| 1. |
- Becker, K., et al.
(författare)
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Antibacterial activity of apramycin at acidic pH warrants wide therapeutic window in the treatment of complicated urinary tract infections and acute pyelonephritis
- 2021
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Ingår i: EBioMedicine. - : Elsevier B.V.. - 2352-3964. ; 73
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical-stage drug candidate EBL-1003 (apramycin) represents a distinct new subclass of aminoglycoside antibiotics for the treatment of drug-resistant infections. It has demonstrated best-in-class coverage of resistant isolates, and preclinical efficacy in lung infection models. However, preclinical evidence for its utility in other disease indications has yet to be provided. Here we studied the therapeutic potential of EBL-1003 in the treatment of complicated urinary tract infection and acute pyelonephritis (cUTI/AP). Methods: A combination of data-base mining, antimicrobial susceptibility testing, time-kill experiments, and four murine infection models was used in a comprehensive assessment of the microbiological coverage and efficacy of EBL-1003 against Gram-negative uropathogens. The pharmacokinetics and renal toxicology of EBL-1003 in rats was studied to assess the therapeutic window of EBL-1003 in the treatment of cUTI/AP. Findings: EBL-1003 demonstrated broad-spectrum activity and rapid multi-log CFU reduction against a phenotypic variety of bacterial uropathogens including aminoglycoside-resistant clinical isolates. The basicity of amines in the apramycin molecule suggested a higher increase in positive charge at urinary pH when compared to gentamicin or amikacin, resulting in sustained drug uptake and bactericidal activity, and consequently in potent efficacy in mouse infection models. Renal pharmacokinetics, biomarkers for toxicity, and kidney histopathology in adult rats all indicated a significantly lower nephrotoxicity of EBL-1003 than of gentamicin. Interpretation: This study provides preclinical proof-of-concept for the efficacy of EBL-1003 in cUTI/AP. Similar efficacy but lower nephrotoxicity of EBL-1003 in comparison to gentamicin may thus translate into a higher safety margin and a wider therapeutic window in the treatment of cUTI/API. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section. © 2021 The Author(s)
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| 2. |
- Lindmark, Evelina
(författare)
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Studies on peripheral tolerance in Aire-deficient mice
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autoimmune diseases such as diabetes mellitus and multiple sclerosis are increasing today, but the mechanism behind these diseases remains largely unknown. Autoimmunity arise when the immune system of an individual start to attack its own organs and tissues. Immune cells go through a selection in central and peripheral organs where they are taught to be non-reactive to self structures, a process referred to as tolerance. In this thesis we have investigated the function of the autoimmune regulator (AIRE), a gene that is important for the establishment of tolerance. The autoimmune polyendocrine syndrome type 1 (APS I) is a rare severe autoimmune disease caused by a single mutation in the AIRE gene. These patients suffer from a range of endocrine and non-endocrine manifestations such as hypoparathyroidism and chronic mucocutaneous candida infections. Aire deficient mice have been created in order to enable the investigation on how tolerance is lost in APS I patients. These mice have revealed that AIRE is involved in the deletion of autoreactive T-lymphocytes in the thymus. AIRE is thought to induce the expression of tissue specific antigens (TSAs) that are presented to T-lymphocytes in the thymus. However, Aire deficient mice display a phenotype suggesting that additional tolerance mechanisms are affected. In the first paper presented in this thesis we show that AIRE is involved in the regulation of T-cell independent B cell responses and that Aire-/- mice display an increased activation of B cells. This increased activation was demonstrated to be due to increased serum levels of the B cell activating factor of the TNF-family (BAFF) in Aire-/- mice and APS I patients. The increased levels of BAFF were in turn found to be due to uninhibited signaling of IFN-γ through the STAT1-pathway in absence of AIRE. In the second paper it was demonstrated that AIRE is expressed by a specific dendritic cell in the marginal zone of the spleen. These dendritic cells were found to regulate the activation of T lymphocytes in germinal center reactions and displayed a phenotype suggesting their involvement in tolerance mechanisms. In the third project we demonstrated that the expression of Aire in the marginal zone dendritic cells was regulated by IFN-γ. Upon IFN-γ stimulation both the expression of Aire and the TSA insulin was quickly down-regulated while the expression of inflammatory cytokines was up-regulated. These data suggest that the marginal zone dendritic cells are able to participate in tolerance induction during steady state and switch to an immunogenic state during an immune response. In the last project we investigated the development of the marginal zone dendritic cell in the bone marrow and found that Aire is expressed in a precursor cell to the dendritic cell in the spleen. Further, it was found that in absence of AIRE the regulation of transcription factors important for the development of this particular dendritic cell subset was impaired. The findings from this thesis suggest that AIRE play an important function in the periphery and adds to the view that AIRE regulates both central and peripheral tolerance.
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| 3. |
- Näsman, Mattias, 1989-, et al.
(författare)
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A promised land? : First summary of the research program
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This document lays out the background for the research program “A promised land? Drivers, challenges and opportunities related to the (green) industrialization of Northern Sweden,” (nr. M22-0029) awarded by the Swedish Riksbankens Jubileumsfond’s in 2022. The document summarizes work in progress and may therefore be updated and republished in different versions according to the requirements of the program. This interdisciplinary program aims to understand the economic, social, and political challenges and opportunities of the ongoing industrial transformation in northern Sweden. A key element of the program is to identify drivers, obstacles, and preconditions in a historical, present, and forward-looking process-perspective.
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| 4. |
- Åkerlund, Thomas, et al.
(författare)
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Stable IgG-antibody levels in patients with mild SARS-CoV-2 infection
- 2021
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Ingår i: Medrxiv. - : Cold Spring Harbor Laboratory.
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Tidskriftsartikel (refereegranskat)abstract
- More knowledge regarding persistence of antibody response to SARS-CoV-2 infections in the general population with mild symptoms is needed. We measured and compared levels of SARS CoV-2 spike- and nucleocapsid-specific IgG-antibodies in serum samples from 145 laboratory confirmed COVID-19 cases and 324 non-cases. The IgG-antibody levels against the spike protein in cases were stable over the time-period studied (14 to 256 days), while antibody levels against the nucleocapsid protein decreased over time
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