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  • Warfvinge, Rebecca, et al. (författare)
  • Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 129:17, s. 2384-2394
  • Tidskriftsartikel (refereegranskat)abstract
    • Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC-population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI-treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI-therapy compared to subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CML stem cell markers CD25, CD26, and IL1RAP is high on all subpopulations at diagnosis, but downregulated and unevenly distributed across subpopulations in response to TKI-treatment. The most TKI-insensitive cells of the LSC-compartment can be captured within the CD45RA- fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Together, our results expose a considerable heterogeneity of the CML stem cell population and propose a Lin(-)CD34(+)CD38(-/low)CD45RA(-)cKIT(-)CD26(+) population as potential therapeutic target for improved therapy response.
  • Dyrager, Christine, 1975, et al. (författare)
  • Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors
  • 2011
  • Ingår i: Journal of Medicinal Chemistry. ; 54:20, s. 7427-7431
  • Tidskriftsartikel (refereegranskat)abstract
    • 3-(4-Fluorophenyl)-2-(4-pyridyl)chromone derivatives were synthesized and evaluated as p38 MAP kinase inhibitors. Introduction of an amino group in the 2-position of the pyridyl moiety gave p38α inhibitors with IC(50) in the low nanomolar range (e.g., IC(50) = 17 nm). The inhibitors showed excellent selectivity profiles when tested on a panel of 62 kinases, as well as efficient inhibition of p38 signaling in human breast cancer cells.
  • Tidskriftsartikel (refereegranskat)
  • Spjuth, Ola, 1977-, et al. (författare)
  • E-Science technologies in a workflow for personalized medicine using cancer screening as a case study
  • 2017
  • Ingår i: JAMIA Journal of the American Medical Informatics Association. - : Oxford University Press. - 1067-5027 .- 1527-974X. ; 24:5, s. 950-957
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: We provide an e-Science perspective on the workflow from risk factor discovery and classification of disease to evaluation of personalized intervention programs. As case studies, we use personalized prostate and breast cancer screenings.Materials and Methods: We describe an e-Science initiative in Sweden, e-Science for Cancer Prevention and Control (eCPC), which supports biomarker discovery and offers decision support for personalized intervention strategies. The generic eCPC contribution is a workflow with 4 nodes applied iteratively, and the concept of e-Science signifies systematic use of tools from the mathematical, statistical, data, and computer sciences.Results: The eCPC workflow is illustrated through 2 case studies. For prostate cancer, an in-house personalized screening tool, the Stockholm-3 model (S3M), is presented as an alternative to prostate-specific antigen testing alone. S3M is evaluated in a trial setting and plans for rollout in the population are discussed. For breast cancer, new biomarkers based on breast density and molecular profiles are developed and the US multicenter Women Informed to Screen Depending on Measures (WISDOM) trial is referred to for evaluation. While current eCPC data management uses a traditional data warehouse model, we discuss eCPC-developed features of a coherent data integration platform.Discussion and Conclusion: E-Science tools are a key part of an evidence-based process for personalized medicine. This paper provides a structured workflow from data and models to evaluation of new personalized intervention strategies. The importance of multidisciplinary collaboration is emphasized. Importantly, the generic concepts of the suggested eCPC workflow are transferrable to other disease domains, although each disease will require tailored solutions.
  • Cicortas Gunnarsson, Lavinia, et al. (författare)
  • Evolution of a carbohydrate binding module into a protein-specific binder
  • 2006
  • Ingår i: Biomolecular Engineering. - : Elsevier. - 1389-0344 .- 1878-559X. ; 23:2-3, s. 111-117
  • Tidskriftsartikel (refereegranskat)abstract
    • A carbohydrate binding module, CBM4-2, derived front the xylanase (Xyn 10A) of Rhodothermus marinus has been used as a scaffold for molecular diversification. Its binding specificity has been evolved to recognise a quite different target, a human monoclonal IgG4. In order to understand the basis for this drastic change in specificity we have further investigated the target recognition of the IgG4-specific CBMs. Firstly, we defined that the structure target recognised by the selected CBM-variants was the protein and not the carbohydrates attached to the glycoprotein. We also identified key residues involved in the new specificity and/or responsible for the swap in specificity, from xylan to human IgG4. Specific changes present in all these CBMs included mutations not introduced in the design of the library from which the specific clones were selected. Reversion of such mutations led to a complete loss of binding to the target molecule, suggesting that they are critical for the recognition of human IgG4. Together with the mutations introduced at will, they had transformed the CBM scaffold into a protein binder. We have thus shown that the scaffold of CBM4-2 is able to harbour molecular recognition for either carbohydrate or protein structures. (c) 2005 Elsevier B.V. All rights reserved.
  • Forsell, M. N. E., et al. (författare)
  • Regulation of subunit-specific germinal center B cell responses to the HIV-1 envelope glycoproteins by antibody-mediated feedback
  • 2017
  • Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224 .- 1664-3224. ; 8:JUN
  • Tidskriftsartikel (refereegranskat)abstract
    • The regulation of germinal center (GC) B cell responses to single epitopes is well investigated. How monoclonal B cells are regulated within the polyclonal B cell response to protein antigens is less so. Here, we investigate the primary GC B cell response after injection of mice with HIV-1 envelope glycoproteins. We demonstrate that single GCs are seeded by a diverse number of B cell clones shortly after a single immunization and that the presence of Env-specific antibodies can inhibit the development of early GC B cells. Importantly, the suppression was dependent on the GC B cells and the infused antibodies to target the same subunit of the injected HIV-1 envelope glycoproteins. An affinity-dependent antibody feedback has previously been shown to regulate GC B cell development. Here, we propose that this antibody-based feedback acts on GC B cells only if they target the same or overlapping epitopes. This study provides important basic information of GC B cell regulation, and for future vaccine designs with aim to elicit neutralizing antibodies against HIV-1.
  • Gellerstedt, Linda, et al. (författare)
  • Nursing care and management of patients' sleep during hospitalisation : A cross-sectional study.
  • 2019
  • Ingår i: Journal of Clinical Nursing. - 0962-1067 .- 1365-2702. ; 28:19-20, s. 3400-3407
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: To explore and describe how patients' sleep is addressed at acute-care hospitals in Sweden with regard to nursing care, management and the development of knowledge in this area.BACKGROUND: Sleep is a basic human need and thus important for health and health maintenance. Patients describe sleeping in hospital as a stressor, and research shows that nurses tend to underestimate patients' perceived problems with sleep during hospitalisation. How do nursing staff at acute hospitals address patients' sleep and the development of knowledge in this area?DESIGN/METHOD: A cross-sectional descriptive study was conducted based on data collected through a web survey. Head nurses, registered nurses, nursing care developers and local training supervisors at 36 randomised acute-care hospitals in Sweden were invited to participate. This study was executed and reported in accordance with SQUIRE 2.0.RESULTS: The results of the survey (53 responses from 19 wards at 15 acute-care hospitals) showed that no policy documents exist and no current training addresses sleep during hospital stay. All participants agreed that sleep should be considered a nursing topic and that it is important for hospitalised patients.CONCLUSION: Patients' sleep during hospitalisation is undermanaged at acute-care hospitals. Nurses, health care managers and organisations face challenges if they are to achieve better outcomes.RELEVANCE TO CLINICAL PRACTICE: This study shows that nurses do consider patients' sleep important and addressing sleep as part of nursing care. Future studies in the area should focus on what kinds of support and education are needed in the clinical context.
  • Haq, S Raza, et al. (författare)
  • Side-Chain Interactions Form Late and Cooperatively in the Binding Reaction between Disordered Peptides and PDZ Domains
  • 2012
  • Ingår i: Journal of the American Chemical Society. - : American Chemical Society. - 0002-7863 .- 1520-5126. ; 134:1, s. 599-605
  • Tidskriftsartikel (refereegranskat)abstract
    • Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. Here we have used short peptides as a model system for intrinsically disordered proteins. Linear free energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding and in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins toward their targets are generally governed by their association rate constants. Instead, we observed the opposite for peptide-PDZ interactions, namely, that changes in K-d correlate with changes in k(off).
  • Holmquist Mengelbier, Linda, et al. (författare)
  • Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
  • 2015
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 6
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
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