| 1. |
- Enroth, Stefan, 1976-, et al.
(författare)
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A two-step strategy for identification of plasma protein biomarkers for endometrial and ovarian cancer
- 2018
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Ingår i: Clinical Proteomics. - : Springer Science and Business Media LLC. - 1542-6416 .- 1559-0275. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOver 500,000 women worldwide are diagnosed with ovarian or endometrial cancer each year. We have used a two-step strategy to identify plasma proteins that could be used to improve the diagnosis of women with an indication of gynecologic tumor and in population screening.MethodsIn the discovery step we screened 441 proteins in plasma using the proximity extension assay (PEA) and five Olink Multiplex assays (CVD II, CVD III, INF I, ONC II, NEU I) in women with ovarian cancer (n=106), endometrial cancer (n=74), benign ovarian tumors (n=150) and healthy population controls (n=399). Based on the discovery analyses a set of 27 proteins were selected and two focused multiplex PEA assays were developed. In a replication step the focused assays were used to study an independent set of cases with ovarian cancer (n=280), endometrial cancer (n=228), women with benign ovarian tumors (n=76) and healthy controls (n=57).ResultsIn the discovery step, 27 proteins that showed an association to cancer status were identified. In the replication analyses, the focused assays distinguished benign tumors from ovarian cancer stage III-IV with a sensitivity of 0.88 and specificity of 0.92 (AUC=0.92). The assays had a significantly higher AUC for distinguishing benign tumors from late stage ovarian cancer than using CA125 and HE4 (p=9.56e-22). Also, population controls could be distinguished from ovarian cancer stage III-IV with a sensitivity of 0.85 and a specificity of 0.92 (AUC=0.89).ConclusionThe PEA assays represent useful tools for identification of new biomarkers for gynecologic cancers. The selected protein assays could be used to distinguish benign tumors from ovarian and endometrial cancer in women diagnosed with an unknown suspicious pelvic mass. The panels could also be used in population screening, for identification of women in need of specialized gynecologic transvaginal ultrasound examination.FundingThe Swedish Cancer Foundation, Vinnova (SWELIFE), The Foundation for Strategic Research (SSF), Assar Gabrielsson Foundation.
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| 2. |
- Enroth, Stefan, 1976-, et al.
(författare)
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High throughput proteomics identifies a high-accuracy 11 plasma protein biomarker signature for ovarian cancer
- 2019
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer is usually detected at a late stage and the overall 5-year survival is only 30-40%. Additional means for early detection and improved diagnosis are acutely needed. To search for novel biomarkers, we compared circulating plasma levels of 593 proteins in three cohorts of patients with ovarian cancer and benign tumors, using the proximity extension assay (PEA). A combinatorial strategy was developed for identification of different multivariate biomarker signatures. A final model consisting of 11 biomarkers plus age was developed into a multiplex PEA test reporting in absolute concentrations. The final model was evaluated in a fourth independent cohort and has an AUC = 0.94, PPV = 0.92, sensitivity = 0.85 and specificity = 0.93 for detection of ovarian cancer stages I-IV. The novel plasma protein signature could be used to improve the diagnosis of women with adnexal ovarian mass or in screening to identify women that should be referred to specialized examination.
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| 3. |
- Tengvall, Katarina, 1980-, et al.
(författare)
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Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk
- 2019
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : NATL ACAD SCIENCES. - 0027-8424 .- 1091-6490. ; 116:34, s. 16955-16960
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 x 10(-36)) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95% CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15: 01 carriage, absence of HLA-A*02: 01, and high anti-EBNA1 antibody levels (OR = 24.9; 95% CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLADRB1*04: 01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95% CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.
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| 4. |
- Albrecht, Inka, et al.
(författare)
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Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies
- 2015
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 125:12, s. 4612-4624
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Tidskriftsartikel (refereegranskat)abstract
- Mutations of the gene encoding four-and-a-half LIM domain 1 (FHL1) are the causative factor of several X-linked hereditary myopathies that are collectively termed FHL1-related myopathies. These disorders are characterized by severe muscle dysfunction and damage. Here, we have shown that patients with idiopathic inflammatory myopathies (IIMs) develop autoimmunity to FHL1, which is a muscle-specific protein. Anti-FHL1 autoantibodies were detected in 25% of IIM patients, while patients with other autoimmune diseases or muscular dystrophies were largely anti-FHL1 negative. Anti-FHL1 reactivity was predictive for muscle atrophy, dysphagia, pronounced muscle fiber damage, and vasculitis. FHL1 showed an altered expression pattern, with focal accumulation in the muscle fibers of autoantibody-positive patients compared with a homogeneous expression in anti-FHL1-negative patients and healthy controls. We determined that FHL1 is a target of the cytotoxic protease granzyme B, indicating that the generation of FHL1 fragments may initiate FHL1 autoimmunity. Moreover, immunization of myositis-prone mice with FHL1 aggravated muscle weakness and increased mortality, suggesting a direct link between anti-FHL1 responses and muscle damage. Together, our findings provide evidence that FHL1 may be involved in the pathogenesis not only of genetic FHL1-related myopathies but also of autoimmune IIM. Importantly, these results indicate that anti-FHL1 autoantibodies in peripheral blood have promising potential as a biomarker to identify a subset of severe IIM.
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| 5. |
- Anheden, Marie, et al.
(författare)
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Value chains for production of Renewable Transportation Fuels Using Intermediates
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- An increased share of renewable transportation fuels requires utilisation of new low-cost sources of bio-based raw materials other than what is currently used in the pulp and paper industry and for power and district heat generation in the bioenergy sector. Currently, proposed raw material includes forest residues (branches and tops), stumps, waste round wood and different by-products from pulp and pa-per industry and sawmills. Of these, forest residues and stumps have, by far, the largest potential for increased utilisation. However, these types of raw materials are often voluminous and heterogeneous and are difficult to handle in existing refineries for production of transportation fuels. The cost of transporting this type of raw material over large distances in order to supply a larger plant is often said to be high. This report includes an analysis of the possible advantages and disadvantages of transform-ing forest-based biomass to an intermediate product with a higher energy density that is more homo-geneous and easier to handle during transport and during final conversion to transportation fuel.Two value chains are investigated as case studies a) bio-SNG production using forest residues, bark and sawdust as raw material and b) bio-oil production from forest residues, lignin in black liquor and tall oil, which can be upgraded to transportation fuels at a refinery. In the study we have assumed that the conversion of the original biomass to an intermediate product mainly takes place at a pulp mill. The intermediate conversion technologies included for value chain a) are drying and pelletizing and for value chain b) pyrolysis and distillation. The final conversion to end product bio-SNG takes place in connection to a district heating system, and the final deoxygenation and upgrading of bio-oil to hydrodeoxygenated (HDO) oil takes place at an oil refinery. The value chains with intermediates are compared with value chains without intermediates where the entire conversion process to final product is located in connection to a district heating system in value chain a) and at a stand-alone plant near to a refinery in value chain b). The value chains are studied from a well-to-gate perspective, from extrac-tion of the forest biomass to produced bio-SNG/HDO bio-oil. A direct comparison between value chains for bio-SNG and bio-oil production should be avoided. They are based on different reference data that are not synchronized. A direct comparison between the chains should in addition be done in a well-to-wheel perspective.The results show that the initial hypothesis that local production of a more energy dense intermediate would reduce transportation costs could not be verified. The reason is primarily the introduction of a second transport step to transport the intermediate to the final conversion site in addition to the transport of the raw material. The transport costs are associated with relatively high fixed cost espe-cially for ship and train transport, so the introduction of a second relatively high fixed transport cost of the intermediate has a dominating effect. Further, it can be concluded that the transport cost make up a relatively small share of the total production cost of the final product, in the order of 10%, and in a few cases up to 20%. There is therefore a relatively small difference in total specific production cost for the final product between value chains with and without intermediates considering the level of uncer-tainty in the input data and the assumptions behind the scenarios studied.Summarizing, the results indicate that the production costs are highly sensitive to the economies of scale, oxygen content in the bio-crude oil and raw material costs (forest residues price or electricity price in the case where lignin is used as raw material). Transportation costs have, comparatively, a little effect in the total production cost.
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| 6. |
- Berggrund, Malin, et al.
(författare)
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Identification of candidate plasma protein biomarkers for cervical cancer using the multiplex proximity extension assay
- 2019
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 18:4, s. 735-743
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Tidskriftsartikel (refereegranskat)abstract
- Human papillomavirus (HPV) is recommended as the primary test in cervical cancer screening, with co-testing by cytology for HPV-positive women to identify cervical lesions. Cytology has low sensitivity and there is a need to identify biomarkers that could identify dysplasia that are likely to progress to cancer. We searched for plasma proteins that could identify women with cervical cancer using the multiplex proximity extension assay (PEA). The abundance of 100 proteins were measured in plasma collected at the time of diagnosis of patients with invasive cervical cancer and in population controls using the Olink Multiplex panels CVD II, INF I, and ONC II. Eighty proteins showed increased levels in cases compared to controls. We identified a signature of 11 proteins (PTX3, ITGB1BP2, AXIN1, STAMPB, SRC, SIRT2, 4E-BP1, PAPPA, HB-EGF, NEMO and IL27) that distinguished cases and controls with a sensitivity of 0.96 at a specificity of 1.0. This signature was evaluated in a prospective replication cohort with samples collected before, at or after diagnosis and achieved a sensitivity of 0.78 and a specificity 0.56 separating samples collected at the time of diagnosis of invasive cancer from samples collected prior to diagnosis. No difference in abundance was seen between samples collected prior to diagnosis or after treatment as compared to population controls, indicating that this protein signature is mainly informative close to time of diagnosis. Further studies are needed to determine the optimal window in time prior to diagnosis for these biomarker candidates.
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| 7. |
- Chang, Ya-Ting, et al.
(författare)
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Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension
- 2015
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:1, s. 20-31
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Tidskriftsartikel (refereegranskat)abstract
- Aims Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH. Methods and results In normoxia, Hspg2(Delta 3/Delta 3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Delta 3/Delta 3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Delta 3/Delta 3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Delta 3/Delta 3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Delta 3/Delta 3) compared with wild type. Conclusions Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.
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| 8. |
- Dahlberg, Anna-Karin, et al.
(författare)
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Hydroxylated and methoxylated polybrominated diphenyl ethers in long-tailed ducks (Clangula hyemalis) and their main food, Baltic blue mussels (Mytilus trossulus x Mytilus edulis)
- 2016
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Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535 .- 1879-1298. ; 144, s. 1475-1483
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Tidskriftsartikel (refereegranskat)abstract
- Long-tailed ducks (Clangula hyemalis) that breed in northern Europe and western Siberia and commonly winter in the Baltic Sea, are threatened by a significant population decrease. The ducks are, by primarily feeding on Baltic blue mussels (Mytilus trossulus x Mytilus edulis) while wintering in the Baltic Sea, potentially subjected to high levels of toxic hydroxylated polybrominated diphenyl ethers (OH-PBDEs). To assess long-tailed ducks exposure to polybrominated phenols (PBPs), polybrominated anisoles (PBAs), hydroxylated polybrominated diphenyl ethers (OH-PBDEs), their methylated counterparts (MeO-PBDEs) and polybrominated diphenyl ethers (PBDEs), livers of ten long-tailed ducks wintering in the Baltic Sea were analysed. Pattern and levels of analytes in long-tailed ducks (liver) and blue mussels sampled in March and May at nine sites in the Baltic Sea were compared. The geometric mean concentration (ng/g l.w.) in livers of long-tailed ducks and Baltic blue mussels were: ∑2PBPs: 0.57 and 48; ∑2PBAs: 0.83 and 11; ∑7OH-PBDEs: 6.1 and 45; ∑7MeO-PBDEs: 3.8 and 69; ∑7PBDEs: 8.0 and 7.2, respectively. Based on an estimated daily intake of 450 g fresh blue mussel meat, long-tailed ducks daily dietary intake of brominated substances while foraging in the Baltic Sea in March-May was estimated to; 390 ng ∑2PBPs, 90 ng ∑2PBAs, 370 ng ∑7OH-PBDEs, 590 ng ∑7MeO-PBDEs and 59 ng ∑7PBDEs. The low levels of PBPs, PBAs, OH-PBDEs and MeO-PBDEs in the long-tailed duck livers compared to blue mussel, despite a continuous daily intake, suggest that these compounds are poorly retained in long-tailed ducks.
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| 9. |
- Edvardsson, Karin, 1980-, et al.
(författare)
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Objektiv mätmetod för tillståndsbedömning av grusväglag
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Fram tills nu har tillståndsmätningar på grusvägnätet gjorts subjektivt enligt Trafikverkets metodbeskrivning. I denna rapport redovisas en objektiv metodik för kontinuerlig mätning av ojämnheter, löst grus, damm och tvärfall på grusväg. Projektet som redovisas i rapporten syftar till att utveckla en tillförlitlig, objektiv och mobil metodik för kontinuerlig mätning av tillståndsparametrarna på grusväg samt att rekommendera en objektiv inventeringsmetod för dräneringstillståndet i en grusvägskonstruktion. Metodiken har tagits fram för att ge större möjligheter till bedömningar av optimal åtgärd och åtgärdstidpunkt samt för att kunna ligga till grund för nya metod- och standardbeskrivningar samt definition av lägsta acceptabla standard. Resultatet visar att de objektiva tillståndsmått som bäst tycks beskriva efterfrågad funktionalitet på grusväg är acceleration uppmätt med en applikation i en smarttelefon vad gäller jämnhet, samt uppmätt med laserutrustad mätbil: makrotextur vad gäller löst grus och laserpulsens genomsnittliga reflektionstid över vägens tvärprofil vad gäller damm. Som en objektiv inventeringsmetod för dräneringstillståndet hos en grusväg föreslås dikesmätningar (med sveplaserteknik) som säkerställer tillfredställande dikesdjup, tvärfallsmätningar (med laserutrustad mätbil), mätningar av stödremsan (med sveplaserteknik) som säkerställer att det inte förekommer kanthäng etc. som i sin tur förhindrar vattenavrinning från vägen, samt mätning av återkommande och/eller snabbt tillväxande ojämnheter. Eftersom grusväglagstillståndet är så snabbt föränderligt på en grusväg behövs en snabb och förenklad variant av vägytemätning om det ska vara kostnadseffektivt med dessa typer av mätningar på vägnätsnivå. Att använda en smarttelefon med en applikation för jämnhetsmätning är ett enkelt och kostnadseffektivt sätt att generera aktuell tillståndsdata för grusvägnätet. Applikationen skulle också kunna kompletteras med en knapp för att allmänheten ska kunna rapportera och märka ut skador på vägen eller kopplas ihop med entreprenörens GPS-uppkopplade inrapporteringssystem för att märka ut speciellt intressanta platser, såsom platser för tjällyftning eller erosion.
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| 10. |
- Engström, Marianne, et al.
(författare)
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Increased citrullination and expression of peptidylarginine deiminases independently of P. gingivalis and A. actinomycetemcomitans in gingival tissue of patients with periodontitis
- 2018
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A relationship between rheumatoid arthritis (RA) and periodontitis has been suggested from findings that individuals with RA are prone to have advanced periodontitis and vice versa. In search of possible common pathogenetic features of these two diseases, we investigated the presence of citrullinated proteins and expression of endogenous peptidylarginine deiminases (PAD2 and PAD4), in periodontal tissue of individuals with periodontitis and healthy controls, in relation to the periodontal pathogens Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), producing leukotoxin as virulence factor. These two oral bacteria have been suggested to be linked to anti-citrullinated protein antibodies in patients with RA.METHODS: Gingival tissue biopsies were obtained from 15 patients with periodontitis and 15 individuals without periodontal disease. Presence of CD3-positive lymphocytes, citrullinated proteins, PAD2, PAD4, P. gingivalis as well as A. actinomycetemcomitans and Mannheimia haemolytica produced leukotoxins were analysed by immunohistochemistry, followed by triple-blind semi-quantitative analysis. Mann-Whitney and Fisher's exact tests were used to analyse differences between groups. PADI2 and PADI4 mRNA levels were assessed by RT-qPCR and analysed using Wilcoxon signed rank test.RESULTS: Increased staining of citrullinated proteins was observed in gingival connective tissue from subjects with periodontitis (80%, 12/15) compared to healthy gingival tissue (27%, 4/15), whereas no differences were observed in gingival epithelium. There was also an increased staining of the citrullinating enzymes PAD2 and PAD4 in gingival connective tissue of patients with periodontitis whereas similar levels of PAD2 and PAD4 were observed in the gingival epithelium of the two groups. Similarly, the mRNA levels of PADI2 and PADI4 were also increased in the gingival tissue of patients with periodontitis compared to healthy controls. Furthermore, presence of P. gingivalis and leukotoxins was comparable in both epithelium and connective tissue, from the different investigated individuals with and without periodontitis, and there were no correlations between the presence of periodontal pathogens and the expression of citrullinated proteins or PAD enzymes.CONCLUSION: Chronic gingival inflammation is associated with increased local citrullination and PAD2 and PAD4 expression in periodontitis. The increased citrullination and PAD2 and PAD4 expression in periodontitis were, however, independent of the presence of periodontal pathogen P. gingivalis and A. actinomycetemcomitans leukotoxin.
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