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1.
  • Gad, Helge, et al. (författare)
  • MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
  • 2014
  • Ingår i: Nature. - 1476-4687. ; 508:7495, s. 215-
  • Tidskriftsartikel (refereegranskat)abstract
    • Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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2.
  • Hägg, Daniel, 1974-, et al. (författare)
  • Expression profiling of macrophages from subjects with atherosclerosis to identify novel susceptibility genes.
  • 2008
  • Ingår i: International journal of molecular medicine. - 1107-3756. ; 21:6, s. 697-704
  • Tidskriftsartikel (refereegranskat)abstract
    • Although a number of environmental risk factors for atherosclerosis have been identified, heredity seems to be a significant independent risk factor. The aim of our study was to identify novel susceptibility genes for atherosclerosis. The screening process consisted of three steps. First, expression profiles of macrophages from subjects with atherosclerosis were compared to macrophages from control subjects. Secondly, the subjects were genotyped for promoter region polymorphisms in genes with altered gene expression. Thirdly, a population of subjects with coronary heart disease and control subjects were genotyped to test for an association with identified polymorphisms that affected gene expression. Twenty-seven genes were differentially expressed in both macrophages and foam cells from subjects with atherosclerosis. Three of these genes, IRS2, CD86 and SLC11A1 were selected for further analysis. Foam cells from subjects homozygous for the C allele at the -765C-->T SNP located in the promoter region of IRS2 had increased gene expression compared to foam cells from subjects with the nonCC genotype. Also, macrophages and foam cells from subjects homozygous for allele 2 at a repeat element in the promoter region of SLC11A1 had increased gene expression compared to macrophages and foam cells from subjects with the non22 genotype. Genotyping of 512 pairs of subjects with coronary heart disease (CHD) and matched controls revealed that subjects homozygous for C of the IRS2 SNP had an increased risk for CHD; odds ratio 1.43, p=0.010. Immunohistochemical staining of human carotid plaques showed that IRS2 expression was localised to macrophages and endothelial cells in vivo. Our method provides a reliable approach for identifying susceptibility genes for atherosclerosis, and we conclude that elevated IRS2 gene expression in macrophages may be associated with an increased risk of CHD.
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3.
  • Nyström, Per, et al. (författare)
  • Complementary Bibliometric Analysis : MDH Library
  • 2014
  • Ingår i: MER14, MDH:s Evaluation for improved Research quality : Research evaluation conducted at Mälardalen University in 2013-14 - Research evaluation conducted at Mälardalen University in 2013-14 : Research evaluation conducted at Mälardalen University in 2013-14. - Mälardalen University Press. - 978-91-7485-153-3 (ISBN) ; s. 179-206
  • Bokkapitel (populärvet., debatt m.m.)
4.
  • Paul-Visse, Gesine, et al. (författare)
  • Safety and tolerability of intracerebroventricular PDGF-BB in Parkinson's disease patients
  • 2015
  • Ingår i: Journal of Clinical Investigation. - Am Soc Clin Investig. - 0021-9738. ; 125:3, s. 1339-1346
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND. Recombinant human PDGF-BB (rhPDGF-BB) reduces Parkinsonian symptoms and increases dopamine transporter (DAT) binding in several animal models of Parkinson's disease (PD). Effects of rhPDGF-BB are the result of proliferation of ventricular wall progenitor cells and reversed by blocking mitosis. Based on these restorative effects, we assessed the safety and tolerability of intracerebroventricular (i.c.v.) rhPDGF-BB administration in individuals with PD. METHODS. We conducted a double-blind, randomized, placebo-controlled phase I/IIa study at two clinical centers in Sweden. Twelve patients with moderate PD received rhPDGF-BB via an implanted drug infusion pump and an investigational i.c.v. catheter. Patients were assigned to a dose cohort (0.2, 1.5, or 5 mu g rhPDGF-BB per day) and then randomized to active treatment or placebo (3:1) for a 12-day treatment period. The primary objective was to assess safety and tolerability of i.c.v.-delivered rhPDGF-BB. Secondary outcome assessments included several clinical rating scales and changes in DAT binding. The follow-up period was 85 days. RESULTS. All patients completed the study. There were no unresolved adverse events. Serious adverse events occurred in three patients; however, these were unrelated to rhPDGF-BB administration. Secondary outcome parameters did not show dose-dependent changes in clinical rating scales, but there was a positive effect on DAT binding in the right putamen. CONCLUSION. At all doses tested, i.c.v. administration of rhPDGF-BB was well tolerated. Results support further clinical development of rhPDGF-BB for patients with PD.
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7.
  • Ahlin, Sofie, 1985-, et al. (författare)
  • Macrophage Gene Expression in Adipose Tissue is Associated with Insulin Sensitivity and Serum Lipid Levels Independent of Obesity.
  • 2013
  • Ingår i: Obesity (Silver Spring, Md.). - 1930-739X. ; 21:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Obesity is linked to both increased metabolic disturbances and increased adipose tissue macrophage infiltration. However, whether macrophage infiltration directly influences human metabolism is unclear. The aim of this study was to investigate if there are obesity-independent links between adipose tissue macrophages and metabolic disturbances. Design and Methods: Expression of macrophage markers in adipose tissue was analyzed by DNA microarrays in the SOS Sib Pair study and in patients with type 2 diabetes and a BMI-matched healthy control group. Results: The expression of macrophage markers in adipose tissue was increased in obesity and associated with several metabolic and anthropometric measurements. After adjustment for BMI, the expression remained associated with insulin sensitivity, serum levels of insulin, C-peptide, high density lipoprotein cholesterol (HDL-cholesterol) and triglycerides. In addition, the expression of most macrophage markers was significantly increased in patients with type 2 diabetes compared to the control group. Conclusion: Our study shows that infiltration of macrophages in human adipose tissue, estimated by the expression of macrophage markers, is increased in subjects with obesity and diabetes and associated with insulin sensitivity and serum lipid levels independent of BMI. This indicates that adipose tissue macrophages may contribute to the development of insulin resistance and dyslipidemia.
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8.
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9.
  • Anveden, Åsa, et al. (författare)
  • ITIH-5 Expression in Human Adipose Tissue Is Increased in Obesity.
  • 2012
  • Ingår i: Obesity. - 1930-7381. ; 20:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Adipocytes secrete many proteins that regulate metabolic functions. The gene inter-α (globulin) inhibitor H5 (ITIH-5) encodes a secreted protein and is known to be expressed abundantly in the placenta. However, using gene expression profiles data we observed high expression of ITIH-5 in adipose tissue. The aim of this study was to test the hypothesis that ITIH-5 is strongly expressed in human adipocytes and adipose tissue, and is related to obesity and clinical metabolic variables. ITIH-5 adipose tissue mRNA expression was analyzed with DNA microarray and real-time PCR, and its association with clinical variables was examined. ITIH-5 protein expression was analyzed using western blot. ITIH-5 mRNA expression was abundant in human adipose tissue, adipocytes, and placenta, and higher in subcutaneous (sc) compared to omental adipose tissue (P < 0.0001). ITIH-5 mRNA and protein expression in sc adipose tissue were higher in obese compared to lean subjects (P < 0.0001 and P < 0.001, respectively). ITIH-5 mRNA expression was reduced after diet-induced weight loss (P < 0.0001). ITIH-5 mRNA expression was associated with anthropometry and clinical metabolic variables. In conclusion, ITIH-5 is highly expressed in sc adipose tissue, increased in obesity, down regulated after weight loss, and associated with measures of body size and metabolism. Together, this indicates that ITIH-5 merits further investigation as a regulator of human metabolism.
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10.
  • Avby, Gunilla (författare)
  • Evidence in Practice On Knowledge Use and Learning in Social Work
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • <p>Ett i allt högre grad vetenskapsbaserat samhälle har lett till att kunskapsbasen i många verksamheter ifrågasatts, däribland socialt arbete. Avhandlingen behandlar kunskapsanvändning och lärande i utredningsarbetet inom den sociala barn- och ungdomsvården. Syfte är att öka kunskapen kring hur individer använder kunskap och lär sig i och genom sin dagliga praktik.</p><p>Avhandlingen baseras på fyra delstudier som genomförts i tre svenska kommuners socialtjänst. Det empiriska materialet består av deltagande observationer, intervjuer, reflekterande dialoger och dokumentanalyser. Studien tar sin utgångspunkt i ett kognitivt perspektiv på lärande med teoretiska rötter i pragmatism. Ett grundläggande antagande bakom studien är att lärandet utgår från hur individen tolkar och förstår den situation som hen möter och därefter handlar.</p><p>Resultaten visar att utredningsarbetet företrädesvis baseras på praktikbaserad kunskap som erhålls från tidigare erfarenheter och kollegor. Forskningsbaserad kunskap används huvudsakligen för att bekräfta och legitimera en uppfattning och inte för att ifrågasätta och utmana existerande åsikter och antaganden. Lärandet kan främst karaktäriseras som ett anpassningsinriktat lärande där praktikern med stöd i tidigare erfarenheter och utifrån befintlig kunskapsbas skapar rutiner för att hantera arbetet.</p><p>Kunskapsanvändningen inom den sociala barn- och ungdomsvården ligger långt ifrån idealen för evidensbaserad praktik. Reproduktionen av professionell kunskap sker främst implicit och utan frågasättande. Förståelse för praktikers faktiska kunskapsanvändning och lärande har central betydelse för hur verksamheter kan organiseras för att stödja lärande i arbetet.</p>
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