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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Cleynen, Isabelle, et al.
(författare)
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Inherited determinants of Crohn's disease and ulcerative colitis phenotypes : a genetic association study
- 2016
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Ingår i: The Lancet. - New York, USA : Elsevier. - 0140-6736 .- 1474-547X. ; 387:10014, s. 156-167
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Tidskriftsartikel (refereegranskat)abstract
- Background: Crohn's disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohn's disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases.Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34,819 patients (19,713 with Crohn's disease, 14,683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype-phenotype associations across 156,154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohn's disease, ileal Crohn's disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile.Findings: After quality control, the primary analysis included 29,838 patients (16,902 with Crohn's disease, 12,597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10(-78)), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10(-18)). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohn's disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10(-4)).Interpretation: Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohn's disease, colonic Crohn's disease, and ulcerative colitis) than by Crohn's disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patient's disease, in part genetically determined, and the major driver to changes in disease behaviour over time.Funding: International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).
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| 4. |
- Brynjólfsson, Siggeir Fannar, et al.
(författare)
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An Antibody Against Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) Dampens Proinflammatory Cytokine Secretion by Lamina Propria Cells from Patients with IBD.
- 2016
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Ingår i: Inflammatory bowel diseases. - 1536-4844. ; 22:8, s. 1803-11
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Tidskriftsartikel (refereegranskat)abstract
- Triggering receptor expressed on myeloid cells 1 (TREM-1) is a potent amplifier of inflammation. Recently, the antimicrobial peptide PGLYRP-1 was shown to be the ligand of TREM-1. Here, the ability of an anti-TREM-1 antibody to dampen the release of proinflammatory cytokines by colon lamina propria cells (LPCs) from patients with IBD was investigated and correlated with PGLYRP-1 levels.Biopsies from patients with ulcerative colitis (UC, n = 45) or Crohn's disease (CD, n = 26) were compared with those from individuals undergoing colonoscopy for other reasons (n = 17). TREM-1 expression was analyzed on myeloid cells by flow cytometry. Cell culture experiments with LPCs were used to analyze PGLYRP-1 and inflammatory cytokine levels and assess the effect of anti-TREM-1 on cytokine secretion.The frequency of TREM-1-expressing neutrophils and recruited macrophages was higher in inflamed than in noninflamed biopsies. The PGLYRP-1 level in inflamed tissue was higher than in noninflamed tissue; it was produced primarily by neutrophils, and its level correlated with the secretion of proinflammatory cytokines. Secretion of myeloperoxidase, tumor necrosis factor-α, interleukin-1β, and interleukin-8 by LPCs stimulated with the potent TREM-1 agonist consisting of PGLYRP-1 complexed with peptidoglycan was reduced in the presence of anti-TREM-1. Moreover, a blocking effect of anti-TREM-1 was apparent when LPCs from a subset of inflamed individuals with elevated PGLYRP-1 were stimulated with killed bacteria.An anti-TREM-1 antibody can dampen secretion of proinflammatory cytokines in inflamed patients with elevated PGLYRP-1. Moreover, PGLYRP-1 + myeloperoxidase is a potential biomarker for predicting the effect of anti-TREM-1 therapy.
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| 5. |
- Lundemann, Michael, et al.
(författare)
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Feasibility of multi-parametric PET and MRI for prediction of tumour recurrence in patients with glioblastoma
- 2019
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1619-7070 .- 1619-7089. ; 46:3, s. 603-613
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recurrence in glioblastoma patients often occur close to the original tumour and indicates that the current treatment is inadequate for local tumour control. In this study, we explored the feasibility of using multi-modality imaging at the time of radiotherapy planning. Specifically, we aimed to identify parameters from pre-treatment PET and MRI with potential to predict tumour recurrence. Materials and methods: Sixteen patients were prospectively recruited and treated according to established guidelines. Multi-parametric imaging with 18 F-FET PET/CT and 18 F-FDG PET/MR including diffusion and dynamic contrast enhanced perfusion MRI were performed before radiotherapy. Correlations between imaging parameters were calculated. Imaging was related to the voxel-wise outcome at the time of tumour recurrence. Within the radiotherapy target, median differences of imaging parameters in recurring and non-recurring voxels were calculated for contrast-enhancing lesion (CEL), non-enhancing lesion (NEL), and normal appearing grey and white matter. Logistic regression models were created to predict the patient-specific probability of recurrence. The most important parameters were identified using standardized model coefficients. Results: Significant median differences between recurring and non-recurring voxels were observed for FDG, FET, fractional anisotropy, mean diffusivity, mean transit time, extra-vascular, extra-cellular blood volume and permeability derived from scans prior to chemo-radiotherapy. Tissue-specific patterns of voxel-wise correlations were observed. The most pronounced correlations were observed for 18 F-FDG- and 18 F-FET-uptake in CEL and NEL. Voxel-wise modelling of recurrence probability resulted in area under the receiver operating characteristic curve of 0.77 from scans prior to therapy. Overall, FET proved to be the most important parameter for recurrence prediction. Conclusion: Multi-parametric imaging before radiotherapy is feasible and significant differences in imaging parameters between recurring and non-recurring voxels were observed. Combining parameters in a logistic regression model enabled patient-specific maps of recurrence probability, where 18 F-FET proved to be most important. This strategy could enable risk-adapted radiotherapy planning.
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| 6. |
- Nielsen, Torsten O, et al.
(författare)
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Abstract P2-03-01: Analytical validation of a standardized scoring protocol for Ki67 assessed on breast excision whole sections: An international multicenter collaboration
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Aims: (i) Determine whether between-observer reproducibility for Ki67 when assessed on whole sections according to a standardized scoring protocol is adequate for clinical application. (ii) Compare between-observer reproducibility of Ki67 scores assessed on hot-spots to scores using a global method that averages across a tissue section.Background: The nuclear proliferation biomarker Ki67 has multiple potential roles in breast cancer, including aiding decisions based on prognosis, but unacceptable levels of between-laboratory variability have been observed. The International Ki67 in Breast Cancer Working Group has undertaken a systematic program to determine whether Ki67 measurement can be analytically validated and standardized across labs. In phase 1, variability in visual interpretation was identified as an important source of variability. Phases 2 and 3a showed that adherence to defined scoring methods substantially improved reproducibility in scoring tissue microarrays and core-cut biopsies. We now assess whether acceptable reproducibility can be achieved on whole sections.Methods: Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 to assemble 4 sets of 30 stained tumor sections, circulated around 23 labs in 12 countries. Ki67 was scored by 2 methods by all labs: (a) global: 4 fields of 100 tumor cells each were selected to reflect observed heterogeneity in nuclear staining (b) hot-spot: the field with highest Ki67 percentage of tumor cells with nuclear staining was selected and up to 500 cells scored. Ki67 scores were log2-transformed for statistical analyses and back-transformed for presentation. The primary objective was to assess whether either method could achieve an intraclass correlation coefficient (ICC) significantly greater than 0.8, considered substantial to almost-perfect reproducibility. Secondary objectives were to assess which method had highest observed ICC and to assess whether observers identified the same “hot-spots”.Results: ICC for the global method was 0.87 (95%CI: 0.799-0.93), marginally meeting the prespecified success criterion. The ICC for the hot-spot method was 0.83 (95%CI: 0.74-0.90) and had a CI extending below the success criterion. Across the 23 labs, geometric mean value of the 30 scores ranged from 8.5 to 19.6 for the global method and from 12.8 to 30.3 for the hot-spot method. The overall mean (95% CI) of these values was 12.9 (11.9-14.0) and 20.9 (19.1-22.8), respectively. Visually, between-laboratory agreement in location of selected hot-spot varies between cases. The median times for scoring were 9 and 6 minutes for global and hot-spot methods respectively.Conclusions: The global method marginally met the prespecified criterion of success; it should now be evaluated for clinical validity in appropriate cohorts of cases. The hot-spot method was observed to have slightly less reproducibility between labs. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between labs further
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| 7. |
- Nilsen, Bo W., et al.
(författare)
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Analysis of organic components in resin-modified pulp capping materials: Critical considerations
- 2017
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Ingår i: European Journal of Oral Sciences. - : Wiley. - 0909-8836 .- 1600-0722.
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 European Journal of Oral Sciences. The purpose of this study was to elucidate the organic composition and eluates of three resin-based pulp-capping materials in relation to their indications and safety data sheets. Uncured samples of Theracal LC, Ultra-Blend Plus, and Calcimol LC were investigated using gas chromatography-mass spectrometry (GC-MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Identification/quantification of 7-d leachables of cured samples was performed using GC-MS for 2-hydroxyethyl methacrylate (HEMA), 2-(dimethylamino)ethyl methacrylate (DMAEMA), camphorquinone (CQ), ethylene glycol dimethacrylate (EGDMA), ethyl-4-(dimethylamino)benzoate (DMABEE), and triethylene glycol dimethacrylate (TEGDMA). A similar organic composition was found for Ultra-Blend and Calcimol; however, only Ultra-Blend is indicated for direct pulp-capping. In contrast to the other materials analysed, Theracal contained substances of high molecular weight. The safety data sheets of all materials were incomplete. We detected HEMA, CQ, and TEGDMA in eluates from Ultra-Blend and Calcimol, and it was considered that HEMA might have originated from decomposition of diurethane dimethacrylate (UDMA) in the GC-injector. For Theracal, additives associated with light curing (DMABEE and CQ) were detected in higher amounts (4.11 and 19.95 μg mm-2) than in the other materials. Pores were quantified in all samples by micro-computed tomography (micro-CT) analysis, which could influence leaching. The organic substances in the investigated materials might affect their clinical suitability as capping agents, especially for direct capping procedures.
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| 8. |
- Nilsen, Bo W, et al.
(författare)
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Dose- and time-dependent effects of triethylene glycol dimethacrylate on the proteome of human THP-1 monocytes.
- 2018
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Ingår i: European journal of oral sciences. - : Wiley. - 1600-0722 .- 0909-8836. ; 126:5, s. 345-358
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Tidskriftsartikel (refereegranskat)abstract
- Triethylene glycol dimethacrylate (TEGDMA) is commonly used in polymer resin-based dental materials. This study investigated the molecular mechanisms of TEGDMA toxicity by identifying its time- and dose-dependent effects on the proteome of human THP-1 monocytes. The effects of different concentrations (0.07-5mM) and exposure times (0-72h) of TEGDMA on cell viability, proliferation, and morphology were determined using a real-time viability assay, automated cell counting, and electron microscopy, and laid the fundament for choice of exposure scenarios in the proteomic experiments. Solvents were not used, as TEGDMA is soluble in cell culture medium (determined by photon correlation spectroscopy). Cells were metabolically labeled [using the stable isotope labeled amino acids in cell culture (SILAC) strategy], and exposed to 0, 0.3 or 2.5 mM TEGDMA for 6 or 16h before liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses. Regulated proteins were analyzed in the STRING database. Cells exposed to 0.3mM TEGDMA showed increased viability and time-dependent upregulation of proteins associated with stress/oxidative stress, autophagy, and cytoprotective functions. Cells exposed to 2.5mM TEGDMA showed diminished viability and a protein expression profile associated with oxidative stress, DNA damage, mitochondrial dysfunction, and cell cycle inhibition. Altered expression of immune genes was observed in both groups. The study provides novel knowledge about TEGDMA toxicity at the proteomic level. Of note, even low doses of TEGDMA induced a substantial cellular response.
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| 9. |
- Nilsson, Simon R O, et al.
(författare)
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A mouse model of the 15q13.3 microdeletion syndrome shows prefrontal neurophysiological dysfunctions and attentional impairment
- 2016
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Ingår i: Psychopharmacologia. - : Springer Science and Business Media LLC. - 0033-3158. ; 233:11, s. 2151-2163
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. Objectives: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. Method: Experiments 1–2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAAreceptor antagonism. Experiments 4–6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7–12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. Results: In experiments 1–3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAAreceptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4–6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial α7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7–12. Conclusion: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function.
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