90
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Journal article (peer-reviewed)abstract
- Gender mainstreaming (GM) has been on the agenda of organisations at various levels in Sweden and worldwide since the 1990s. Research has shown that GM is difficult to apply and has yet to be clearly defined, and additionally that organisations are uncertain about how to implement it. Research also suggests that the dominance of the new public management (NPM) approach within organisations has made GM work more challenging. In this article, we examine GM in a medium-sized Swedish municipality that is reorganising itself to become gender mainstreamed while introducing trust-based governance (TBG). This municipality provides a unique opportunity to study how GM is constructed in a municipality at the intersection of NPM and TBG. Applying a critical perspective, this article analyses documents from reorganisation based on Bacchi’s (2009) policy analysis. The results demonstrate that GM is mainly translated into TBG-inspired practices and that efficiency becomes an overarching concept that entangles GM, TBG and NPM. GM becomes part of cultural change together with TBG, while NPM maintains its dominance in the structural change of the organisation.
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| 4. |
- Bandopadhayay, Pratiti, et al.
(author)
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BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
- 2014
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 20:4, s. 912-925
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Journal article (peer-reviewed)abstract
- Purpose:MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.Experimental Design:We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.Results:Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.Conclusion:JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.
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| 5. |
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| 6. |
- Bergström, Christel A S, et al.
(author)
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Hepatitis C virus NS3 protease inhibitors : large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells
- 2009
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In: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 38:5, s. 556-563
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Journal article (peer-reviewed)abstract
- The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.
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| 7. |
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Bolin, Sara, 1988-, et al.
(author)
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Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
- 2018
-
In: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 37:21, s. 2850-2862
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Journal article (peer-reviewed)abstract
- Medulloblastoma (MB) is the most common malignant brain tumor in children. MYC genes are frequently amplified and correlate with poor prognosis in MB. BET bromodomains recognize acetylated lysine residues and often promote and maintain MYC transcription. Certain cyclin-dependent kinases (CDKs) are further known to support MYC stabilization in tumor cells. In this report, MB cells were suppressed by combined targeting of MYC expression and MYC stabilization using BET bromodomain inhibition and CDK2 inhibition, respectively. Such combination treatment worked synergistically and caused cell cycle arrest as well as massive apoptosis. Immediate transcriptional changes from this combined MYC blockade were found using RNA-Seq profiling and showed remarkable similarities to changes in MYC target gene expression when MYCN was turned off with doxycycline in our MYCN-inducible animal model for Group 3 MB. In addition, the combination treatment significantly prolonged survival as compared to single-agent therapy in orthotopically transplanted human Group 3 MB with MYC amplifications. Our data suggest that dual inhibition of CDK2 and BET bromodomains can be a novel treatment approach for suppressing MYC-driven cancer.
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| 12. |
- Bolin, Sara, 1988-, et al.
(author)
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Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
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Journal article (peer-reviewed)abstract
- Tumor recurrence is a slow biological process involving therapy resistance, immune escape, and metastasis and is the leading cause of death in medulloblastoma, the most frequent malignant pediatric brain tumor. By studying paired primary-recurrent patient samples and patient-derived xenografts we identified a significant accumulation of SOX9-positive cells in relapses and metastases. They exist as rare, quiescent cells in Group 3 and Group 4 patients that constitute two-thirds of medulloblastoma. To follow relapse at the single-cell level we developed an inducible dual Tet model of MYC-driven MB, where MYC can be directed from treatment-sensitive bulk cells to resistant, dormant SOX9-positive cells by doxycycline. SOX9 promoted immune es-cape, DNA repair suppression and was essential for recurrence. Tumor cell dormancy was non-hierarchical, migratory, and depended on MYC suppression by SOX9 to promote relapse. By using computational modeling and treatment we further showed how doxorubicin and MGMT inhibitors are specifically targeting relapsing cells.
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| 13. |
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| 14. |
- Bolin, Sara
(author)
-
Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies
- 2016
-
Doctoral thesis (other academic/artistic)abstract
- Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative.Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma.Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells.This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.
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| 15. |
- Borgenvik, Anna, 1987-, et al.
(author)
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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
-
In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
-
Journal article (peer-reviewed)abstract
- Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.
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| 16. |
- Cancer, Matko, et al.
(author)
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BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells
- 2019
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In: Cell Death and Disease. - : NATURE PUBLISHING GROUP. - 2041-4889. ; 10
-
Journal article (peer-reviewed)abstract
- Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.
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| 17. |
- Hutter, Sonja, et al.
(author)
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Modeling and Targeting MYC Genes in Childhood Brain Tumors
- 2017
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In: Genes. - : MDPI. - 2073-4425. ; 8:4
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Research review (peer-reviewed)abstract
- Brain tumors are the second most common group of childhood cancers, accounting for about 20%-25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors.
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| 18. |
- Kahn, Suzana A., et al.
(author)
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Notch1 regulates the initiation of metastasis and self-renewal of Group 3 medulloblastoma
- 2018
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9
-
Journal article (peer-reviewed)abstract
- Medulloblastoma is the most common malignant brain tumor of childhood. Group 3 medulloblastoma, the most aggressive molecular subtype, frequently disseminates through the leptomeningeal cerebral spinal fluid (CSF) spaces in the brain and spinal cord. The mechanism of dissemination through the CSF remains poorly understood, and the molecular pathways involved in medulloblastoma metastasis and self-renewal are largely unknown. Here we show that NOTCH1 signaling pathway regulates both the initiation of metastasis and the self-renewal of medulloblastoma. We identify a mechanism in which NOTCH1 activates BMI1 through the activation of TWIST1. NOTCH1 expression and activity are directly related to medulloblastoma metastasis and decreased survival rate of tumor-bearing mice. Finally, medulloblastoma-bearing mice intrathecally treated with anti-NRR1, a NOTCH1 blocking antibody, present lower frequency of spinal metastasis and higher survival rate. These findings identify NOTCH1 as a pivotal driver of Group 3 medulloblastoma metastasis and self-renewal, supporting the development of therapies targeting this pathway.
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| 19. |
- Kjellgren, Maria, 1973-
(author)
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Skolkuratorns samtalspraktik : en studie om individuella samtal med barn i den svenska grundskolan
- 2024
-
Doctoral thesis (other academic/artistic)abstract
- This thesis fills part of the existing knowledge gap regarding school social workers (SSW) individual counselling practice. The overall aim is to investigate the individual SSW counselling in Swedish elementary schools, as part of the pupil health team (PHT). This will be achieved by exploring the following three basic research questions: What characterizes school social work regarding structure, process and interventions in individual counselling sessions held by SSWs with children? How do SSWs describe the difficulties and opportunities in school social work, interventions and performance, and collaboration with other actors in pupil health teams? What characterises SSWs’ individual counselling according to the adolescents’ experiences and expressed needsThis thesis consisted of four research studies. The first one concentrated on SSWs personal experiences of counselling children, in which focus group studies were conducted with 22 SSWs (four groups). In the second study, the SSWs described their experiences of being a part of a multi-disciplinary team, the PHT, during the focus group interviews. These two studies were analysed by content analysis. The third study consisted of a quantitative protocol study regarding child characteristics, counselling strategies and interventions analysed by descriptive statistics. The purpose on the fourth study was to increase knowledge about the individual counselling from the adolescents’ perspective. Individual interviews were conducted and analysed through content analysis.This thesis highlighted the necessity for children to express themselves, in regards to their life situation, concerns and problems. SSWs could be one prominent actor in the children’s lives by providing individual counselling sessions. SSWs are described as the PHT psychosocial expert with specialised knowledge regarding the impact of negative psychosocial factors on children.In addition, this thesis concluded that available regulations and guidelines meant insure that children are listened and able to express their narrative in a safe and trustful school counselling environment are limited.
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| 20. |
- Kjölstad, Henrik, 1980-
(author)
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A European Declaration of Fascism? : En analys av Anders Behring Breiviks manifest 2083
- 2020
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Licentiate thesis (other academic/artistic)abstract
- The terror attacks in Oslo, July 22, 2011, executed by Anders Behring Breivik, showed the deadliest outbreak of political violence in Norway since World War II. After the subsequent apprehension of Breivik, discussions about his ideological positioning soon emerged. While Breivik was initially described as an Islamophobic, right wing-extremist, a few expert witnesses and scholars labeled him and his manifesto 2083: A Declaration of European Independence as fascist. Some analysts disagreed with such a categorization and argued that Breivik's views had little to do with fascism. Other commentators and academics partly agreed with the fascist label but added that Breivik's ideology differed from classical fascism in several ways. The aim of this research is to examine whether the manifesto 2083 can be classified as fascist according to various established definitions and ideal types of fascism. In particular, this research draws on the theories, definitions, and ideal types of fascism of established scholars Roger Griffin, Stanley G. Payne, and Emilio Gentile to inform a content analysis of 2083.The study's relevance concerns the ideology of and behind certain violent political activism, and if fascism is undergoing a transformation which urges updates of established definitions of the phenomenon. 2083 is treated as an outlier or deviant case of fascism.This research finds that 2083 does fulfill several fascist criteria, and even concepts central to the ideal types. However, the results are at times ambiguous and open to further interpretation. Fascist concepts such as national rebirth, a glorification of violence, and religiously tinged activism are expressed in the manifesto, but crucial details regarding them remain unexplored or unspecified. 2083's violent strategies for achieving desired societal change have striking similarities with certain contemporary race radicalism; while descriptions of societal condition and utopian goals share certain fascism characteristics, but also resemble late 19th Century German revolutionary conservatism or proto-fascism. Thus, one might rather see 2083 as hybrid form of different, already existing, fascist ideological traits rather than a “new” form of fascism.
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| 21. |
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| 22. |
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| 23. |
- Nyhlén, Sara, et al.
(author)
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Att studera lokalt beslutsfattande
- 2015
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In: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144105154 ; , s. 73-77
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Book chapter (other academic/artistic)
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| 24. |
- Nyhlén, Sara, 1980-, et al.
(author)
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Att studera lokalt beslutsfattande
- 2022. - 2
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In: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144155937 ; , s. 87-90
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Book chapter (other academic/artistic)
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| 25. |
- Nyhlén, Sara, 1980-, et al.
(author)
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When social inequality goes beyond the nation state : analyzing how Swedish municipalities handle vulnerable EU-migrants
- 2017
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Conference paper (peer-reviewed)abstract
- Since 2012 Sweden has faced a seemingly new situation with social inequality displaying itself as an increasing amount of homeless people making a living mainly as beggars in Swedish cities and towns. With the Swedish welfare state and the far reaching local autonomy this situation with social inequality is left to each municipality to decide upon how to handle. The situation is growing in complexity since the majority of the people in the precarious situation are so called “EU-migrants” which means that they are people traveling within EU seeking a better life trying to avoid poverty, unemployment and many times harassments and racism. In this study we have analyzed how it comes that this situation is handled differently by local authorities. Applying a most similar system design we look at how 7 municipalities within a region in the northern parts of Sweden handle the situation with social vulnerability. Given that the municipalities have the same political majority, are located in the same region and are ruled by the same national policies, we pose the question why is the outcome so different? The study shows how the local public officials and politicians are negotiating rights, citizenship and needs and how boundaries are drawn within the welfare state.
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| 26. |
- Olausson, Pär M., et al.
(author)
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Lokalt beslutsfattande - en introduktion
- 2015
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In: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144105154 ; , s. 11-20
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Book chapter (other academic/artistic)
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| 27. |
- Olausson, Pär M., Docent, 1968-, et al.
(author)
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Lokalt beslutsfattande - en introduktion
- 2022. - 2
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In: Lokalt beslutsfattande. - Lund : Studentlitteratur AB. - 9789144155937 ; , s. 13-24
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Book chapter (other academic/artistic)
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| 28. |
- Olofsdotter, Gunilla, 1957-, et al.
(author)
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Study protocol: Local labour market programs–institutional structures, organizational forms and lived experiences
- 2024
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In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 19:1
-
Journal article (peer-reviewed)abstract
- In this programme, we map and examine local labour market programmes (LLMPs) at the municipal level in Sweden. This includes their institutional structure and organisation, as well as the experiences of participants in the programmes, using a longitudinal approach with the aim to improve LLMPs. The long-term goal is to increasing the inclusion of LLMP participants in working life. To answer the programme’s questions, data will be collected and analysed within the four work packages. In each work package, a mixed-method approach is applied with a combination of quantitative and qualitative methods. The programme is informed by three overarching general theoretical approached, tying together institutional ethnography, intersectional studies of structural inequalities on different levels, and the role of emotions in everyday work. At the organisational level (WP 1), we will investigate the circumstances under which LLMPs are performed and negotiated by those involved. Here, the internal organisation, activities and methods are the focus. This approach will result in knowledge about the characteristics of these organisations and the factors promoting the inclusion of underrepresented groups in working life. By examining the activities in LLMPs (WP 2), we will be able to determine how their institutional structure differs between regions in Sweden, how the different municipalities work with labour market policy, how they translate national policy into the local context, how they organise their work and which initiatives they choose to adopt. By examining the individual experiences of those who are directly affected by such incentives (WP 3), knowledge and understanding will be obtained of the connections between experiences and labour market policies. This will give important insights into the functioning of local programmes and of the opportunities to create entry into the labour market. Furthermore, in WP4 we will develop and test an effect evaluation of work methods used in LLMPs and their effect on clients’ progress over time.
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| 29. |
- Rahmanto, Aldwin Suryo, et al.
(author)
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FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
- 2016
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In: EMBO Journal. - : EMBO. - 0261-4189 .- 1460-2075. ; 35:20, s. 2192-2212
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Journal article (peer-reviewed)abstract
- SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCFFBW7 alpha. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.
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| 30. |
- Roy, Ananya, et al.
(author)
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Mast Cell Chymase Degrades the Alarmins Heat Shock Protein 70, Biglycan, HMGB1, and Interleukin-33 (IL-33) and Limits Danger-induced Inflammation
- 2014
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In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 289:1, s. 237-250
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Journal article (peer-reviewed)abstract
- During infection and tissue damage, virulence factors and alarmins are pro-inflammatory and induce activation of various immune cells including macrophages and mast cells (MCs). Activated MCs instantly release preformed inflammatory mediators, including several proteases. The chymase mouse mast cell protease (MCPT)-4 is thought to be pro-inflammatory, whereas human chymase also degrades pro-inflammatory cytokines, suggesting that chymase instead limits inflammation. Here we explored the contribution of MCPT4 and human chymase to the control of danger-induced inflammation. We found that protein extracts from wild type (WT), carboxypeptidase A3-, and MCPT6-deficient mice and MCs and recombinant human chymase efficiently degrade the Trichinella spiralis virulence factor heat shock protein 70 (Hsp70) as well as endogenous Hsp70. MC-(W-sash)-, serglycin-, NDST2-, and MCPT4-deficient extracts lacked this capacity, indicating that chymase is responsible for the degradation. Chymase, but not MC tryptase, also degraded other alarmins, i.e. biglycan, HMGB1, and IL-33, a degradation that was efficiently blocked by the chymase inhibitor chymostatin. IL-7, IL-22, GM-CSF, and CCL2 were resistant to chymase degradation. MCPT4-deficient conditions ex vivo and in vivo showed no reduction in added Hsp70 and only minor reduction of IL-33. Peritoneal challenge with Hsp70 resulted in increased neutrophil recruitment and TNF- levels in the MCPT4-deficient mice, whereas IL-6 and CCL2 levels were similar to the levels found in WT mice. The rapid and MC chymase-specific degradation of virulence factors and alarmins may depend on the presence of accessible extended recognition cleavage sites in target substrates and suggests a protective and regulatory role of MC chymase during danger-induced inflammation.
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| 31. |
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| 32. |
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| 33. |
- Swartling, Fredrik J., 1975-, et al.
(author)
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Signals that regulate the oncogenic fate of neural stem cells and progenitors
- 2014
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In: Experimental Neurology. - : Elsevier BV. - 0014-4886 .- 1090-2430. ; 260, s. 56-68
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Research review (peer-reviewed)abstract
- Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors.
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| 34. |
- Wallmann, Tatjana, et al.
(author)
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Microglia Induce PDGFRB Expression in Glioma Cells to Enhance Their Migratory Capacity
- 2018
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In: iScience. - : Elsevier BV. - 2589-0042. ; 9, s. 71-83
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Journal article (peer-reviewed)abstract
- High-grade gliomas (HGGs) are the most aggressive and invasive primary brain tumors. The platelet-derived growth factor (PDGF) signaling pathway drives HGG progression, and enhanced expression of PDGF receptors (PDGFRs) is a well-established aberration in a subset of glioblastomas (GBMs). PDGFRA is expressed in glioma cells, whereas PDGFRB is mostly restricted to the glioma-associated stroma. Here we show that the spatial location of TAMMs correlates with the expansion of a subset of tumor cells that have acquired expression of PDGFRB in both mouse and human low-grade glioma and HCGs. Furthermore, M2-polarized microglia but not bone marrow (BM)-derived macrophages (BMDMs) induced PDGFRB expression in glioma cells and stimulated their migratory capacity. These findings illustrate a heterotypic cross-talk between microglia and glioma cells that may enhance the migratory and invasive capacity of the latter by inducing PDGFRB.
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