| 1. |
- Arne, Gabriella, et al.
(author)
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Gastrointestinal stromal tumors (GISTs) express somatostatin receptors and bind radiolabeled somatostatin analogs.
- 2013
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In: Acta oncologica (Stockholm, Sweden). - 1651-226X .- 0284-186X. ; 52:4, s. 783-792
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Journal article (peer-reviewed)abstract
- Background. Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptor-mediated radiotherapy (PRRT). Material and methods. Expression profiling of SSTR1-5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ((111)In-octreotide) and measurement of (111)In activity in tumor specimens was performed in seven patients. Uptake and internalization of (177)Lu- octreotate was studied in primary cell cultures from two patients. Results. Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3-5 were expressed at low levels. Immunohistochemical analysis confirmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3-5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using (111)In-octreotide, demonstrated tumor uptake of (111)In in three of six GIST patients. Measurement of (111)In activity in excised tumor specimens from five patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifically bound and internalized (177)Lu when incubated with the therapeutic compound (177)Lu-octreotate for 4-48 hours (p < 0.05). Conclusion. Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.
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| 2. |
- Idborg, Helena, et al.
(author)
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STRATIFICATION OF SLE PATIENTS FOR IMPROVED DIAGNOSIS AND TREATMENT
- 2013
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 72, s. A80-A80
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Journal article (other academic/artistic)abstract
- Background. Systemic autoimmune diseases (SAIDs) affect about 2% of the population in Western countries. Sufficient diagnostic criteria are lacking due to the heterogeneity within diagnostic categories and apparent overlap regarding symptoms and patterns of autoantibodies between different diagnoses. Systemic lupus erythematosus (SLE) is regarded as a prototype for SAIDs and we hypothesise that subgroups of patients with SLE may have different pathogenesis and should consequently be subject to different treatment strategies.Objectives. Our goal is to find new biomarkers to be used for the identification of more homogenous patient populations for clinical trials and to identify sub-groups of patients with high risk of for example cardiovascular events.Methods. In this study we have utilised 320 SLE patients from the Karolinska lupus cohort and 320 age and gender matched controls. The SLE cohort was characterised based on clinical, genetic and serological data and combined by multivariate data analysis in a systems biology approach to study possible subgroups. A pilot study was designed to verify and investigate suggested subgroups of SLE. Two main subgroups were defined: One group was defined as having SSA and SSB antibodies and a negative lupus anticoagulant test (LAC), i.e., a “Sjögren-like” group. The other group was defined as being negative for SSA and SSB antibodies but positive in the LAC test.i.e. an “APS-like” group. EDTA-plasma from selected patients in these two groups and controls were analysed using a mass spectrometry (MS) based proteomic and metabolomic approach. Pathway analysis was then performed on the obtained data.Results. Our pilot study showed that differences in levels of proteins and metabolites could separate disease groups from population controls. The profile/pattern of involved factors in the complement system supported a division of SLE in two major subgroups, although each individual factor was not significantly different between subgroups. Complement factor 2 (C2) and membrane attack complex (MAC) were analysed in the entire cohort with complementary methods and C2 verifies our results while the levels of MAC did not differ between SLE subgroups. The generated metabolomics data clearly separated SLE patients from controls in both gas chromatography (GC)-MS and liquid chromatography (LC)-MS data. We found for example that tryptophan was lower in the SLE patients compared to controls.Conclusions. Our systems biology approach may lead to a better understanding of the disease and its pathogenesis, and assigning patients into subgroups will result in improved diagnosis and better outcome measures of SLE.
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| 3. |
- Mårtensson, Johanna, et al.
(author)
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Spatial analysis of diffusion tensor tractography statistics along the inferior fronto-occipital fasciculus with application in progressive supranuclear palsy
- 2013
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In: Magnetic Resonance Materials in Physics, Biology and Medicine. - : Springer Science and Business Media LLC. - 0968-5243 .- 1352-8661. ; 26:6, s. 527-537
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Journal article (peer-reviewed)abstract
- The purpose of the study was to develop a method for analysis of diffusion parameters along white matter (WM) tracts, using spatial normalization based on anatomical landmarks, and to introduce the apparent area coefficient (AAC). The method's applicability was tested in the inferior fronto-occipital fasciculus (IFO) in patients with progressive supranuclear palsy (PSP) and healthy controls (HCs). A framework for analysis of diffusion parameters was developed. Spatial normalization of the tracts was performed using anatomical landmarks, to avoid deformations caused by cerebral atrophy. Initially, 38 HCs were used to optimize a threshold for the minimal size of regions that differ between groups. The fractional anisotropy, mean diffusivity, AAC, and the hemispheric asymmetry index (AI), were compared between 11 PSP patients and 15 HCs. The method was feasible for analysis of PSP patients and HCs. The AI showed that the observed hemispheric asymmetry of AAC was significantly larger in PSP patients compared with HCs in small regions of the IFO. The method was successfully employed for analysis of diffusion parameters along the IFO in a patient group. This method can be potentially useful in studies of WM diseases, with or without cerebral atrophy.
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| 4. |
- Nilsson, Johanna, et al.
(author)
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Characterization of site-specific O-glycan structures within the mucin-like domain of alpha-dystroglycan from human skeletal muscle.
- 2010
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In: Glycobiology. - : Oxford University Press (OUP). - 1460-2423 .- 0959-6658. ; 20:9, s. 1160-9
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Journal article (peer-reviewed)abstract
- The glycosylation of the extracellular protein alpha-dystroglycan is important for its ligand-binding activity, and altered or blocked glycosylation is associated with several forms of congenital muscular dystrophies. By immunoprecipitation and sialic acid capture-and-release enrichment strategies, we isolated tryptic glycopeptides of alpha-dystroglycan from human skeletal muscle. Nano-liquid chromatography tandem mass spectrometry was used to identify both glycopeptides and peptides corresponding to the mucin-like and C-terminal domain of alpha-dystroglycan. The O-glycans found had either Hex-O-Thr or HexNAc-O-Ser/Thr anchored structures, which were often elongated and frequently, but not always, terminated with sialic acid. The HexNAc-O-Ser/Thr, but not Hex-O-Thr glycopeptides, displayed heterogeneity regarding glycan core structures and level of glycosylation site occupancy. We demonstrate for the first time glycan attachment sites of the NeuAcHexHexNAcHex-O structure corresponding to the anticipated Neu5Acalpha3Galbeta4GlcNAcbeta2Man-O-glycan (sLacNAc-Man), within the mucin-like domain of human alpha-dystroglycan from human skeletal muscle. Twenty-five glycopeptides were characterized from human alpha-dystroglycan, which provide insight to the complex in vivo O-glycosylation of alpha-dystroglycan.
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| 5. |
- Nilsson, Johanna, et al.
(author)
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LC-MS/MS characterization of combined glycogenin-1 and glycogenin-2 enzymatic activities reveals their self-glucosylation preferences.
- 2014
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In: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1844:2, s. 398-405
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Journal article (peer-reviewed)abstract
- Glycogen synthesis is initiated by self-glucosylation of the glycosyltransferases glycogenin-1 and -2 that, in the presence of UDP-glucose, form both the first glucose-O-tyrosine linkage, and then stepwise add a series of α1,4-linked glucoses to a growing chain of variable length. Glycogen-1 and -2 coexist in liver glycogen preparations where the proteins are known to form homodimers, and they also have been shown to interact with each other. In order to study how glycogenin-1 and -2 interactions may influence each other's glucosylations we setup a cell-free expression system for in vitro production and glucosylation of glycogenin-1 and -2 in various combinations, and used a mass spectrometry based workflow for the characterization and quantitation of tryptic glycopeptides originating from glycogenin-1 and -2. The analysis revealed that the self-glucosylation endpoint was the incorporation of 4-8 glucose units on Tyr 195 of glycogenin-1, but only 0-4 glucose units on Tyr-228 of glycogenin-2. The glucosylation of glycogenin-2 was enhanced to 2-4 glucose units by the co-presence of enzymatically active glycogenin-1. Glycogenin-2 was, however, unable to glucosylate inactive glycogenin-1, at least not an enzymatically inactivated Thr83Met glycogenin-1 mutant, recently identified in a patient with severe glycogen depletion.
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| 6. |
- Nilsson, Johanna, et al.
(author)
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Molecular pathogenesis of a new glycogenosis caused by a glycogenin-1 mutation.
- 2012
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In: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002. ; 1822:4, s. 493-9
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Journal article (peer-reviewed)abstract
- Glycogenin-1 initiates the glycogen synthesis in skeletal muscle by the autocatalytic formation of a short oligosaccharide at tyrosine 195. Glycogenin-1 catalyzes both the glucose-O-tyrosine linkage and the α1,4 glucosidic bonds linking the glucose molecules in the oligosaccharide. We recently described a patient with glycogen depletion in skeletal muscle as a result of a non-functional glycogenin-1. The patient carried a Thr83Met substitution in glycogenin-1. In this study we have investigated the importance of threonine 83 for the catalytic activity of glycogenin-1. Non-glucosylated glycogenin-1 constructs, with various amino acid substitutions in position 83 and 195, were expressed in a cell-free expression system and autoglucosylated in vitro. The autoglucosylation was analyzed by gel-shift on western blot, incorporation of radiolabeled UDP-(14)C-glucose and nano-liquid chromatography with tandem mass spectrometry (LC/MS/MS). We demonstrate that glycogenin-1 with the Thr83Met substitution is unable to form the glucose-O-tyrosine linkage at tyrosine 195 unless co-expressed with the catalytically active Tyr195Phe glycogenin-1. Our results explain the glycogen depletion in the patient expressing only Thr83Met glycogenin-1 and why heterozygous carriers without clinical symptoms show a small proportion of unglucosylated glycogenin-1.
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| 7. |
- Santillo, Alexander Frizell, et al.
(author)
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Diffusion Tensor Tractography versus Volumetric Imaging in the Diagnosis of Behavioral Variant Frontotemporal Dementia
- 2013
-
In: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:7, s. e66932-
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Journal article (peer-reviewed)abstract
- MRI diffusion tensor imaging (DTI) studies of white matter integrity in behavioral variant frontotemporal dementia have consistently shown involvement of frontal and temporal white matter, corresponding to regional loss of cortical volume. Volumetric imaging has a suboptimal sensitivity as a diagnostic tool and thus we wanted to explore if DTI is a better method to discriminate patients and controls than volumetric imaging. We examined the anterior cingulum bundle in 14 patients with behavioral variant frontotemporal dementia and 22 healthy controls using deterministic manual diffusion tensor tractography, and compared DTI parameters with two measures of cortical atrophy, VBM and cortical thickness, of the anterior cingulate cortex (ACC). Statistically significant changes between patients and controls were detected in all DTI parameters, with large effect sizes. ROC-AUC was for the best DTI parameters: 0.92 (fractional anisotropy) to 0.97 (radial diffusivity), 0.82 for the best cortical parameter, VBM of the ACC. Results from the AUC were confirmed with binary logistic regression analysis including demographic variables, but only for fractional anisotropy and mean diffusivity. Ability to classify patient/nonpatient status was significantly better for mean diffusivity vs. VBM (p = 0.031), and borderline significant for fractional anisotropy vs. VBM (p = 0.062). The results indicate that DTI could offer advantages in comparison with the assessment of cortical volume in differentiating patients with behavioral variant frontotemporal dementia and controls.
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| 8. |
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| 9. |
- Tengdelius-Brunell, Johanna, et al.
(author)
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Anpassning av HYPE-modellen för läckage-koefficienter och typhalter för att möjliggöra användandet av läckagekoefficienter och typhal-ter från jordbruk, hyggen, skog, myr, fjäll och öppen mark i HYPE-modellen Anpassning av HYPE-modellen för läckage-koefficienter och typhalter Anpassning av HYPE-modellen för läckage-koefficienter och typhalter Anpassning av HYPE-modellen för läckage-koefficienter och typhalter
- 2013
-
Reports (other academic/artistic)abstract
- Projektets huvudsyfte är att sammanfoga HYPE-modellens (SMHI:s vattenkvalitets modell) beräkningar av vattenflöde samt kväve- och fosforprocesser med beräk-nade markläckagekoefficienter och typhalter. I projektet utreds även behovet av att tillföra en säsongsdynamik i läckaget av fosfor från åkermark.De typhalter för skog, myr, öppen mark, fjäll och hygge som använts vid PLC5-beräkningarna samt jordbruksläckage från NLeCCS har applicerats på alla delav-rinningsområden i S-HYPE 2010.De ursprungliga markprocesserna i HYPE-modellen är helt bortkopplade så att inget kväve- och fosforläckage beräknas. Istället beräknas markläckaget utifrån läckagekoefficienter och typhalter samt det vatten som lämnar varje markanvänd-ning. Markanvändningen i dessa beräkningar skiljer sig något från markanvänd-ningen i S-HYPE, därför viktas markläckaget mellan beräkningarna enligt en kopp-lingstabell. För de flesta markanvändningar finns en månadsvariation i form av en månadskoefficient som läggs till markläckaget från varje markanvändning för att skapa en årsdynamik.Efter att markläckaget, beräknat utifrån läckagekoefficienterna och typhalterna, implementerats sker inga förändringar av de processer som finns i originalversion-en av HYPE. Alltså vidtar de inbyggda sjö- och vattendragsprocesser som existerar sedan tidigare i modellen.Projektet, som enbart syftar till att sammanfoga HYPE-modellens beräkningar med beräknade markläckagekoefficienter från NLeCCS och övriga typhalter, innebär inte att modellen är färdig för beräkningarna till PLC6. En omfattande validering av modellen återstår för att utvärdera resultatets kvalitet och bedöma huruvida eventuella problem bör hanteras innan modellen kan tas i bruk för PLC6-arbetet. Dessutom behöver modellens atmosfärsdeposition och källfördelning ses över.Slutsatsen gällande säsongsdynamik i läckaget av fosfor från åkermark är att fos-forförluster, som orsakas av enstaka regntillfällen som skapar ytavrinning och makroporflöden, överskuggar eventuella tendenser till säsongsvariation av fosfors rörlighet och därmed även av fosforkoncentrationen i avrinnande vatten från åker-marken. Dynamiken av fosfor- och kväveförlusten bedöms vara mer flödesbero-ende än årstidsberoende.
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| 10. |
- Abelev, Betty, et al.
(author)
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Long-range angular correlations on the near and away side in p-Pb collisions at root S-NN=5.02 TeV
- 2013
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In: Physics Letters. Section B: Nuclear, Elementary Particle and High-Energy Physics. - : Elsevier BV. - 0370-2693. ; 719:1-3, s. 29-41
-
Journal article (peer-reviewed)abstract
- Angular correlations between charged trigger and associated particles are measured by the ALICE detector in p-Pb collisions at a nucleon-nucleon centre-of-mass energy of 5.02 TeV for transverse momentum ranges within 0.5 < P-T,P-assoc < P-T,P-trig < 4 GeV/c. The correlations are measured over two units of pseudorapidity and full azimuthal angle in different intervals of event multiplicity, and expressed as associated yield per trigger particle. Two long-range ridge-like structures, one on the near side and one on the away side, are observed when the per-trigger yield obtained in low-multiplicity events is subtracted from the one in high-multiplicity events. The excess on the near-side is qualitatively similar to that recently reported by the CMS Collaboration, while the excess on the away-side is reported for the first time. The two-ridge structure projected onto azimuthal angle is quantified with the second and third Fourier coefficients as well as by near-side and away-side yields and widths. The yields on the near side and on the away side are equal within the uncertainties for all studied event multiplicity and p(T) bins, and the widths show no significant evolution with event multiplicity or p(T). These findings suggest that the near-side ridge is accompanied by an essentially identical away-side ridge. (c) 2013 CERN. Published by Elsevier B.V. All rights reserved.
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