| 1. |
- Albertsen, Birgitte Klug, et al.
(författare)
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Asparaginase treatment in infants with acute lymphoblastic leukemia; pharmacokinetics and asparaginase hypersensitivity in Interfant-06
- 2019
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Ingår i: Leukemia and Lymphoma. - : TAYLOR & FRANCIS LTD. - 1042-8194 .- 1029-2403. ; 60:6, s. 1469-1475
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Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac((R))) and PEG-asparaginase (Oncaspar((R))) as well as hypersensitivity reactions during treatment in Interfant-06 (www.clinicaltrials.gov: NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.
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| 2. |
- Harila, Kirsi, et al.
(författare)
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The Vpu-regulated endocytosis of HIV-1 Gag is clathrin-independent
- 2007
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Ingår i: Virology. - : Elsevier BV. - 0042-6822 .- 1096-0341. ; 369:2, s. 299-308
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Tidskriftsartikel (refereegranskat)abstract
- Recent results by us and others have shown that the accessory protein Vpu determines plasma membrane versus endosomal accumulation of the HIV-1 core protein Gag and progeny virions in the HeLa model of HIV-1 infection, since Vpu suppresses endocytosis of cell surface-associated Gag. In this report, we used pulse-chase studies and subcellular fractionations to investigate endocytosis of newly synthesized Gag in HeLa HI cells. The uptake of Gag in Delta Vpu-virus background was not blocked by inhibitors of clathrin-mediated endocytosis and macropinocytosis. The cholesterol-sequestering drug filipin inhibited the uptake, but only if the drug was applied before extensive multimerization of Gag had taken place. Thus, the uptake mechanism most likely is only indirectly dependent on cholesterol. Our results also indicated that targeting phenotype of Gag was different in confluent versus subconfluent cell cultures, which could perhaps explain some of the controversies in intracellular targeting of Gag. (c) 2007 Elsevier Inc. All rights reserved.
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| 3. |
- Harila, Kirsi, et al.
(författare)
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Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag
- 2006
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Ingår i: Journal of Virology. - 0022-538X .- 1098-5514. ; 80:8, s. 3765-3772
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Tidskriftsartikel (refereegranskat)abstract
- Assembly of human immunodeficiency virus type 1 (HIV-1) is directed by the viral core protein Pr55gag. Depending on the cell type, Pr55 gag accumulates either at the plasma membrane or on late endosomes/multivesicular bodies. Intracellular localization of Pr55 gag determines the site of virus assembly, but molecular mechanisms that define cell surface or endosomal targeting of Pr55gag are poorly characterized. We have analyzed targeting of newly synthesized Pr55 gag in HeLa H1 cells by pulse-chase studies and subcellular fractionations. Our results indicated that Pr55gag was inserted into the plasma membrane and, when coexpressed with the viral accessory protein Vpu, Pr55gag remained at the plasma membrane and virions assembled at this site. In contrast, Pr55gag expressed in the absence of Vpu was initially inserted into the plasma membrane, but subsequently endocytosed, and virus assembly was partially shifted to internal membranes. This endocytosis of Pr55gag required the host protein Tsg101. These results identified a previously unknown role for Vpu and Tsg101 as regulators for the endocytic uptake of Pr55gag and suggested that the site of HIV-1 assembly is determined by factors that regulate the endocytosis of Pr55gag. Copyright © 2006, American Society for Microbiology. All Rights Reserved.
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| 4. |
- Harila, Kirsi
(författare)
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Vpu-mediated intracellular targeting of HIV-1 core protein precursor Pr55[gag] and association of Pr55[gag] with lipid microdomains
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- HIV-1 has been suggested to use lipid rafts for assembly and budding. Lipid rafts can be separated from the bulk membranes by extraction with non-ionic detergents, such as Triton X-100 at cold, followed by a density gradient centrifugation. The analysis of intracellular Pr55gag on iodixanol density gradients yielded intermediate density buoyant complexes while raft-associated proteins floated to the light-density fractions. Extracellular virus-like particles (VLPs) showed a similar intermediate flotation pattern after TX-100 extraction suggesting that Pr55gag was not a genuine raft-associated protein. The lipid analysis of TX-100 extracted VLPs suggested that the intermediate buoyant complexes were largely devoid of membrane cholesterol and phospholipids. We also tested the extractability of the membranes with Brij98 which has been shown to detect rafts at physiological temperatures. Our analyses showed that intracellular Pr55gag as well as VLPs were largely resistant to Brij98-extraction. We concluded that Pr55gag associates with lipid microdomains distinct from the classical TX-100-resistant lipid rafts. We also analyzed the intracellular targeting of Pr55gag. It has been under an intense debate at which cellular membrane the productive assembly takes place, as Pr55gag has been seen to accumulate at both the internal membranes and the plasma membrane depending on the cell type. To resolve this issue, we performed our analyses in HeLa H1-cells, where the Pr55gag can be found both at the plasma membrane and the internal membranes. We employed pulse-chase studies and a subcellular fractionation assay by which an efficient separation of the plasma membrane from the internal membrane fraction is achieved. The kinetic analyses revealed that in the HeLa H1-cells newly synthesized Pr55gag is exclusively targeted to the plasma membrane. To our surprise, the plasma membrane-associated Pr55gag was subsequently endocytosed, if the viral accessory protein Vpu was defective in our proviral construct. Our work was the first to implicate that Vpu had an important role in the subcellular localization of Pr55gag. We probed by which mechanism the Pr55gag is taken up into the cells in the absence of Vpu. Our analyses implicated that neither clathrin-mediated endocytosis nor macropinocytosis was involved in Pr55gag uptake. In contrast, the cholesterol depletion affected the uptake of Gag thus suggesting the possibility that cholesterol-mediated uptake might be involved. However, cholesterol depletion had a more pronounced effect if it was applied before the maximal membrane insertion and at least some level of the higher-order multimerization of Pr55gag were achieved. This implicated that the cholesterol-dependent uptake pathway was only indirectly associated with the endocytosis of Pr55gag as cholesterol depletion most likely interfered with Gag multimerization and virus assembly.
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| 5. |
- Ranta, Susanna, et al.
(författare)
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Presenting features and imaging in childhood acute myeloid leukemia with central nervous system involvement.
- 2017
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Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 64:12
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Tidskriftsartikel (refereegranskat)abstract
- Central nervous system (CNS) involvement in childhood acute myeloid leukemia (AML) can manifest as leukemic cells in the cerebrospinal fluid, a solid CNS tumor, or as neurological symptoms. We evaluated the presenting symptoms and neuroimaging findings in 33 of 34 children with AML and CNS involvement at diagnosis in the period 2000-2012 in Sweden, Finland, and Denmark. Imaging was performed in 22 patients, of whom 16 had CNS-related symptoms. Seven patients, including all but two with facial palsy, had mastoid cell opacification, considered an incidental finding. The frequent involvement of the mastoid bone with facial palsy warrants evaluation in larger series.
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| 6. |
- Turunen, S. Pauliina, et al.
(författare)
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Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis
- 2015
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Ingår i: Innate Immunity. - : SAGE Publications. - 1753-4259 .- 1753-4267. ; 21:4, s. 370-85
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Tidskriftsartikel (refereegranskat)abstract
- Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL.
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| 7. |
- Turunen, S. Pauliina, et al.
(författare)
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Recognition of Porphyromonas gingivalis gingipain epitopes by natural IgM binding to malondialdehyde modified low-density lipoprotein.
- 2012
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Increased risk for atherosclerosis is associated with infectious diseases including periodontitis. Natural IgM antibodies recognize pathogen-associated molecular patterns on bacteria, and oxidized lipid and protein epitopes on low-density lipoprotein (LDL) and apoptotic cells. We aimed to identify epitopes on periodontal pathogen Porphyromonas gingivalis recognized by natural IgM binding to malondialdehyde (MDA) modified LDL.METHODS AND RESULTS: Mouse monoclonal IgM (MDmAb) specific for MDA-LDL recognized epitopes on P. gingivalis on flow cytometry and chemiluminescence immunoassays. Immunization of C57BL/6 mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and apoptotic cells. Immunization of LDLR(-/-) mice with P. gingivalis induced IgM, but not IgG, immune response to MDA-LDL and diminished aortic lipid deposition. On Western blot MDmAb bound to P. gingivalis fragments identified as arginine-specific gingipain (Rgp) by mass spectrometry. Recombinant domains of Rgp produced in E. coli were devoid of phosphocholine epitopes but contained epitopes recognized by MDmAb and human serum IgM. Serum IgM levels to P. gingivalis were associated with anti-MDA-LDL levels in humans.CONCLUSION: Gingipain of P. gingivalis is recognized by natural IgM and shares molecular identity with epitopes on MDA-LDL. These findings suggest a role for natural antibodies in the pathogenesis of two related inflammatory diseases, atherosclerosis and periodontitis.
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