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| 3. |
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| 4. |
- Hofving, Tobias, 1989, et al.
(författare)
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The Microenvironment of Small Intestinal Neuroendocrine Tumours Contains Lymphocytes Capable of Recognition and Activation after Expansion
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:17
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The body's immune system can recognize tumors because they often contain proteins that are either different from or more abundant than in normal cells. Here, we characterised the immune cells of a rare tumor type called small-intestinal neuroendocrine tumors (SINET). We find that so called tumour-infiltrating lymphocytes (TILs) can be grown in the laboratory and activated by challenging them with digested tumor. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET. Traditionally, immune evasion and immunotherapy have been studied in cancers with a high mutational load such as melanoma or lung cancer. In contrast, small intestinal neuroendocrine tumours (SINETs) present a low frequency of somatic mutations and are described as genetically stable tumours, rendering immunotherapies largely unchartered waters for SINET patients. SINETs frequently metastasise to the regional lymph nodes and liver at the time of diagnosis, and no curative treatments are currently available for patients with disseminated disease. Here, we characterised the immune landscape of SINET and demonstrated that tumour-infiltrating lymphocytes (TILs) can be expanded and activated during autologous tumour challenge. The composition of lymphocyte subsets was determined by immunophenotyping of the SINET microenvironment in one hepatic and six lymph node metastases. TILs from these metastases were successfully grown out, enabling immunophenotyping and assessment of PD-1 expression. Expansion of the TILs and exposure to autologous tumour cells in vitro resulted in increased T lymphocyte degranulation. This study provides insights into the largely unknown SINET immune landscape and reveals the anti-tumour reactivity of TILs, which might merit adoptive T cell transfer as a feasible treatment option for patients with SINET.
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| 5. |
- Jokiranta, T S, et al.
(författare)
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Complement C3b interactions studied with surface plasmon resonance technique
- 2001
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Ingår i: International Immunopharmacology. - 1567-5769 .- 1878-1705. ; 1:3, s. 495-506
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Tidskriftsartikel (refereegranskat)abstract
- The surface plasmon resonance (SPR) phenomenon is utilized in a number of new real time biosensors. In this study, we have used this technique to study interactions between the central complement component C3b and its multiple ligands by using the Biacore equipment. The SPR technique is particularly suitable for analysis of the alternative complement pathway (AP) because the inherent nature of the latter is to amplify deposition of C3b on various surfaces. C3b was coupled onto the sensor surface and the coupling efficiency was compared under various conditions on both polystyrene and carboxymethylated dextran surfaces. After enzymatic C3b coupling or standard amine C3b coupling, we analyzed and compared the binding of four C3b ligands to the surface: factor B, factor H, C5 and the soluble complement receptor 1 (sCR1, CD35). Binding of each ligand to C3b was detected when C3b had been coupled either enzymatically or using the amine coupling, but the half-lives of the interactions were found to vary depending on the coupling procedure. Factor H binds to C3b via three interaction sites. The target sites are exposed on the C3b, C3c and C3d fragments of C3, respectively. Therefore, we also tested by using the Biacore whether factor B, C5 and sCR1 bind to C3c and/or C3d. It was found that factor B bound to C3d, but not to C3c. On the other hand, both C5 and sCR1 bound to C3c, but not to C3d. In conclusion, this study shows that SPR is a powerful tool in analyzing and mapping the interactions of C3b with its multiple ligands.
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| 6. |
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| 7. |
- Nilsson, Ulf R., et al.
(författare)
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Two conformational forms of target-bound iC3b that distinctively bind complement receptors 1 and 2 and two specific monoclonal antibodies
- 2011
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Ingår i: Upsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 116:1, s. 26-33
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Tidskriftsartikel (refereegranskat)abstract
- Introduction. The complement system is an essential part of the immune system of vertebrates. The central event of the complement activation cascade is the sequential proteolytic activation of C3, which is associated with profound alterations in the molecule's structure and conformation and is responsible for triggering most of the biological effects of complement. Material and methods. Here, we have studied the conformation of C3 fragments deposited onto an IgG-coated surface from human serum during complement activation, using a set of unique monoclonal antibodies (mAbs) that are all specific for the C3dg portion of bound iC3b. Results. We were able to identify two conformational forms of target-bound iC3b: the first recognized by mAb 7D18.1, and the second by mAb 7D323.1. The first species of iC3b bound recombinant complement receptor 1 (CR1), while the second bound CR2. Since CR1 and CR2 are expressed by different subsets of leukocytes, this difference in receptor-binding capacity implies that there is a biological difference between the two forms of surface-bound iC3b. Conclusion. We propose that mAbs 7D18.1 and 7D323.1 can act as surrogate markers for CR1 and CR2, respectively, and that they may be useful tools for studying the immune complexes that are generated in various autoimmune diseases.
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| 9. |
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| 10. |
- Bergh, Anders, et al.
(författare)
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Didecyl squarate — A practical amino-reactive cross-linking reagent for neoglycoconjugate synthesis
- 2001
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Ingår i: Glycoconjugate Journal. - 1573-4986. ; 18:8, s. 615-621
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Tidskriftsartikel (refereegranskat)abstract
- The present paper describes the synthesis and use of the hydrophobic squaric decyl ester glycosides in neoglycoconjugate chemistry. The 2-aminoethyl glycosides of agr-D-mannopyranose, lactose, globotriose, globotetraose, GM3, and sialyl Lewisx, as well as the 2-(2-aminoethylthio)ethyl glycoside of agr-D-mannopyranose, beta-D-glucopyranose, and galabiose were reacted with squaric acid didecyl ester to afford the hydrophobic squaric decyl ester glycosides. These glycosides were efficient reagents for the conjugation to amino-functional microtiter plates, BSA and aminated Sepharose EAH 4B. The decyl ester moiety of the squaric decyl ester glycosides constitutes a traceless hydrophobic tag, which has the major advantage, as compared to the corresponding ethyl esters, that it enables easy purification of the glycosides with silica chromatography and that unreacted excesses glycosides from conjugation reaction mixtures can easily be recovered by means of C18 solid phase extraction.
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| 11. |
- Bhattacharyya, Sumita, et al.
(författare)
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The p-methoxybenzyl ether as an in situ-removable carbohydrate-protecting group : A simple one-pot synthesis of the globotetraose tetrasaccharide
- 2001
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Ingår i: Journal of the Chemical Society - Perkin Transactions 1. - : Royal Society of Chemistry (RSC). - 1472-7781 .- 1364-5463. ; :8, s. 886-890
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Tidskriftsartikel (refereegranskat)abstract
- A one-pot synthesis of the globotetraose tetrasaccharide is reported. The synthetic method relies on the use of a p-methoxybenzyl ether as an in situ-removable protecting group. N-Iodosuccinimide/trifluoromethanesulfonic acid-promoted glycosylation of 2-bromoethyl-2,3,6-tri-O-benzoyl-4-O-(2,3,6-tri-O-benzoyl-β-D-galactopyranosyl)-β-D-glucopyranoside 5 at −45 °C with phenyl 2,4,6-tri-O-benzyl-3-O-(4-methoxybenzyl)-1-thio-β-D-galactopyranoside 6 gives an intermediate trisaccharide from which the p-methoxybenzyl ether is removed by allowing the reaction temperature to rise to 0 °C for 40 min. Again lowering the temperature to −45 °C, followed by addition of methyl 3,4,6-tri-O-acetyl-2-trichloroethoxycarbonylamino-2-deoxy-1-thio-β-D-galactopyranoside 8, affords the globotetraose tetrasaccharide 11 in one-pot in an excellent yield of 76%.
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| 12. |
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| 13. |
- Bozzola, Tiago, et al.
(författare)
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Direct Sialic Acid 4-OAc Substitution by Nitrogen, Sulfur and Carbon Nucleophiles with Retention of Stereochemistry
- 2022
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Ingår i: RSC Advances. - 2046-2069. ; 12:19, s. 11992-11995
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Tidskriftsartikel (refereegranskat)abstract
- A direct one-step nucleophilic substitution of the 4-OAc of acetyl protected Neu5Ac is presented. Previously published methods for direct substitution of the 4-OAc are limited to cyclic secondary amines. Here we present conditions that allow for a much wider range of nitrogen nucleophiles as well as thiols and cyanide, to be used. The present investigation significantly broadens the scope of 4-aminations and allows for the introduction of a wide variety of different nucleophiles.
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| 14. |
- Bozzola, Tiago, et al.
(författare)
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Sialic Acid 4-N-Piperazine and Piperidine Derivatives Bind with High Affinity to the P. mirabilis Sialic Acid Sodium Solute Symporter
- 2022
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 17:23
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Tidskriftsartikel (refereegranskat)abstract
- In search for novel antibacterial compounds, bacterial sialic acid uptake inhibition represents a promising strategy. Sialic acid plays a critical role for growth and colonisation of several pathogenic bacteria, and its uptake inhibition in bacteria was recently demonstrated to be a viable strategy by targeting the SiaT sodium solute symporters from Proteus mirabilis and Staphylococcus aureus. Here we report the design, synthesis and evaluation of potential sialic acid uptake inhibitors bearing 4-N-piperidine and piperazine moieties. The 4-N-derivatives were obtained via 4-N-functionalization with piperidine and piperazine nucleophiles in an efficient direct substitution of the 4-O-acetate of Neu5Ac. Evaluation for binding to bacterial transport proteins with nanoDSF and ITC revealed compounds possessing nanomolar affinity for the P. mirabilis SiaT symporter. Computational analyses indicate the engagement of a previously untargeted portion of the binding site.
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| 15. |
- Bozzola, Tiago, et al.
(författare)
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Sialic Acid Derivatives Inhibit SiaT Transporters and Delay Bacterial Growth
- 2022
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Ingår i: Acs Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 17:7, s. 1890-1900
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Tidskriftsartikel (refereegranskat)abstract
- Antibiotic resistance is a major worldwide concern, and new drugs with mechanistically novel modes of action are urgently needed. Here, we report the structure-based drug design, synthesis, and evaluation in vitro and in cellular systems of sialic acid derivatives able to inhibit the bacterial sialic acid symporter SiaT. We designed and synthesized 21 sialic acid derivatives and screened their affinity for SiaT by a thermal shift assay and elucidated the inhibitory mechanism through binding thermodynamics, computational methods, and inhibitory kinetic studies. The most potent compounds, which have a 180-fold higher affinity compared to the natural substrate, were tested in bacterial growth assays and indicate bacterial growth delay in methicillin-resistant Staphylococcus aureus. This study represents the first example and a promising lead in developing sialic acid uptake inhibitors as novel antibacterial agents.
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| 16. |
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| 17. |
- Diehl, Carl, et al.
(författare)
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Protein Flexibility and Conformational Entropy in Ligand Design Targeting the Carbohydrate Recognition Domain of Galectin-3.
- 2010
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 132, s. 14577-14589
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Tidskriftsartikel (refereegranskat)abstract
- Rational drug design is predicated on knowledge of the three-dimensional structure of the protein-ligand complex and the thermodynamics of ligand binding. Despite the fundamental importance of both enthalpy and entropy in driving ligand binding, the role of conformational entropy is rarely addressed in drug design. In this work, we have probed the conformational entropy and its relative contribution to the free energy of ligand binding to the carbohydrate recognition domain of galectin-3. Using a combination of NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography, we characterized the binding of three ligands with dissociation constants ranging over 2 orders of magnitude. (15)N and (2)H spin relaxation measurements showed that the protein backbone and side chains respond to ligand binding by increased conformational fluctuations, on average, that differ among the three ligand-bound states. Variability in the response to ligand binding is prominent in the hydrophobic core, where a distal cluster of methyl groups becomes more rigid, whereas methyl groups closer to the binding site become more flexible. The results reveal an intricate interplay between structure and conformational fluctuations in the different complexes that fine-tunes the affinity. The estimated change in conformational entropy is comparable in magnitude to the binding enthalpy, demonstrating that it contributes favorably and significantly to ligand binding. We speculate that the relatively weak inherent protein-carbohydrate interactions and limited hydrophobic effect associated with oligosaccharide binding might have exerted evolutionary pressure on carbohydrate-binding proteins to increase the affinity by means of conformational entropy.
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| 18. |
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| 19. |
- Ekdahl, Kristina N., et al.
(författare)
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Use of serum or buffer-changed EDTA-plasma in a rapid, inexpensive, and easy-to-perform hemolytic complement assay for differential diagnosis of systemic lupus erythematosus and monitoring of patients with the disease
- 2007
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Ingår i: Clinical and Vaccine Immunology. - 1556-6811 .- 1556-679X. ; 14:5, s. 549-555
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Tidskriftsartikel (refereegranskat)abstract
- We previously described a simplified quantitative hemolytic assay for classical pathway (CP) hemolytic function in serum that has been shown to correlate with the 50% hemolytic complement (CH50) assay. In the present study, we used this assay to compare CP functions; plasma levels of C3, C4, and C3dg; and ratios of C3dg to C3 in healthy individuals and patients with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) with different degrees of complement activation. A significant depression in CP function and levels of C4 and C3 and increased C3dg levels and C3dg/C3 ratios were observed in the SLE patients. In patients with RA, CP function was normal, whereas C3, C4, and C3dg levels and the C3dg/C3 ratio were elevated. The SLE results are compatible with systemic complement consumption, whereas the RA data suggest an acute-phase reaction with a normal C3 catabolic rate. To facilitate the handling of patient samples, we also developed a method to restore the hemolytic function of EDTA-plasma by transferring it to Veronal-buffered saline containing the thrombin inhibitor lepirudin. This process inhibits coagulation and enables complement activation, allowing a longer time lag between sample harvesting and testing. These results, combined with previous correlation studies, suggest that the CP hemolytic assay can effectively replace the CH50 assay for routine SLE differential diagnosis and monitoring of disease activity.
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| 20. |
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| 21. |
- Ekström, Magnus Pär, et al.
(författare)
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The association of body mass index, weight gain and central obesity with activity-related breathlessness : the Swedish Cardiopulmonary Bioimage Study
- 2019
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Ingår i: Thorax. - : BMJ Publishing Group Ltd. - 0040-6376 .- 1468-3296. ; 74:10, s. 958-964
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m(2)) is rapidly increasing globally and its impact on breathlessness is unclear.Methods: This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score >= 1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex.Results: We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m(2); and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness.Conclusion: Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.
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| 22. |
- Ekström, Ulf, et al.
(författare)
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An individual with a healthy phenotype in spite of a pathogenic LDL receptor mutation (C240F)
- 1999
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Ingår i: Clinical Genetics. - : Wiley. - 0009-9163. ; 55:5, s. 332-339
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Tidskriftsartikel (refereegranskat)abstract
- Familial hypercholesterolemia (FH) is caused by a defect in the function of the low density lipoprotein (LDL) receptor and inherited in an autosomal, codominant way. In this study we present a 13-year-old girl, compound heterozygote for the LDL receptor mutations C240F and Y167X. Fibroblasts from the patient showed very low cholesterol esterification rate, LDL uptake, and degradation compared to normal fibroblasts (< 2%, 8%, and < 2%, respectively). The C240F mutant was expressed in LDL receptor deficient CHOMldlA7 cells. Analysis of cell extracts by immunoblotting demonstrated delayed processing of the mutated LDL receptor, which was accumulated as a precursor protein of normal size. A high molecular weight form of the receptor was also detectable in these cells, which probably reflects cross-linking through the unpaired cysteine residue in the binding domain. Cells expressing the C240F mutant protein were unable to mediate uptake and degradation of LDL. The two siblings of the index case also carried the C240F mutation, but surprisingly one of them (a 17-year-old brother) showed no signs of hypercholesterolemia. This observation is consistent with the view that there may be cholesterol lowering mechanisms that can be activated, perhaps by mutations in known or hitherto unknown genes.
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| 23. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 24. |
- Forsberg, Per-Olof, et al.
(författare)
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In vitro phosphorylation of human complement factor C3 by protein kinase A and protein kinase C : Effects on the classical and alternative pathways
- 1990
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 265:5, s. 2941-2946
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Tidskriftsartikel (refereegranskat)abstract
- Complement factor C3, recently found to contain covalently bound phosphate, was phosphorylated in vitro by cyclic AMP-dependent protein kinase (protein kinase A) and Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C). Both protein kinases phosphorylated the same serine residue(s) located in the C3a portion of the alpha-chain. In addition, protein kinase C phosphorylated the beta-chain to a lesser extent. Protein kinase A gave a maximal incorporation of 1 mol of phosphate/mol of C3 while that value with protein kinase C was 1.5 mol of phosphate/mol of C3. The velocity in pmol of [32P]phosphate/(min x unit kinase) was 20 times higher for protein kinase C than for protein kinase A although a 10 times lower ratio of protein kinase to C3 was used in the former case. The apparent Kmfor C3 was 2.6 µM when protein kinase C was used. The phosphorylated C3 was found to be more resistant to partial degradation by trypsin than unphosphorylated C3. It was also found that phosphorylation of C3 in the C3a portion of the alpha-chain inhibited both the classical and alternative complement activation pathways on an approximately stoichiometric basis.
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| 25. |
- Fritzson, Ingela, et al.
(författare)
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Inhibition of Human DHODH by 4-Hydroxycoumarins, Fenamic Acids, and N-(Alkylcarbonyl)anthranilic Acids Identified by Structure-Guided Fragment Selection
- 2010
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Ingår i: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 5:4, s. 608-617
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Tidskriftsartikel (refereegranskat)abstract
- A strategy that combines virtual screening and structureguided selection of fragments was used to identify three unexplored classes of human DHODH inhibitor compounds: 4-hydroxycoumarins, fenamic acids, and N-(alkylcarbonyl)anthranilic acids. Structure-guided selection of fragments targeting the inner subsite of the DHODH ubiquinone binding site made these findings possible with screening of fewer than 300 fragments in a DHODH assay. Fragments from the three inhibitor classes identified were subsequently chemically expanded to target an additional subsite of hydrophobic character. All three classes were found to exhibit distinct structure–activity relationships upon expansion. The novel N-(alkylcarbonyl anthranilic acid class shows the most promising potency against human DHODH, with IC50 values in the low nanomolar range. The structure of human DHODH in complex with an inhibitor of this class is presented.
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| 26. |
- Gorcenco, Sorina, et al.
(författare)
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Ataxia-pancytopenia syndrome with SAMD9L mutations
- 2017
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Ingår i: Neurology: Genetics. - 2376-7839. ; 3:5
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We describe the neurologic, neuroradiologic, and ophthalmologic phenotype of 1 Swedish and 1 Finnish family with autosomal dominant ataxia-pancytopenia (ATXPC) syndrome and SAMD9L mutations.METHODS: Members of these families with germline SAMD9L c.2956C>T, p.Arg986Cys, or c.2672T>C, p.Ile891Thr mutations underwent structured interviews and neurologic and ophthalmologic examinations. Neuroimaging was performed, and medical records were reviewed. Previous publications on SAMD9L-ATXPC were reviewed.RESULTS: Twelve individuals in both families were affected clinically. All mutation carriers examined had balance impairment, although severity was very variable. All but 1 had nystagmus, and all but 1 had pyramidal tract signs. Neurologic features were generally present from childhood on and progressed slowly. Two adult patients, who experienced increasing clumsiness, glare, and difficulties with gaze fixation, had paracentral retinal dysfunction verified by multifocal electroretinography. Brain MRI showed early, marked cerebellar atrophy in most carriers and variable cerebral periventricular white matter T2 hyperintensities. Two children were treated with hematopoietic stem cell transplantation for hematologic malignancies, and the neurologic symptoms of one of these worsened after treatment. Three affected individuals had attention deficit hyperactivity disorder or cognitive problems. Retinal dysfunction was not previously reported in individuals with ATXPC.CONCLUSIONS: The neurologic phenotype of this syndrome is defined by balance or gait impairment, nystagmus, hyperreflexia in the lower limbs and, frequently, marked cerebellar atrophy. Paracentral retinal dysfunction may contribute to glare, reading problems, and clumsiness. Timely diagnosis of ATXPC is important to address the risk for severe hemorrhage, infection, and hematologic malignancies inherent in this syndrome; regular hematologic follow-up might be beneficial.
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| 27. |
- Goto, Junko, et al.
(författare)
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Interdialytic weight gain of less than 2.5% seems to limit cardiac damage during hemodialysis
- 2021
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Ingår i: International Journal of Artificial Organs. - : SAGE Open. - 0391-3988 .- 1724-6040. ; 44:8, s. 539-550
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate if a single low-flux HD induces a rise in cardiac biomarkers and if a change in clinical approach may limit such mechanism.Material and methods: A total of 20 chronic HD patients each underwent three different study-dialyses. Dialyzers (low-flux polysulfone, 1.8 sqm) had been stored either dry or wet (Wet) and the blood level in the venous chamber kept low or high. Laboratory results were measured at baseline, 30 and 180 min, adjusted for the effect of fluid shift. Ultrasound measured microemboli signals (MES) within the return line.Results: Hemodialysis raised cardiac biomarkers (p < 0.001): Pentraxin 3 (PTX) at 30 min (by 22%) and at 180 min PTX (53%), Pro-BNP (15%), and TnT (5%), similarly for all three HD modes. Baseline values of Pro-BNP correlated with TnT (rho = 0.38, p = 0.004) and PTX (rho = 0.52, p < 0.001). The changes from pre- to 180 min of HD (delta-) were related to baseline values (Pro-BNP: rho = 0.91, p < 0.001; TnT: rho = 0.41, p = 0.001; PTX: rho = 0.29, p = 0.027). Delta Pro-BNP (rho = 0.67, p < 0.001) and TnT (rho = 0.38, p = 0.004) correlated with inter-dialytic-weight-gain (IDWG). Biomarkers behaved similarly between the HD modes. The least negative impact was with an IDWG <= 2.5%. Multiple regression analyses of the Wet-High mode does not exclude a relation between increased exposure of MES and factors such as release of Pro-BNP.Conclusion: Hemodialysis, independent of type of dialyzer storage, was associated with raised cardiac biomarkers, more profoundly in patients with higher pre-dialysis values and IDWG. A limitation in IDWG to <2.5% and prolonged ultrafiltration time may limit cardiac strain during HD, especially in patients with cardiovascular risk.
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| 28. |
- Grimvall, E, et al.
(författare)
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Monitoring of polychlorinated biphenyls in human blood plasma: methodological developments and influence of age, lactation, and fish consumption
- 1997
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Ingår i: Archives of Environmental Contamination and Toxicology. - : Springer Science and Business Media LLC. - 0090-4341 .- 1432-0703. ; 32:3, s. 329-336
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Tidskriftsartikel (refereegranskat)abstract
- Human plasma samples from 50 wives of fishermen have been analyzed with respect to PCBs. The non-ortho-substituted PCB congeners CB-126 and CB-169 were determined by mass spectrometry in negative ion chemical ionization mode, which demonstrated a limit of detection of 30 fg. The recoveries of the internal standards used for determination of ortho-substituted CBs were approximately 95%. Two methods, one gravimetric and the other based on enzymatic determinations of triglycerides, cholesterol and phospholipids, were compared for the determination of total amount of lipids in the plasma samples; the correlation coefficient was 0.82 and the slope 0.98. For practical reasons, enzymatic determinations are recommended for further use. The total, lipid-adjusted concentrations of PCBs in plasma were influenced by age, total lactation time and consumption of fatty fish from the Baltic Sea.
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| 29. |
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| 30. |
- Hägg, Sara, 1977-, et al.
(författare)
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Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2 : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n=66/tissue) and atherosclerotic and unaffected arterial wall (n=40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n=15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n=3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n=49/48) and one visceral fat (n=59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n=55/54) relating to carotid stenosis (P=0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n=16/17, P<10-27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, cellular and lesion expression of LDB2, and the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and together with LDB2 merits further attention in CAD research.
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| 31. |
- Kadhirvel, Saraboji, et al.
(författare)
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The Carbohydrate-Binding Site in Galectin-3 Is Preorganized To Recognize a Sugarlike Framework of Oxygens: Ultra-High-Resolution Structures and Water Dynamics
- 2012
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Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 51:1, s. 296-306
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Tidskriftsartikel (refereegranskat)abstract
- The recognition of carbohydrates by proteins is a fundamental aspect of communication within and between living cells. Understanding the molecular basis of carbohydrate-protein interactions is a prerequisite for the rational design of synthetic ligands. Here we report the high- to ultrahigh-resolution crystal structures of the carbohydrate recognition domain of galectin-3 (Gal3C) in the ligand-free state (1.08 angstrom at 100 K, 1.25 angstrom at 298 K) and in complex with lactose (0.86 angstrom) or glycerol (0.9 angstrom). These structures reveal striking similarities in the positions of water and carbohydrate oxygen atoms in all three states, indicating that the binding site of Gal3C is preorganized to coordinate oxygen atoms in an arrangement that is nearly optimal for the recognition of beta-galactosides. Deuterium nuclear magnetic resonance (NMR) relaxation dispersion experiments and molecular dynamics simulations demonstrate that all water molecules in the lactose-binding site exchange with bulk water on a time scale of nanoseconds or shorter. Nevertheless, molecular dynamics simulations identify transient water binding at sites that agree well with those observed by crystallography, indicating that the energy landscape of the binding site is maintained in solution. All heavy atoms of glycerol are positioned like the corresponding atoms of lactose in the Gal3C complexes. However, binding of glycerol to Gal3C is insignificant in solution at room temperature, as monitored by NMR spectroscopy or isothermal titration calorimetry under conditions where lactose binding is readily detected. These observations make a case for protein cryo-crystallography as a valuable screening method in fragment-based drug discovery and further suggest that identification of water sites might inform inhibitor design.
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| 32. |
- Kald, A, et al.
(författare)
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Reoperation as surrogate endpoint in hernia surgery. A three year follow-up of 1565 herniorrhaphies.
- 1998
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Ingår i: European Journal of Surgery. - : Oxford University Press (OUP). - 1102-4151 .- 1741-9271. ; 164:1, s. 45-50
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Analysis of reoperation and recurrence rates three years after repair of groin hernias.DESIGN: Prospective audit by questionnaire and selective follow-up.SETTING: Eight Swedish hospitals.SUBJECTS: All groin hernia operations done during 1992 on patients between the ages of 15 and 80 years.MAIN OUTCOME MEASURES: Postoperative complications, reoperation for recurrence, and recurrence.RESULTS: During 1992, 1565 hernia operations were done. The postoperative complication rate was 8% (125/1565). At 36 months postoperatively 108 recurrences had already been reoperated on, six patients with recurrences were on the waiting list for reoperation and a further 36 recurrences had been detected at follow-up. The interhospital variation in recurrence rate ranged from 3% to 20%. Postoperative complications, recurrent hernia, direct hernia and hospital catchment area over 100000 inhabitants were all factors associated with an increased relative risk of recurrence.CONCLUSIONS: The recurrence rate exceeded the reoperation rate for recurrence by almost 40% which should be taken into account if the reoperation rate is used as the endpoint after repairs of groin hernia. An audit scheme, based on prospective recording, reoperation rate, and (periodic) calculation of the recurrence rate may be used to identify risk factors for recurrence and areas in need of improvement.
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| 33. |
- Kumar, Rohit, et al.
(författare)
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Structure and Energetics of Ligand–Fluorine Interactions with Galectin-3 Backbone and Side-Chain Amides : Insight into Solvation Effects and Multipolar Interactions
- 2019
-
Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 14:16, s. 1528-1536
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Tidskriftsartikel (refereegranskat)abstract
- Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyze the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine–main-chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.
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| 34. |
- Kumar, Rohit, et al.
(författare)
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Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects
- 2019
-
Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0520 .- 1477-0539. ; 17:5, s. 1081-1089
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Tidskriftsartikel (refereegranskat)abstract
- In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (<1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding affinities are rationalised with the help of the three-dimensional structures and quantum-mechanical calculations. Three effects seem to be involved: Firstly, the binding pocket is too small for the largest ligands with ethyl and methyl. Secondly, for the other ligands, the affinity seems to be determined mainly by desolvation effects, disfavouring the polar substituents, but this is partly counteracted by the cation-π interaction with Arg144, which stacks on top of the substituted tetrafluorophenyl group in all complexes. The results provide detailed insight into interactions of fluorinated phenyl moieties with arginine-containing protein binding sites and the complex interplay of different energetic components in defining the binding affinity.
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| 35. |
- Lagerström-Fermér, Maria, et al.
(författare)
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Amelogenin signal peptide mutation : correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta
- 1995
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Ingår i: Genomics. - : Elsevier BV. - 0888-7543 .- 1089-8646. ; 26:1, s. 159-162
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Tidskriftsartikel (refereegranskat)abstract
- Formation of tooth enamel is a poorly understood biological process. In this study we describe a 9-bp deletion in exon 2 of the amelogenin gene (AMGX) causing X-linked hypoplastic amelogenesis imperfecta, a disease characterized by defective enamel. The mutation results in the loss of 3 amino acids and exchange of 1 in the signal peptide of the amelogenin protein. This deletion in the signal peptide probably interferes with translocation of the amelogenin protein during synthesis, resulting in the thin enamel observed in affected members of the family. We compare this mutation to a previously reported mutation in the amelogenin gene that causes a different disease phenotype. The study illustrates that molecular analysis can help explain the various manifestations of a tooth disorder and thereby provide insights into the mechanisms of tooth enamel formation.
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| 36. |
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| 37. |
- Liang, Frank, et al.
(författare)
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A Fraction of CD8+T Cells from Colorectal Liver Metastases Preferentially Repopulate Autologous Patient-Derived Xenograft Tumors as Tissue-Resident Memory T Cells
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:12
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Treatment options for colorectal cancer (CRC) patients with liver metastases are often limited to liver surgery with or without chemotherapy. However, not all patients present operable colorectal liver metastases (CRLMs). Thus, alternative therapies that exploit the anti-tumor potential of tumor-infiltrating lymphocytes (TILs) are being evaluated. The establishment of markers connecting the phenotype to the function of tumor-reactive CD8+ TILs could aid diagnostic and therapeutic advances. In this regard, tissue-resident memory T cells (T-RM cells) could be a potential candidate for therapies targeting TILs. Putative tumor-reactive T-RM cells among CD8+ TILs likely co-express CD103 and CD39, since these markers indicate stable tumor residency and repeated response to antigens from the tumor environment, respectively. Our phenotypic and functional analyses of TILs in CRLM, with a specific focus on CD103+CD8+ T-RM cells, may guide the improvement of TIL-mediated CRC treatments. The diversity of T cells in the human liver may reflect the composition of TILs in CRLM. Our ex vivo characterization of CRLM vs. adjacent liver tissue detected CD103+CD39+CD8+ T-RM cells predominantly in CRLM, which prompted further assessments. These T-RM cells responded to cognate antigens in vitro. As functional activities of autologous TILs are central to the implementation of personalized cancer treatments, we applied a patient-derived xenograft (PDX) model to monitor TILs' capacity to control CRLM-derived tumors in vivo. We established PDX mice with CRLMs from two patients, and in vitro expansion of their respective TILs resulted in opposing CD4+ vs. CD8+ TIL ratios. These CRLMs also displayed mutated KRAS, which enabled trametinib-mediated inhibition of MEK. Regardless of the TIL subset ratio, persistent or transient control of CRLM-derived tumors of limited size by the transferred TILs was observed only after trametinib treatment. Of note, a portion of transferred TILs was observed as CD103+CD8+ T-RM cells that strictly accumulated within the autologous CRLM-derived tumor rather than in the spleen or blood. Thus, the predominance of CD103+CD39+CD8+ T-RM cells in CRLM relative to the adjacent liver and the propensity of CD103+CD8+ T-RM cells to repopulate the autologous tumor may identify these TILs as strategic targets for therapies against advanced CRC.
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| 38. |
- Ljungberg, Ulla K, et al.
(författare)
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The interaction between different domains of staphylococcal protein A and human polyclonal IgG, IgA, IgM and F(ab')2: separation of affinity from specificity
- 1993
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Ingår i: Molecular Immunology. - 1872-9142. ; 30:14, s. 1279-1285
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Tidskriftsartikel (refereegranskat)abstract
- Binding properties of staphylococcal protein A (SpA) to different human immunoglobulins have been investigated. In this analysis, intact SpA as well as SpA-derived fragments containing one to five IgG-binding domains of different compositions, were used. The affinity binding constants of the different proteins to human polyclonal IgG, IgA, IgM and F(ab')2-fragments as well as their binding capacity to the immunoglobulin molecules were determined. The results show that although all the proteins bound to IgG, regardless of size or composition, the binding strength differed significantly. Proteins containing five domains have a stronger affinity for IgG than those containing one or two. There were no marked differences in binding strength between different domains. However, the binding ability to IgA and IgM showed a marked difference between the various SpA-derived proteins of different compositions. This discrepancy was correlated to differences in their relative binding properties to isolated F(ab')2-fragments of IgG. Hence, we conclude that the binding affinity is mainly affected by the number of domains, whereas the binding specificity is to a large extent determined by which domains are selected.
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| 39. |
- Marsell, Richard, et al.
(författare)
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GSK-3 inhibition by an orally active small molecule increases bone mass in rats
- 2012
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Ingår i: Bone. - : Elsevier BV. - 8756-3282 .- 1873-2763. ; 50:3, s. 619-627
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Tidskriftsartikel (refereegranskat)abstract
- Glycogen synthase kinase 3β (GSK-3β) actions are central in the canonical Wnt pathway, important in many biological processes and a potential drug target for treating several diseases. It is appreciated that a balanced Wnt canonical signaling is crucial for the maintenance of normal bone mass. In this study we investigated the effects of a potent orally active GSK-3 inhibitor, AZD2858, on bone mass in rats. Treatment (1μM) of human osteoblast cells with AZD2858 in vitro increased β-catenin levels after a short period of time. In rats, oral AZD2858 treatment caused a dose-dependent increase in trabecular bone mass compared to control after a two-week treatment with a maximum effect at a dose of 20mg/kg once daily (total BMC: 172% of control; p<0.001). A small but significant effect was also seen at cortical sites (total BMC: 111% of control; p<0.001). Biomechanical testing demonstrated an increase in both vertebral compression strength at a dose of 20mg/kg once daily (Load at failure: 370% of control, p<0.001) and diaphyseal strength of femora subjected to a three point bending test (Load at failure: 115% of control; p<0.01). Furthermore, histomorphometry showed a dramatic increase in bone formation indices, and serum markers of both bone formation (Osteocalcin, 146% of control; p<0.001) and resorption (CTX, 189% of control; p<0.001) were elevated. Our conclusion is that a GSK-3 inhibitor drug may prove effective as an anabolic strategy in the treatment of diseases characterized by low bone mass, since AZD2858 has extensive bone building effects at predominantly trabecular sites.
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| 40. |
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| 41. |
- Nilsson, Erika, et al.
(författare)
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Effects of stream predator richness on the prey community and ecosystem attributes.
- 2008
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Ingår i: Oecologia. - : Springer Science and Business Media LLC. - 1432-1939 .- 0029-8549. ; 157:4, s. 641-651
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Tidskriftsartikel (refereegranskat)abstract
- It is important to understand the role that different predators can have to be able to predict how changes in the predator assemblage may affect the prey community and ecosystem attributes. We tested the effects of different stream predators on macroinvertebrates and ecosystem attributes, in terms of benthic algal biomass and accumulation of detritus, in artificial stream channels. Predator richness was manipulated from zero to three predators, using two fish and one crayfish species, while density was kept equal (n = 6) in all treatments with predators. Predators differed in their foraging strategies (benthic vs. drift feeding fish and omnivorous crayfish) but had overlapping food preferences. We found effects of both predator species richness and identity, but the direction of effects differed depending on the response variable. While there was no effect on macroinvertebrate biomass, diversity of predatory macroinvertebrates decreased with increasing predator species richness, which suggests complementarity between predators for this functional feeding group. Moreover, the accumulation of detritus was affected by both predator species richness and predator identity. Increasing predator species richness decreased detritus accumulation and presence of the benthic fish resulted in the lowest amounts of detritus. Predator identity (the benthic fish), but not predator species richness had a positive effect on benthic algal biomass. Furthermore, the results indicate indirect negative effects between the two ecosystem attributes, with a negative correlation between the amount of detritus and algal biomass. Hence, interactions between different predators directly affected stream community structure, while predator identity had the strongest impact on ecosystem attributes.
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| 42. |
- Nilsson, Göran, et al.
(författare)
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Huvudled och regleringar i korsningar
- 2005
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- På uppdrag av Vägverket har VTI närmare försökt belysa frågan om regleringar i korsningar och huvudledsbegreppet. När en väg klassas som huvudled följer automatiskt att korsningarna skall vara reglerade. Detta gäller hela huvudvägnätet. Det är också möjligt att klassa andra vägar eller vägavsnitt som huvudled. I det senare fallet är det primära syftet att införa reglering av anslutande vägar genom väjningsplikt eller stopplikt. Länsstyrelserna som fattar beslut om en väg skall vara huvudled får därför ansökningar om att införa huvudled på vissa vägar eller vägavsnitt. Om detta beslut överklagas görs detta till Vägverket VTI har försökt beskriva kunskapsläget, studerat körbeteendet vid olika regleringsformer i tätortskorsningar, analyserat kör- och hastighetsförlopp vid passage av reglerade korsningar och analyserat miljöeffekter av olika korsningsregleringar
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| 43. |
- Nilsson, Gunilla S., et al.
(författare)
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Determination of the degree of branching in normal and amylopectin type potato starch with 1H-NMR spectroscopy : Improved resolution and two-dimensional spectroscopy
- 1996
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Ingår i: Starch/Staerke. - : Wiley. - 0038-9056 .- 1521-379X. ; 48:10, s. 352-357
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Tidskriftsartikel (refereegranskat)abstract
- Starch from genetically modified potatoes was found to be highly branched compared with normal potato varieties through the use of 1H-NMR spectroscopy. The average chain length, blue-value,and the wavelength at maximum absorptivity clearly show that the new potato varieties produce amylopectin starch. Correlation between the degree of branching as determined by 1H-NMR and starch-iodine complexation, expressed as blue-value, was good and the NMR-method gives low standard deviation. For the first time, the anomeric proton, H-I, of a (1→4)-α-linked D-glucose residue and the H-I of the glucose residue of a non-reducing end have been assigned separate chemical shifts in starch. Assignments were made as determined from two-dimensional homonuclear and 1H-13C heteronuclear spectroscopy (COSY, HMQC, and HMBC). The molecular weight in degraded starch and pullulan were determined by means of NMR-spectroscopy. These results were in accordance with determinations by size exclusion chromatography and with the known molecular weights of pullulan standards.
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| 44. |
- Nilsson, Hanna, 1979-, et al.
(författare)
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Mortality after groin hernia surgery : delay of treatment and cause of death
- 2011
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Ingår i: Hernia. - Paris : Springer. - 1265-4906 .- 1248-9204. ; 15:3, s. 301-307
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Emergency hernia surgery, in contrast to elective hernia surgery, is associated with appreciable mortality. Incarcerated hernia is the second most common cause of small bowel obstruction after adhesions, and the leading cause of bowel strangulation.METHODS: Information on patients who died within 30 days of groin hernia surgery was retrieved from the Swedish Hernia Register, from the Cause-of-Death Register, and from hospital notes.RESULTS: Of 103,710 groin hernia operations between 1992 and 2004, 292 patients died within 30 days of surgery. Hospital notes and cause of death were retrieved for 242 cases (82%). In 5 of these patients, the hernia operation was done in addition to more urgent surgery and therefore excluded from further analyses; 152 patients were admitted as emergency cases and 55 of these patients underwent bowel resection. A total of 107 patients had signs of bowel obstruction when admitted. For 37% of these patients, physical examination of the groin was not documented. Patients with bowel obstruction without a note on a palpable groin lump were more likely to undergo imaging investigation preoperatively (P < 0.001) and they had an increased time to surgery compared to patients with a palpable lump. Women and patients with femoral hernia were significantly less likely to undergo a groin examination compared to other patients. Local anaesthesia was used in 7% of all patients who died postoperatively, and in 3% of emergency cases. Pulmonary disease, sepsis and malignant disease were more common as causes of death after emergency surgery than after elective surgery.CONCLUSIONS: Groin examination of patients presenting with bowel obstruction is of utmost importance in order to minimise delay to hernia surgery.
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| 45. |
- Nilsson, Johan L.Å., et al.
(författare)
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N,N'-Bis(2-mercaptoethyl)isophthalamide Binds Electrophilic Paracetamol Metabolites and Prevents Paracetamol-Induced Liver Toxicity
- 2018
-
Ingår i: Basic and Clinical Pharmacology and Toxicology. - : Wiley. - 1742-7835. ; 123:5, s. 589-593
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol overdosing may cause liver injury including fulminant liver failure due to generation of the toxic metabolites, N-acetyl-p-benzoquinone imine (NAPQI) and p-benzoquinone (p-BQ). Herein, the chelating agent, N,N'-Bis(2-mercaptoethyl)isophthalamide (NBMI), was examined for its potential ability to entrap NAPQI and p-BQ and to prevent paracetamol-induced liver injury. Both NBMI and the conventional paracetamol antidote N-acetylcysteine (NAC) were investigated with regard to their abilities to scavenge the NAPQI and p-BQ in a Transient Receptor Potential Ankyrin 1-dependent screening assay. Stoichiometric evaluations indicated that NBMI was able to entrap these metabolites more efficiently than NAC. Furthermore, oral administration of either NBMI (680 mg/kg) or NAC (680 mg/kg) prevented the development of the characteristic liver necrosis and elevation of serum alanine aminotransferase in a mouse model for paracetamol-induced liver injury. In summary, these results show that NBMI is able to entrap the toxic metabolites NAPQI and p-BQ and to prevent paracetamol-induced liver injury in mice.
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| 46. |
- Nilsson, Johan, et al.
(författare)
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Paracetamol analogues conjugated by FAAH induce TRPV1-mediated antinociception without causing acute liver toxicity
- 2021
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 213
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Tidskriftsartikel (refereegranskat)abstract
- Paracetamol, one of the most widely used pain-relieving drugs, is deacetylated to 4-aminophenol (4-AP) that undergoes fatty acid amide hydrolase (FAAH)-dependent biotransformation into N-arachidonoylphenolamine (AM404), which mediates TRPV1-dependent antinociception in the brain of rodents. However, paracetamol is also converted to the liver-toxic metabolite N-acetyl-p-benzoquinone imine already at therapeutic doses, urging for safer paracetamol analogues. Primary amine analogues with chemical structures similar to paracetamol were evaluated for their propensity to undergo FAAH-dependent N-arachidonoyl conjugation into TRPV1 activators both in vitro and in vivo in rodents. The antinociceptive and antipyretic activity of paracetamol and primary amine analogues was examined with regard to FAAH and TRPV1 as well as if these analogues produced acute liver toxicity. 5-Amino-2-methoxyphenol (2) and 5-aminoindazole (3) displayed efficient target protein interactions with a dose-dependent antinociceptive effect in the mice formalin test, which in the second phase was dependent on FAAH and TRPV1. No hepatotoxicity of the FAAH substrates transformed into TRPV1 activators was observed. While paracetamol attenuates pyrexia via inhibition of brain cyclooxygenase, its antinociceptive FAAH substrate 4-AP was not antipyretic, suggesting separate mechanisms for the antipyretic and antinociceptive effect of paracetamol. Furthermore, compound 3 reduced fever without a brain cyclooxygenase inhibitory action. The data support our view that analgesics and antipyretics without liver toxicity can be derived from paracetamol. Thus, research into the molecular actions of paracetamol could pave the way for the discovery of analgesics and antipyretics with a better benefit-to-risk ratio.
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| 47. |
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| 48. |
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| 49. |
- Nilsson, Johan, et al.
(författare)
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The influence of acute-phase levels of haemostatic factors on reperfusion and mortality in patients with acute myocardial infarction treated with streptokinase
- 2008
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Ingår i: Journal of Thrombosis and Thrombolysis. - Berlin : Springer. - 0929-5305 .- 1573-742X. ; 26:3, s. 188-195
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Tidskriftsartikel (refereegranskat)abstract
- Background The fibrinolytic system and von Willebrand factor (vWF) have been shown to play a role as risk factors for myocardial infarction. We performed this prospective cohort study to determine if components in the fibrinolytic system or vWF before or during treatment of AMI with streptokinase (SK) could predict reperfusion, recurrent ischaemia, reinfarction or mortality at one year, or mortality at five years. Reperfusion and recurrent ischaemia were assessed by continuous vectorcardiography. The setting was Umeå university hospital and Skellefteå county hospital, Sweden. Results 139 patients were included; successful reperfusion was obtained in 53%. tPA activity, PAI-activity, PAI-mass concentration and vWF were analysed immediately on arrival and after 4 and 10 h. High fibrinolytic activity, measured as tPA activity > 25 U/L after the start of treatment, was associated with reperfusion. No significant associations between pre-treatment levels of the fibrinolytic variables or vWF and reperfusion or recurrent ischaemia were found. Elevated levels of PAI-1 mass concentration and PAI-1 activity after the start of SK treatment were associated with a higher risk for death at one year, but not at five years. High levels of vWF were associated with worse prognosis but not when corrected for age. Conclusion Pre-treatment levels of PAI-1, vWF and tPA activity showed no association with reperfusion or recurrent ischaemia. Elevated levels of PAI-1 activity after the start of treatment were associated with worse prognosis.
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| 50. |
- Nilsson, Rickard, et al.
(författare)
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Utredning och provning av kostnadseffektiva metoder för bullerminimering av spårfordon
- 2013
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Ingår i: Transportforum 2013. - Linköping : Statens väg- och transportforskningsinstitut. ; , s. 122-135
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Konferensbidrag (refereegranskat)abstract
- Den här artikeln avser att för ett befintligt spårtrafiksystem översiktligt beskriva olika bullerreducerande åtgärders effekt, deras ekonomiska aspekter samt indirekt inverkan på systemet och dess omgivning. SL (AB Storstockholms Lokaltrafik) arbetar aktivt för att minska tågtrafikens störning till omgivningen, med den långsiktiga strävan att hela SLs spårsystem ska innehålla riktvärden för ny- och ombyggd järnväg enligt infrastrukturpropositionen. Ett viktigt medel för att nå denna ambition är succesivt byte av fordonsparken till nya och tystare fordon, detta kommer dock inte ge tillräcklig bullerreduktion, ytterligare åtgärder kommer att krävas. Beroende på problembilden kan det innebära att en enstaka åtgärd eller flera åtgärder i kombination behöver tas till. För att kartlägga, utvärdera och skapa kunskap om olika åtgärdsalternativ har SL därför arbetat långsiktigt och systematiskt med att utvärdera ett antal olika metoder. En viktig aspekt i sammanhanget är att då SLs spår till stor del går mycket nära bostäder är det önskvärt att hitta effektiva bullerskyddsåtgärder med så liten påverkan som möjligt avseende landskapsbild och barriäreffekt. Med hänsyn till ägardirektivet om ekonomi i balans är det även viktigt att se till total nytta relativt total kostnad vid val av åtgärd.
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