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1.
  • Altai, Mohamed, et al. (författare)
  • Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with In-111 using a maleimido derivative of NODAGA
  • 2012
  • Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 39:4, s. 518-529
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-l-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule. Methods: The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to Z(HER2:2395) Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) were studied. Biodistribution of [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) and [In-111-MMA-DOTA-Cys(61)]-Z(HER2:2395) was compared in mice. Results: The affinity of [MMA-NODAGA-Cys(61)]-Z(HER2:2395) binding to HER2 was 67 pM. The In-1111-labeling yield was 99.6%+/- 0.5% after 30 min at 60 degrees C. [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [In-111-MMA-NODAGA-Cys(61)]-ZHER(2:2395) in mice bearing DU-145 xenografts (4.7%+/- 0.8% ID/g) was lower than uptake of [In-111-MMA-DOTA-Cys(61)]-Z(HER2:2395) (7.5%+/- 1.6% ID/g). However, tumor-to-organ ratios were higher for [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) due to higher clearance rate from normal tissues. Conclusions: MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.
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2.
  • Andersson, Magnus, et al. (författare)
  • Fiskbestånd och miljö i hav och sötvatten : Resurs- och miljööversikt 2012
  • 2012
  • Rapport (övrigt vetenskapligt/konstnärligt)abstract
    • Detta är den nionde utgåvan av den samlade översikten över fisk- och kräftdjursbeståndens status i våra vatten. Kunskap om fiskbestånden och miljön är en förutsättning för att utnyttjandet av fiskresurserna skall bli bärkraftigt. För svenska vattenområden beskrivs miljöutvecklingen i ett ekosystemsperspektiv, dels för att tydliggöra fiskens ekologiska roll och beskriva yttre miljöfaktorer som påverkar fiskbestånden, dels för att belysa fiskets effekter på miljön.Fiskbestånd och miljö i hav och sötvatten är utarbetad av Sveriges lantbruksuniversitet (SLU), Institutionen för akvatiska resurser (SLU Aqua), på uppdrag av Havs- och vattenmyndigheten. Rapporten sammanfattar utveckling och beståndsstatus för de kommersiellt viktigaste fisk- och kräftdjursarterna i våra vatten. Bedömningar och förvaltningsråd är baserade på Internationella Havsforskningsrådets (ICES) rådgivning, SLU Aquas nationella och regionala provfiskedata, samt yrkesfiskets rapportering.
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3.
  • Ivarsson, Anneli, et al. (författare)
  • Prevalence of Childhood Celiac Disease and Changes in Infant Feeding
  • 2013
  • Ingår i: Pediatrics. - : American Academy of Pediatrics. - 0031-4005 .- 1098-4275. ; 131:3, s. E687-E694
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: Between 1984 and 1996, Sweden experienced an "epidemic" of clinical celiac disease in children andlt;2 years of age, attributed partly to changes in infant feeding. Whether infant feeding affects disease occurrence and/or the clinical presentation remains unknown. We investigated and compared the total prevalence of celiac disease in 2 birth cohorts of 12-year-olds and related the findings to each cohorts ascertained infant feeding. less thanbrgreater than less thanbrgreater thanMETHODS: A 2-phase cross-sectional screening study was performed in which 13 279 children from 2 birth cohorts participated: children born during the epidemic (1993) and children born after the epidemic (1997). Previously diagnosed cases were reported and confirmed. Blood samples were analyzed for serological markers and children with positive values were referred for small intestinal biopsy. Infant feeding practices in the cohorts were ascertained via questionnaires. Prevalence comparisons were expressed as prevalence ratios. less thanbrgreater than less thanbrgreater thanRESULTS: The total prevalence of celiac disease was 29 in 1000 and 22 in 1000 for the 1993 and 1997 cohorts, respectively. Children born in 1997 had a significantly lower risk of having celiac disease compared with those born in 1993 (prevalence ratio: 0.75; 95% confidence interval: 0.60-0.93; P = .01). The cohorts differed in infant feeding (specifically, in the proportion of infants introduced to dietary gluten in small amounts during ongoing breastfeeding). less thanbrgreater than less thanbrgreater thanCONCLUSIONS: A significantly reduced prevalence of celiac disease in 12-year-olds indicates an option for disease prevention. Our findings suggest that the present infant feeding recommendation to gradually introduce gluten-containing foods from 4 months of age, preferably during ongoing breastfeeding, is favorable. Pediatrics 2013;131:e687-e694
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4.
  • Malmberg, Jennie, et al. (författare)
  • Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with 111In using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts.
  • 2012
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:3, s. 481-492
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. METHODS: A synthetic variant of the anti-HER2 Z(HER2:342) Affibody molecule, Z(HER2:S1), was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with (111)In, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. RESULTS: The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1), respectively. A comparative study of (111)In-labelled DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1) in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. (111)In-NODAGA-Z(HER2:S1) had the most rapid clearance from blood and healthy tissues. (111)In-NOTA-Z(HER2:S1) showed high hepatic uptake and was excluded from further evaluation. (111)In-DOTA-Z(HER2:S1) and (111)In-NODAGA-Z(HER2:S1) demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of (111)In-NODAGA-Z(HER2:S1), 5.6 ± 0.4%ID/g, was significantly lower than the uptake of (111)In-DOTA-Z(HER2:S1), 7.4 ± 0.5%ID/g, presumably because of lower bioavailability due to more rapid clearance. (111)In-NODAGA-Z(HER2:S1) provided higher tumour-to-blood ratio, but somewhat lower tumour-to-liver, tumour-to-spleen and tumour-to-bone ratios. CONCLUSION: Since distant prostate cancer metastases are situated in bone or bone marrow, the higher tumour-to-bone ratio is the most important. This renders (111)In-DOTA-Z(HER2:S1) a preferable agent for imaging of HER2 expression in disseminated prostate cancer.
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5.
  • Malmberg, Jennie, et al. (författare)
  • Comparative evaluation of synthetic anti-HER2 Affibody molecules site-specifically labelled with In-111 using N-terminal DOTA, NOTA and NODAGA chelators in mice bearing prostate cancer xenografts
  • 2012
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:3, s. 481-492
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose In disseminated prostate cancer, expression of human epidermal growth factor receptor type 2 (HER2) is one of the pathways to androgen independence. Radionuclide molecular imaging of HER2 expression in disseminated prostate cancer might identify patients for HER2-targeted therapy. Affibody molecules are small (7 kDa) targeting proteins with high potential as tracers for radionuclide imaging. The goal of this study was to develop an optimal Affibody-based tracer for visualization of HER2 expression in prostate cancer. Methods A synthetic variant of the anti-HER2 Z(HER2:342) Affibody molecule, Z(HER2:S1), was N-terminally conjugated with the chelators DOTA, NOTA and NODAGA. The conjugated proteins were biophysically characterized by electrospray ionization mass spectroscopy (ESI-MS), circular dichroism (CD) spectroscopy and surface plasmon resonance (SPR)-based biosensor analysis. After labelling with In-111, the biodistribution was assessed in normal mice and the two most promising conjugates were further evaluated for tumour targeting in mice bearing DU-145 prostate cancer xenografts. Results The HER2-binding equilibrium dissociation constants were 130, 140 and 90 pM for DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1), respectively. A comparative study of In-111-labelled DOTA-Z(HER2:S1), NOTA-Z(HER2:S1) and NODAGA-Z(HER2:S1) in normal mice demonstrated a substantial influence of the chelators on the biodistribution properties of the conjugates. In-111-NODAGA-Z(HER2:S1) had the most rapid clearance from blood and healthy tissues. In-111-NOTA-Z(HER2:S1) showed high hepatic uptake and was excluded from further evaluation. In-111-DOTA-Z(HER2:S1) and In-111-NODAGAZHER2: S1 demonstrated specific uptake in DU-145 prostate cancer xenografts in nude mice. The tumour uptake of In-111-NODAGA-Z(HER2:S1), 5.6 +/- 0.4% ID/g, was significantly lower than the uptake of In-111-DOTA-Z(HER2:S1), 7.4 +/- 0.5% ID/g, presumably because of lower bioavailability due to more rapid clearance. In-111-NODAGA-Z(HER2:S1) provided higher tumour-to-blood ratio, but somewhat lower tumour-to-liver, tumour-to-spleen and tumour-to-bone ratios. Conclusion Since distant prostate cancer metastases are situated in bone or bone marrow, the higher tumour-to-bone ratio is the most important. This renders In-111-DOTA-Z(HER2:S1) a preferable agent for imaging of HER2 expression in disseminated prostate cancer.
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7.
  • Sandström, Olof, et al. (författare)
  • Transglutaminase IgA antibodies in a celiac disease mass screening and the role of HLA-DQ genotyping and endomysial antibodies in a sequential testing
  • 2013
  • Ingår i: Journal of Pediatric Gastroenterology and Nutrition - JPGN. - : Lippincott Williams & Wilkins. - 0277-2116 .- 1536-4801. ; 57:4, s. 472-476
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: The aim of this study was to evaluate hypothetical screening strategies in a Swedish celiac disease (CD) mass screening.Methods: Of 10,041 Swedish sixth graders born in 1993 invited to a population-based CD mass screening, 7208 participated. Anti-tissue transglutaminase (tTG) immunoglobulin (Ig) A were analyzed in all children and total serum IgA (s-IgA) in 7161 children. Additional analyses of tTG-IgG, endomysial antibodies (EMA) IgA and IgG, and human leukocyte antigen (HLA) alleles were performed according to a standardized protocol. Children with elevated levels of serological markers were recommended to undergo a small intestinal biopsy to verify diagnosis, and 153 children with CD were thus identified. Sensitivity, specificity, positive predictive values (PPVs) and negative predictive values (NPVs) were calculated and receiver operating characteristic curves were plotted.Results: By lowering the cutoff for tTG-IgA, 17 additional cases of CD were identified at the cost of 32 biopsies. All children with tTG-IgA >50 U/mL (10 times the recommended upper limit of normal) had gluten enteropathy. Area under the receiver operating characteristic curve for tTG-IgA was 0.988. All cases carried HLA-DQ2 or HLA-DQ8, as did 53% of the controls. For different hypothetical screening strategies, sensitivity, specificity, PPV, and NPV ranged between 87.6% and 100%, 99.5% and 99.9%, 79.7% and 89.7%, and 99.7% and 100%, respectively. Efforts to increase sensitivity by lowering tTG-IgA cutoff would result in increased number of small intestinal biopsies and lower PPV. Sequential testing for both EMA and HLA-DQ genotyping would reduce the number of negative small intestinal biopsies.Conclusions: tTG-IgA is a robust marker when used in CD mass screening and its performance can be enhanced by sequential testing for EMA or HLA-DQ genotyping.
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8.
  • Tolmachev, Vladimir, et al. (författare)
  • Evaluation of a Maleimido Derivative of NOTA for Site-Specific Labeling of Affibody Molecules
  • 2011
  • Ingår i: Bioconjugate chemistry. - : American Chemical Society (ACS). - 1043-1802 .- 1520-4812. ; 22:5, s. 894-902
  • Tidskriftsartikel (refereegranskat)abstract
    • Radionuclide molecular imaging has the potential to improve cancer treatment by selection of patients for targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. The NOTA chelator forms stable complexes with a number of radionuclides suitable for SPECT or PET imaging. A maleimidoethylmonoamide NOTA (MMA-NOTA) has been prepared for site-specific labeling of Affibody molecules having a unique C-terminal cysteine. Coupling of the MMA-NOTA to the anti-HER2 Affibody molecule Z(HER2:239S) resulted in a conjugate with an affinity (dissociation constant) to HER2 of 72 pM. Labeling of [MMA-NOTA-Cys(61)]-Z(HER2:239S) with In-111 gave a yield of >95% after 20 min at 60 degrees C. In vitro cell tests demonstrated specific binding of [In-111-MMA-NOTA-Cys(61)]-Z(HER2:239S) to HER2-expressing cell lines. In mice bearing prostate cancer DU-145 xenografts, the tumor uptake of [In-111-MMA-NOTA-Cys(61)]-Z(HER2:239S) was 8.2 +/- 0.9% IA/g and the tumor-to-blood ratio was 31 +/- 1 (4 h postinjection). DU-145 xenografts were clearly visualized by a gamma camera. Direct in vivo comparison of [In-111-MMA-NOTA-Cys(61)]-Z(HER2:239S) and [In-111-MMA-DOTA-Cys(61)]-Z(HER2:239S) demonstrated that both conjugates provided equal radioactivity uptake in tumors, but the tumor-to-organ ratios were better for [In-111-MMA-NOTA-Cys(61)]-Z(HER2:239S) due to more efficient clearance from normal tissues. In conclusion, coupling of MMA-NOTA to a cysteine-containing Affibody molecule resulted in a site-specifically labeled conjugate, which retains high affinity, can be efficiently labeled, and allows for high-contrast imaging.
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9.
  • Tolmachev, Vladimir, et al. (författare)
  • Imaging of Insulinlike Growth Factor Type 1 Receptor in Prostate Cancer Xenografts Using the Affibody Molecule (111)In-DOTA-Z(IGF1R:4551)
  • 2012
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 53:1, s. 90-97
  • Tidskriftsartikel (refereegranskat)abstract
    • One of the pathways leading to androgen independence in prostate cancer involves upregulation of insulinlike growth factor type 1 receptor (IGF-1R). Radionuclide imaging of IGF-1R in tumors might be used for selection of patients who would most likely benefit from IGF-1R-targeted therapy. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of IGF-1R expression in prostate cancer xenografts using a small nonimmunoglobulin-derived binding protein called an Affibody molecule. Methods: The IGF-1R-binding Z(IGF1R:4551) Affibody molecule was site-specifically conjugated with a maleimido derivative of DOTA and labeled with (111)In. The binding of radiolabeled Z(IGF1R:4551) to IGF-1R-expressing cells was evaluated in vitro and in vivo. Results: DOTA-Z(IGF1R:4551) can be stably labeled with (111)In with preserved specific binding to IGF-1R-expressing cells in vitro. In mice, (111)In-DOTAZ(IGF1R):(4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung, and salivary gland). Receptor saturation experiments demonstrated that targeting of DU-145 prostate cancer xenografts in NMRI nu/nu mice was IGF-1R-specific. The tumor uptake was 1.1 +/- 0.3 percentage injected dose per gram, and the tumor-to-blood ratio was 3.2 +/- 0.2 at 8 h after injection. Conclusion: This study demonstrates the feasibility of in vivo targeting of IGF-1R-expressing prostate cancer xenografts using an Affibody molecule. Further development of radiolabeled Affibody molecules might provide a useful clinical tool for stratification of patients with prostate cancer for IGF-1R-targeting therapy.
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10.
  • Abdullah, M Ailieen, et al. (författare)
  • Building Networks for Delivering Integrated Product-Service Offerings (IPSOs)
  • 2010
  • Ingår i: Industrial product-service systems -IPS². - Linköping : CIRP. - 9789173933810 - 9173933813
  • Konferensbidrag (refereegranskat)abstract
    • The paper describes the effect of forming business networks and collaborations for the purpose of developing an Integrated Product-Service Offering (IPSO) using the Product/Service Systems (PSS). The research method is an in-depth case study of a joint venture formed by four companies developing a new technology for chemical extraction from water sludge waste within the pulp and paper industry.Combining literature from PSS, network theories and collaborative product development, this paper puts forward the benefits for SMEs to collaborate in business networks and produce IPSOs when introducing a new technology in an emerging market. The case study shows that working towards the new market would not have been possible if each party acted individually or maintained their traditional buyer-supplieroperator roles, and that IPSOs can reduce the business risk.
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11.
  • Ahlgren, Sara, et al. (författare)
  • Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
  • 2010
  • Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 51:7, s. 1131-1138
  • Tidskriftsartikel (refereegranskat)abstract
    • Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer. Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques. Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats. Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.
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12.
  • Altai, Mohamed, et al. (författare)
  • 188Re-ZHER2:V2, a promising affibody-based targeting agent against HER2-expressing tumors : preclinical assessment
  • 2014
  • Ingår i: Journal of nuclear medicine : official publication, Society of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:11, s. 8-1842
  • Tidskriftsartikel (refereegranskat)abstract
    • UNLABELLED: Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of (99m)Tc-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated ZHER2:V2) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate (188)Re-ZHER2:V2 as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors.METHODS: ZHER2:V2 was labeled with (188)Re using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment.RESULTS: Binding of (188)Re-ZHER2:V2 to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 ± 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 ± 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 ± 2, 12 ± 2, 5 ± 2, and 1.8 ± 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 ± 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that (188)Re-ZHER2:V2 would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible.CONCLUSION: (188)Re-ZHER2:V2 can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.
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14.
  • Altai, Mohamed, et al. (författare)
  • Selection of an optimal cysteine-containing peptide-based chelator for labeling of affibody molecules with (188)Re.
  • 2014
  • Ingår i: European Journal of Medicinal Chemistry. - : Elsevier BV. - 0223-5234 .- 1768-3254. ; 87, s. 519-28
  • Tidskriftsartikel (refereegranskat)abstract
    • Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of (188)Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all (188)Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The (188)Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of (188)Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental (188)Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of (188)Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.
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15.
  • Altai, Mohamed, et al. (författare)
  • Selection of an optimal cysteine-containing peptide-based chelator for labeling of Affibody molecules with 188-Re
  • 2013
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:Suppl. 2, s. S219-S220
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of 188Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all 188Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The 188Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of 188Re-ZHER2:V2 (3.1±0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental 188Re-ZHER2:2395 (172±32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of 188Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.
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  • Berggren, Anna, et al. (författare)
  • Små avlopp i kretslopp
  • 2012
  • Rapport (refereegranskat)abstract
    • The certification system has provided the prerequisites for recycling fractions from small-scale sewage systems and larger source-separating sewage system to arable land in a quality-assured and trusted manner. Realisation of these ‘ecocycle solutions’ will be highly dependent upon progress by additional municipalities in establishing facilities for treating and recycling fractions from small-scale sewage systems and larger source-separating sewage systems. Key words: slam, avloppsfraktioner, reningsverk, minireningverk, SPCR 178, EN 12566-3, REVAQ, återföring, näring, näringsämnen, wastewater, sewage, sludge
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20.
  • Bjelke, Ulf, et al. (författare)
  • Crustacea : Kräftdjur - crustaceans
  • 2010
  • Ingår i: The 2010 Red List of Swedish Species. Rödlistade arter i Sverige 2010. - Uppsala : ArtDatabanken, SLU. - 9789188506351 ; , s. 487-493
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)
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21.
  • Buhot, Yann, et al. (författare)
  • Impact of hydroelectric power development on reindeer husbandry: the case of Suorva
  • 2010
  • Ingår i: Rangifer. Report. - 0808-2359. ; , s. 86-86
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
    • Reindeer husbandry in Sapmi continuously coexists and competes with other land users, such as forestry, tourism, hydroelectric power and mine activities. The impact of water regulation for hydroelectric power, on reindeer herding use is rather unknown. In Sirges reindeer herding community in northern Sweden a large part of their range are affected by hydroelectric power developments, which have forced the reindeer herding to change the use of their ranges. Here we study these changes in relation to the Suorva dam within Lule river system, one of 15 dams within Sirges reindeer husbandry community. We compiled topographic maps from 1890 and 2007 and included the Renbruksplan (reindeer husbandry plan) developed by Sirges reindeer husbandry community. The Renbruksplan consists of the reindeer herder's documentation of seasonal grazing ranges within their reindeer husbandry community, in relation to vegetation type, intensity of use and quality of forage. Using topographic maps the losses of pasture in relation to the regulation of the Suorva dam were calculated using GIS software. The impacts on Unna Tjerusj reindeer herding community north of the dam Suorva are not included in this study. The results of the study showed that after the four water regulations (1923, 1941, 1944 and 1972) the reindeer lost calving areas and autumn pastures composed of birch forest and mires. In Sirges 55 km² has been lost as a direct result of the flooding of grazing areas. This constitutes 6 % of the ranges used during the bare-ground season in the Vaisa-group of Sirges herding ranges. This also includes the loss of important movement areas, which formerly connected seasonal grazing areas along the flooded rivers system and currently force the reindeer to use steeper less productive hillsides above the dam. In conclusion, this study gives a good overview of how water regulation may affect reindeer herding. Due to the losses, the reindeer herders in this area had to change their migration routes and herding routines in relation to use of the calving grounds and the autumn pastures. These losses most likely had negative effects on reindeer husbandry production, because of the lack of good and rich forage during important parts of the grazing season, however this loss cannot be traced today
  •  
22.
  • Carlsson-Jonsson, Anna, et al. (författare)
  • N-terminal truncations of substance P1-7 amide affect its action on spinal cord injury-induced mechanical allodynia in rats
  • 2014
  • Ingår i: European Journal of Pharmacology. - : Elsevier BV. - 0014-2999 .- 1879-0712. ; 738, s. 319-325
  • Tidskriftsartikel (refereegranskat)abstract
    • Central neuropathic pain can arise from injury of the spinal cord and can become chronic. Treatment is difficult and, because complete pain relief is currently very hard to achieve, there is a need for new, more effective treatment options. In this study we used an animal model of spinal cord injury to evaluate the potency of a bioactive fragment of substance P (SP), i.e. SP1-7, in alleviating signs of allodynia and acute pain. SP1-7 is known from earlier studies to possess antinociceptive properties. We also studied the effects of intraperitoneal injection of an amidated analog of this heptapeptide and of its truncated analogs, all of which had high affinity to the SP1-7 binding site, to evaluate the importance of the removed amino acids for the bioclistribution and stability of the peptides. Most of the examined compounds alleviated mechanical alloclynia without any signs of sedation or motor impairment in the rats. In contrast, the response threshold to acute nociceptive stimulation was not affected by arty of the compounds tested. Most of the amino acids in the heptapepticle structure were essential for retaining the biological effect after peripheral injection. These observations suggest that the heptapepticle and its N-Lerminal truncated hexa- and pentapeptide analogs could be of interest for further development of analgesics in the management of mechanical allodynia.
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23.
  • Dexlin Mellby, Linda, et al. (författare)
  • Design of recombinant antibody microarrays for membrane protein profiling of cell lysates and tissue extracts.
  • 2011
  • Ingår i: Proteomics. - : Wiley. - 1615-9861 .- 1615-9853. ; 11, s. 1550-1554
  • Tidskriftsartikel (refereegranskat)abstract
    • Generating global protein expression profiles, including also membrane proteins, will be crucial for our understanding of biological processes in health and disease. In this study, we have expanded our antibody microarray technology platform and designed the first human recombinant antibody microarray for membrane proteins targeting crude cell lysates and tissue extracts. We have optimized all key technological parameters and successfully developed a setup for extracting, labeling and analyzing non-fractionated membrane proteomes under non-denaturing conditions. Finally, the platform was also extended and shown to be compatible with simultaneous profiling of both membrane proteins and water-soluble proteins.
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24.
  • Dexlin Mellby, Linda, et al. (författare)
  • Tissue proteome profiling of preeclamptic placenta using recombinant antibody microarrays
  • 2010
  • Ingår i: Proteomics Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 4:10-11, s. 794-807
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: preeclampsia (PE) is a severe, multi-system pregnancy disorder of yet unknown cause, missing means of treatment, and our fundamental understanding of the disease is still impaired. The purpose of this discovery study was to define candidate placenta tissue protein biomarker signatures to further decipher the molecular features of PE.EXPERIMENTAL DESIGN: we used recombinant antibody microarrays for multiplexed protein expression profiling of preeclamptic placenta tissue (n=25) versus normal placenta (n=11) targeting mainly immunoregulatory water-soluble proteins and membrane proteins. Furthermore, the three known subgroups of PE were profiled, including women with early onset preeclampsia and late onset preeclampsia, as well as women with PE and bilateral notching and intrauterine growth restrictions.RESULTS: the data showed that the first generation of candidate PE-associated placenta tissue protein signatures were delineated, indicating that PE (receiver operating characteristics (ROC) AUC value of 0.83) and the subgroups thereof (ROC AUC values ≤ 0.91) could be distinguished. Notably, the data implied that all subgroups, but preeclampsia with bilateral notching and IUGR, could be further classified into novel subsets (ROC AUC values of 1.0) displaying different inflammatory signatures.CONCLUSIONS AND CLINICAL RELEVANCE: we have taken one step further toward de-convoluting the complex features of PE at the molecular level using affinity proteomics.
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25.
  • Fransson, Rebecca, et al. (författare)
  • Exploration and pharmacokinetic profiling of phenylalanine based carbamates as novel substance p 1-7 analogues
  • 2014
  • Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:12, s. 1272-1277
  • Tidskriftsartikel (refereegranskat)abstract
    • The bioactive metabolite of Substance P, the heptapeptide SP1-7 (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown to attenuate signs of hyperalgesia in diabetic mice, which indicate a possible use of compounds targeting the SP1-7 binding site as analgesics for neuropathic pain. Aiming at the development of drug-like SP1-7 peptidomimetics we have previously reported on the discovery of H-Phe-Phe-NH2 as a high affinity lead compound. Unfortunately, the pharmacophore of this compound was accompanied by a poor pharmacokinetic (PK) profile. Herein, further lead optimization of H-Phe-Phe-NH2 by substituting the N-terminal phenylalanine for a benzylcarbamate group giving a new type of SP1-7 analogues with good binding affinities is reported. Extensive in vitro as well as in vivo PK characterization is presented for this compound. Evaluation of different C-terminal functional groups, i.e., hydroxamic acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole, suggested hydroxamic acid as a bioisosteric replacement for the original primary amide.
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26.
  •  
27.
  • Gising, Johan, 1981-, et al. (författare)
  • Achiral Pyrazinone-Based Inhibitors of the Hepatitis C Virus NS3 Protease and Drug-Resistant Variants with Elongated Substituents Directed Toward the S2 Pocket
  • 2014
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 57:5, s. 1790-1801
  • Tidskriftsartikel (refereegranskat)abstract
    • Herein we describe the design, synthesis, inhibitory potency, and pharmacokinetic properties of a novel class of achiral peptidomimetic HCV NS3 protease inhibitors. The compounds are based on a dipeptidomimetic pyrazinone glycine P3P2 building block in combination with an aromatic acyl sulfonamide in the P1P1′ position. Structure–activity relationship data and molecular modeling support occupancy of the S2 pocket from elongated R6 substituents on the 2(1H)-pyrazinone core and several inhibitors with improved inhibitory potency down to Ki = 0.11 μM were identified. A major goal with the design was to produce inhibitors structurally dissimilar to the di- and tripeptide-based HCV protease inhibitors in advanced stages of development for which cross-resistance might be an issue. Therefore, the retained and improved inhibitory potency against the drug-resistant variants A156T, D168V, and R155K further strengthen the potential of this class of inhibitors. A number of the inhibitors were tested in in vitro preclinical profiling assays to evaluate their apparent pharmacokinetic properties. The various R6 substituents were found to have a major influence on solubility, metabolic stability, and cell permeability.
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28.
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29.
  • Haylock, Anna-Karin, et al. (författare)
  • In vivo characterization of the novel CD44v6-targeting Fab fragment AbD15179 for molecular imaging of squamous cell carcinoma : a dual-isotope study
  • 2014
  • Ingår i: EJNMMI Research. - 2191-219X. ; 4
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Patients with squamous cell carcinoma in the head and neck region (HNSCC) offer a diagnostic challenge due to difficulties to detect small tumours and metastases. Imaging methods available are not sufficient, and radio-immunodiagnostics could increase specificity and sensitivity of diagnostics. The objective of this study was to evaluate, for the first time, the in vivo properties of the radiolabelled CD44v6-targeting fragment AbD15179 and to assess its utility as a targeting agent for radio-immunodiagnostics of CD44v6-expressing tumours.METHODS: The fully human CD44v6-targeting Fab fragment AbD15179 was labelled with 111In or 125I, as models for radionuclides suitable for imaging with SPECT or PET. Species specificity, antigen specificity and internalization properties were first assessed in vitro. In vivo specificity and biodistribution were then evaluated in tumour-bearing mice using a dual-tumour and dual-isotope setup.RESULTS: Both species-specific and antigen-specific binding of the conjugates were demonstrated in vitro, with no detectable internalization. The in vivo studies demonstrated specific tumour binding and favourable tumour targeting properties for both conjugates, albeit with higher tumour uptake, slower tumour dissociation, higher tumour-to-blood ratio and higher CD44v6 sensitivity for the 111In-labelled fragment. In contrast, the 125I-Fab demonstrated more favourable tumour-to-organ ratios for liver, spleen and kidneys.CONCLUSIONS: We conclude that AbD15179 efficiently targets CD44v6-expressing squamous cell carcinoma xenografts, and particularly, the 111In-Fab displayed high and specific tumour uptake. CD44v6 emerges as a suitable target for radio-immunodiagnostics, and a fully human antibody fragment such as AbD15179 can enable further clinical imaging studies.
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30.
  • Hovik, Sissel, et al. (författare)
  • Management of protected areas in Norway and Sweden : challenges in combining central governance and local participation
  • 2010
  • Ingår i: Journal of Environmental Policy and Planning. - : Routledge. - 1523-908X .- 1522-7200. ; 12:2, s. 159-177
  • Tidskriftsartikel (refereegranskat)abstract
    • Neither Norway nor Sweden has fulfilled international commitments to the principles of direct public involvement in nature conservation, which involve (we believe) the state adopting an 'enabling' role, mobilizing governance resources to support decentralized decision-making while retaining powers to intervene when necessary to defend important minority interests or support international objectives. We analyse four attempts to establish nature conservation areas with substantial levels of direct public involvement in the two countries and argue that in each case, flaws in the setting of the areas' boundaries, the framework for participation and conflict resolution mechanisms have undermined public involvement. Hence, there is a need to design more effective, enabling rules to encourage local actor involvement in nature conservation and resolve any political issues that arise as a consequence of such involvement, before the international commitments can be fulfilled.
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31.
  • Kullman, Eric, et al. (författare)
  • Covered versus uncovered self-expandable nitinol stents in the palliative treatment of malignant distal biliary obstruction: results from a randomized, multicenter study
  • 2010
  • Ingår i: GASTROINTESTINAL ENDOSCOPY. - : Elsevier Science B. V., Amsterdam. - 0016-5107 .- 1097-6779. ; 72:5, s. 915-923
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Covered biliary metal stents have been developed to prevent tumor ingrowth. Previous comparative studies are limited and often include few patients. Objective: To compare differences in stent patency, patient survival, and complication rates between covered and uncovered nitinol stents in patients with malignant biliary obstruction. Design: Randomized, multicenter trial conducted between January 2006 and October 2008. Setting: Ten sites serving a total catchment area of approximately 2.8 million inhabitants. Patients: A total of 400 patients with unresectable distal malignant biliary obstruction. Interventions: ERCP with insertion of covered or uncovered metal stent. Follow-up conducted monthly for symptoms indicating stent obstruction. Main Outcome Measurements: Time to stent failure, survival time, and complication rate. Results: The patient survival times were 116 days (interquartile range 242 days) and 174 days (interquartile range 284 days) in the covered and uncovered stent groups, respectively (P = .320). The first quartile stent patency time was 154 days in the covered stent group and 199 days in the uncovered stent group (P = .326). There was no difference in the incidence of pancreatitis or cholecystitis between the 2 groups. Stent migration occurred in 6 patients (3%) in the covered group and in no patients in the uncovered group (P = .030). Limitations: Randomization was not blinded. Conclusions: There were no significant differences in stent patency time, patient survival time, or complication rates between covered and uncovered nitinol metal stents in the palliative treatment of malignant distal biliary obstruction. However, covered stents migrated significantly more often compared with uncovered stents, and tumor ingrowth was more frequent in uncovered stents.
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32.
  • Lampa, Anna (författare)
  • Design and Synthesis of Acyclic and Macrocyclic Peptidomimetics as Inhibitors of the Hepatitis C Virus NS3 Protease
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease. The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.
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33.
  • Lampa, Anna, et al. (författare)
  • Improved P2 phenylglycine-based hepatitis C virus NS3 protease inhibitors with alkenylic prime-side substituents
  • 2010
  • Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:14, s. 5413-5424
  • Tidskriftsartikel (refereegranskat)abstract
    • Phenylglycine has proved to be a useful P2 residue in HCV NS3 protease inhibitors. A novel pi-pi-interaction between the phenylglycine and the catalytic H57 residue of the protease is postulated. We hypothesized that the introduction of a vinyl on the phenylglycine might strengthen this pi-pi-interaction. Thus, herein is presented the synthesis and inhibitory potency of a series of acyclic vinylated phenylglycine-based HCV NS3 protease inhibitors. Surprisingly, inhibitors based on both D- and L-phenylglycine were found to be effective inhibitors, with a slight preference for the d-epimers. Furthermore, prime-side alkenylic extension of the C-terminal acylsulfonamide group gave significantly improved inhibitors with potencies in the nanomolar range (approximately 35 nM), potencies which were retained on mutant variants of the protease.
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34.
  • Lampa, Anna, et al. (författare)
  • Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2–P1′ Region
  • 2014
  • Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:3, s. 249-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Herein, novel hepatitis C virus NS3/4A protease inhibitors based on a P2 pyrimidinyloxyphenylglycine in combination with various regioisomers of an aryl acyl sulfonamide functionality in P1 are presented. The P1′ 4-(trifluoromethyl)phenyl side chain was shown to be particularly beneficial in terms of inhibitory potency. Several inhibitors with Ki-values in the nanomolar range were developed and included identification of promising P3-truncated inhibitors spanning from P2–P1′. Of several different P2 capping groups that were evaluated, a preference for the sterically congested Boc group was revealed. The inhibitors were found to retain inhibitory potencies for A156T, D168V, and R155K variants of the protease. Furthermore, in vitro pharmacokinetic profiling showed several beneficial effects on metabolic stability as well as on apparent intestinal permeability from both P3 truncation and the use of the P1′ 4-(trifluoromethyl)phenyl side chain.
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35.
  • Lampa, Anna, et al. (författare)
  • P2-P1 ' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis
  • 2011
  • Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 19:16, s. 4917-4927
  • Tidskriftsartikel (refereegranskat)abstract
    • Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial pi-pi interaction between the P2 fragment and H57, which proved to be especially deleterious for the D-phenylglycine epimers.
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36.
  • Lampa, Anna, et al. (författare)
  • Vinylated linear P2 pyrimidinyloxyphenylglycine based inhibitors of the HCV NS3/4A protease and corresponding macrocycles
  • 2014
  • Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 22:23, s. 6595-6615
  • Tidskriftsartikel (refereegranskat)abstract
    • With three recent market approvals and several inhibitors in advanced stages of development, the hepatitis C virus (HCV) NS3/4A protease represents a successful target for antiviral therapy against hepatitis C. As a consequence of dealing with viral diseases in general, there are concerns related to the emergence of drug resistant strains which calls for development of inhibitors with an alternative binding-mode than the existing highly optimized ones. We have previously reported on the use of phenylglycine as an alternative P2 residue in HCV NS3/4A protease inhibitors. Herein, we present the synthesis, structure-activity relationships and in vitro pharmacokinetic characterization of a diverse series of linear and macrocyclic P2 pyrimidinyloxyphenylglycine based inhibitors. With access to vinyl substituents in P3, P2 and P1' positions an initial probing of macrocyclization between different positions, using ring-closing metathesis (RCM) could be performed, after addressing some synthetic challenges. Biochemical results from the wild type enzyme and drug resistant variants (e.g., R155 K) indicate that P3-P1' macrocyclization, leaving the P2 substituent in a flexible mode, is a promising approach. Additionally, the study demonstrates that phenylglycine based inhibitors benefit from p-phenylpyrimidinyloxy and m-vinyl groups as well as from the combination with an aromatic P1 motif with alkenylic P1' elongations. In fact, linear P2-P1' spanning intermediate compounds based on these fragments were found to display promising inhibitory potencies and drug like properties.
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37.
  • Ledman, Anna-Lill, 1974-, et al. (författare)
  • Vänd på perspektiven Umeå2014
  • 2013
  • Ingår i: Västerbottens Kuriren. - Umeå : Västerbottens Kuriren. - 1104-0246.
  • Tidskriftsartikel (populärvet., debatt m.m.)
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38.
  • Liljeholm, Maria, et al. (författare)
  • Congenital dyserythropoietic anemia type III (CDA III) is caused by a mutation in kinesin family member, KIF23
  • 2013
  • Ingår i: Blood. - Washington : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:23, s. 4791-4799
  • Tidskriftsartikel (refereegranskat)abstract
    • Haplotype analysis and targeted next-generation resequencing allowed us to identify a mutation in the KIF23 gene and to show its association with an autosomal dominant form of congenital dyserythropoietic anemia type III (CDA III). The region at 15q23 where CDA III was mapped in a large Swedish family was targeted by array-based sequence capture in a female diagnosed with CDA III and her healthy sister. Prioritization of all detected sequence changes revealed 10 variants unique for the CDA III patient. Among those variants, a novel mutation c.2747C>G (p.P916R) was found in KIF23, which encodes mitotic kinesin-like protein 1 (MKLP1). This variant segregates with CDA III in the Swedish and American families but was not found in 356 control individuals. RNA expression of the 2 known splice isoforms of KIF23 as well as a novel one lacking the exons 17 and 18 was detected in a broad range of human tissues. RNA interference-based knock-down and rescue experiments demonstrated that the p.P916R mutation causes cytokinesis failure in HeLa cells, consistent with appearance of large multinucleated erythroblasts in CDA III patients. We conclude that CDA III is caused by a mutation in KIF23/MKLP1, a conserved mitotic kinesin crucial for cytokinesis.
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39.
  • Lindkvist, Anna, et al. (författare)
  • Attitudes on intensive forestry : an investigation into perceptions of increased production requirements in Swedish forestry
  • 2012
  • Ingår i: Scandinavian Journal of Forest Research. - : Taylor & Francis Group. - 0282-7581 .- 1651-1891. ; 27:5, s. 438-448
  • Tidskriftsartikel (refereegranskat)abstract
    • In 2008, the Swedish government launched an inquiry into the possibilities, benefits and requirements for conducting intensive forestry in part of the Swedish countryside, including fertilization, genetically improved plant material and fastgrowing species beyond what is currently allowed in Swedish legislation. Drawing upon part of that governmental investigation, this paper analyzes attitudes toward intensive forestry over time. The study draws upon studies of points of conflict written in the 1970s and 1980s, attitudes among different stakeholder groups, and interviews with forest owners and stakeholder groups potentially affected by intensive forestry. The study concludes that the diverging opinions as to what constitutes acceptable forest use have remained largely the same over the years. Radical landscape change is generally not seen as desirable, but views diverge over the use of novel tree species and the use of fertilization.
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40.
  • Lundqvist, Anette, et al. (författare)
  • Reported dietary intake in early pregnant compared to non-pregnant women : a cross-sectional study
  • 2014
  • Ingår i: BMC Pregnancy and Childbirth. - : BioMed Central. - 1471-2393 .- 1471-2393. ; 14:373
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: A woman's nutritional status before conception and during pregnancy is important for maternal health and the health of the foetus. The aim of the study was to compare diet intake in early pregnant women with non-pregnant women. Methods: Between September 2006 and March 2009, 226 women in early pregnancy were consecutively recruited at five antenatal clinics in Northern Sweden. Referent women (n = 211) were randomly selected from a current health screening project running in the same region (the Vasterbotten Intervention Program; VIP). We collected diet data with a self-reported validated food frequency questionnaire with 66 food items/food aggregates, and information on portion size, alcohol consumption, and supplement intake. Data were analysed using descriptive, comparative statistics and multivariate partial least square modelling. Results: Intake of folate and vitamin D from foods was generally low for both groups. Intake of folate and vitamin D supplements was generally high in the pregnant group and led to significantly higher total estimated intake of vitamin D and folate in the pregnant group. Iron intake from foods tended to be lower in pregnant women although iron supplement intake evened out the difference with respect to iron intake from foods only. Energy intake was slightly lower in pregnant women but not significant, a reflection of that they reported consuming significantly less of potatoes/rice/pasta, meat/fish, and vegetables (grams/day) than the women in the referent group. Conclusions: In the present study, women in early pregnancy reported less intake of vegetables, potatoes, meat, and alcohol than non-pregnant women. As they also had a low intake (below the Nordic Nutritional Recommendations) of folate, vitamin D, and iron from foods, some of these women and their unborn children are possibly at risk for adverse effects on the pregnancy and birth outcome.
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41.
  • Malmberg, Jennie, et al. (författare)
  • Comparative biodistribution of imaging agents for in vivo molecular profiling of disseminated prostate cancer in mice bearing prostate cancer xenografts : focus on (111)In- and (125)I-labeled anti-HER2 humanized monoclonal trastuzumab and ABY-025 Affibody
  • 2011
  • Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 38:8, s. 1093-1102
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Human epidermal growth factor receptor type 2 (HER2) overexpression supports proliferation of androgen-independent prostate cancer (PC). Radionuclide molecular imaging of HER2 expression in disseminated PC would aid in the selection of patients who are likely responders to HER2 targeting therapy. In this study, we evaluated whether ABY-025 Affibody molecule, a small (similar to 7-kDa) HER2-binding scaffold protein, produces superior tumor-to-nontumor ratios compared with those obtained through the use of radiolabeled humanized anti-HER2 antibody, trastuzumab. The influence of (111)In vs. (125)I radiolabel was evaluated for both tracers.Methods: ABY-025 was labeled with (111)In using 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid chelator, site-specifically coupled to the C-terminus via the maleimido derivative. Trastuzumab was labeled with (111)In using a CHX-A" diethylene triamine pentaacetic acid (DTPA) chelator. An indirect radioiodination with [(125)I]-N-succinimidyl-para-iodobenzoate was used for both targeting proteins. Biodistribution of all labeled targeting proteins was evaluated in mice bearing DU-145 PC xenografts.Results: The use of residualizing (111)In-label facilitated better tumor uptake and better tumor-to-nontumor ratios for both targeting agents. [(111)In]-ABY-025 provided tumor uptake of 7.1 +/- 0.8% injected dose per gram of tissue (% ID/g) and tumor-to-blood ratio of 47 +/- 13 already at 6 h postinjection. The maximum tumor-to-nontumor ratios with [(111)In]-CHX-DTPA-trastuzumab were achieved at 72 h postinjection, whereas tumor uptake was 11 +/- 4% ID/g and tumor-to-blood ratio was 18 +/- 7. The biodistribution data were confirmed with gamma-camera imaging.Conclusions: Radiolabeled ABY-025 Affibody molecule provides higher contrast in imaging of HER2-expressing PC xenografts than radiolabeled trastuzumab. Residualizing radiometal label for ABY-025 provides better contrast in imaging of HER2-expressing PC xenografts than nonresidualizing radiohalogen.
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42.
  • Notér Hooshidar, Annika (författare)
  • Dansundervisning som förkroppsligad multimodal praktik : en studie om kommunikation och interaktion i dansundervisning
  • 2014
  • Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Dansundervisning som förkroppsligad multimodal praktikEn studie om kommunikation och interaktion i dansundervisning. ABSTRACTDance teaching as embodied multimodal practiceA study about communication and interaction in dance teaching. The overall aim of this study is to increase the knowledge about how communication and interaction between students and teachers is manifested in dance teaching and learning, with a special focus on the students’ agency and how that can be assumed to affect their conditions for learning.In a dance class, teachers and students engage in the dance practice by using different semiotic modes of communication; body movements and gestures, touch, hearing, gaze, sound and speech. The teaching and learning situation can be described as a complex multimodal configuration of signs in different time and space based modes. The object of study is to examine students’ and teachers’ interaction and communication in detail, with a focus on how different semiotic resources are being used and how that affects the design of the dance class.The data consist of video recordings of dance classes in dance college education and more specifically the daily dance practice, the dance class. Video recordings were made in jazz dance, contemporary dance and ballet classes. These genres are, in various degrees, bearers of a tradition of dance teaching where students repeat the movement material that the teacher demonstrates. I base my choice on the fact that this is a common way of teaching dance both in dance college education and elsewhere.  By using a multimodal analysis, different modes of communication and their interplay were brought into focus. Employing the perspective of a social semiotic multimodal theory the analyzed data were interpreted and discussed. The result has shown the importance of the body in communication and interaction between students and teachers in dance teaching and learning. Communication and interaction involve and combine different embodied semiotic resources. Signs are being made, interpreted and remade/redesigned with, through and in the body. The way the teachers use their voices in combination with body movements and gestures in instructions and feedback, makes these resources appear hierarchically more important than the verbal language. The result shows that the students make rhetoric choices in their learning processes. It is shown by the way they choose to attend to what the teacher communicates. The students’ choices in responding are mostly by showing how they understand. Further the results show that the teacher is responsible for the overall design of the dance class. The study material consists mostly of movements that the teacher has created in relation to a genre’s esthetics, the teacher chooses what aspects to focus on and how time is disposed. The students’ agency seems limited in terms of how they can affect and influence the design of the dance class. This means that the knowledge that is produced to a great extent is dependent on the teacher’s choices, her esthetic values and her own knowledge. From a didactic point of view this needs to be addressed in dance education in terms of how dance classes are designed, it concerns questions of esthetics, values and power.Keywords: dance teaching and learning, communication, interaction, multimodality, semiotic resource, design
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43.
  • Ohsawa, Masahiro, et al. (författare)
  • The dipeptide Phe-Phe amide attenuates signs of hyperalgesia, allodynia and nociception in diabetic mice using a mechanism involving the sigma receptor system
  • 2011
  • Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 7, s. 85-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Previous studies have demonstrated that intrathecal administration of the substance P amino-terminal metabolite substance P1-7 (SP1-7) and its C-terminal amidated congener induced antihyperalgesic effects in diabetic mice. In this study, we studied a small synthetic dipeptide related to SP1-7 and endomorphin-2, i.e. Phe-Phe amide, using the tail-flick test and von Frey filament test in diabetic and non-diabetic mice. Results: Intrathecal treatment with the dipeptide increased the tail-flick latency in both diabetic and non-diabetic mice. This effect of Phe-Phe amide was significantly greater in diabetic mice than non-diabetic mice. The Phe-Phe amide-induced antinociceptive effect in both diabetic and non-diabetic mice was reversed by the σ1 receptor agonist (+)-pentazocine. Moreover, Phe-Phe amide attenuated mechanical allodynia in diabetic mice, which was reversible by (+)-pentazocine. The expression of spinal σ1 receptor mRNA and protein did not differ between diabetic mice and non-diabetic mice. On the other hand, the expression of phosphorylated extracellular signal-regulated protein kinase 1 (ERK1) and ERK2 proteins was enhanced in diabetic mice. (+)-Pentazocine caused phosphorylation of ERK1 and ERK2 proteins in non-diabetic mice, but not in diabetic mice. Conclusions: These results suggest that the spinal σ1 receptor system might contribute to diabetic mechanical allodynia and thermal hyperalgesia, which could be potently attenuated by Phe-Phe amide.
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44.
  • Ohsawa, Masahiro, et al. (författare)
  • The effect of substance P1-7 amide on nociceptive threshold in diabetic mice
  • 2011
  • Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 32:1, s. 93-98
  • Tidskriftsartikel (refereegranskat)abstract
    • We previously demonstrated that intrathecal treatment with substance P metabolite substance P1-7 induced anti-hyperalgesia in diabetic mice. In the present study, we have used a synthetic analog of this peptide, the substance P1-7 amide, showing higher binding affinitiy than the native heptapeptide, for studies of the tail-flick response in diabetic and non-diabetic mice. Intrathecal injection of substance P1-7 amide produced prolongation of the tail-flick latency in both diabetic and non-diabetic mice, an effect that was more pronounced in diabetic mice than non-diabetic mice. Moreover, the observed antinociceptive potency of the substance P1-7 amide was higher in both diabetic and non-diabetic mice in comparison with the native substance P1-7. The antinociceptive effect of substance P1-7 amide was reversed by naloxone but not by the selective opioid receptor antagonist beta-funaltrexamine, naltrindole or nor-binaltorphimine, selective for the mu-, delta- or kappa-opioid receptor, respectively. In addition, the antinociceptive effect induced by substance P1-7 amide was partly reversed by the sigma(1) receptor agonist (+)-pentazocine, suggesting a possible involvement of the sigma(1) receptor for the action of this peptide. These results suggest that the actions of substance P1-7 amide mimic the effects of the native substance P fragment but with higher potency and that the mechanisms for its action may involve the sigma(1) receptor system.
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45.
  • Olsen, Jessica M., et al. (författare)
  • Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation
  • 2014
  • Ingår i: Journal of Cell Biology. - : Rockefeller University Press. - 0021-9525 .- 1540-8140. ; 207:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Brown adipose tissue is the primary site for thermogenesis and can consume, in addition to free fatty acids, a very high amount of glucose from the blood, which can both acutely and chronically affect glucose homeostasis. Here, we show that mechanistic target of rapamycin (mTOR) complex 2 has a novel role in β3-adrenoceptor-stimulated glucose uptake in brown adipose tissue. We show that β3-adrenoceptors stimulate glucose uptake in brown adipose tissue via a signaling pathway that is comprised of two different parts: one part dependent on cAMP-mediated increases in GLUT1 transcription and de novo synthesis of GLUT1 and another part dependent on mTOR complex 2-stimulated translocation of newly synthesized GLUT1 to the plasma membrane, leading to increased glucose uptake. Both parts are essential for β3-adrenoceptor-stimulated glucose uptake. Importantly, the effect of β3-adrenoceptor on mTOR complex 2 is independent of the classical insulin-phosphoinositide 3-kinase-Akt pathway, highlighting a novel mechanism of mTOR complex 2 activation.
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46.
  • Orlova, Anna, et al. (författare)
  • [99mTc(CO)3]+-(HE)3-Z IGF1R45514551 : a new Affibody conjugate for visualization of insulin-like growth factor-1 receptor expression in malignant tumours.
  • 2013
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 40:3, s. 439-449
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: Radionuclide imaging of insulin-like growth factor type 1 receptor (IGF-1R) expression in tumours might be used for selection of patients who would benefit from IGF-1R-targeted therapy. We have previously shown the feasibility of IGF-1R imaging using the Affibody molecule (111)In-DOTA-His(6)-Z(IGF1R:4551). The use of (99m)Tc instead of (111)In should improve sensitivity and resolution of imaging, and reduce the dose burden to patients. We hypothesized that inclusion of a HEHEHE tag instead of a His(6) tag in Z(IGF1R:4551) would permit its convenient purification using IMAC, enable labelling with [(99m)Tc(CO)(3)](+), and improve its biodistribution. METHODS: Z(IGF1R:4551) was expressed with a HEHEHE tag in the N terminus. The resulting (HE)(3)-Z(IGF1R:4551) construct was labelled with [(99m)Tc(CO)(3)](+). Targeting of IGF-1R-expressing cells using [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) was evaluated in vitro and in vivo. RESULTS: (HE)(3)-Z(IGF1R:4551) was stably labelled with (99m)Tc with preserved specific binding to IGF-1R-expressing DU-145 prostate cancer cells in vitro. In mice, [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung and salivary gland). [(99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) demonstrated 3.6-fold lower accumulation in the liver and spleen than (111)In-DOTA-Z(IGF1R:4551). In NMRI nu/nu mice with DU-145 prostate cancer xenografts, the tumour uptake was 1.32 ± 0.11 %ID/g and the tumour-to-blood ratio was 4.4 ± 0.3 at 8 h after injection. The xenografts were visualized using a gamma camera 6 h after injection. CONCLUSION: (99m)Tc(CO)(3)](+)-(HE)(3)-Z(IGF1R:4551) is a promising candidate for visualization of IGF-1R expression in malignant tumours.
  •  
47.
  • Rosén, Anna, 1975- (författare)
  • Mass screening for celiac disease in 12-year-olds : Finding them and then what?
  • 2012
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background Mass screening for celiac disease (CD) as a public health intervention is controversial. Before implementation, a suitable screening strategy should be outlined, and the acceptability of the screening scrutinized. Also, the benefits of early detection and possible negative consequences should be explored and compared. The overall aim of this thesis was to evaluate different strategies for finding 12-year-olds with undiagnosed CD in the general population, and to explore the experiences of those receiving the diagnosis in a mass screening.Methods A school-based CD screening of 12-year-olds was conducted in five study sites across Sweden. Out of 10041 children who were invited, 7208 had a blood sample analyzed for CD-marker tissue transglutaminase of isotype IgA (tTG-IgA) and 7161 for total serum IgA (s-IgA). If the s-IgA value was low, tTG-IgG was also measured. Additional analysis of endomysial antibodies (EMA) was performed if borderline values of tTG were found. In total, 192 had elevated CD-markers, 184 underwent a small intestinal biopsy and 153 eventually had CD diagnosed. Before receiving knowledge about their CD status, children and their parents filled in questionnaires regarding symptoms and CD-associated conditions. Questionnaires were returned by 7054 children (98%) and 6294 parents (88%). Later, all adolescents who had been diagnosed with CD more than one year ago (n=145), and their parents, were invited to a mixed-method follow-up study in which they shared their experiences in questionnaires, written narratives and focus group discussions. In total, we have information on 117 (81%) of these adolescents, either from the adolescents themselves (n=101) and/or from their parent/s (n=125). Data were analyzed using a combination of descriptive and analytical quantitative and qualitative methodologies.Results We found that information on symptoms and CD-associated conditions were poor predictors for finding undiagnosed CD in the study population. Questionnaire-based case-finding by asking for CD-associated symptoms and conditions would have identified 52 cases (38% of all cases) at a cost of blood-sampling 2282 children (37% of the study population). The tTG-IgA test had an excellent diagnostic accuracy with the area under the receiver operating characteristic curve of 0.988. If using the recommended cut-off for tTG-IgA (>5 U/mL) 151 had fulfilled biopsy criteria and 134 CD cases had been identified. The strategy of lowering the cut-off to tTG-IgA>4 U/mL, and adding the EMA analysis in those with tTG-IgA between 2-4 U/mL, identified another 17 cases (a 12% increase) at the cost of performing 32 additional biopsies. Measuring total s-IgA in 7161 children discovered only two additional cases at the cost of performing 5 additional biopsies. The positive predictive value of our screening strategy was 80%. Results from the follow-up study of the screening-detected CD cases illustrated that 54% reported health improvement after initiated treatment, but also that these health benefits had to be balanced against social sacrifices. We also found that although the screening-detected diagnosis was met with surprise and anxiety, the adolescents and their parents were grateful for being made aware of the diagnosis. A majority of parents (92%) welcomed a future screening, but both adolescents and parents suggested that it should be conducted earlier in life.Conclusion Obtaining information on symptoms and CD-associated conditions was not a useful step in finding undiagnosed CD cases in a general population. The serological marker tTG-IgA, however, had excellent diagnostic accuracy also when lowering the cut-off. The diagnosis had varying impact on adolescents’ quality of life, and their perceived change in health had to be balanced against the social sacrifices resulting from the diagnosis. Overall, CD mass screening seemed acceptable to most of those who were diagnosed and their parents.
  •  
48.
  • Rosén, Anna, et al. (författare)
  • Usefulness of symptoms to screen for celiac disease
  • 2014
  • Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 0031-4005 .- 1098-4275. ; 133:2, s. 211-218
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: To describe the frequency of symptoms and associated conditions among screening-detected celiac disease (CD) cases and non-CD children and to evaluate questionnaire-based case-finding targeting the general population.METHODS: In a population-based CD screening of 12-year-olds, children and their parents completed questionnaires on CD-associated symptoms and conditions before knowledge of CD status. Questionnaire data for those who had their CD detected in the screening (n = 153) were compared with those of children with normal levels of CD markers (n = 7016). Hypothetical case-finding strategies were also evaluated. Questionnaires were returned by 7054 (98%) of the children and by 6294 (88%) of their parents.RESULTS: Symptoms were as common among screening-detected CD cases as among non-CD children. The frequency of children with screening-detected CD was similar when comparing the groups with and without any CD-related symptoms (2.1% vs 2.1%; P = .930) or CD-associated conditions (3.6% vs 2.1%; P = .07). Case-finding by asking for CD-associated symptoms and/or conditions would have identified 52 cases (38% of all cases) at a cost of analyzing blood samples for 2282 children (37%) in the study population.CONCLUSIONS: The current recommended guidelines for finding undiagnosed CD cases, so-called active case-finding, fail to identify the majority of previously undiagnosed cases if applied in the general population of Swedish 12-year-olds. Our results warrant further studies on the effectiveness of CD case-finding in the pediatric population, both at the clinical and population-based levels.
  •  
49.
  • Rosik, Daniel, et al. (författare)
  • Direct comparison of In-111-labelled two-helix and three-helix Affibody molecules for in vivo molecular imaging
  • 2012
  • Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 39:4, s. 693-702
  • Tidskriftsartikel (refereegranskat)abstract
    • Radiolabelled Affibody molecules have demonstrated a potential for visualization of tumour-associated molecular targets. Affibody molecules (7 kDa) are composed of three alpha-helices. Recently, a smaller two-helix variant of Affibody molecules (5.1 kDa) was developed. The aim of this study was to compare two- and three-helix HER2-targeting Affibody molecules directly in vivo. The three-helix Affibody molecule ABY-002 and the two-helix Affibody molecule PEP09239 were labelled with In-111 at the N-termini via DOTA chelator. Tumour-targeting properties were directly compared at 1 and 4 h after injection in mice bearing SKOV-3 xenografts with high HER2 expression and LS174T xenografts with low HER2 expression. The dissociation constants (K (D)) for HER2 binding were 78 pM for the three-helix Affibody molecule and 2.1 nM for the two-helix Affibody molecule. In-111-PEP09239 cleared more rapidly from the blood. In xenografts with high HER2 expression, the uptake of In-111-ABY-002 was significantly higher than that of In-111-PEP09239. The tumour-to-blood ratio was higher for In-111-PEP09239 at 4 h after injection, while there was no significant difference in other tumour-to-organ ratios. The tumour uptake of In-111-ABY-002 was eightfold higher than that of In-111-PEP09239 in xenografts with low expression. Tumour-to-blood ratios were equal in this case, but other tumour-to-organ ratios were appreciably higher for the three-helix variant. For tumours with high HER2 expression, two-helix HER2-targeting Affibody molecules can provide higher tumour-to-blood ratio at the cost of lower tumour uptake. In the case of low expression, both tumour uptake and tumour-to-organ ratios are appreciably higher for three-helix than for two-helix HER2-targeting Affibody molecules.
  •  
50.
  • Sakao, Tomohiko, et al. (författare)
  • Uncovering benefits and risks of integrated product service offerings - Using a case of technology encapsulation
  • 2013
  • Ingår i: Journal of Systems Science and Systems Engineering. - : Springer Science and Business Media LLC. - 1004-3756 .- 1861-9576. ; 22:4, s. 421-439
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this article is to uncover benefits and risks of Integrated Product Service Offering (IPSO) in a systematic manner. To do so, it adopts an explorative longitudinal in-depth case study (development of an IPSO based on a new technology) and adds insights to the existing literature. The article first proposes a theoretical and generic framework termed the PCP (Provider - Customer - Product) triangle with associated information flow and uncertainty. Second, various types of benefits and risks are presented based on the framework. Among others, the benefit of keeping IPR (Intellectual Property Rights) with the provider and the risk of regulation change are new findings from the case study. In addition, the case study reveals that IPSO is regarded as a positive contributor to innovation. Applying the framework and classification of benefits and risks as norms to other cases has yet to be done for verification. However, the framework contributes scientifically to a better understanding of the benefits and risks of IPSO. In addition, this framework is advantageous with its easiness to understand, which contributes practically to the dissemination of IPSO insight to industry.
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