| 1. |
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| 2. |
- Malinovschi, Andrei, 1978-, et al.
(författare)
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Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry
- 2023
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Ingår i: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 208:4, s. 461-471
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Post-bronchodilator (BD) spirometry is used for diagnosis of chronic obstructive pulmonary disease (COPD). However, pre-BD reference values are used for spirometry interpretation.OBJECTIVES: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or post-BD reference values generated within the Swedish CArdioPulmonary bioImage Study (SCAPIS) when interpreting post-BD spirometry in a general population.METHODS: SCAPIS reference values for post-BD and pre-BD spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or post-BD reference values, with respiratory burden in the SCAPIS general population (28,851 individuals).MEASUREMENTS AND MAIN RESULTS: Bronchodilation resulted in higher predicted median and lower limit of normal (LLN) for FEV1/FVC ratio. The prevalence of post-BD FEV1/FVC < pre-bronchodilator LLN was 4.8% and that of post-BD FEV1/FVC < post-bronchodilator LLN was 9.9% for the general population. An additional 5.1% was identified as having an abnormal post-BD FEV1/FVC ratio and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%, p<0.001) and self-reported physician-diagnosed COPD (2.8% vs. 0.5%, p<0.001) than subjects with post-BD FEV1/FVC ratio > LLN for both pre- and post-bronchodilation).CONCLUSIONS: Pre- and post-bronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of post-bronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using post-bronchodilator reference values when interpreting post-bronchodilator spirometry might enable identification of individuals with mild disease and be clinically relevant.
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| 3. |
- Mezheyeuski, Artur, et al.
(författare)
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An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 88
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression.Methods: Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations.Findings: By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy.Interpretation: Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types.
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| 4. |
- Mezheyeuski, Artur, et al.
(författare)
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The ratio of CD8+ lymphocytes to CD68+CD163+ macrophages is prognostic in immunogenic tumors and predicts immunotherapy response
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Immune cells in the microenvironment shape tumor development and progression. Through in situ analyses we assessed 15 immune cell classes in 352 colorectal cancers and identified a simpleprognostic signature based on the ratio of anti-tumoral CD8+ lymphocytes to tumor-supportiveCD68+CD163+ macrophages in the tumor microenvironment. The prognostic ability of this signature was superior to the state-of-art immune score and was also demonstrated in four other tumor types. Single-cell analyses identified these CD68+CD163+ macrophages as the source of complement C1q, and the ratio of CD8A to C1QA gene expression levels in bulk RNA predicted survival in five tumor types. In single cell analyses, RNA-based versions of the signature also predicted response to checkpoint inhibitor therapy. This supports broad clinical applicability of immune scores considering CD68+CD163+ macrophages as prognostic and predictive biomarkers in common cancers.
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| 5. |
- Micke, Patrick, et al.
(författare)
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The prognostic impact of the tumour stroma fraction : A machine learning-based analysis in 16 human solid tumour types
- 2021
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 65
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Tidskriftsartikel (refereegranskat)abstract
- Background: The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed.Methods: Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns.Findings: The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR (95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59 (1.49-8.62)) associations of the tumour stroma fraction with survival.Interpretation: Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance.
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| 6. |
- Alexanderson, Helena, et al.
(författare)
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An Arctic perspective on dating Mid-Late Pleistocene environmental history
- 2014
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 92, s. 9-31
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Forskningsöversikt (refereegranskat)abstract
- To better understand Pleistocene climatic changes in the Arctic, integrated palaeoenvironmental andpalaeoclimatic signals from a variety of marine and terrestrial geological records as well as geochronologicage control are required, not least for correlation to extra-Arctic records. In this paper we discuss,from an Arctic perspective, methods and correlation tools that are commonly used to date ArcticPleistocene marine and terrestrial events. We review the state of the art of Arctic geochronology, withfocus on factors that affect the possibility and quality of dating, and support this overview by examples ofapplication of modern dating methods to Arctic terrestrial and marine sequences.Event stratigraphy and numerical ages are important tools used in the Arctic to correlate fragmentedterrestrial records and to establish regional stratigraphic schemes. Age control is commonly provided byradiocarbon, luminescence or cosmogenic exposure ages. Arctic Ocean deep-sea sediment successionscan be correlated over large distances based on geochemical and physical property proxies for sedimentcomposition, patterns in palaeomagnetic records and, increasingly, biostratigraphic data. Many of theseproxies reveal cyclical patterns that provide a basis for astronomical tuning.Recent advances in dating technology, calibration and age modelling allow for measuring smallerquantities of material and to more precisely date previously undatable material (i.e. foraminifera for 14C,and single-grain luminescence). However, for much of the Pleistocene there are still limits to the resolutionof most dating methods. Consequently improving the accuracy and precision (analytical andgeological uncertainty) of dating methods through technological advances and better understanding ofprocesses are important tasks for the future. Another challenge is to better integrate marine andterrestrial records, which could be aided by targeting continental shelf and lake records, exploringproxies that occur in both settings, and by creating joint research networks that promote collaborationbetween marine and terrestrial geologists and modellers.
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| 7. |
- Andersson, Per A., et al.
(författare)
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Anger and disgust shape judgments of social sanctions across cultures, especially in high individual autonomy societies
- 2024
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Ingår i: Scientific Reports. - : Nature Research. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- When someone violates a social norm, others may think that some sanction would be appropriate. We examine how the experience of emotions like anger and disgust relate to the judged appropriateness of sanctions, in a pre-registered analysis of data from a large-scale study in 56 societies. Across the world, we find that individuals who experience anger and disgust over a norm violation are more likely to endorse confrontation, ostracism and, to a smaller extent, gossip. Moreover, we find that the experience of anger is consistently the strongest predictor of judgments of confrontation, compared to other emotions. Although the link between state-based emotions and judgments may seem universal, its strength varies across countries. Aligned with theoretical predictions, this link is stronger in societies, and among individuals, that place higher value on individual autonomy. Thus, autonomy values may increase the role that emotions play in guiding judgments of social sanctions.
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| 8. |
- Backman, Annica, 1972-, et al.
(författare)
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Characteristics of nursing home units with high versus low levels of person-centred care in relation to leadership, staff- resident- and facility factors : findings from SWENIS, a cross-sectional study in Sweden
- 2021
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Ingår i: BMC Geriatrics. - : BioMed Central. - 1471-2318. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The context of care consists of factors that determines the extent to which staff can offer person-centred care. However, few studies have investigated factors that can explain variation in levels of person-centred care among nursing home units. The aim of this study was to explore factors characterizing nursing home units with high and low degree of person-centred care, with focus on leadership, staff, resident and facility factors.Methods: Cross-sectional data from residents, staff, and managers in 172 randomly selected nursing homes in Sweden were collected in 2014. Activities of Daily Living Index, Gottfries' cognitive scale, Person-centred Care Assessment Tool together with demographic information and estimations of leadership engagement was used. Independent samples t-test and Chi2 test were conducted.Results: Highly person-centred units were characterised by leaders engaging in staff knowledge, professional development, team support and care quality. In highly person-centred units' staff also received supervision of a nurse to a larger extent. Highly person-centred units were also characterised as dementia specific units, units with fewer beds and with a larger proportion of enrolled nurses. No differences in degree of person-centred care were seen between public or private providers.Conclusions: This study provides guidance for practitioners when designing, developing and adapting person-centred units in aged care contexts. Managers and leaders have an important role to promote the movement towards a person-centred practice of care, by supporting their staff in daily care, and engaging in staff knowledge and professional development. Targeting and adjusting environmental factors, such as provide small and dementia adapted environments to match the residents' personal preferences and capacity are also important when striving towards person-centredness.
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| 9. |
- Backman, Anders, et al.
(författare)
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Evaluation of an extended diagnostic PCR assay for detection and verification of the common causes of bacterial meningitis in CSF and other biological samples
- 1999
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Ingår i: Molecular and Cellular Probes. - : Elsevier BV. - 0890-8508 .- 1096-1194. ; 13:1, s. 49-60
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Tidskriftsartikel (refereegranskat)abstract
- A seminested polymerase chain reaction (PCR)-based diagnostic assay was evaluated for detection and verification of Neisseria meningitidis, Haemophilus influenzae, Streptococcus pneumoniae, Steptococcus agalactiae and Listeria monocytogenes in cerebrospinal fluid (CSF) and other biological samples. A general bacterial amplicon from the 16S rRNA gene was amplified in a first step, and species-specific regions in a second. The detection level was 4 fg DNA/reaction, corresponding to about one bacterial genome per reaction tube. Sample preparations (Dynabeads DNA DIRECT kit) were assayed from 140 bacterial strains suspended in saline. In CSF the detection level for bacteria was 103 CFU ml-1 for N. meningitidis, H. influenzae and S. pneumoniae, 104 CFU ml-1 for Escherichia coli and 105 CFU ml-1 for S. agalactiae and L. monocytogenes. The detection levels for these bacteria were the same in the other tested biological samples, like blood with or without culture media. Clinical CSF samples were evaluated from 71 patients with proven bacterial meningitis, as were 61 CSF samples from individuals without bacterial meningitis. The diagnostic sensitivity of the assay in detecting bacteria in general was 0.97, and for the specific species in the clinical CSF samples 0.87-0.94. The specificity was 1.0 for detecting bacteria in general. Some cross-reactions were noted within the streptococcus group. The PCR results were verified by banding patterns of HaeIII digested PCR products.
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| 10. |
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| 11. |
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| 12. |
- Backman, Samuel, et al.
(författare)
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Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations
- 2017
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue.
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| 13. |
- Backman, Samuel, 1994-
(författare)
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Molecular studies of endocrine tumors : Insights from genetics and epigenetics
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Endocrine tumors may be benign or malignant and may occur in any of the hormone producing tissues. They share several biological characteristics, including a low mutation-burden, and may co-occur in several hereditary tumor syndromes. The aim of this thesis was to identify genetic and epigenetic aberrations in endocrine tumors.In paper I we performed a comprehensive DNA methylation analysis of 39 pheochromocytomas/paragangliomas as well as 4 normal adrenal medullae on the HumanMethylation27 BeadChip array. We validated two previously described clusters based on DNA methylation with distinct genetic associations.In Paper II we performed a transcriptomic analysis of 15 aldosterone producing adenomas. CTNNB1-mutated tumors were found to form a distinct subgroup based on gene expression and to share gene expression similarities with non-aldosterone producing adrenocortical tumors with CTNNB1 mutations, including overexpression of AFF3 and ISM1.In paper III we used whole genome sequencing to identify germline genetic variants in 14 patients with Multiple Endocrine Neoplasia type 1 previously found to be wildtype for the MEN1 gene on routine clinical testing. Three patients were found to carry previously undetected MEN1 mutations. Two patients were confirmed to have phenocopies caused by variants affecting CASR or CDC73. In total 9/14 patients were not found to have a disease-causing germline variant, suggesting that the syndrome may in some cases be due to chance co-occurrence of several sporadic tumors.In paper IV RNA-Seq and whole genome sequencing of a cohort of SI-NETs selected on the basis of unusually short or long survival was performed in order to identify disease causing genes and potential prognostic factors. We confirmed known genetic aberrations and found rare variants in known cancer driver genes. Based on gene expression two clusters that differ in prognosis were detected. Moreover, through integration of copy number variation data and gene expression, we identied novel potential disease causing genes.
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| 14. |
- Backman, Samuel, et al.
(författare)
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Potential prognostic markers and candidate genetic drivers in small intestine neuroendocrine tumours
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundSmall intestinal neuroendocrine tumours (SI-NETs) are the most common tumour of the small intestine. The disease often has a favourable outcome with long survival even in the context of metastatic disease. However, some patients fare worse and succumb to the disease soon after diagnosis despite similar stage and grade. Molecular prognostic markers are lacking. The most common genetic aberration is loss of chromosome 18q, although the oncogenic mechanism of this is unknown. The only recurrently mutated gene is CDKN1B, which is mutated in 9% of cases.AimsTo identify molecular derangements in SI-NETs and identify potential prognostic markers.MethodsForty tumour samples from thirty patients with unusually long or unusually short survival after diagnosis were subjected to whole genome sequencing. Twenty of the samples were also included for RNA Sequencing.ResultsIn addition to mutations in CDKN1B we find rare variants in known cancer genes including NF1, MAX and SPEN. Unsupervised clustering based on gene expression resulted in two clusters with prognostic significance. We identify potential prognostic markers based on gene expression. Finally, we identify genes whose expression is affected by the most common copy number variations in these tumours, including SOCS6 on chromosome 18 and ATM on chromosome 11.
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| 15. |
- Backman, Samuel, et al.
(författare)
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RNA Sequencing Provides Novel Insights into the Transcriptome of Aldosterone Producing Adenomas
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Aldosterone producing adenomas (APAs) occur in the adrenal glands of around 30% of patients with primary aldosteronism, the most common form of secondary hypertension. Somatic mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D and CTNNB1 have been described in similar to 60% of these tumours. We subjected 15 aldosterone producing adenomas (13 with known mutations and two without) to RNA Sequencing and Whole Genome Sequencing (n = 2). All known mutations were detected in the RNA-Seq reads, and mutations in ATP2B3 (G123R) and CACNA1D (S410L) were discovered in the tumours without known mutations. Adenomas with CTNNB1 mutations showed a large number of differentially expressed genes (1360 compared to 106 and 75 for KCNJ5 and ATP1A1/ATP2B3 respectively) and clustered together in a hierarchical clustering analysis. RT-PCR in an extended cohort of 49 APAs confirmed higher expression of AFF3 and ISM1 in APAs with CTNNB1 mutations. Investigation of the expression of genes involved in proliferation and apoptosis revealed subtle differences between tumours with and without CTNNB1 mutations. Together our results consolidate the notion that CTNNB1 mutations characterize a distinct subgroup of APAs.
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| 16. |
- Backman, Samuel, et al.
(författare)
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The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
- 2024
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (refereegranskat)abstract
- Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omics analysis of 32 longitudinal samples from six metastatic PanNET patients. Following MEN1 inactivation, PanNETs exhibit genetic heterogeneity on both spatial and temporal dimensions with parallel and convergent tumuor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs develop mismatch repair deficiency and acquire a hypermutator phenotype. This DNA hypermutation phenotype was only found in cases that also showed transformation into a high-grade PanNET. Overall, our findings contribute to broaden the understanding of metastatic PanNET, and suggests that therapy driven disease evolution is an important hallmark of this disease.
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| 17. |
- Backman, Samuel, et al.
(författare)
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Whole genome sequencing of apparently mutation-negative MEN1 patients
- 2020
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Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 182:1, s. 35-45
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.
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| 18. |
- Bourdieu, Pierre, et al.
(författare)
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Leve idrottspedagogiken : En vänbok tillägnad Lars-Magnus Engström
- 2005
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Vem ägnar sig åt idrott? Vilken betydelse har fritiden i barns och ungdomars liv? Vad innebär hälsa i skolämnet idrott och hälsa?Leve idrottspedagogiken! tillägnas Lars-Magnus Engström. Texterna i boken speglar delar av det idrottspedagogiska forskningsområdet i Sverige, vars framväxt Lars-Magnus Engström varit den främste företrädaren för. Läsaren får här ta del av exempelvis idrottskulturen, fritidskulturen och skolans ämne idrott och hälsa. Genomgående handlar texterna om villkoren för barns och ungdomars deltagane och om de olika lärprocesser som sker i anslutning till idrottsutövning.Lars-Magnus Engström har gjort betydande insatser som forskare och lärare samt som professor vid Lärarhögskolan i Stockholm och vid Gymnastik- och idrottshögskolan. I snart fyrtion år har han arbetat med studier kring påverkans- och lärprocesser i idrott. Hans forskning har främst kretsat kring människors idrottsvanor och vilka som utvecklar en fysiskt aktiv livsstil. Idrotts- och motionsutövningar ger både ett så kallat egenvärde och investeringsvärde. Med dessa begrepp bland många andra har Lars-Magnus Engström bidragit till en fördjupad vetenskaplig förståelse av idrottskulturen.De flesta författarna har eller har haft Lars-Magnus Engström som handledare och tillhör forskningsgruppen för pedagogik, idrott och fritidskultur. Redaktörer för boken är Karin Redelius och Håkan Larsson.
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| 19. |
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| 20. |
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| 21. |
- Crona, Joakim, et al.
(författare)
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RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective
- 2018
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 10:12
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Tidskriftsartikel (refereegranskat)abstract
- Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.
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| 22. |
- Crona, Joakim, et al.
(författare)
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Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.
- 2015
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 21:19, s. 4451-4460
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter- and intratumor genetic heterogeneity has not yet been defined.EXPERIMENTAL DESIGN: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.RESULTS: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.CONCLUSIONS: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.
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| 23. |
- de Brun, Maryam, 1991-
(författare)
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Hyperglycaemia during pregnancy : The challenge of screening and deciding diagnostic criteria for gestational diabetes in Sweden
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperglycaemia during pregnancy is one of the most common complicationsof pregnancy. In 2013, the World Health Organisation recommended diagnostic criteria (WHO-2013) for gestational diabetes mellitus (GDM), whichremains controversial due to an expected increase in prevalence, and the uncertainty as to the clinical relevance of treating these additional women or its cost-effectiveness.Paper I involves a cross-sectional study of 4 918 pregnant women using riskfactor screening, which was poorly predictive of the WHO-2013 criteria, with an area under the curve of 40% (95% CI 24–32). In Paper II, a systematic review and meta-analysis of the prevalence of GDM according to the WHO2013 criteria in 136 705 women showed a 75% (RR 1.75, 95% CI 1.53-2.01) increased prevalence compared to the other GDM criteria. In Papers III-IV, a national stepped wedge cluster randomised controlled trial of 26 160 pregnancies before and 28 509 after the implementation of the WHO-2013 criteria across eight clusters during 2018 led to a 2.90 fold increase in GDM prevalence. No significant decrease was seen in the primary outcome, large for gestational age (LGA). There were, however, health benefits in secondary outcomes for the mother and neonate. There was a significant decrease in LGA dependent on the definition used, including the clinically used in Sweden (>2SD) with adjusted OR of 0.89 (95% CI 0.82-0.97). In Paper IV, the WHO2013 criteria led to increased resource use and incremental costs (€341.1 (195.9)) per pregnancy. The cost-effectiveness needs to be related to health benefits for the mother and/or neonate.In conclusion, the current screening methods for GDM are in need of revision considering their poor predictive characteristics in finding GDM according to the WHO-2013 criteria. Implementing the WHO-2013 criteria in Sweden resulted in higher GDM prevalence with short-term increased resource use with uncertainty in costs savings and considerable healthcare benefits for the mother and neonate. This thesis provides evidence regarding the consequences of implementing the WHO-2013 criteria compared to former Swedish GDM criteria and may assist future decision-making.
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| 24. |
- Edvardsson, David, et al.
(författare)
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The Umeå Ageing and health research programme (U-age) : exploring person-centred care and health promoting living conditions for an ageing population
- 2016
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Ingår i: Nordic journal of nursing research. - : Sage Publications. - 2057-1585 .- 2057-1593. ; 36:3, s. 168-174
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this article is to describe the Umeå ageing and health research programme that explores person-centred care and health-promoting living conditions for an ageing population in Sweden, and to place this research programme in a national and international context of available research evidence and trends in aged care policy and practice. Contemporary trends in aged care policy includes facilitating ageing in place and providing person-centred care across home and aged care settings, despite limited evidence on how person-centred care can be operationalised in home care services and sheltered housing accommodation for older people. The Umeå ageing and health research programme consists of four research projects employing controlled, cross-sectional and longitudinal designs across ageing in place, sheltered housing, and nursing homes. The research programme is expected to provide translational knowledge on the structure, content and outcomes of person-centred care and health-promoting living conditions in home care, sheltered housing models, and nursing homes for older people and people with dementia.
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| 25. |
- Ehrhardt, Carsten, et al.
(författare)
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Current Progress Toward a Better Understanding of Drug Disposition Within the Lungs : Summary Proceedings of the First Workshop on Drug Transporters in the Lungs
- 2017
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 106:9, s. 2234-2244
-
Tidskriftsartikel (refereegranskat)abstract
- The School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin hosted the "1st Workshop on Drug Transporters in the Lungs" in September 2016 to discuss the impact of transporters on pulmonary drug disposition and their roles as drug targets in lung disease. The workshop brought together about 30 scientists from academia and pharmaceutical industry from Europe and Japan and addressed the primary questions: What do we know today, and what do we need to know tomorrow about transporters in the lung? The 3 themes of the workshop were: (1) techniques to study drug transporter expression and actions in the lungs; (2) drug transporter effects on pulmonary pharmacokinetics-case studies; and (3) transporters as drug targets in lung disease. Some of the conclusions of the workshop were: suitable experimental models that allow studies of transporter effects are available; data from these models convincingly show a contribution of both uptake and efflux transporters on pulmonary drug disposition; the effects of transporters on drug lung PK is now better conceptualized; some transporters are associated with lung diseases. However, more work is needed to establish which of the available models best translate to the clinical situation.
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| 26. |
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| 27. |
- Eriksson, Kimmo, et al.
(författare)
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Perceptions of the appropriate response to norm violation in 57 societies
- 2021
-
Ingår i: Nature Communications. - : Nature Research. - 2041-1723. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate. Little is known about peoples preferred responses to norm violations across countries. Here, in a study of 57 countries, the authors highlight cultural similarities and differences in peoples perception of the appropriateness of norm violations.
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| 28. |
- Eriksson, Per, 1958-
(författare)
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Renal disease in primary Sjögren's syndrome
- 1996
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Primary Sjögren's syndrome (SS) is characterised by inflammation in the lacrimal and salivary glands. The kidneys may be involved, e.g. tubulointerstitial nephritis (TIN) and distal renal tubular acidosis (dRTA). dRTA is often associated with hypocitraturia, and both represent risk factors for the development of urolithiasis. The present investigations were undertaken to evaluate renal tubular function (including -dRTA), glomerular filtration rate (GFR), renal histopathology and mechanisms of stone formation, as well as the serum IgG subclass pattern in patients with SS. Furthermore, patients presenting with urolithiasis and dRTA in absence of sicca symptoms, as well as patients with urolithiasis andhypocitraturia, were studied with respect to autoantibodies and clinical features of SS. Renal tubular dysfunction, such as dRTA; impaired urine concentrating ability; hypocitraturia; and decreased tubular reabsorption of phosphate (1RP%), was conunonly detected in the SS-patients. Tubular proteinuria (al-microglobulin) and tubular enzymuria (NAG) were primarily associated with decreased GFR. GFR, investigated with 5Icr-EDTA plasma clearance, was below the reference limit in 33% of SS-patients. An inverse correlation was found between GFR and the extent of tubulointerstitial nephritis (adjusted CTIN score). Decreased GFR was mostly due to TIN, although urolithiasis and upper urinary tract infections may have contributed in some patients. TIN was demonstrated in most biopsied patients with SS, and the histopathological picture was characterised by mainly focal interstitial inflanunation, tubular atrophy, interstitial fibrosis and a varying extent of glomerular sclerosis. Fourty-one percent of the SS-patients had formed at least one stone, and calcium phosphate was the main constituent in most stones. All stone formers had dRTA, and most of them had hypocitraturia. Urinary calcium and urate excretion was also significantly higher than in non-stone formers. The SS-patients often had low serum levels of IgG2, despite high levels of total IgG. Low levels of IgG2 were sometimes associated with infections. A high IgG lngG2 ratio indicated autoimmune disease. Of 10 patients presenting with urolithiasis and dRTA, anti-SS-A antibodies were detected in eight. Subjective sicca symptoms subsequently developed l-48 years after the presentation of urolithiasis, and objective signs of SS were found in 7 patients. In a large population of hypocitraturic stone formers, ANA and anti-SS-A antibodies were commonly detected in the women but not in the men. Four of 14 evaluated hypocitraturic women with anti-SS-A antibodies or ANA, fulfilled the criteria for SS. In conclusion, the present investigations show that 24-hour urinary excretion of citrate is a valuable tool for detection of renal disease in SS, slightly-moderately decreased GFR is not unusual in SS-patients with. renal disease, the "adjusted CTIN score" can be a useful tool for quantifying the extent of tu'bulointerstitial nephritis, and the urine composition in stone formers with SS is similar to that of other dRT A-patients. The possibility of a Sjögren-related renal disease charcterised by urolithiasis and/or dRTA and antibodies to SS-A, regardless of whether subjective sicca symptoms are present or not, is hypothesised.
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| 29. |
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| 30. |
- Guldstrand, Marie, et al.
(författare)
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Alteration of the counterregulatory responses to insulin-induced hypoglycemia and of cognitive function after massive weight reduction in severely obese subjects
- 2003
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Ingår i: Metabolism, Clinical and Experimental. - 1532-8600. ; 52:7, s. 900-907
-
Tidskriftsartikel (refereegranskat)abstract
- The autonomic nervous system (ANS) and hypothalamic-pituitary-adrenal (HPA) axis are reported as activated in excess in the morbidly obese state and, therefore, changes after weight loss can be anticipated. The aim of this study was to investigate the impact of a massive (similar to30%) weight reduction on the activation of the HPA axis and the ANS following bariatric surgery. Eight (7 women, 1 man) severely obese (125 +/- 12 kg; body mass index [BMI], 45 +/- 4 kg/m(2)) nondiabetic subjects, underwent a 3-hour hyperinsulinemic (1,034 pmol/kg/h) glucose clamp study at hypoglycemia of arterial B-glucose concentration of 3.4 mmol/L. Cognitive function was evaluated by a visuospatial computerized problem-solving test, the Perceptual Maze Test (PMT). The mean weight loss was 40 +/- 9 kg approximately 12 months postsurgery when their weight was stabilized (85 6 kg; BMI, 31 +/- 3 kg/m(2)), and insulin sensitivity improved to an average increase of 376% +/- 250% (P < .01) of initial value. Before weight reduction, all patients demonstrated brisk peak responses in glucagon, epinephrine, pancreatic polypeptide (PP), norepinephrine, and cortisol, indicative of preserved or exaggerated activation of ANS and HPA axis. In the reduced-obese state, all these responses were attenuated and most markedly so for glucagon, which was totally abolished. In contrast, the growth hormone (GH) response was increased after weight reduction. The cognitive function was clearly modified by weight reduction both during normoglycemia and hypoglycemia and was changed preferentially to a speed-preferring strategy in the reduced-obese state compared with a more accuracy preferred problem-solving process of PMT test presurgery. These results demonstrate a reduction of the glucose counterregulatory hormonal responses, increased insulin sensitivity, and perturbed cognitive function after massive weight reduction. It may be speculated on if the increased insulin sensitivity and reduced counterregulation to hypoglycemia could predispose to low plasma glucose concentrations.
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| 31. |
- Hammerman, Malin, 1984-
(författare)
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Tendon Healing : Mechanical Loading, Microdamage and Gene Expression
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.
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| 32. |
- Henein, Michael, et al.
(författare)
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Long mitral valve leaflets determine left ventricular outflow tract obstruction during exercise in hypertrophic cardiomyopathy
- 2016
-
Ingår i: International Journal of Cardiology. - : Elsevier. - 0167-5273 .- 1874-1754. ; 212, s. 47-53
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Development of left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic cardiomyopathy (HCM) is important for explaining symptoms and designing management. LVOTO is mostly caused by a combination of septal hypertrophy and systolic anterior movement of the mitral valve (SAM). The aim of the present study was to determine predictors of exercise induced LVOTO in a group of HCM patients.METHODS: We performed supine exercise Doppler echocardiography, including measurements of LV morphology and function and anterior mitral leaflet length, in 51 mildly symptomatic HCM (septal thickness≥15mm) and compared them with 50 healthy controls. Measurements were made at 1) rest, 2) Valsalva maneuver, 3) peak exercise and 4) post exercise. LVOTO was diagnosed as a LVOT gradient of >30mmHg at rest, after Valsalva and after exercise or ≥50mmHg at peak exercise.RESULTS: All patients stopped exercise because of exhaustion. 35% of the patients had resting LVOTO and 48% during Valsalva. At peak exercise, only 37% had LVOTO, who increased to 64% post exercise. Patients who developed LVOTO at peak exercise were more prone to continue having it post exercise (p<0.001), to have attenuated systolic blood pressure rise (p=0.011) and to have long anterior mitral valve leaflets (p<0.001). Backward multiple regression analysis showed the anterior mitral leaflet length as the strongest single independent predictor (β=0.36, p=0.010) for increased LVOT velocities, followed by basal septal thickness.CONCLUSION: In patients with HCM, LV outflow tract obstruction seems to be relatively uncommon during exercise but rather occurring minutes after stopping exercise. Exercise LVOTO seems to be determined by long anterior mitral leaflets in addition to the well established septal hypertrophy.
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| 33. |
- Hohner, Per, et al.
(författare)
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Anaesthesia for abdominal vascular surgery in patients with coronary artery disease (CAD), Part I : Isoflurane produces dose-dependent coronary vasodilation
- 1994
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Ingår i: Acta Anaesthesiol Scand. ; 38:8, s. 780-92
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of anaesthesia for major abdominal vascular surgery on coronary flow regulation and mechanisms of myocardial ischaemia were studied in 56 patients with CAD, using a randomized, partly double-blinded protocol. After induction with fentanyl (3 micrograms.kg-1) and thiopentone (2-4 mg.kg-1) and tracheal intubation, principal anaesthetics were nitrous oxide/oxygen (60/40) with isoflurane (n = 20), halothane (n = 19) or fentanyl (15-20 micrograms.kg-1) (n = 17). Conventional invasive techniques and coronary venous retrograde thermodilution were used to assess systemic and coronary haemodynamics. Coronary vascular resistance was estimated from myocardial oxygen extraction. Myocardial ischaemia was diagnosed by 12-lead ECG and/or anterior wall motion abnormalities by cardiokymography and/or myocardial lactate production. When adjustment of anaesthetic dose was insufficient for haemodynamic control, i.v. phenylephrine and nitroglycerine were administered to treat hypotension and hypertension or cardiac failure respectively. Measurements were performed at four specific intervals; awake, before surgery and 10 and 30 min after abdominal incision. Comparable changes of systemic haemodynamics and myocardial oxygen consumption were observed in the three groups. Coronary vasodilation was evidenced in isoflurane patients only and was linearly dose-dependent (P < 0.001). Partial Least Squares Projections to Latent Structures modelling with cross validation confirmed this dose-dependency and ruled out a clinically measurable influence by intervention drugs or simultaneous systemic haemodynamic abnormalities. The incidence of myocardial ischaemia during anaesthesia and surgery was comparable in the three groups (35, 37 and 24%, respectively) and there was an association with systemic haemodynamic aberrations in 19 of the 27 ischaemic episodes. In contrast to ischaemic halothane and fentanyl patients, isoflurane patients with ischaemia had significantly lower myocardial oxygen extraction (P = 0.008 and P = 0.001, respectively), indicating that the oxygen extraction reserve was not utilized in a normal way during ischaemia.
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| 34. |
- Holmgren, Per, 1982-
(författare)
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Entrained flow studies on biomass fuel powder conversion and ash formation
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Reducing the global dependence on fossil fuels is of paramount importance in tackling the environmental challenges we face, not only tomorrow, but already today. Biomass offers a renewable supply of CO2-neutral raw material that can be converted into many different forms of fuels and valuable chemicals, making it a prime candidate for the technologies of tomorrow. However, the heterogeneous nature and distinctly different elemental composition of biomass compared to traditional fossil sources present new challenges to be solved. When it comes to thermochemical technologies, key issues concern fuel conversion efficiency, ash formation, ash/fuel interactions and ash/reactor material interactions.The objective of the present thesis was to provide new knowledge and insights into thermochemical fuel conversion, in particular its application in entrained flow technologies. A laboratory-scale reactor was constructed, evaluated and was used to study several aspects of high-temperature entrained flow biomass fuel conversion. Pulverized fuel particles from different biomass sources were used, and their physical and chemical interactions with the surrounding atmosphere, the concurrent ash element release, ash formation, and phase interactions were also studied in detail. In addition to the entrained flow reactor designed and constructed for this purpose, the main method for data collection was in situ optical studies of converting particles, either while entrained in the flow or when impacting upon surfaces. Elemental composition analysis of collected samples and gas analysis were also performed, allowing for a deeper understanding of ash element fractionation and interactions and thus explaining the observed properties of the resulting deposits or slag.The degree of conversion of fuels with very low ash content, such as stem wood, was well described and modeled by a novel method using optical data, offering a non-intrusive and non-destructive alternative to traditional techniques. Coupling computational fluid dynamics with optical data allowed for improved experimental data interpretation and provided improved accuracy for fuel particle residence time estimations, which is an important parameter when studying fast chemical reactions such as those taking place in reactors for entrained flow conditions. The results from studies on ash formation gave new insights into the feasibility of using dry-mixed K-rich additives for improving slag properties during gasification of Ca-rich and Si-rich fuels. Interpretations of the experimental results were supported by thermodynamic equilibrium calculations, and the conclusions highlight both possibilities and challenges in gasification with high fuel flexibility while at the same time producing a flowing slag. Applications and future implications are discussed, and new topics of interest are presented.
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| 35. |
- Holmgren, Per, et al.
(författare)
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Slag Formation during Entrained Flow Gasification : Silicon Rich Grass Fuel with KHCO3 Additive
- 2018
-
Ingår i: Energy & Fuels. - : American Chemical Society (ACS). - 0887-0624 .- 1520-5029. ; 32:10, s. 10720-10726
-
Tidskriftsartikel (refereegranskat)abstract
- Prediction of ash particle adherence to walls, melting, and flow properties are important for successful operation of slagging entrained flow gasifiers. In the present study, silicon-rich reed canary grass was gasified at 1000 and 1200 °C with solid KHCO3 added at 0, 1, or 5 wt % to evaluate the impact and efficiency of the dry mixed additive on slag properties. The fuel particles collided with an angled flat impact probe inside the hot reactor, constructed to allow for particle image velocimetry close to the surface of the probe. Ash deposit layer buildup was studied in situ as well as ash particle shape, size, and velocity as they impacted on the probe surface. The ash deposits were analyzed using scanning electron microscopy–energy-dispersive X-ray spectroscopy, giving detailed information on morphology and elemental composition. Results were compared to thermodynamic equilibrium calculations for phase composition and viscosity. The experimental observations (slag melting, flow properties, and composition) were in good qualitative agreement with the theoretical predictions. Accordingly, at 1000 °C, no or partial melts were observed depending upon the potassium/silicon ratio; instead, high amounts of additive and a temperature of at least 1200 °C were needed to create a flowing melt.
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| 36. |
- Holmgren, Per, et al.
(författare)
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Slag Formation during Entrained Flow Gasification : Calcium-Rich Bark Fuel with KHCO3 Additive
- 2020
-
Ingår i: Energy & Fuels. - : American Chemical Society (ACS). - 0887-0624 .- 1520-5029. ; 34:6, s. 7112-7120
-
Tidskriftsartikel (refereegranskat)abstract
- Slag property management is of utmost importance for successful operation of entrained flow gasifiers. The present study investigates the influence of potassium introduced as KHCO3 on the ash and slag formation of softwood bark, a calcium-rich fuel, during entrained flow gasification. The bark contained only minor mineral inclusions causing the ash composition to be dominated by calcium and potassium. Wood bark with and without KHCO3 additive was gasified between 850 and 1400 degrees C at O-2 stoichiometric ratio (lambda) 0.6. The ash particles collided with a flat impact probe inside the hot reactor at particle impact angles set to 90 degrees, 60 degrees, and 30 degrees. The reactor and probe allowed long-distance microscope data collection close to the probe surface. Particle deposition was optically monitored and resulting deposits were analyzed by SEM-EDS and XRD. Thermodynamic equilibrium and viscosity calculations were used to assist interpretation of experimental results. The predicted temperature window for liquid carbonate formation was experimentally verified, but the melt fraction of the deposit was too low to cause efficient flow and removal of ash from the probe under the prevailing experimental conditions. At higher temperatures, spherical particles indicated lower ash melting temperatures than expected from the bulk ash composition, and a detailed mechanism was proposed.
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| 37. |
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| 38. |
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| 39. |
- Ihse, E, et al.
(författare)
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Amyloid fibril composition is related to the phenotype of hereditary transthyretin V30M amyloidosis
- 2008
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 216:2, s. 253-61
-
Tidskriftsartikel (refereegranskat)abstract
- Swedish familial systemic amyloidosis with polyneuropathy (FAP) depends on a mutation leading to a methionine-for-valine substitution in transthyretin. The disease appears with different clinical manifestations, including age of onset and involvement of the heart. Liver transplantation is currently the only curative treatment, but progressive cardiomyopathy may occur post-transplant. Two amyloid deposition patterns have previously been described in the heart. In one, the amyloid consists partially of transthyretin fragments and is weakly stainable by Congo red, while in the other, only full-length molecules are found and the fibrils have a strong affinity for Congo red. The present study aimed to see whether these morphological and biochemical variations have clinical implications. Subcutaneous adipose tissue biopsies were taken from 33 patients with Val30Met FAP and examined by microscopy, electrophoresis and western blot. Clinical data included age, sex, duration of disease and echocardiographic determination of the interventricular septum (IVS) thickness. It was found that fibrils composed of only full-length transthyretin were associated with early age of onset (44.8 +/- 12.9 years), no clinical cardiac involvement and a strong affinity for Congo red. In contrast, presence of transthyretin fragments in the amyloid was associated with late age of onset (67.3 +/- 7.0 years), signs of cardiac involvement and weak Congo red staining. For each individual, the same molecular type of amyloid was found in different organs. This is the first report showing that variations in clinical appearance of familial ATTR amyloidosis are associated with specific structural differences in the amyloid fibrils, and therefore may have a molecular cause. The molecular type of amyloid can be determined from a subcutaneous fat tissue biopsy.
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| 40. |
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| 41. |
- Kotova, Natalia, et al.
(författare)
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(32)P-HPLC analysis of N1-(2-carboxy-2-hydroxyethyl)deoxyadenosine : A DNA adduct of the acrylamide-derived epoxide glycidamide
- 2011
-
Ingår i: Toxicology Letters. - : Elsevier BV. - 0378-4274 .- 1879-3169. ; 207:1, s. 18-24
-
Tidskriftsartikel (refereegranskat)abstract
- Acrylamide (AA) is produced in many types of food products cooked or processed at high temperature. AA is metabolized to the epoxide glycidamide (GA), which can bind to deoxyguanosine and deoxyadenosine in DNA. The GA-derived N7-guanine and N3-adenine adducts are the only products which so far have been analysed in vivo. Because of previous excellent experience from analysis of adducts to N1-adenine, the aim of our study was to investigate if the N1-adenine adduct of GA could be used as a biomarker of AA exposure. A (32)P-postlabelling method was developed and tested (a) on DNA modified in vitro with GA, (b) on cells treated with GA and (c) on liver DNA from mice treated with M. The N1-adenine adduct of GA (analysed after conversion to N(6)-GA-deoxyadenosine-5'-monophosphate) was easily detected in DNA reacted with GA and in DNA from cells exposed to GA, but not in DNA from mice treated with AA. The reason for this is currently not clearly understood, but some of the possible contributing factors are discussed. The application of the method in other experimental conditions should be further pursued in order to solve this matter.
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| 42. |
- Lampinen, Maria, et al.
(författare)
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Different regulation of eosinophil activity in Crohn's disease compared with ulcerative colitis
- 2008
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:6, s. 1392-1399
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this investigation was to study the involvement of eosinophil and neutrophil granulocytes in different stages of Crohn's disease (CD) and ulcerative colitis (UC). Biopsy samples were taken from the right flexure of the colon and from the rectum in patients with active (n=12) and inactive colonic CD (n=7), patients with active (n=33) and inactive UC (n=24), and from control subjects (n=11). Cell suspensions from biopsies and blood were analyzed by flow cytometry with regards to activation markers and viability. Immunohistochemistry was used to evaluate cell number and degranulation. Blood eosinophils were cultured with Th1 and Th2 cytokines, and the expression of activity markers was assessed by flow cytometry. Eosinophil number, viability, and activity were increased during active CD and UC compared with controls. The activity, assessed as CD44 expression, tended to diminish during inactive CD but was increased further in quiescent UC. Neutrophil number and activity were increased only during inflammation in both diseases. Culture of blood eosinophils with IL-5 and IL-13 caused increased CD44 expression, whereas IL-5 and IFN-gamma induced elevated CD69 expression. We observed different patterns of eosinophil activation in CD and UC, with the highest CD44 expression during quiescent UC. Our in vitro experiments with recombinant cytokines suggest that the diverse mechanisms of eosinophil activation in CD and UC are a result of different cytokine milieus (Th1 vs. Th2). In contrast, neutrophil activation reflects the disease activity in CD and UC, irrespective of Th cell skewing.
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| 43. |
- Lindqvist, Per, et al.
(författare)
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Pulsed tissue Doppler and strain imaging discloses early signs of infiltrative cardiac disease: a study on patients with familial amyloidotic polyneuropathy.
- 2006
-
Ingår i: Eur J Echocardiogr. ; 7:1, s. 22-30
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Familial amyloidotic polyneuropathy (FAP) is a hereditary systemic amyloidosis with cardiac involvement. As early identification of the cardiac involvement is of major clinical interest we performed this study to test the hypothesis that tissue Doppler imaging (TDI) and strain imaging (SI) might disclose cardiac involvement in patients with early stages of FAP. METHODS: Twenty-two patients with FAP and 36 healthy controls were studied. Standard M-mode and Doppler echocardiography were performed. TDI and SI were used to assess the regional longitudinal left ventricular (LV) lateral and septal and right ventricular (RV) wall functions. All time intervals were corrected for heart rate by dividing with R-R interval and presented as percentage. RESULTS: We found that patients in comparison with controls had increased LV and RV wall thickness and by using TDI a prolonged isovolumic relaxation time (IVRt) at the septal segment (15.0+/-7.0 vs 10.7+/-4.1%, p<0.05) and prolonged isovolumic contraction time (IVCt) at LV lateral (12.8+/-4.3 vs 10.1+/-3.3%, p<0.05), septal (12.5+/-3.5 vs 8.9+/-1.9%, p<0.001) and RV free wall segments (12.0+/-3.6 vs 8.3+/-2.1%, p<0.001). Strain was reduced at LV lateral basal segment (-4.6+/-14.0 vs -20.2+9.1, p<0.001), RV free wall mid segment (-16.2+/-12.8 vs -29.4+/-15.2) as well as both septal segments (-4.1+/-11.7 vs -16.2+/-9.0%, p<0.001, -8.8+/-11.5 vs -19.4+/-8.4%, p<0.001 for septal basal and mid-segment). Even in the absence of septal hypertrophy the septal strain was reduced and the regional IVCt was prolonged. CONCLUSIONS: This is the first clinical study using TDI and strain in patients with FAP showing functional abnormalities before any morphological echocardiographic abnormalities were present. Both the left and right heart functions are involved and the disease should therefore be regarded as biventricular.
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| 44. |
- Lindqvist, Per, et al.
(författare)
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Ventricular dysfunction in type 1 myotonic dystrophy : Electrical, mechanical, or both?
- 2010
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Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 143:3, s. 378-384
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Myotonic dystrophy type 1 (DM1) is a systemic disease which affects the heart and may be a cause of sudden death. Conduction disturbances are the major cardiac abnormalities seen in this condition. We sought to assess electrical and mechanical cardiac functions to identify abnormalities that might explain sudden cardiac death in DM1. METHODS: Thirty six patients with DM1 and 16 controls were studied using echocardiography including myocardial Doppler. ECG recordings were also obtained. RESULTS: Left ventricular (LV) dimensions were maintained but systolic function was reduced (p<0.001), including stroke volume (p<0.05). LV segmental myocardial isovolumic contraction time was prolonged (p<0.001) and correlated with PR interval (p<0.001). Isovolumic relaxation time was prolonged (p<0.05) and filling time was reduced (p<0.001). LV cavity was significantly asynchronous demonstrated by prolonged total isovolumic time (t-IVT) (p<0.001), high Tei index (p<0.001) and low ejection index (p<0.001). Right ventricular (RV) strain was reduced (p<0.001) as were its systolic and diastolic velocities (p<0.05 for both). 22/36 patients had prolonged LV t-IVT>12.3 s/min (upper 95% normal CI), 13 of whom had PR>/=200 ms, 11 had QRS duration >120 ms (5 had combined abnormality) and the remaining 5 had neither. Over the 3 years follow up 10 patients had events, 6 of them cardiac. t-IVT was prolonged in 5/6 patients, PR interval in 4 and QRS duration in one. CONCLUSIONS: In DM1 patients, LV conventional measurements are modestly impaired but cardiac time relations suggest marked asynchronous cavity function. Although our findings were primarily explained on the basis of long PR interval or broad QRS duration a minority presented an evidence for myocardial cause of asynchrony rather than electrical. Early identification of such abnormalities may guide towards a need for additional electrical resynchronization therapy which may improve survival in a way similar to what has been shown in heart failure trials.
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| 45. |
- Maharjan, Rajani, et al.
(författare)
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Comprehensive analysis of CTNNB1 in adrenocortical carcinomas : Identification of novel mutations and correlation to survival
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- The Wnt/β-Catenin signaling pathway is one of the most frequently altered pathways in adrenocortical carcinomas (ACCs). The aim of this study was to investigate the status of Wnt/β-Catenin signaling pathway by analyzing the expression level of β-Catenin and the mutational status of APC, AXIN2, CTNNB1, and ZNRF3 in ACCs. Mutations in APC, CTNNB1, ZNRF3 and homozygous deletions in ZNRF3 were observed in 3.8% (2/52), 11.5% (6/52), 1.9% (1/52) and 17.3% (9/52) of the cohort respectively. Novel interstitial deletions in CTNNB1 spanning intron 1 to exon 3/intron 3 were also found in 7.7% (4/52) of the tumours. All the observed alterations were mutually exclusive. Nuclear accumulation of β-Catenin, increased expression of Cyclin D1 and significantly higher expression of AXIN2 (p = 0.0039), ZNRF3 (p = 0.0032) and LEF1(p = 0.0090) observed in the tumours harbouring the deletion in comparison to tumours without CTNNB1 mutation demonstrates that the truncated β-Catenin is functionally active and erroneously activates the downstream targets. Significantly lower overall survival rate in patients with tumours harbouring alterations in APC/CTNNB1/ZNRF3 in comparison to those without mutation was observed. In conclusion, the discovery of novel large deletions in addition to the point mutations in CTNNB1 infers that activation of Wnt/β-Catenin pathway via alterations in CTNNB1 occurs frequently in ACCs. We also confirm that alterations in Wnt/β-Catenin signaling pathway members have a negative effect on overall survival of patients.
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- Mezheyeuski, Artur, et al.
(författare)
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The Immune Landscape of Colorectal Cancer
- 2021
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 13:21
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Tidskriftsartikel (refereegranskat)abstract
- We sought to provide a detailed overview of the immune landscape of colorectal cancer in the largest study to date in terms of patient numbers and analyzed immune cell types. We applied a multiplex in situ staining method in combination with an advanced scanning and image analysis pipeline akin to flow cytometry, and analyzed 5968 individual multi-layer images of tissue defining in a total of 39,078,450 cells. We considered the location of immune cells with respect to the stroma, and tumor cell compartment and tumor regions in the central part or the invasive margin. To the best of our knowledge, this study is the first comprehensive spatial description of the immune landscape in colorectal cancer using a large population-based cohort and a multiplex immune cell identification.While the clinical importance of CD8+ and CD3+ cells in colorectal cancer (CRC) is well established, the impact of other immune cell subsets is less well described. We sought to provide a detailed overview of the immune landscape of CRC in the largest study to date in terms of patient numbers and in situ analyzed immune cell types. Tissue microarrays from 536 patients were stained using multiplexed immunofluorescence panels, and fifteen immune cell subclasses, representing adaptive and innate immunity, were analyzed. Overall, therapy-naive CRC patients clustered into an 'inflamed' and a 'desert' group. Most T cell subsets and M2 macrophages were enriched in the right colon (p-values 0.046-0.004), while pDC cells were in the rectum (p = 0.008). Elderly patients had higher infiltration of M2 macrophages (p = 0.024). CD8+ cells were linked to improved survival in colon cancer stages I-III (q = 0.014), while CD4+ cells had the strongest impact on overall survival in metastatic CRC (q = 0.031). Finally, we demonstrated repopulation of the immune infiltrate in rectal tumors post radiation, following an initial radiation-induced depletion. This study provides a detailed analysis of the in situ immune landscape of CRC paving the way for better diagnostics and providing hints to better target the immune microenvironment.
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