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1.
  • Maksimovic, M., et al. (författare)
  • The Solar Orbiter Radio and Plasma Waves (RPW) instrument
  • 2020
  • Ingår i: Astronomy and Astrophysics. - : EDP SCIENCES S A. - 0004-6361 .- 1432-0746. ; 642
  • Tidskriftsartikel (refereegranskat)abstract
    • The Radio and Plasma Waves (RPW) instrument on the ESA Solar Orbiter mission is described in this paper. This instrument is designed to measure in-situ magnetic and electric fields and waves from the continuous to a few hundreds of kHz. RPW will also observe solar radio emissions up to 16 MHz. The RPW instrument is of primary importance to the Solar Orbiter mission and science requirements since it is essential to answer three of the four mission overarching science objectives. In addition RPW will exchange on-board data with the other in-situ instruments in order to process algorithms for interplanetary shocks and type III langmuir waves detections.
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2.
  • Botling, Johan, et al. (författare)
  • Biomarker Discovery in Non-Small Cell Lung Cancer : Integrating Gene Expression Profiling, Meta-analysis, and Tissue Microarray Validation
  • 2013
  • Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 19:1, s. 194-204
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multigene signatures in clinical practice is unclear, and the biologic importance of individual genes is difficult to assess, as the published signatures virtually do not overlap.Experimental Design: Here, we describe a novel single institute cohort, including 196 non-small lung cancers (NSCLC) with clinical information and long-term follow-up. Gene expression array data were used as a training set to screen for single genes with prognostic impact. The top 450 probe sets identified using a univariate Cox regression model (significance level P < 0.01) were tested in a meta-analysis including five publicly available independent lung cancer cohorts (n = 860).Results: The meta-analysis revealed 14 genes that were significantly associated with survival (P < 0.001) with a false discovery rate < 1%. The prognostic impact of one of these genes, the cell adhesion molecule 1 (CADM1), was confirmed by use of immunohistochemistry on tissue microarrays from 2 independent NSCLC cohorts, altogether including 617 NSCLC samples. Low CADM1 protein expression was significantly associated with shorter survival, with particular influence in the adenocarcinoma patient subgroup.Conclusions: Using a novel NSCLC cohort together with a meta-analysis validation approach, we have identified a set of single genes with independent prognostic impact. One of these genes, CADM1, was further established as an immunohistochemical marker with a potential application in clinical diagnostics. Clin Cancer Res; 19(1); 194-204. (c) 2012 AACR.
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3.
  • Holleboom, Adriaan G, et al. (författare)
  • Heterozygosity for a Loss-of-Function Mutation in GALNT2 Improves Plasma Triglyceride Clearance in Man
  • 2011
  • Ingår i: Cell Metabolism. - : Elsevier. - 1550-4131 .- 1932-7420. ; 14:6, s. 811-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Genome-wide association studies have identified GALNT2 as a candidate gene in lipid metabolism, but it is not known how the encoded enzyme ppGalNAc-T2, which contributes to the initiation of mucin-type O-linked glycosylation, mediates this effect. In two probands with elevated plasma high-density lipoprotein cholesterol and reduced triglycerides, we identified a mutation in GALNT2. It is shown that carriers have improved postprandial triglyceride clearance, which is likely attributable to attenuated glycosylation of apolipoprotein (apo) C-III, as observed in their plasma. This protein inhibits lipoprotein lipase (LPL), which hydrolyses plasma triglycerides. We show that an apoC-III-based peptide is a substrate for ppGalNAc-T2 while its glycosylation by the mutant enzyme is impaired. In addition, neuraminidase treatment of apoC-III which removes the sialic acids from its glycan chain decreases its potential to inhibit LPL. Combined, these data suggest that ppGalNAc-T2 can affect lipid metabolism through apoC-III glycosylation, thereby establishing GALNT2 as a lipid-modifying gene.
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4.
  • Maksimovic, M., et al. (författare)
  • First observations and performance of the RPW instrument on board the Solar Orbiter mission
  • 2021
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 656
  • Tidskriftsartikel (refereegranskat)abstract
    • The Radio and Plasma Waves (RPW) instrument on the ESA Solar Orbiter mission is designed to measure in situ magnetic and electric fields and waves from the continuum up to several hundred kHz. The RPW also observes solar and heliospheric radio emissions up to 16 MHz. It was switched on and its antennae were successfully deployed two days after the launch of Solar Orbiter on February 10, 2020. Since then, the instrument has acquired enough data to make it possible to assess its performance and the electromagnetic disturbances it experiences. In this article, we assess its scientific performance and present the first RPW observations. In particular, we focus on a statistical analysis of the first observations of interplanetary dust by the instrument's Thermal Noise Receiver. We also review the electro-magnetic disturbances that RPW suffers, especially those which potential users of the instrument data should be aware of before starting their research work.
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5.
  • Hellquist, H. B., et al. (författare)
  • Bcl-2 immunoreactivity in salivary gland neoplasms is unrelated to the expression of mRNA for natural killer cell stimulatory cytokines interleukin (IL)-2 and IL-12
  • 1996
  • Ingår i: Virchows Archiv. - New York, USA : Springer. - 0945-6317 .- 1432-2307. ; 429:2-3, s. 149-158
  • Tidskriftsartikel (refereegranskat)abstract
    • Certain cytokines are involved in the generation of natural killer (NK) cells and participate in the regulation of the proto-oncogene bcl-2. We aimed to study the mRNA expression of interleukin (IL)-2, IL-4 and IL-5, the composition of the tumour infiltrating lymphocytes (TIL), and the expression of bcl-2 in 14 benign and malignant human parotid tumours. T IL were predominantly composed of T lymphocytes and NK cells. We found evidence for the homing of T cells, and for generation of NK cells in the vicinity of the tumours. mRNA for IL-2 and IL-12, were identified but IL-4 mRNA was not found. The cytokine profiles and the composition of TIL of the two tumour categories were indistinguishable, suggesting that these host-response variables do not explain the differences in biological behaviour of these particular tumours. The results support a shift towards Th 1 (T helper 1) cells and interferon-gamma production, and that IL-12 also in vivo may play an important role in the regulatory interaction between innate resistance and adaptive immunity in tumour diseases. Most infiltrating lymphocytes showed strong expression of bcl-2; an interesting observation with regard to lymphocytic apoptosis in neoplastic diseases. The immunoreactivity for the bcl-2 protein varied considerably between and within tumours, and almost all benign tumours showed strong bcl-2 positively whereas several of the malignant tumours showed weak or absent staining. The variable expression of bcl-2 protein suggests a different susceptibility of tumour cells to apoptosis. The results also indicate that bcl-2 cannot pla a major role as protective agent in the specific apoptotic pathway induced by NK cells.
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6.
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7.
  • Mattsson, Johanna Sofia Margareta, 1985-, et al. (författare)
  • Prognostic impact of COX-2 in non-small cell lung cancer : a comprehensive compartment-specific evaluation of tumor and stromal cell expression
  • 2015
  • Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835 .- 1872-7980. ; 356:2, s. 837-845
  • Tidskriftsartikel (refereegranskat)abstract
    • Cyclooxygenase-2 (COX-2) is an enzyme that has been extensively investigated as a prognostic marker in cancer. In non-small cell lung cancer (NSCLC) previous results regarding the prognostic impact of COX-2 expression are inconsistent. Therefore we evaluated the association between transcript levels and overall survival in nine publicly available gene expression data sets (total n = 1337) and determined in situ compartment-specific tumor and stromal cell protein expression in two independent cohorts (n = 616). Gene expression did not show any correlation with clinical parameters or with overall survival. Protein expression in tumor and stromal cells did not correlate with any clinical parameter or with overall survival in one of the analyzed cohorts, while a significant association of high stromal expression with longer survival was observed in both univariate and multivariate analysis in the other cohort. Stromal expression of COX-2 has not been separately evaluated in NSCLC previously and may be a subject of further investigation, whereas the presented findings from this comprehensive compartment specific evaluation clearly reject the hypothesis of COX-2 tumor cell expression having a prognostic value in NSCLC. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
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8.
  • van der Wouden, C. H., et al. (författare)
  • Implementing Pharmacogenomics in Europe : Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium
  • 2017
  • Ingår i: Clinical Pharmacology and Therapeutics. - : WILEY. - 0009-9236 .- 1532-6535. ; 101:3, s. 341-358
  • Tidskriftsartikel (refereegranskat)abstract
    • Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multi-healthcare system approach.
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9.
  • Watanabe, A, et al. (författare)
  • Gunnar Fant 60 years
  • 1979
  • Ingår i: TMH-QPSR. ; 20:2, s. 1-45
  • Tidskriftsartikel (refereegranskat)
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10.
  • Bale, S. D., et al. (författare)
  • The FIELDS Instrument Suite for Solar Probe Plus
  • 2016
  • Ingår i: Space Science Reviews. - : Springer Science and Business Media LLC. - 0038-6308 .- 1572-9672. ; 204:1-4, s. 49-82
  • Forskningsöversikt (refereegranskat)abstract
    • NASA's Solar Probe Plus (SPP) mission will make the first in situ measurements of the solar corona and the birthplace of the solar wind. The FIELDS instrument suite on SPP will make direct measurements of electric and magnetic fields, the properties of in situ plasma waves, electron density and temperature profiles, and interplanetary radio emissions, amongst other things. Here, we describe the scientific objectives targeted by the SPP/FIELDS instrument, the instrument design itself, and the instrument concept of operations and planned data products.
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11.
  • Baverel, Paul G, et al. (författare)
  • Predictive performance of internal and external validation procedures
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Purpose: To compare estimates of predictive performance between internal (IV) and external data-splitting (EV) validation procedures. Methods: Datasets of different study size (n=6, 12, 24, 48, 96, 192, or 384 individuals) were simulated from a one compartment, first-order absorption, pharmacokinetic model and both parametric (FOCE), and nonparametric (NONP) parameter estimates were obtained in NONMEM. From these, three different validation procedures (IV, EV, and a population validation (PV)) were undertaken by means of numerical predictive checks (NPCs) to provide estimates of predictive performance, the PV procedure serving as a reference to assess performance of IV and EV. The predictive performance of NONP versus FOCE estimates was further assessed. Results: Estimates of predictive performance for predicting the median of the population distribution had in general significantly lower imprecision for IV than EV, with little bias for both procedures. For small study sizes, n=6-12 (FOCE) or n=6-24 (NONP), the tails of the population distribution were significantly more biased with IV than EV, but similar imprecision was obtained. The predictive performance for FOCE was similar or superior to that of NONP. Conclusions: Data-splitting is inferior to IV when evaluating predictive models to retain sufficient precision both in predictions and in estimates of predictive performance.
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12.
  • Cullberg, Marie, 1958- (författare)
  • Direct Thrombin Inhibitors in Treatment and Prevention of Venous Thromboembolism: Dose – Concentration – Response Relationships
  • 2006
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • For prevention and treatment of thrombotic diseases with an anticoagulant drug it is important that an adequate dose is given to avoid occurrence or recurrence of thrombosis, without increasing the risk of bleeding and other adverse events to unacceptable levels. The aim of this thesis was to develop mathematical models that describe the dose-concentration (pharmacokinetic) and concentration-response (pharmacodynamic) relationships of direct thrombin inhibitors, in order to estimate optimal dosages for treatment and long-term secondary prevention of venous thromboembolism (VTE).Population pharmacokinetic-pharmacodynamic models were developed, based on data from clinical investigations in healthy volunteers and patients receiving intravenous inogatran, subcutaneous melagatran and/or its oral prodrug ximelagatran. The benefit-risk profiles of different ximelagatran dosages were estimated using clinical utility functions. These functions were based on the probabilities and fatal consequences of thrombosis, bleeding and elevation of the hepatic enzyme alanine aminotransferase (ALAT).The studies demonstrate that the pharmacokinetics of melagatran and ximelagatran were predictable and well correlated to renal function. The coagulation marker, activated partial thromboplastin time (APTT), increased non-linearly with increasing thrombin inhibitor plasma concentration. Overall, the systemic melagatran exposure (AUC) and APTT were similarly predictive of thrombosis and bleedings. The identified relationship between the risk of ALAT-elevation and melagatran AUC suggests that the incidence approaches a maximum at high exposures. The estimated clinical utility was favourable compared to placebo in the overall study population and in special subgroups of patients following fixed dosing of ximelagatran for long-term secondary prevention of VTE. Individualized dosing was predicted to add limited clinical benefit in this indication.The models developed can be used to support the studied dosage and for selection of alternative dosing strategies that may improve the clinical outcome of ximelagatran treatment. In addition, the models may be extrapolated to aid the dose selection in clinical trials with other direct thrombin inhibitors.
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13.
  • Dreifaldt, Mats, 1959- (författare)
  • Conduits in coronary artery bypass grafting surgery : Saphenous vein, radial and internal thoracic arteries
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • A novel technique for saphenous vein (SV) graft harvesting, the No-touch technique (NT), has been developed at the Dept. of Cardiovascular surgery, Örebro University hospital. With NT the SV is harvested with a pedicle of surrounding tissue. This avoids graft spasm and eliminates the need for distension. The surrounding tissue acts as a structural support and is a rich source of vaso-dilating agents. A randomized controlled trial (RCT) has shown a significantly higher patency rate for NT SV grafts compared to SV grafts harvested with conventional technique (CT). This thesis evaluates some of the properties of the surrounding tissue and compares patency rates between NT SV and radial artery (RA) grafts and patency rates for internal thoracic artery (ITA) grafts harvested with and without surrounding tissue. Paper I investigated vasa vasorum (VV) in SV grafts and showed that the NT preserves an intact VV whereas CT does not. This could be one of the mechanisms underlying the improved patency for NT SV grafts. Paper II evaluated VV and associated nitric oxide (NO) in SV and arterial grafts. SV grafts showed a higher number and larger VV, which correlated with NO production, compared to arterial grafts. NT SV grafts showed higher activity for e-NOS compared to CT SV grafts. Paper III is a RCT comparing patency rates between NT SV and RA grafts, three years after surgery, showing a significantly higher patency rate for NT SV grafts. Paper IV is a RCT comparing patency rates for ITA graft harvested with and without surrounding tissue and did not show any difference between graft preparations. In conclusion, the NT for SV graft harvesting preserves an intact vasa vasorum and associated NO production. NT SV grafts show a higher patency rate than RA grafts. Harvesting of ITA with or without surrounding tissue does not affect patency rate. 
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14.
  • Dreifaldt, Mats, et al. (författare)
  • The ‘‘no-touch’’ harvesting technique for vein grafts in coronary artery bypass surgery preserves an intact vasa vasorum
  • 2011
  • Ingår i: The Internet Journal of Thoracic and Cardiovascular Surgery. - New York, USA : Elsevier. - 1524-0274 .- 0022-5223. ; 141:1, s. 145-150
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Our objective was to evaluate the impact of vein graft harvesting technique on structure and function of vasa vasorum.Methods: Paired segments of great saphenous veins harvested either with conventional harvesting technique or no-touch technique were obtained from 9 consecutive patients undergoing coronary artery bypass grafting. Quantitative measurements, using immunohistochemistry and morphometry, were performed. Ultrastructural analyses of vasa vasorum were performed with electron microscopy. Video footage of superficial vasa vasorum in an implanted saphenous vein graft harvested with the no-touch technique was captured during a coronary bypass operation and is presented for online viewing.Results: The total area of vasa vasorum in vein grafts harvested with the conventional technique was significantly reduced both in the media (P¼.007) and in the adventitia (P¼.014) compared with vein grafts harvested with the no-touch technique. Ultrastructural findings indicated that the no-touch technique preserved an intact vasa vasorum whereas the conventional technique did not. Video footage showed retrograde flow in the vasa vasorum in vein graft harvested with the no-touch technique.Conclusions: These findings showthat the no-touch technique for saphenous vein graft harvesting for coronary bypass grafting preserves an intact vasa vasorum. This could represent one of the mechanisms underlying the improved patency of saphenous vein grafts harvested with this technique.
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15.
  • Falck, Eva, et al. (författare)
  • Loss of Glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
  • 2010
  • Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.
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16.
  • Hadgu, Endale, et al. (författare)
  • Distribution and characteristics of androgen receptor (AR) in breast cancer among women in Addis Ababa, Ethiopia : A cross sectional study
  • 2020
  • Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 15:5
  • Tidskriftsartikel (refereegranskat)abstract
    • Evaluation of the role of androgen receptor (AR) in the biology of breast cancer is an emerging area of research. There are compelling evidences that AR expression may be used to further refine breast cancer molecular subtyping with prognostic and therapeutic implications. Many studies indicated co-expression of AR with the hormonal receptors in breast cancer has a favorable prognosis. AR is also investigated by many researchers as a potential therapeutic target in treatment of breast cancer. Studies on the frequency and distribution of AR in breast cancer among Africans is barely available. Given the heightened interest to understand its role in breast cancer, we determined AR expression and assessed its association with clinicopathological parameters among Ethiopian women. In this study, 112 newly diagnosed patient with invasive breast cancer at Tikur Anbessa Specialized Hospital were enrolled. Immunohistochemical assessment of AR, ER, PR, Ki67 and HER2 were performed using tissue microarrays (TMA) constructed from their primary tumor block. Out of the 112 participants, 91 (81%) were positive for AR expression and the remaining 21 participants (19%) were negative for AR expression. Expression of AR in ER+, HER2+ and TNBC cases were 93%, 83% and 48% respectively. Our study reveals AR is expressed in a significant number of breast cancers patients and this may indicate that breast cancers cases in Ethiopia have favorable prognosis and could benefit from progresses in AR targeted treatments. Since AR expression has important consequences on the prognosis and treatment of breast cancer, further studies with an increased number of participants is necessary to confirm our reports.
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17.
  • Hoffman, Tove, et al. (författare)
  • Association between guilds of birds in the African-Western Palaearctic region and the tick species Hyalomma rufipes, one of the main vectors of Crimean-Congo hemorrhagic fever virus.
  • 2022
  • Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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18.
  • Hoffman, Tove, et al. (författare)
  • Co-occurrence of Francisella and spotted fever group Rickettsia in avian-associated Hyalomma rufipes
  • 2022
  • Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The migratory behaviour of wild birds aids in the geographical spread of ticks and their microorganisms. Ticks are known to harbor both pathogenic and symbiotic bacteria - such as species of the genera Francisella, Rickettsia,and Midichloria - and multiple bacterial species may occur within them. Francisella occurs in different tick taxa andconsists of closely related pathogenic and non-pathogenic species. Spotted fever group Rickettsia are transmitted to humans by different tick genera and are emerging human pathogens in Europe. The aims of this study were to investigate dispersal of Francisella as well as co-occurrence of Francisella and spotted fever group Rickettsia in ticks infesting northward migrating birds in the African-Western Palaearctic region.Materials and methods: Birds were trapped using mist nets at bird observatories in Spain, Italy, Greece, and Israel during their spring migration of 2014 and 2015. Ticks were screened for the genus Francisella, the species Francisella tularensis, and spotted fever group Rickettsia by microfluidic qPCR. Ticks with putative positive results for F. tularensiswere subjected to confirmation analyses, metagenomics analysis, enrichment, and whole genome sequencing.Results: There was a high prevalence of Francisella species (76.7%) and co-occurrence of Francisella species and spotted fever group Rickettsia (50.6%) in the tick species Hyalomma rufipes. Two H. rufipes yielded putative positive test results for the human pathogen F. tularensis during initial screening. Metagenomics analysis revealed presence of Francisella sp., Rickettsia sp., and Midichloria sp. DNA in the two H. rufipes ticks. The levels of Rickettsia and Midichloria DNA were relatively high while the level of Francisella DNA was low and required enrichment for the construction of metagenome-assembled genomes. Phylogenetic inference and calculations of the average nucleotide identity (ANI) indicated that: i) the Francisella genomes belonged to the Francisella-like endosymbiont (FLE) group in Clade 1 of Francisella and had highest sequence identity to an FLE found in Ornithodoros moubata (ANI: 96.7/97.0%), ii) the Rickettsia genomes had highest resemblance to Rickettsia aeschlimannii (ANI: 98.8 - 99.9%), and iii) the Midichloria genomes resembled Midichloria mitochondrii (ANI: 91.5 - 92.3%).Conclusions: The results of this study suggest ticks containing Francisella species, FLEs, and spotted fever groupRickettsia are dispersed by northbound migratory birds in the African-Western Palaearctic and suggest H. rufipes may not be involved in the transmission of F. tularensis in the study region. Future studies should aim at confirming the prevalence of Francisella spp. and spotted fever group Rickettsia in H. rufipes, in addition to focusing on the influence of FLEs on H. rufipes and their interaction with pathogenic and symbiotic bacteria of the genera Rickettsia and Midichloria. 
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19.
  • Hoffman, Tove, et al. (författare)
  • Co-Occurrence of Francisella, Spotted Fever Group Rickettsia, and Midichloria in Avian-Associated Hyalomma rufipes
  • 2022
  • Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
  • Tidskriftsartikel (refereegranskat)abstract
    • The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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20.
  • Jahnson, S., et al. (författare)
  • p53 and Rb immunostaining in locally advanced bladder cancer : relation to prognostic variables and predictive value for the local response to radical radiotherapy
  • 1995
  • Ingår i: European Urology. - Basel, Switzerland : S. Karger. - 0302-2838 .- 1873-7560. ; 28:2, s. 135-142
  • Tidskriftsartikel (refereegranskat)abstract
    • The association between known prognostic variables and altered immunostaining for the nuclear proteins retinoblastoma (Rb) and p53 was studied in a homogeneous series of locally advanced bladder cancer. The predictive value of this immunostaining for the local response to intended radical radiotherapy was investigated. Among 262 patients treated with intended radical radiotherapy between 1967 and 1986, a total of 154 patients were evaluable with respect to local response to treatment. The paraffin-embedded specimen from the tumour prior to irradiation was immunostained with the monoclonal antibodies PMG3-245 for Rb and 1801 for p53 nuclear proteins after heating in a microwave oven for 40 min at 650 W. An altered expression of Rb and p53 was observed in 18 and 42% of the tumours, respectively. p53 overexpression was associated with higher tumour grade. However, the results of the p53 and Rb immunostaining procedures had no predictive value for tumor response to radiation treatment, local control or cancer-specific mortality.
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21.
  • Karlsson, Christina, et al. (författare)
  • Effects of long-term storage on the detection of proteins, DNA, and mRNA in tissue microarray slides
  • 2011
  • Ingår i: Journal of Histochemistry and Cytochemistry. - : Sage Publications. - 0022-1554 .- 1551-5044. ; 59:12, s. 1113-1121
  • Tidskriftsartikel (refereegranskat)abstract
    • Storage of tissue slides has been claimed to induce dramatically reduced antigen detection particularly for immunohistochemistry (IHC). With tissue microarrays, the necessity to serially cut blocks in order to obtain as much material as possible is obvious. The presumed adverse effect of storage might hamper such an approach. The authors designed an experimental setting consisting of four different storage conditions with storage time of tissue slides of up to 1 year. Detection of proteins, DNA, and mRNA was performed using IHC and in situ hybridization techniques. Slight but significant changes in IHC occurred over time. The most important factor is the primary antibody used: four showed no significant changes, whereas limited decreases in 8 antibodies could be detected by image analysis. Whether the antigen was nuclear or cytoplasmic/membranous did not matter. No major differences between different storage conditions could be shown, but storage at 4C was overall the best procedure. Furthermore, gene copy number aberrations, chromosomal translocations, and the presence of mRNA could be detected on slides stored up to 1 year. In conclusion, in tissues optimally formalin fixed and using modern histological techniques, only minute changes in tissue antigenicity are induced by long-term storage.
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22.
  • Karlsson, Christina, et al. (författare)
  • Estrogen receptor α phosphorylation and EGFR in non-small cell lung carcinoma
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Non small cell lung carcinoma (NSCLC) occurs in two major histological types, squamous cell carcinoma (SCC) and adenocarcinoma (ADCA). There are well characterized differences in the carcinogenesis between these types. For example, epidermal growth factor receptor (EGFR) is frequently amplified and over expressed in SCC whilst mutations occur in ADCA. There are also gender associated differences in the relative incidence of SCC and ADCA. Estrogen receptor (ER) driven signalling have been proposed to play a role in this context. ER occurs in two different forms, α and β. The presence of ERα in NSCLC has been a matter of discussion. Immunohistochemical (IHC) analysis has reported divergent results, but the presence of ERα transcripts has been established to be widespread in NSCLC. ERα could be activated/phosphorylated in several ways, either ligand (estradiol) dependent or ligand independent. A potential crosstalk between EGFR and ERα has been proposed by a mechanism where EGFR signalling induces phosphorylation at specific sites within the ERα receptor.We investigated in the present study, in a material of 262 NSCLC, by IHC the presence of a phosphorylated form of ERα, pERαS118, and correlated these findings to EGFR over expression as well as an ERα co-activator, CREB, which has been associated to ligand independent phosphorylation of ERα at that specific site.We describe a widespread occurrence of pERαS118 in both SCC and ADCA. Furthermore, pERαS118is correlated to EGFR over expression in SCC. We propose a combined targeting of ERα and EGFR crosstalk as a possibility in the targeted therapy of SCC.
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23.
  • Karlsson, Christina, et al. (författare)
  • Estrogen receptor β in NSCLC : prevalence, proliferative influence, prognostic impact and smoking
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • In non-small cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for estrogen receptor (ER) signalling has been proposed and experimental as well as epidemiological data supports this view. In a material of NSCLC (n=262), ERβ and cyclins A and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ERβ) and cyclin A1 were performed. Data was correlated to histology, gender, smoking habits, stage and clinical outcome.ERβ was expressed in 86% of the cases. ERβ was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ERβ expression and cyclins was observed in ADCA, also with a male predominance. ERβ transcripts had a positive prognostic impact in ADCA. ERβ transcripts were also increased in NSCLC among smokers compared to non-smokers.In conclusion, we report data supporting a role for ERβ in lung ADCAs where ERβ could be a biomarker for future targeted therapies.
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24.
  • Karlsson, Christina, et al. (författare)
  • Nuclear HER-4 (4ICD) and Estrogen Receptor α in non-small-cell lung carcinoma
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • In non-small cell lung carcinoma (NSCLC) squamous cell carcinomas (SCC) occurs more frequently among men and adenocarcinomas (ADCA) in females. The presence of estrogen receptors (ERs) in NSCLC have been proposed as a factor contributing to the gender associated differences. HER-4, a member of the epidermal growth factor receptor family, has recently been identified as a co-activator to ER by action of the shredded intracellular domain, 4ICD.Our study was performed on tissue material from 262 NSCLC. In 137 cases, frozen material was available. HER-4/4ICD, ERα, PgR and aromatase was determined by immunohistochemistry. HER-4 gene copy number and HER-4 and ERα transcripts was also studied. Data was correlated to proliferation, histology, gender, smoking habits and clinical outcome.We report the presence of n4ICD, significantly more frequently occurring in ADCA than in SCC. Furthermore, n4ICD and ERα expression was associated with the concomitant expression of aromatase. n4ICD was negatively correlated to proliferation in ADCA. Interestingly, a strong correlation between never smoking and n4ICD positivity was found among females and in the ADCA group.In breast carcinomas, n4ICD is a biomarker for anti-ER treatment. A number of observations including our finding of n4ICD can constitute support for anti-ER treatment strategies in NSCLC.
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25.
  • Karlsson, Christina, 1968-, et al. (författare)
  • Oestrogen receptor ss in NSCLC : prevalence, proliferative influence, prognostic impact and smoking
  • 2012
  • Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS). - Malden, USA : Wiley-Blackwell. - 0903-4641 .- 1600-0463. ; 120:6, s. 451-458
  • Tidskriftsartikel (refereegranskat)abstract
    • In non-small-cell lung carcinoma (NSCLC) there are gender differences. The female gender is associated with more adenocarcinomas (ADCA), among both smokers and non-smokers compared to men. Women with NSCLC have a better prognosis compared to men, regardless of other factors. A possible role for oestrogen receptor (ER) signalling has been proposed. The role for ER beta in NSCLC is still not clear, especially concerning the impact of smoking. In a material of NSCLC (n = 262), ER beta and cyclins A1 and A2 were studied by immunohistochemistry on formalin-fixed paraffin embedded tissue. In 137 of those cases, frozen material was available, on which expression analysis of ESR2 (ER beta) and cyclin A1 were performed. Data were correlated to histology, gender, smoking habits, stage and clinical outcome. ER beta was expressed in 86% of the cases. ER beta was most frequently expressed in Stage I ADCAs, especially in male subjects. A correlation between ER beta expression and cyclins was observed in ADCA, also with a male predominance. ER beta transcripts had a positive prognostic impact in ADCA. ER beta transcripts were increased in NSCLC among smokers compared to non-smokers. In conclusion, our data support a role for ER beta in lung ADCAs, proposing a role for ER beta in lungcarcinogenesis, especially among smokers.
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26.
  • Karlsson, Christina, et al. (författare)
  • Tissue microarray validation : a methodologic study with special reference to lung cancer
  • 2009
  • Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 18:7, s. 2014-2021
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Although tissue microarray (TMA) studies of histopathologic material have been frequently reported in studies of malignant diseases, the question of sample size (i.e., the diameter and the number of tissue cylinders investigated) has been rarely discussed. This study addresses the methodologic question of sample size in a variety of tumor types.MATERIAL AND METHODS: Material from 29 cases of lung carcinoma (small cell, squamous cell, and adenocarcinomas) was examined immunohistochemically for Ki-67 and p53 expression in virtually constructed cylinders of different diameters. The influence of tissue sample size (i.e., different numbers of virtual cylinders) was also investigated. Results from Ki-67 evaluation were analyzed as a continuous variable, whereas p53 expression was scored. p53 evaluations based on scoring in cylinders versus scoring of whole sections were also compared. Furthermore, 10 cases of endometrial and breast carcinomas were evaluated for estrogen receptor, Ki-67, and HER2 by scoring up to five cylinders.RESULTS AND CONCLUSIONS: Tissue cylinders of 0.6 and 1.0 mm diameters were compared and found equally informative about Ki-67 expression (intraclass correlation, 0.96). A statistical approach considering intraindividual and interindividual variation data is presented, indicating that in this specific setting three cylinders per case is an adequate sample size for TMA studies. Further sampling yields only a small gain in accuracy as determined by Ki-67 quantification and p53 scoring (kappa-coefficient, 0.9). For endometrial and breast tissues, TMA scoring of three cylinders yielded excellent agreement (kappa, >0.75) compared with whole-section scoring.
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27.
  • Karlsson, Helen, et al. (författare)
  • Wear Particles from Studded Tires and Granite Pavement Induce Pro-inflammatory Alterations in Human Monocyte-Derived Macrophages : A Proteomic Study.
  • 2011
  • Ingår i: Chemical Research in Toxicology. - : American Chemical Society. - 0893-228X .- 1520-5010. ; 24, s. 45-53
  • Tidskriftsartikel (refereegranskat)abstract
    • Airborne particulate matter is considered to be one of the environmental contributors to the mortality in cancer, respiratory, and cardiovascular diseases. For future preventive actions, it is of major concern to investigate the toxicity of defined groups of airborne particles and to clarify their pathways in biological tissues. To expand the knowledge beyond general inflammatory markers, this study examined the toxicoproteomic effects on human monocyte derived macrophages after exposure to wear particles generated from the interface of studded tires and a granite-containing pavement. As comparison, the effect of endotoxin was also investigated. The macrophage proteome was separated using two-dimensional gel electrophoresis. Detected proteins were quantified, and selected proteins were identified by matrix-assisted laser desorption/ionization time of flight mass spectrometry. Among analyzed proteins, seven were significantly decreased and three were increased by exposure to wear particles as compared to unexposed control cells. Endotoxin exposure resulted in significant changes in the expression of six proteins: four decreased and two increased. For example, macrophage capping protein was significantly increased after wear particle exposure only, whereas calgizzarin and galectin-3 were increased by both wear particle and endotoxin exposure. Overall, proteins associated with inflammatory response were increased and proteins involved in cellular functions such as redox balance, anti-inflammatory response, and glycolysis were decreased. Investigating the effects of characterized wear particles on human macrophages with a toxicoproteomic approach has shown to be useful in the search for more detailed information about specific pathways and possible biological markers.
  •  
28.
  • Le Lay, G., et al. (författare)
  • Nature of the root 3 alpha to 3 x 3 reversible phase transition at low temperature in Sn/Ge (111)
  • 2001
  • Ingår i: Applied Surface Science. - 0169-4332 .- 1873-5584. ; 175, s. 201-206
  • Tidskriftsartikel (refereegranskat)abstract
    • Metal-induced superstructures on semiconductors at sub-monolayer coverages have been mostly studied at, or above, room temperature. Yet, recently, several reversible phase transitions, like, e.g. the root3 x root3 alpha to 3 x 3 transition in the Pb, Sn/Ge (111) prototypical systems, have been discovered below RT. The origin of these new reconstructions is very intriguing and is a matter of strong debate. Some groups privilege electronic instabilities leading to charge ordered states at low temperature (LT), while other favor dynamical effects and the formation a kind of bond density waves (BDW's) at LT. Besides these intrinsic behaviors, the role played by inevitable defects has also been emphasized by several authors. Focussing especially on the Sn/Ge (111) system, we present a detailed analysis of the spectroscopic signatures of each phase in photoemission measurements. We show that static models are impossible to reconcile with these measurements.
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29.
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30.
  • Mattsson, Johanna Sofia Margareta, 1985-, et al. (författare)
  • Inconsistent results in the analysis of ALK rearrangements in non-small cell lung cancer
  • 2016
  • Ingår i: BMC Cancer. - London, United Kingdom : Springer Science and Business Media LLC. - 1471-2407. ; 16
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Identification of targetable EML4-ALK fusion proteins has revolutionized the treatment of a minor subgroup of non-small cell lung cancer (NSCLC) patients. Although fluorescence in situ hybridization (FISH) is regarded as the gold standard for detection of ALK rearrangements, ALK immunohistochemistry (IHC) is often used as screening tool in clinical practice. In order to unbiasedly analyze the diagnostic impact of such a screening strategy, we compared ALK IHC with ALK FISH in three large representative Swedish NSCLC cohorts incorporating clinical parameters and gene expression data.Methods: ALK rearrangements were detected using FISH on tissue microarrays (TMAs), including tissue from 851 NSCLC patients. In parallel, ALK protein expression was detected using IHC, applying the antibody clone D5F3 with two different protocols (the FDA approved Ventana CDx assay and our in house Dako IHC protocol). Gene expression microarray data (Affymetrix) was available for 194 patients.Results: ALK rearrangements were detected in 1.7% in the complete cohort and 2.0% in the non-squamous cell carcinoma subgroup. ALK protein expression was observed in 1.9% and 1.5% when applying the Ventana assay or the in house Dako protocol, respectively. The specificity and accuracy of IHC was high (>99%), while the sensitivity was between 69% (Ventana) and 62% (in house Dako protocol). Furthermore, only 67% of the ALK IHC positive cases were positive in both IHC assays. Gene expression analysis revealed that 6/194 (3%) tumors showed high ALK gene expression (≥6AU) and of them only three were positive by either FISH or IHC.Conclusion: The overall frequency of ALK rearrangements based on FISH was lower than previously reported. The sensitivity of both IHC assays was low, and the concordance between the FISH and the IHC assays poor, questioning current strategies to screen with IHC prior to FISH or completely replace FISH by IHC.
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31.
  • Rad, M. G., et al. (författare)
  • Influence of charged impurities on the surface phases of Sn/Ge(111)
  • 2001
  • Ingår i: Surface Science. - 0039-6028 .- 1879-2758. ; 477:03-feb, s. 227-234
  • Tidskriftsartikel (refereegranskat)abstract
    • The root3 alpha and 3 x 3 reconstructions on the Ge(111)-Sn surface have been perturbed by small amounts of iodine and potassium to test the spectral response in the course of a synchrotron radiation photoemission study. We demonstrate the inadequacy of the static model of the root3 alpha phase at room temperature and of the surface charge density wave model of the 3 x 3 phase at low temperature. Instead, the influence of the charged impurities is consistently explained when considering that dynamical fluctuations in the tin adatom positions are frozen in upon passing the phase transition temperature.
  •  
32.
  • Risberg, Björn, et al. (författare)
  • Dissociated expression of Bcl-2 and Ki-67 in endometrial lesions : diagnostic and histogenetic implications
  • 2002
  • Ingår i: International Journal of Gynecological Pathology. - Philadelphia, USA : Lippincott Williams & Wilkins. - 0277-1691 .- 1538-7151. ; 21:2, s. 155-160
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of the present study was to analyze the expression of the proliferation marker, Ki-67, and the anti-apoptotic protein, bcl-2, in various endometrial lesions. Ki-67 and bcl-2 expressions were studied in 194 specimens of endometrial hyperplasia, polyps, carcinomas, and cyclic endometrium from a defined geographic area. Results were statistically analyzed with respect to marker expression, localization to the stromal or glandular component, and intraglandular topography. The lowest glandular Ki-67 expression was seen in secretory endometrium, in polyps, and in atypical hyperplasia. The Ki-67 score was significantly higher and less heterogeneous in endometrial carcinomas than in hyperplasia (p<0.001). Endometrial hyperplasia of all types was characterized by a markedly heterogeneous glandular expression of Ki-67. The glandular expression of bcl-2 was highest in proliferative endometrium and polyps. Bcl-2 expression was significantly lower in adenocarcinomas than in hyperplastic lesions (p=0.002). Ki-67 and bcl-2 expression showed a significant association in proliferative endometrium (p=0.003). Endometrial polyps demonstrated a unique pattern of very low expression of Ki-67 and high bcl-2 expression in both stroma and glands. Our findings indicate that an imbalance between proliferation and apoptosis may be an important factor in the development of different endometrial lesions, benign as well as malignant. The specific finding of inter- and intraglandular Ki-67 heterogeneity may be valuable as an adjunct to morphology in the differential diagnosis of endometrial hyperplasia.
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33.
  • Spetz, Anna-Clara, et al. (författare)
  • Change in testosterone concentrations over time is a better predictor than the actual concentrations for symptoms of late onset hypogonadism
  • 2011
  • Ingår i: The Aging Male. - : Informa Healthcare. - 1368-5538 .- 1473-0790. ; 14:4, s. 249-256
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Symptoms of late-onset hypogonadism (LOH) and concentrations of testosterone (T) and bioavailable testosterone (BT) were studied in relation to the data from the same men 5 years earlier. less thanbrgreater than less thanbrgreater thanMethods. In 2008, 282 men, aged 60-82 years, answered a questionnaire regarding demographic data, medical history, different symptoms of LOH and the 10 questions from the Androgen Decline in Aging Males (ADAM)-questionnaire. Blood samples were analysed for concentrations of T and calculations were made for BT. less thanbrgreater than less thanbrgreater thanResults. A total of 87.2% of the questionnaires were returned and analysed, and 75.2% of the responders gave blood samples. The oldest third of the men were most affected by LOH symptoms (p andlt; 0.05). Both T and BT concentrations decreased during the 5 years (p andlt; 0.05) but only the symptom less strong erections changed significantly (p andlt; 0.05). Men reporting one of the four specific symptoms from the ADAM-questionnaire for the first time in 2008 had a higher loss of T and BT than men who had unchanged or fewer symptoms than that reported in 2003. less thanbrgreater than less thanbrgreater thanConclusions. The magnitude of the decrease in concentrations is a better predictor of LOH than are the actual concentrations of T and BT. A combination of symptoms predicts LOH better than any single symptom.
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34.
  • Steinz, Maarten M, et al. (författare)
  • Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis
  • 2019
  • Ingår i: JCI Insight. - : American Society for Clinical Investigation (ASCI). - 2379-3708 .- 2324-7703 .- 2325-4556. ; 4:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Skeletal muscle weakness in patients suffering from rheumatoid arthritis (RA) adds to their impaired working abilities and reduced quality of life. However, little molecular insight is available on muscle weakness associated with RA. Oxidative stress has been implicated in the disease pathogenesis of RA. Here, we show that oxidative posttranslational modifications of the contractile machinery targeted to actin result in impaired actin polymerization and reduced force production. Using mass spectrometry, we identified the actin residues targeted by oxidative 3-nitrotyrosine (3-NT) or malondialdehyde (MDA) adduct modifications in weakened skeletal muscle from mice with arthritis and patients afflicted by RA. The residues were primarily located in 3 distinct regions positioned at matching surface areas of the skeletal muscle actin molecule from arthritic mice and patients with RA. Moreover, molecular dynamics simulations revealed that these areas, here coined "hotspots," are important for the stability of the actin molecule and its capacity to generate filaments and interact with myosin. Together, these data demonstrate how oxidative modifications on actin promote muscle weakness in RA patients and may provide novel leads for targeted therapeutic treatment to improve muscle function.
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35.
  • Stjernström, Annika, et al. (författare)
  • Alterations of INPP4B, PIK3CA and pAkt of the PI3K pathway are associated with squamous cell carcinoma of the lung
  • 2014
  • Ingår i: Cancer Medicine. - : John Wiley & Sons. - 2045-7634. ; 3:2, s. 337-348
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim of the study was to investigate how alterations in the PI3K pathway correlate with non-small cell lung cancer subtypes squamous cell carcinoma (SSC) and adenocarcinoma (ADCA). We analyzed copy number variation and protein expression of INPP4B, protein expression of pAkt, PDPK1, and PTEN and mutational status of PIK3CA and PTEN in 180 cases. Nineteen% displayed loss of INPP4B copy, whereas 47% lacked expression, both showing correlation with SCC. Elevated pAkt expression was seen in 63% of all cases, also correlating to SCC. PDPK1 was expressed in 70%, more in male than female patients. Regarding PTEN, 50% displayed loss of expression, of which seven were identified with mutations in the phosphatase domain. We detected nine cases (5%) of PIK3CA mutations, all identified as the E545K hot spot mutation in the helical domain, all except one in SCC. When analyzing all PI3K pathway components together, we show that patients with at least one alteration in the PI3K pathway are twice as likely to have SCC, than ADCA. Interestingly, we also found a strong correlation between high pAkt expression and PTEN expression. As comparison, we also analyzed mitogen-activated protein kinase (MAPK) pathway genes, where we identified fifteen KRAS mutations (8%) and one BRAF mutation (1%), significantly associated to ADCA. No association was found to the Gly972Arg polymorphism of IRS-1, involved in activation of both PI3K and MAPK pathways. In conclusion, we show here that several components of the PI3K pathway, alone and in combination, are correlated to development of SCC of the lung.
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36.
  • Swat, M. J., et al. (författare)
  • Pharmacometrics Markup Language (PharmML) : Opening New Perspectives for Model Exchange in Drug Development
  • 2015
  • Ingår i: CPT. - : American Society for Clinical Pharmacology & Therapeutics. - 2163-8306. ; 4:6, s. 316-319
  • Tidskriftsartikel (refereegranskat)abstract
    • The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.
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37.
  • Acharya, Shikha, 1986, et al. (författare)
  • Reduced sialyl-Lewis(x) on salivary MUC7 from patients with burning mouth syndrome
  • 2019
  • Ingår i: Molecular Omics. - : Royal Society of Chemistry (RSC). - 2515-4184. ; 15:5, s. 331-339
  • Tidskriftsartikel (refereegranskat)abstract
    • We analysed and compared MUC7 O-glycosylation and inflammatory biomarkers in saliva from female patients with burning mouth syndrome (BMS) and gender/age-matched controls. Oligosaccharides from salivary MUC7 from BMS and controls were released. Inflammatory mediators were measured by multiplex proximity extension assay. Presence of sialyl-Lewis(x) (Si-Le(x)) epitope on MUC7 was confirmed using Western blot. MUC7 O-glycans and measured inflammatory biomarkers were found to be similar between BMS and controls. However, oligosaccharides sialyl-Lewis(x) (Si-Le(x)) was found to be reduced in samples from BMS patients. Positive correlation (combined patients and controls) was found between levels of C-C motif chemokine 19 (CCL-19) and the amount of core-2 oligosaccharides on MUC7 as well as fractalkine (CX3CL1) and level of sialylation. Patients with BMS were shown to represent a heterogeneous group in terms of inflammatory biomarkers. This indicates that BMS patients could be further stratified on the basis of low-level inflammation. The results furthermore indicate that reduced sialylation of MUC7, particularly Si-Le(x), may be an important feature in patients with BMS. However, the functional aspects and potential involvement in immune regulation of Si-Le(x) remains unclear. Our data suggests a chemokine driven alteration of MUC7 glycosylation.
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38.
  • Amiri, Shahnaz, 1962- (författare)
  • Economic and Environmental Benefits of CHP-based District Heating Systems in Sweden
  • 2013
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Future energy systems and thus the climate are affected by many factors, such as energy resources, energy demand, energy policy and the choice of energy technologies. Energy systems of the future are facing three main challenges; the steady growth of global energy demand, the energy resource depletion, as well as the increasing emissions of carbon dioxide (CO2) and other greenhouse gases and their impact on climate change. To meet the mentioned challenges with sustainability in mind, actions that increase energy efficiency and choosing an energy-efficient energy system which is cost efficient will be essential. Combined heat and power (CHP) plants and district heating and cooling could contribute greatly to increased system efficiency by using energy otherwise wasted.The aim of this study is to increase the understanding of how CHP-based district heating and cooling systems using different primary energy sources can contribute to more cost-efficient energy systems, which reduce global CO2 emissions, and to highlight the impact of some important parameters and measures on Swedish municipal district heating systems. An important assumption in this study is the estimation of CO2 emissions from electricity production, which is based on marginal electricity perspectives. In the short term, the marginal electricity is assumed to come from coal-fired condensing power plants while in the long term it consists of electricity produced by natural gas-fired combined cycle condensing power plants. This means that the local electricity production will replace the marginal electricity production. The underlying assumption is an ideal fully deregulated European electricity market where trade barriers are removed and there are no restrictions on transfer capacity.The results show that electricity generation in CHP plants, particularly in higher efficiency combined steam and gas turbine heat and power plants using natural gas, can reduce the global environmental impact of energy usage to a great extent. The results confirm, through the scenarios presented in this study, that waste as a fuel in CHP-based district heating systems is fully utilised since it has the lowest operational costs. The results also show how implementation of a biogas-based CHP plant in a biogas system contributes to an efficient system, as well as lowering both CO2 emissions and system costs. The results show that replacing electricity-driven (e.g. compression) cooling by heat-driven cooling using district heating (e.g. absorption chillers) in a CHP system is a cost-effective and climate friendly technology as electricity consumption is reduced while at the same time the electricity generation will be increased. The results of the study also show that there is potential to expand district heating systems to areas with lower heat density, with both environmental and economic benefits for the district heating companies.The results reveal that the operation of a studied CHP-based district heating system with an imposed emission limit is very sensitive to the way CO2 emissions are accounted, i.e., local CO2 emissions or emissions from marginal electricity production. The results show how the electricity production increases in the marginal case compared with the local one in order to reduce global CO2 emissions. The results also revealed that not only electricity and fuel prices but also policy instruments are important factors in promoting CHP-based district heating and cooling systems. The use of electricity certificates has a large influence for the introduction of biogas-based cogeneration. Another conclusion from the modelling is that present Swedish policy instruments are strong incentives for cogeneration with similar impact as applying external costs.
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39.
  • Andersson, Patiyan, 1978-, et al. (författare)
  • Genome-wide analysis of penile cancer using high-density single nucleotide polymorphism arrays
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • The availability of genome-wide high-density single nucleotide polymorphism (SNP) arrays makes it possible to in a structured manner study chromosome aberrations in penile cancer where little is known of disruptive genetic events. In this study 19 penile squamous cell carcinomas were analyzed using the 250k NspI SNP array from Affymetrix. We find major regions of frequent copy number gain in chromosome arms 3q, 5p and 8q, and slightly less frequent in 1p, 16q and 20q. The chromosomal regions of most frequent copy number losses were 3p, 4q, 11p and 13q. We identified four candidate genes residing in the major chromosomal regions of aberration. Eight tumours showed copy number gain of the PIK3CA gene located to 3q26.3. Five of the remaining tumours carried an activating mutation of the PIK3CA gene and these tumours showed very few chromosomal aberrations. Collectively, disruption of the PIK3CA gene was found in 13/19 samples, and presence of active phosphorylated AKT was confirmed immunohistochemically in these tumours indicating an active signalling pathway. We found copy number gain of the hTERT gene (5p15.33) in 7 samples and of the Myc gene (8q24.21) in 7 samples. Copy number loss of the tumoursuppressor gene FHIT (3p14.2) was observed in 8 samples, the same 8 samples that showed copy number gain of the PIK3CA gene. In total the PI3K/AKT and RAS/MAPK pathways were found to be activated through mutation or amplification in 64% of the cases, indicating the significance of these pathways in the aetiology of penile cancer.
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40.
  • Andersson, Patiyan, 1978-, et al. (författare)
  • PIK3CA, HRAS and KRAS gene mutations in human penile cancer
  • 2008
  • Ingår i: Journal of Urology. - New York, USA : Ovid Technologies (Wolters Kluwer Health). - 0022-5347 .- 1527-3792. ; 179:5, s. 2030-2034
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways. Materials and Methods: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors. Results: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma. Conclusions: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.
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41.
  • André, Mats, et al. (författare)
  • Lower hybrid waves at comet 67P/Churyumov-Gerasimenko
  • 2017
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 469, s. S29-S38
  • Tidskriftsartikel (refereegranskat)abstract
    • We investigate the generation of waves in the lower hybrid frequency range by density gradients in the near plasma environment of comet 67P/Churyumov-Gerasimenko. When the plasma is dominated by water ions from the comet, a situation with magnetized electrons and unmagnetized ions is favourable for the generation of lower hybrid waves. These waves can transfer energy between ions and electrons and reshape the plasma environment of the comet. We consider cometocentric distances out to a few hundred km. We find that when the electron motion is not significantly interrupted by collisions with neutrals, large average gradients within tens of km of the comet, as well as often observed local large density gradients at larger distances, are often likely to be favourable for the generation of lower hybrid waves. Overall, we find that waves in the lower hybrid frequency range are likely to be common in the near plasma environment.
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42.
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43.
  • Bagni, T., et al. (författare)
  • Modeling Results of the Quench Behavior of a Nb-Ti Canted-Cosine-Theta Corrector Magnet for LHC
  • 2024
  • Ingår i: IEEE transactions on applied superconductivity (Print). - : IEEE. - 1051-8223 .- 1558-2515. ; 34:5
  • Tidskriftsartikel (refereegranskat)abstract
    • A newly designed superconducting magnet of the Canted-Cosine-Theta (CCT) type was developed as a result of a collaboration between Swedish universities (Uppsala and Linneaus) and Swedish industries. This magnet was designed to function as a replacement of the present LHC orbit corrector magnets, which are approaching their end of life due to the radiation load. As a result, the new CCT magnet was developed to be more radiation tolerant and to constitute a one-to-one replacement to the currently installed version, which is a 1 m long 70 mm double aperture dipole magnet. The final magnet, which is currently under construction, will be tested at FREIA laboratory at Uppsala University and generate a magnetic field of 3.3 T and an integrated field of 2.8 Tm at about 85 A. To examine the magnet quench behavior and to identify a suitable quench protection system, the 3D electro-magnetic and thermal behavior of the coil was modeled using the RAT-Raccoon software. Based on the simulation results, a Metrosil varistor was selected to protect the magnet during the test. In this article, we report the results of the numerical analysis. The magnet model is equipped with a spot heater to initialize the quench and the temperature and voltages are monitored during the avalanche effect. The simulated current decay and the hot-spot temperature are analyzed with a focus on the impact of quench-back on the magnet protection.
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44.
  • Baverel, Paul G., et al. (författare)
  • Dose-Exposure-Response Relationship of the Investigational Anti-Interleukin-13 Monoclonal Antibody Tralokinumab in Patients With Severe, Uncontrolled Asthma
  • 2018
  • Ingår i: Clinical Pharmacology and Therapeutics. - : Wiley. - 0009-9236 .- 1532-6535. ; 103:5, s. 826-835
  • Tidskriftsartikel (refereegranskat)abstract
    • Interleukin (IL)-13 is involved in the pathogenesis of some types of asthma. Tralokinumab is a human immunoglobulin G(4) monoclonal antibody that specifically binds to IL-13. Two placebo-controlled phase II studies (phase IIa, NCT00873860 and phase IIb, NCT01402986) have been conducted in which tralokinumab was administered subcutaneously. This investigation aimed to characterize tralokinumab's dose-exposure-response (forced expiratory volume in 1 s (FEV1)) relationship in patients with asthma and to predict the most appropriate dose for phase III. An integrated population pharmacokinetic-pharmacodynamic (PK/PD) modeling analysis was required for phase III dose selection, due to differing phase II patient populations, designs, and regimens. Analysis of combined datasets enabled the identification of tralokinumab's dose-exposure-FEV1 response relationship in patients with asthma. Near-maximal FEV1 increase was predicted at a dose of 300 mg SC once every 2 weeks (Q2W). This dose was chosen for tralokinumab in the phase III clinical development program for treatment of severe, uncontrolled asthma.
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45.
  • Baverel, Paul G., et al. (författare)
  • Two bootstrapping routines for obtaining imprecision estimates for nonparametric parameter distributions in nonlinear mixed effects models
  • 2011
  • Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 38:1, s. 63-82
  • Tidskriftsartikel (refereegranskat)abstract
    • When parameter estimates are used in predictions or decisions, it is important to consider the magnitude of imprecision associated with the estimation. Such imprecision estimates are, however, presently lacking for nonparametric algorithms intended for nonlinear mixed effects models. The objective of this study was to develop resampling-based methods for estimating imprecision in nonparametric distribution (NPD) estimates obtained in NONMEM. A one-compartment PK model was used to simulate datasets for which the random effect of clearance conformed to a (i) normal (ii) bimodal and (iii) heavy-tailed underlying distributional shapes. Re-estimation was conducted assuming normality under FOCE, and NPDs were estimated sequential to this step. Imprecision in the NPD was then estimated by means of two different resampling procedures. The first (full) method relies on bootstrap sampling from the raw data and a re-estimation of both the preceding parametric (FOCE) and the nonparametric step. The second (simplified) method relies on bootstrap sampling of individual nonparametric probability distributions. Nonparametric 95% confidence intervals (95% CIs) were obtained and mean errors (MEs) of the 95% CI width were computed. Standard errors (SEs) of nonparametric population estimates were obtained using the simplified method and evaluated through 100 stochastic simulations followed by estimations (SSEs). Both methods were successfully implemented to provide imprecision estimates for NPDs. The imprecision estimates adequately reflected the reference imprecision in all distributional cases and regardless of the numbers of individuals in the original data. Relative MEs of the 95% CI width of CL marginal density when original data contained 200 individuals were equal to: (i) -22 and -12%, (ii) -22 and -9%, (iii) -13 and -5% for the full and simplified (n = 100), respectively. SEs derived from the simplified method were consistent with the ones obtained from 100 SSEs. In conclusion, two novel bootstrapping methods intended for nonparametric estimation methods are proposed. In addition of providing information about the precision of nonparametric parameter estimates, they can serve as diagnostic tools for the detection of misspecified parameter distributions.
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46.
  • Bergengren, Lovisa, 1972-, et al. (författare)
  • Effectiveness and costs of an implemented primary HPV cervical screening programme in Sweden : A population based cohort study
  • 2022
  • Ingår i: Preventive Medicine Reports. - : Elsevier. - 2211-3355. ; 25
  • Tidskriftsartikel (refereegranskat)abstract
    • Swedish guidelines recommend cervical screening with primary HPV for women ≥ 30 years of age. The aim of this study was to compare an implemented HPV cervical screening programme in the Region of Örebro County from September 1, 2016, with the former cytology-based screening programme.The clinical effectiveness by means of number of high-grade squamous intraepithelial lesions (HSILs) and cervical cancer cases detected in histology within 12 months after the screening test, together with cost implications were the main outcomes. Data were retrieved from the Swedish National Cervical Screening Registry between the years 2014-2015 (cytology based screening) and 2017-2018(HPV based screening), including screening information such as invitations and cytology and histology diagnoses.The detection rate of HSIL + among women ≥ 30 years of age was 1.2 times higher with HPV screening, but data revealed an increase in direct colposcopy referral rate by 54% and a higher percentage of irrelevant findings (≤LSIL). Screening based on HPV for women ≥ 30 has increased yearly cost from 1 to 1.3 million EUR, while increasing the number of HSIL + identified. Two thirds of the total costs are from visits for screening samples in the programme.HPV screening detected more cases of HSIL + compared to cytology screening among women ≥ 30 although high colposcopy rate, high rate of clinical irrelevant findings and higher costs were shown in the HPV-based screening programme, which implies that alterations in the screening programme in the future are important to consider.
  •  
47.
  • Bergengren, Lovisa, 1971-, et al. (författare)
  • HPV-based screening for cervical cancer among women 55-59 years of age
  • 2019
  • Ingår i: PLOS ONE. - : PLOS. - 1932-6203. ; 14:6
  • Tidskriftsartikel (refereegranskat)abstract
    • AIM: Many cervical cancers occurs among women over 65 and prevalence of HPV genotypes in this age cohort is sparingly studied. One aim of this study was to study the prevalence and distribution of HPV genotypes in women 55-59 years, with normal cytology when exiting the screening program. Secondly, HPV clearance as well as the value of HPV genotyping and/or liquid based cytology as triage tests for identifying histological dysplasia among women with persistent HPV was studied.METHODS: Women that exited the screening program with normal cytology, between the years 2012-2014, in Örebro County, Sweden, were invited to this study. A total of 2946 samples were analyzed with a broad-spectrum assay to detect both hrHPV and lrHPV in order to investigate the distribution of genotypes. In the consent group, women with a positive hrHPV test were offered a follow-up test and a cone biopsy for histological confirmation, and a follow up sample 6 months post cone.RESULTS: The overall prevalence of hrHPV was 7.4% and 59% of them remained hrHPV positive in a follow-up test after 12 months. A total of 99 women had a cone biopsy done, where 19% showed histological dysplasia. HPV 53 was the most common genotype, and among women with histology confirmed LSIL or HSIL, HPV 31 was most common. A positive hrHPV result showed a PPV of 25% for LSIL+ and 12.5%for HSIL+. Using detection of HPV 16/18 genotypes as a triage test for hrHPV positive tests, indicated FNR for histological LSIL+ and HSIL+ of 94% and 87.5% respectively, whilst triage based on cervical cytology had a FNR of 69% for LSIL+ and 37.5% for HSIL+.CONCLUSION: The most common hrHPV genotypes among women 55-59 years of age were non HPV16/18 genotypes, and in this population, these genotypes represented most of the histological verified HSIL lesions. This result does not support the proposition of a HPV 16/18 triaging test after a positive hrHPV test as a marker of histological HSIL+ cervical lesions in women over 55 years of age. Similarly, cytological triage after a positive hrHPV showed no additional benefit in this population. Specific triaging tests should be validated to follow post-menopausal women with a positive hrHPV test.
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48.
  • Bergstrand, Martin, 1977-, et al. (författare)
  • A semi-mechanistic model for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • Methods to study in vivo gastro intestinal (GI) transit and/or regional absorption of pharmaceuticals are available and increasingly used in drug development. A modelling approach to utilize the information generated in such studies for prospective predictions of absorption from newly developed modified release formulations was outlined and tested for the investigational drug AZD0837. This work was a natural extension to the companion article “A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations”. The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of concomitant food intake were estimated with the model. The model was informed by data from a magnetic marker monitoring study and an intubation study with local administration in colon. Disposition estimates were further supported by observations following administration of oral solution and intravenous infusion of AZD0837. Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high for substance released in the stomach and absorbed in duodenum (70%) compared to substance released and absorbed in the small intestine (25%). Bioavailability was once again higher in colon (70%) but on the other hand considerably slower than in the earlier parts of the GI tract. The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
  •  
49.
  • Bergstrand, Martin, 1977-, et al. (författare)
  • A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations
  • Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
    • In vivo prediction of drug release based on in vitro experiments is important for the development of new modified release (MR) formulations. Most efforts to improve such predictions have focused on altering the in vitro experiments to more resemble the in vivo conditions. A novel approach is evaluated in the present article where a computer model is established and used to link results from standard static in vitro experiment to in vivo predictions. A nonlinear mixed-effects model describing the in vitro drug release for 6 closely related hydrophilic matrix based MR formulations across different experimental conditions (pH, rotation speed and ionic strength) was developed. This model was applied to in vivo observations of drug release and tablet gastro intestinal (GI) position assessed with Magnetic Marker Monitoring (MMM). By combining the MMM observations with literature information on pH and ionic strength along the GI tract, the mechanical stress in different parts of the GI tract could be estimated in units equivalent to rotation speed in the in vitro set-up (USP 2 apparatus). The mechanical stress in the upper stomach was estimated to be 94 rpm and 134 rpm in the lower stomach. For the small intestine and colon the estimates of mechanical stress was 93 and 38 rpm respectively. Predictions of in vivo drug release including expected between subject/tablet variability could be made for other newly developed formulations based on the drug release model combined with a model describing tablet GI transit. This exemplifies a modeling approach that can be utilized to predict in vivo behavior from standard in vitro experiments and support formulation development and quality control of MR formulations.
  •  
50.
  • Bergstrand, Martin, 1977-, et al. (författare)
  • A semi-mechanistic modeling strategy for characterization of regional absorption properties and prospective prediction of plasma concentrations following administration of new modified release formulations
  • 2012
  • Ingår i: Pharmaceutical research. - : Springer Science+Business Media B.V.. - 0724-8741 .- 1573-904X. ; 29:2, s. 574-584
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE To outline and test a new modeling approach for prospective predictions of absorption from newly developed modified release formulations based on in vivo studies of gastro intestinal (GI) transit, drug release and regional absorption for the investigational drug AZD0837. METHODS This work was a natural extension to the companion article "A semi-mechanistic model to link in vitro and in vivo drug release for modified release formulations". The drug release model governed the amount of substance released in distinct GI regions over time. GI distribution of released drug substance, region specific rate and extent of absorption and the influence of food intake were estimated. The model was informed by magnetic marker monitoring data and data from an intubation study with local administration in colon. RESULTS Distinctly different absorption properties were characterized for different GI regions. Bioavailability over the gut-wall was estimated to be high in duodenum (70%) compared to the small intestine (25%). Colon was primarily characterized by a very slow rate of absorption. CONCLUSIONS The established model was largely successful in predicting plasma concentration following administration of three newly developed formulations for which no clinical data had been applied during model building.
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