| 1. |
- Susanto, Evelyn, et al.
(författare)
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Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells
- 2020
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 117:33, s. 20127-20138
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using In-duced pluripotent stem (iPS) cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carry-ing a germline mutation in the sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, en-hanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model, we identified LGALS1 to be a GLI target gene that is up-regulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we dem-onstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression and to identify putative targets.
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| 2. |
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| 3. |
- Artman, Henrik, et al.
(författare)
-
Acquisition of usable IT : Acquisition projects to reflect on
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- By examining how several organizations have gone through the process of procuring IT systems, we have seen that there is a great need for procurer organizations themselves to understand their role in systems development. What is their responsibility for the outcome of the acquisition process? What is their responsibility for the outcome of the system-in-use? Can they actually take responsibility for the usability of systems? This collection of papers is meant to be a starting point for procurer organizations to reflect on that responsibility, as well as on how they manage the acquisition process. The papers are informed by academic research and grounded in scientific studies, but they are also to be taken as practical efforts to describe the process. We hope they will nurture reflection, and encourage those who are taking a stand to make IT systems usable. Our assumption is that the sooner an organization comes to terms with how the future system will actually be used, the sooner it will be profitable or beneficial.
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| 4. |
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| 5. |
- Bergström, Anna, et al.
(författare)
-
Health system context and implementation of evidence-based practices-development and validation of the Context Assessment for Community Health (COACH) tool for low- and middle-income settings
- 2015
-
Ingår i: Implementation Science. - : Springer Science and Business Media LLC. - 1748-5908. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The gap between what is known and what is practiced results in health service users not benefitting from advances in healthcare, and in unnecessary costs. A supportive context is considered a key element for successful implementation of evidence-based practices (EBP). There were no tools available for the systematic mapping of aspects of organizational context influencing the implementation of EBPs in low- and middle-income countries (LMICs). Thus, this project aimed to develop and psychometrically validate a tool for this purpose. Methods: The development of the Context Assessment for Community Health (COACH) tool was premised on the context dimension in the Promoting Action on Research Implementation in Health Services framework, and is a derivative product of the Alberta Context Tool. Its development was undertaken in Bangladesh, Vietnam, Uganda, South Africa and Nicaragua in six phases: (1) defining dimensions and draft tool development, (2) content validity amongst in-country expert panels, (3) content validity amongst international experts, (4) response process validity, (5) translation and (6) evaluation of psychometric properties amongst 690 health workers in the five countries. Results: The tool was validated for use amongst physicians, nurse/midwives and community health workers. The six phases of development resulted in a good fit between the theoretical dimensions of the COACH tool and its psychometric properties. The tool has 49 items measuring eight aspects of context: Resources, Community engagement, Commitment to work, Informal payment, Leadership, Work culture, Monitoring services for action and Sources of knowledge. Conclusions: Aspects of organizational context that were identified as influencing the implementation of EBPs in high-income settings were also found to be relevant in LMICs. However, there were additional aspects of context of relevance in LMICs specifically Resources, Community engagement, Commitment to work and Informal payment. Use of the COACH tool will allow for systematic description of the local healthcare context prior implementing healthcare interventions to allow for tailoring implementation strategies or as part of the evaluation of implementing healthcare interventions and thus allow for deeper insights into the process of implementing EBPs in LMICs.
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| 6. |
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| 7. |
- Bolin, Sara, 1988-, et al.
(författare)
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Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
- 2018
-
Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 37:21, s. 2850-2862
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Bolin, Sara, 1988-, et al.
(författare)
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Dormant SOX9-positive cells behind MYC-driven medulloblastoma recurrence
-
Tidskriftsartikel (refereegranskat)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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| 9. |
- Borgenvik, Anna, et al.
(författare)
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CDK2 as a therapeutic target in MYC-driven medulloblastoma
-
Annan publikation (övrigt vetenskapligt/konstnärligt)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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| 10. |
- Borgenvik, Anna, 1987-, et al.
(författare)
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Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma
- 2022
-
Ingår i: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 82:24, s. 4586-4603
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Tidskriftsartikel (refereegranskat)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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| 11. |
- Borgenvik, Anna, 1987-
(författare)
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MYC-driven Medulloblastoma : New Targeted Therapies and Mechanisms of Recurrence
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the posterior fossa but presents with distinct histological and molecular features. Hence, medulloblastoma is divided into four molecular subgroups, WNT, SHH, Group 3, and Group 4. The overall 5-year survival is ~70% across subgroups but varies with high- and low-risk disease. Standard treatment of medulloblastoma consists of maximal safe tumor resection, radiotherapy, and adjuvant chemotherapy. Despite the rather high success rate of treatment for many patients it also comes with severe long-term debilitating side effects. MYC proteins are master regulators of gene expression often deregulated in cancer. MYC family members MYC and MYCN share similar roles and are found overexpressed or amplified in most medulloblastoma subgroups and correlate with a poor prognosis. Medulloblastoma dissemination and recurrence patterns differ between subgroups but are always associated with a poor prognosis. Recurrent medulloblastoma is not yet curable and will lead to death. In this thesis, we present the first transgenic mouse model of medulloblastoma recurrence and highlight the role of the transcription factor SOX9 in MYC-driven relapse mechanisms. By studying this recurrence model and matched primary-recurrent patient samples we propose a mechanism in which treatment-refractory and quiescent SOX9-positive cells in Group 3 medulloblastoma are necessary for tumor relapse, and how the recurrent tumors can be specifically treated with MGMT inhibitors and doxorubicin.In addition, we address efficient treatment options of primary MYC-driven medulloblastoma where BET bromodomain inhibition (JQ1) in combination with CDK2 inhibition (milciclib) of human Group 3 medulloblastoma will lead to apoptosis and prolonged survival of xenografted mice. This is explained by a dual hit on MYC transcriptional output and MYC protein stability exerted by JQ1 and milciclib respectively. Finally, in a different novel transgenic model of MYC-driven medulloblastoma, we show how temporal Cdk2 knock-out has no effect on MYC protein stability but slows down proliferation and prolongs survival of allografted mice. The need for better treatments and increased understanding of recurrent medulloblastoma is huge. To that end, this thesis focuses on and addresses novel treatments, the role of the cell cycle protein CDK2 as well as relapse mechanisms depending on dormant SOX9-positive cells in highly aggressive MYC-driven medulloblastoma.
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| 12. |
- Borgenvik, Anna, et al.
(författare)
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Targeting MYCN in Molecularly Defined Malignant Brain Tumors
- 2021
-
Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 10
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Forskningsöversikt (refereegranskat)abstract
- Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.
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| 13. |
- Čančer, Matko, et al.
(författare)
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Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
- 2019
-
Ingår i: Cell Stem Cell. - : CELL PRESS. - 1934-5909 .- 1875-9777. ; 25:6, s. 855-870
-
Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.
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| 14. |
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| 15. |
- Dalianis, Tina, et al.
(författare)
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Management of BK-virus infection - Swedish recommendations
- 2019
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Ingår i: Infectious Diseases. - : TAYLOR & FRANCIS LTD. - 2374-4235 .- 2374-4243. ; 51:7, s. 479-484
-
Forskningsöversikt (refereegranskat)abstract
- BK-virus (BKV) associated nephropathy (BKVAN) and BKV associated haemorrhagic cystitis (HC) are complications of BKV infection/reactivation in renal and allogeneic haematopoietic stem cell transplantation (HSCT) patients, respectively. The task of how to manage these diseases was given to the chair by the Swedish Reference Group for Antiviral Therapy (RAV). After individual contributions by members of the working group, consensus discussions were held in a meeting on 23 January 2018 arranged by RAV. Thereafter, the recommendations were published in Swedish on November 2018. The current translation to English has been approved by all co-authors. High BKV serum levels suggest an increased risk for BKVAN and potential graft failure. For detection of BKVAN, careful monitoring of BKV DNA levels in serum or plasma is recommended the first year after renal transplantation and when increased creatinine serum levels of unknown cause are observed. Notably, a renal biopsy is mandatory for diagnosis. To reduce the risk for progression of BKVAN, there is no specific treatment, and tailored individual decrease of immunosuppression is recommended. For BKV-HC, BKV monitoring is not recommended, since BK-viruria frequently occurs in HSCT patients and the predictive value of BKV in plasma/serum has not been determined. However, the risk for BKV-HC is higher for patients undergoing myeloablative conditioning, having an unrelated, HLA-mismatched, or a cord blood donor, and awareness of the increased risk and early intervention may benefit the patients. Also for BKV-HC, no specific therapy is available. Symptomatic treatment, e.g. forced diuresis and analgesics could be of use.
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| 16. |
- Eriksson, Elina, 1979-
(författare)
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Situated Reflexive Change : User-Centred Design in(to) Practice
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Technology used in the Swedish workplace is perceived to be controlling, gener- ally still difficult to use, and with a low degree of usability. Even though the field of Human-Computer Interaction (HCI) has been concerned with researching different ways of developing usable systems for at least half a century, there seem to be problems with the diffusion of the results into practice. One of the possible approaches to developing usable systems is user-centred design, and in this thesis I am concerned with the issue of introducing user-centred design and usability work in public authorities and institutions. I will present work done in two different research projects with a focus on change, where the aim has been to introduce or enhance usability work. Through a lens of social construction- ism and reflexivity I will explore the outcome of the projects and the implica- tions for the introduction of user-centred design in practice. Furthermore, I will explore whether the focus on the introduction of usability work might hinder the formation of a sustainable change in the organizations interested in devel- oping usable systems. The research question then becomes; can we introduce usability work in organizations?The answer to this question is no. Instead, we need to change our perspective from introduction to situated reflexive change: focusing on sensemaking and a situated process of ongoing change, where the stakeholders in the organization themselves must play an active and responsible part. This entails a shift from dualism to duality and a reconsideration of what our usability methods can con- tribute with. Furthermore, I will explore possible approaches to working with situated reflexive change with tools that are familiar in the field of HCI, but with an expanded scope. In particular I will discuss field studies conducted by system developers as a tool for making sense of usability issues, personas as a tool for inducing reflexivity in and on practice, and usability coaching as a sensemaking tool for both organizational stakeholders and researchers in order to understand and reflect upon change.
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| 17. |
- Eriksson, Elina, 1979-, et al.
(författare)
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The secret life of a persona : when the personal becomes private
- 2013
-
Ingår i: CHI '13 Proceedings of the SIGCHI Conference on Human Factors in Computing Systems. - New York, NY, USA : ACM. - 9781450318990 ; , s. 2677-2686
-
Konferensbidrag (refereegranskat)abstract
- Some organizations fail to involve users in systems development due to a widespread organization, high workload or secrecy issues. A remedy against this situation could be the persona method in which users and main stakeholders as represented as fictitious characters. Personas help eliciting user needs and requirements, facilitate design choices and are an overall communication aid where users cannot be present. An important part of the persona method, as portrayed in literature, is the personal details that make the personas trustworthy and alive. In this paper we present two cases in which personas have been developed and used, but where the personal is scarce or even non-existent because of a dispersed organisation, the organisational culture and secrecy issues. The paper describes how the personas were developed, used and received and how the method was altered in order to work in these special circumstances.
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| 18. |
- Eriksson, Elina, 1979-, et al.
(författare)
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UCD Guerrilla Tactics : A Strategy for Implementation of UCD in the Swedish Defence
- 2012
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Ingår i: Human Work Interaction Design – HWID2012. ; , s. 116-126
-
Konferensbidrag (refereegranskat)abstract
- The problem of how to implement user-centred design (UCD) is well established as a research topic within HCI. Yet there are unresolved issues in order for UCD to actually be used in practice. This paper will present a case study within the Swedish Defence, concerning the introduction of UCD. The overarching goal of the research was to bridge the gap between work practices and systems development; focusing the efforts on introducing usability in the procurement process. We concluded early on that we needed to develop and formulate an approach that is probably common in practice but not described or used in research. We call this strategy UCD guerrilla tactics. It is to do the unexpected, to introduce UCD through UCD and to choose change projects pragmatically. Our main target group was future users and procurers of UCD methods. We aimed at introducing UCD to them by demonstrating and involving them in the work through user centred activities. It is also a flexible approach based on continuous evaluation of what is feasible and potentially gives the largest outcome. This paper describes the guerrilla tactics, how it was applied in a case study and factors that should be considered when using it.
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| 19. |
- Eriksson, Elina, 1979-, et al.
(författare)
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UCD Guerrilla Tactics : A Strategy for Implementation of UCD in Sweden’s Military Defense Organizations
- 2013
-
Ingår i: Human Work Interaction Design. - Berlin, Heidelberg : Springer Berlin/Heidelberg. - 9783642411441 - 9783642411458 ; , s. 112-123
-
Bokkapitel (refereegranskat)abstract
- The problem of how to implement user-centred design (UCD) is well established as a research topic within HCI. Yet there are unresolved issues in order for UCD to actually be used in practice. This paper will present a case study within Sweden ́s military defense organizations, concerning the introduc- tion of UCD. The overarching goal of the research was to bridge the gap be- tween work practices and systems development; focusing the efforts on intro- ducing usability work in the procurement process. We concluded early on that we needed to develop and formulate an approach that is probably common in practice but not described or used in research. We call this strategy UCD guer- rilla tactics, which entails to do the unexpected, to work pragmatically with change, and to use user centred methods to introduce UCD. Our main target group was future users and procurers of UCD methods. We aimed at demon- strating and involving them in the work through user centred activities. The tac- tics is also a reflexive and flexible approach based on continuous evaluation of what is feasible and potentially gives the largest outcome. This paper describes the guerrilla tactics, how it was applied in a case study and factors that should be considered when using it.
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| 20. |
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| 21. |
- Henriksson, Dorcus Kiwanuka, 1976-
(författare)
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Health systems bottlenecks and evidence-based district health planning : Experiences from the district health system in Uganda
- 2017
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In low-income countries where maternal and child mortality remains high, there is limited use of context-specific evidence for decision making and prioritization of interventions in the planning process at the sub-national level, such as the district level. Knowledge on the utility of tools and interventions to promote use of district-specific evidence in the planning process is limited, yet it could contribute to the prioritization of high-impact interventions for women and children.This thesis aims to investigate, in the planning process, the use of district-specific evidence to identify gaps in service delivery in the district health system in Uganda in order to contribute to improving health services for women and children.Study I evaluated the use of the modified Tanahashi model to identify bottlenecks for service delivery of maternal and newborn interventions. Study II and III used qualitative methods to document the experiences of district managers in adopting tools to facilitate the utilization of district-specific evidence, and the barriers and enablers to the use of these tools in the planning process. Study IV used qualitative methods, and analysis of district annual health work plans and reports.District managers were able to adopt tools for the utilization of district-specific evidence in the planning process. Governance and leadership were a major influence on the use of district-specific evidence. Limited decision space and fiscal space, and limited financial resources, and inadequate routine health information systems were also barriers to the utilization of district-specific evidence.Use of district-specific evidence in the planning process is not an end in itself but part of a process to improve the prioritization of interventions for women and children. In order to prioritize high impact interventions at the district level, a multifaceted approach needs to be taken that not only focuses on use of evidence, but also focuses on broader health system aspects like governance and leadership, the decision and fiscal space available to the district managers, limited resources, and inadequate routine health information systems.
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| 22. |
- Holmberg Olausson, Karl O., et al.
(författare)
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Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies
- 2024
-
Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:9
-
Forskningsöversikt (refereegranskat)abstract
- Simple Summary In this review, we summarize reported molecular mechanisms underlying tumor progression and relapse of medulloblastoma, one of the most frequent malignant pediatric brain tumor entities. Medulloblastoma relapses are difficult to treat, and patients have, overall, a poor prognosis. Apart from describing the biology promoting brain tumor spread, the review will also highlight important preclinical models used to study leptomeningeal disease and recurrence. Finally, we identified clinical trials for medulloblastoma relapse and will discuss novel attempts to target therapy-escaping cancer cells responsible for recurrence.Abstract Medulloblastomas comprise a molecularly diverse set of malignant pediatric brain tumors in which patients are stratified according to different prognostic risk groups that span from very good to very poor. Metastasis at diagnosis is most often a marker of poor prognosis and the relapse incidence is higher in these children. Medulloblastoma relapse is almost always fatal and recurring cells have, apart from resistance to standard of care, acquired genetic and epigenetic changes that correlate with an increased dormancy state, cell state reprogramming and immune escape. Here, we review means to carefully study metastasis and relapse in preclinical models, in light of recently described molecular subgroups. We will exemplify how therapy resistance develops at the cellular level, in a specific niche or from therapy-induced secondary mutations. We further describe underlying molecular mechanisms on how tumors acquire the ability to promote leptomeningeal dissemination and discuss how they can establish therapy-resistant cell clones. Finally, we describe some of the ongoing clinical trials of high-risk medulloblastoma and suggest or discuss more individualized treatments that could be of benefit to specific subgroups.
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| 23. |
- Jönsson, Anna Maria, et al.
(författare)
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Reflections on Science–Stakeholder Interactions in Climate Change Adaptation Research within Swedish Forestry
- 2014
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Ingår i: Society & Natural Resources. - : Informa UK Limited. - 0894-1920 .- 1521-0723. ; 27:11, s. 1130-1144
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Tidskriftsartikel (refereegranskat)abstract
- Stakeholder engagement has become increasingly important in research programs focusing on climate change impact on ecosystem services. Communication between researchers and stakeholders, however, is often impaired by linguistic barriers, different priorities, and time constraints. This article examines the organizational aspects of science–stakeholder interactions, focusing on examples from the Swedish forestry sector. The study highlights the need articulated by the Swedish forestry sector for access to scientific knowledge, and we discuss how to present research findings in formats suitable to serve as decision support. Clear communication about common goals, expectations, resources, and time frames is needed in order to reduce the risk of stakeholder fatigue.
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| 24. |
- Karlsson-Groth, Anna, et al.
(författare)
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Treatment of compensatory hyperhidrosis after sympathectomy with botulinum toxin and anticholinergics
- 2015
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Ingår i: Clinical Autonomic Research. - : Springer Science and Business Media LLC. - 0959-9851 .- 1619-1560. ; 25:3, s. 161-167
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Tidskriftsartikel (refereegranskat)abstract
- Compensatory hyperhidrosis (CH) is the most common adverse complication of sympathectomy. It often has a major negative impact on life quality. No efficient treatment of CH is available. We report nine cases of CH after sympathectomy, which were treated with botulinum toxin A/B (BTX) and anticholinergics. The patients responded to a dermatology life quality index (DLQI) questionnaire before injections with BTX and 3 weeks after treatment. At the follow-up visit, the participants also ranked the effect of the treatment on a five-grade scale. Three patients had residual sweating after BTX treatment, and received additional anticholinergics at the follow-up visit. Those subjects eventually had a third evaluation with the DLQI. The DLQI score was, on average, 16.4 before treatment and decreased to 4.8 after BTX injections. Eight out of nine patients were satisfied with the treatment. The average DLQI score decreased to 2.2 when the patients with residual sweating (n = 3) received additional anticholinergics. Adverse events from BTX were mild and temporary, but dry mouth was substantial in one patient using anticholinergics. A combination of BTX A/B and anticholinergics alleviated the hyperhidrosis with minor side-effects. We consider this treatment safe, effective, and well tolerated.
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| 25. |
- Lundgren, Markus, et al.
(författare)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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Ingår i: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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| 26. |
- Mainwaring, Oliver, et al.
(författare)
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ARF suppression by MYC but not MYCN confers increased malignancy of aggressive pediatric brain tumors
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14
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Tidskriftsartikel (refereegranskat)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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| 27. |
- Plummer, Ryan, et al.
(författare)
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Flood Governance : A multiple country comparison of stakeholder perceptions and aspirations
- 2018
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Ingår i: Environmental Policy and Governance. - : Wiley. - 1756-932X .- 1756-9338. ; 28:2, s. 67-81
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Tidskriftsartikel (refereegranskat)abstract
- Flooding is routinely among the most disastrous annual events worldwide with extensive impacts on human wellbeing, economies and ecosystems. Thus, how decisions are made about floods (i.e. flood governance) is extremely important and evidence shows that it is changing, with non-governmental actors (civil society and the private sector) becoming involved in new and sometimes hybrid governance arrangements. This study investigates how stakeholders perceive floods to be governed and how they believe decision-making ought to occur, with the intent of determining to what extent changing governance is evident on the ground and how well (or poorly) it aligns with desired governance arrangements. Flood governance stakeholders were surveyed in five flood-prone geographical areas from Australia, Canada, Italy, the Netherlands and Sweden. The findings suggest that a reconfiguration of flood governance is underway with relatively little consensus regarding the specific arrangements and mechanisms in place during this transitionary period. Across the five cases, stakeholders indicated that they wanted flood governance to be organized at multiple levels, with strong government involvement and with diverse actor groups, and through mechanisms that match the involvement of these actors, with a lack of desirability for some specific configurations involving the private sector in particular. There was little alignment between stakeholder perceptions of governance currently in place and their desired arrangements, except for government involvement. Future research directions highlight the importance of the inclusion of stakeholder perspectives in assessing flood governance, and following the transition in flood governance over time.
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| 28. |
- Smith, Laura B., et al.
(författare)
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Psychological manifestations of celiac disease autoimmunity in young children
- 2017
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Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 139:3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND OBJECTIVES: Psychological symptoms can be associated with celiac disease; abstract however, this association has not been studied prospectively in a pediatric cohort. We examined mother report of psychological functioning in children persistently positive for tissue transglutaminase autoantibodies (tTGA), defined as celiac disease autoimmunity (CDA), compared with children without CDA in a screening population of genetically at-risk children. We also investigated differences in psychological symptoms based on mothers' awareness of their child's CDA status. METHODS: The Environmental Determinants of Diabetes in the Young study followed 8676 children to identify triggers of type 1 diabetes and celiac disease. Children were tested for tTGA beginning at 2 years of age. The Achenbach Child Behavior Checklist assessed child psychological functioning at 3.5 and 4.5 years of age. RESULTS: At 3.5 years, 66 mothers unaware their child had CDA reported more child anxiety and depression, aggressive behavior, and sleep problems than 3651 mothers of children without CDA (all Ps ≤ .03). Unaware-CDA mothers also reported more child anxiety and depression, withdrawn behavior, aggressive behavior, and sleep problems than 440 mothers aware of their child's CDA status (all Ps ≤.04). At 4.5 years, there were no differences. CONCLUSIONS: In 3.5-year-old children, CDA is associated with increased reports of child depression and anxiety, aggressive behavior, and sleep problems when mothers are unaware of their child's CDA status. Mothers' knowledge of their child's CDA status is associated with fewer reports of psychological symptoms, suggesting that awareness of the child's tTGA test results affects reporting of symptoms.
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| 29. |
- Swartling, Anna, et al.
(författare)
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A Game of Usability : Visualising responsibility for Usability Through a Football Metaphor
- 2009
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Ingår i: Acquisition of Usable IT-systems. ; , s. 21-39
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Bokkapitel (refereegranskat)abstract
- Systems development is such a complex and dynamic process that those involved in it can neglect or even ignore the issue of the system’s usability. Like most complex processes, systems development requires several actors to collaborate and coordinate several more or less dependent activities. Most models of systems development do not capture the dynamics of complex systems development; in particular, they often ignore the complexity of inter-organizational negotiations and responsibilities. Given these problems, we suggest that metaphors present an alternative approach for analyzing these processes. In this paper we use the metaphor of a football game to visualize how usability is handled and understood by a large Swedish governmental organization that specializes in complex systems procurement. Our point of departure was 25 interviews with several stakeholders, both outside and inside the organization. In our first analysis, we saw actors in the procurement process pass usability issues on to each other. This led us to conduct a metaphorical analysis, which makes it possible to see things from a new perspective. The football metaphor highlights how actors in two organizations—the procurer and the developer—cooperate as well as compete. In addition to analyzing structural aspects, such as rules and tactics, 22 that govern the systems development process, we assign and discuss relevant roles to correspond with those in a football game. The approach illustrates how usability is systematically neglected.
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| 30. |
- Swartling, Anna, et al.
(författare)
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Förstudie om FMV:s roll i försvarets beställningsprocess
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- En förstudie har genomförts av KTH i samarbete med Linköpings Universitet och FMV inom ramen för det MSI-uppdrag som finns i FoT6. Syftet har varit att med fokus på FMV analysera hur försvarets beställningsprocess (det generella flödet, inte en formellt definierad process) ser ut, vem som agerar beställare samt hur och vilken roll han/hon har samt var och hur MSI-arbete sker. 27 personer har intervjuats på FMV, Försvarsmakten, Luftfartsverket och industriföretag samt att ett flertal dokument som relaterar till försvarets beställningsprocess har analyserats.
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| 31. |
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| 32. |
- Swartling, Anna, 1967-
(författare)
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The Good Person in Information Systems Development : A Reflexive Investigation of HCI in the Acquisition Process
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is an exploration of why the development of ICT (Information and Communication Technology) systems (IS) does not include more humanistic issues. I argue that this exclusion is one reason for the annoying situation of users and organizations: we are forced to deal with poorly designed systems that cause major frustration. In this reflexive investigation I present theories, data, analysis and arguments in the form of a theatrical script. With the theatre metaphor I aim to make visible the ideological elements not only within IS acquisition but also within research, in particular HCI research. The thesis includes three studies performed during 2003-2005: two interview studies with a total of 47 interviews, and one field study with extensive observations and 22 interviews. The material was analyzed with a focus on power structures and the ways common sense is constructed within the discourses of Information Systems Development (ISD). The theoretical perspective is inspired by discourse theory, social constructionism, and reflexivity. The main argument is that ISD is pervaded by a truth construct in which rationality and logic constitutes the norm and everything else, including humans, becomes subordinate. In my analysis of the research material I see that user participation through informal “methods” and user representation does not lead to meaningful involvement; instead it adds to the power structures in which ICT expertise and technology determination are hegemonic. I distinguish several significant subjects within the discourses of ISD and argue that the ways they are construed and positioned relate to certain functions; for example ICT experts as authority and users as trouble makers both function to exclude users from ISD. HCI has an important role as a resistive discourse but to increase its impact we must refocus our attention on systems development, directing our efforts towards the procurers of ICT systems instead of trying to integrate human perspectives into the functional paradigm.
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| 33. |
- Swartling, Maria, et al.
(författare)
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Population pharmacokinetics of cefotaxime in intensive care patients
- 2022
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:2, s. 251-258
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.METHODS: This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000-3000 mg given 2-6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.RESULTS: A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.CONCLUSION: A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.
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| 34. |
- Törn, Carina, et al.
(författare)
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Complement gene variants in relation to autoantibodies to beta cell specific antigens and type 1 diabetes in the TEDDY Study
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- A total of 15 SNPs within complement genes and present on the ImmunoChip were analyzed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. A total of 5474 subjects were followed from three months of age until islet autoimmunity (IA: n = 413) and the subsequent onset of type 1 diabetes (n = 115) for a median of 73 months (IQR 54-91). Three SNPs within ITGAM were nominally associated (p < 0.05) with IA: rs1143678 [Hazard ratio; HR 0.80; 95% CI 0.66-0.98; p = 0.032], rs1143683 [HR 0.80; 95% CI 0.65-0.98; p = 0.030] and rs4597342 [HR 1.16; 95% CI 1.01-1.32; p = 0.041]. When type 1 diabetes was the outcome, in DR3/4 subjects, there was nominal significance for two SNPs: rs17615 in CD21 [HR 1.52; 95% CI 1.05-2.20; p = 0.025] and rs4844573 in C4BPA [HR 0.63; 95% CI 0.43-0.92; p = 0.017]. Among DR4/4 subjects, rs2230199 in C3 was significantly associated [HR 3.20; 95% CI 1.75-5.85; p = 0.0002, uncorrected] a significance that withstood Bonferroni correction since it was less than 0.000833 (0.05/60) in the HLA-specific analyses. SNPs within the complement genes may contribute to IA, the first step to type 1 diabetes, with at least one SNP in C3 significantly associated with clinically diagnosed type 1 diabetes.
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