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| 2. |
- Mainwaring, Oliver, et al.
(author)
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ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
- 2023
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Journal article (peer-reviewed)abstract
- Medulloblastoma, the most common malignant pediatric brain tumor, often harbors MYC amplifications. Compared to high-grade gliomas, MYC-amplified medulloblastomas often show increased photoreceptor activity and arise in the presence of a functional ARF/p53 suppressor pathway. Here, we generate an immunocompetent transgenic mouse model with regulatable MYC that develop clonal tumors that molecularly resemble photoreceptor-positive Group 3 medulloblastoma. Compared to MYCN-expressing brain tumors driven from the same promoter, pronounced ARF silencing is present in our MYC-expressing model and in human medulloblastoma. While partial Arf suppression causes increased malignancy in MYCN-expressing tumors, complete Arf depletion promotes photoreceptor-negative high-grade glioma formation. Computational models and clinical data further identify drugs targeting MYC-driven tumors with a suppressed but functional ARF pathway. We show that the HSP90 inhibitor, Onalespib, significantly targets MYC-driven but not MYCN-driven tumors in an ARF-dependent manner. The treatment increases cell death in synergy with cisplatin and demonstrates potential for targeting MYC-driven medulloblastoma.
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| 3. |
- Warkander, Philip, et al.
(author)
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Boro som mode och antimode
- 2021
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In: Boro – Nödens Konst. - 9789198606553 ; , s. 11-14
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Book chapter (other academic/artistic)
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| 4. |
- Alajbegovic, Azra, et al.
(author)
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MRTFA overexpression promotes conversion of human coronary artery smooth muscle cells into lipid-laden foam cells
- 2021
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In: Vascular Pharmacology. - : Elsevier BV. - 1537-1891. ; 138
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Journal article (peer-reviewed)abstract
- Objective: Smooth muscle cells contribute significantly to lipid-laden foam cells in atherosclerotic plaques. However, the underlying mechanisms transforming smooth muscle cells into foam cells are poorly understood. The purpose of this study was to gain insight into the molecular mechanisms regulating smooth muscle foam cell formation. Approach and results: Using human coronary artery smooth muscle cells we found that the transcriptional co-activator MRTFA promotes lipid accumulation via several mechanisms, including direct transcriptional control of LDL receptor, enhanced fluid-phase pinocytosis and reduced lipid efflux. Inhibition of MRTF activity with CCG1423 and CCG203971 significantly reduced lipid accumulation. Furthermore, we demonstrate enhanced MRTFA expression in vascular remodeling of human vessels. Conclusions: This study demonstrates a novel role for MRTFA as an important regulator of lipid homeostasis in vascular smooth muscle cells. Thus, MRTFA could potentially be a new therapeutic target for inhibition of vascular lipid accumulation.
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| 5. |
- Aronsson, Karin F. M.
(author)
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Speed characteristics of urban streets based on driver behaviour studies and simulation
- 2006
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Doctoral thesis (other academic/artistic)abstract
- The objective of the study was to gain in-depth knowledge of speed relationships for urban streets. The speed characteristics were examined using a number of methods for data collection. Throughout the research, a special focus was placed on capturing the influence on driver speed of interactions with pedestrians, cyclists and other road users, called sidefriction events in this study. First, driver behaviour and travel time data was collected from field and driving simulator studies for a range of street types and traffic conditions. The collected data was used to calibrate a microscopic traffic simulation model. Production runs with this model were performed for various traffic conditions. Second, aggregated speed data was collected at the link level, i.e. the macro level, for three street types. In combination with street site variables, speed and flow data was analysed using multiple regression techniques with space mean speed as dependent variable. This analysis was also performed for average travel speed data produced by microscopic traffic simulation. Two central results were attained and utilized for the model development: - In-depth knowledge of which factors influence speed choice on urban street links with minor intersections, on a micro and macro level. - A comprehensive research methodology for study of speed characteristics on urban streets in which the knowledge gained at the micro and macro level was applied. Results from the micro study showed that Average number of crossing pedestrians and Traffic flow had significant impact on average travel speed (R2=0.91). Results from the macro study performed for three street types showed that Street function and Number of lanes also had a high degree of explanation (R2 close to 0.70). The variables Separated bicycle lane, Roadside parking permitted and Number of minor intersections per 1 km were significant for some of the street types modelled in the macro study. The variables Ratio of through vehicles and Gender of the driver were also investigated and were found not to influence space-mean speed. The macro study demonstrated that speed choice and driver behaviour were consistent for each street type investigated regardless of city type and population size. The speed-flow relationships of the micro model for an urban street type showed good agreement with the macro model for traffic flows in the upper range. In conclusion, the research effort showed that the included side-friction variables added explanatory value to the estimation of speed, and thus can enhance the knowledge of traffic impacts of different urban street designs.
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| 6. |
- Bergman, Kerstin, et al.
(author)
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Ska vi äta våra döda: Linné mellan tro och nytta
- 2002
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In: I ordets smedja: Festskrift till Per Rydén. - 9172034947 ; , s. 182-191
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Book chapter (other academic/artistic)abstract
- About the struggle between faith and utilitarian aspects in the writings of Carl von Linné.
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| 7. |
- 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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| 8. |
- Borgenvik, Anna, et al.
(author)
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CDK2 as a therapeutic target in MYC-driven medulloblastoma
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Other publication (other academic/artistic)abstract
- Group 3 medulloblastoma (MB) is a malignant pediatric brain tumor that shows aberrant cell cycle activation, therapy resistance, and poor prognosis. Here, we identified that MYC expression and poor prognosis in Group 3 MB correlates with elevated levels of core cell cycle members CDK2 and cyclin A2, suggesting they would be promising targets for direct inhibition. Tumor cells in a novel transgenic MYC-driven MB mouse model further displayed increased p27 levels, decreased viability, and cell growth in vitro upon conditional CDK2 depletion using tamoxifen-induced recombination. Human Group 3 MB cells transduced with dominant-negative CDK2 mutants similarly exhibited decreased viability and increased p27 activation. As compared to controls, CDK2-depleted cells responded less to CDK2-specific inhibitors but were not more sensitive to BET inhibition or CDK4/6 inhibition as previously proposed. We finally used global transcriptional profiling and found that mTOR and B-Myb/ZMYM2 signaling pathways are compensating for CDK2 loss in Group 3MB cells. Our analysis suggests that specific inhibitors of these pathways could in combination with approved cell cycle inhibitors provide more efficient treatments for this severe childhood brain cancer.
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| 9. |
- Borgenvik, Anna, 1987-, et al.
(author)
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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
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In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
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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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| 10. |
- Broman, Göran, et al.
(author)
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Simplicity Without Reduction : Thinking Upstream Towards the Sustainable Society
- 2000
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In: Interfaces. - : INFORMS. - 0092-2102 .- 1526-551X. ; 30:3, s. 13-25
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Journal article (peer-reviewed)abstract
- The natural-step framework is used by over 100 organizations, including many global corporations in Europe and the United States, to provide strategic direction for their sustainability initiatives. The framework is built on the concept of simplicity without reduction. Out of respect for complexity we designed it to provide a compass, a guide for strategic direction. The framework consists of a backcasting planning process for sustainable development based on four principles (system conditions) for sustainability. The framework does not prescribe detailed actions. Once an organization understands the framework it identifies and specifies the detailed means by which to achieve the strategy, because it knows its business best. The steps in the planning process are understanding and discussing the system conditions for sustainability, describing and discussing how the company relates to the system conditions in today's situation, creating a vision of how the company will fulfill its customers' needs in the futur e while complying with the system conditions, and specifying a program of actions that will take the company from today's situation to the future vision.
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