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| 31. |
- Andersen, T. C. B., et al.
(författare)
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The SH3 domains of the protein kinases ITK and LCK compete for adjacent sites on T cell?specific adapter protein
- 2019
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Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 294:42, s. 15480-15494
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Tidskriftsartikel (refereegranskat)abstract
- T-cell activation requires stimulation of specific intracellular signaling pathways in which protein-tyrosine kinases, phosphatases, and adapter proteins interact to transmit signals from the T-cell receptor to the nucleus. Interactions of LCK proto-oncogene, SRC family tyrosine kinase (LCK), and the IL-2?inducible T cell kinase (ITK) with the T cell-specific adapter protein (TSAD) promotes LCK-mediated phosphorylation and thereby ITK activation. Both ITK and LCK interact with TSAD's proline-rich region (PRR) through their Src homology 3 (SH3) domains. Whereas LCK may also interact with TSAD through its SH2 domain, ITK interacts with TSAD only through its SH3 domain. To begin to understand on a molecular level how the LCK SH3 and ITK SH3 domains interact with TSAD in human HEK293T cells, here we combined biochemical analyses with NMR spectroscopy. We found that the ITK and LCK SH3 domains potentially have adjacent and overlapping binding sites within the TSAD PRR amino acids (aa) 239?274. Pulldown experiments and NMR spectroscopy revealed that both domains may bind to TSAD aa 239?256 and aa 257?274. Co-immunoprecipitation experiments further revealed that both domains may also bind simultaneously to TSAD aa 242?268. Accordingly, NMR spectroscopy indicated that the SH3 domains may compete for these two adjacent binding sites. We propose that once the associations of ITK and LCK with TSAD promote the ITK and LCK interaction, the interactions among TSAD, ITK, and LCK are dynamically altered by ITK phosphorylation status.
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| 33. |
- Fagerlund, A. J., et al.
(författare)
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Experiences from patients in mental healthcare accessing their electronic health records : results from a cross-national survey in Estonia, Finland, Norway, and Sweden
- 2024
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Ingår i: BMC Psychiatry. - : BioMed Central (BMC). - 1471-244X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients' online record access (ORA) enables patients to read and use their health data through online digital solutions. One such solution, patient-accessible electronic health records (PAEHRs) have been implemented in Estonia, Finland, Norway, and Sweden. While accumulated research has pointed to many potential benefits of ORA, its application in mental healthcare (MHC) continues to be contested. The present study aimed to describe MHC users' overall experiences with national PAEHR services.METHODS: The study analysed the MHC-part of the NORDeHEALTH 2022 Patient Survey, a large-scale multi-country survey. The survey consisted of 45 questions, including demographic variables and questions related to users' experiences with ORA. We focused on the questions concerning positive experiences (benefits), negative experiences (errors, omissions, offence), and breaches of security and privacy. Participants were included in this analysis if they reported receiving mental healthcare within the past two years. Descriptive statistics were used to summarise data, and percentages were calculated on available data.RESULTS: 6,157 respondents were included. In line with previous research, almost half (45%) reported very positive experiences with ORA. A majority in each country also reported improved trust (at least 69%) and communication (at least 71%) with healthcare providers. One-third (29.5%) reported very negative experiences with ORA. In total, half of the respondents (47.9%) found errors and a third (35.5%) found omissions in their medical documentation. One-third (34.8%) of all respondents also reported being offended by the content. When errors or omissions were identified, about half (46.5%) reported that they took no action. There seems to be differences in how patients experience errors, omissions, and missing information between the countries. A small proportion reported instances where family or others demanded access to their records (3.1%), and about one in ten (10.7%) noted that unauthorised individuals had seen their health information.CONCLUSIONS: Overall, MHC patients reported more positive experiences than negative, but a large portion of respondents reported problems with the content of the PAEHR. Further research on best practice in implementation of ORA in MHC is therefore needed, to ensure that all patients may reap the benefits while limiting potential negative consequences.
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| 36. |
- Wu, K, et al.
(författare)
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Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas
- 2015
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 10131-
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Tidskriftsartikel (refereegranskat)abstract
- The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma.
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| 42. |
- Liaset, B, et al.
(författare)
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Nutritional Regulation of Bile Acid Metabolism Is Associated with Improved Pathological Characteristics of the Metabolic Syndrome
- 2011
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Ingår i: JOURNAL OF BIOLOGICAL CHEMISTRY. - 0021-9258. ; 286:32, s. 28382-28395
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Bile acids (BAs) are powerful regulators of metabolism, and mice treated orally with cholic acid are protected from diet-induced obesity, hepatic lipid accumulation, and increased plasma triacylglycerol (TAG) and glucose levels. Here, we show that plasma BA concentration in rats was elevated by exchanging the dietary protein source from casein to salmon protein hydrolysate (SPH). Importantly, the SPH-treated rats were resistant to diet-induced obesity. SPH-treated rats had reduced fed state plasma glucose and TAG levels and lower TAG in liver. The elevated plasma BA concentration was associated with induction of genes involved in energy metabolism and uncoupling, Dio2, Pgc-1α, and Ucp1, in interscapular brown adipose tissue. Interestingly, the same transcriptional pattern was found in white adipose tissue depots of both abdominal and subcutaneous origin. Accordingly, rats fed SPH-based diet exhibited increased whole body energy expenditure and heat dissipation. In skeletal muscle, expressions of the peroxisome proliferator-activated receptor β/δ target genes (Cpt-1b, Angptl4, Adrp, and Ucp3) were induced. Pharmacological removal of BAs by inclusion of 0.5 weight % cholestyramine to the high fat SPH diet attenuated the reduction in abdominal obesity, the reduction in liver TAG, and the decrease in nonfasted plasma TAG and glucose levels. Induction of Ucp3 gene expression in muscle by SPH treatment was completely abolished by cholestyramine inclusion. Taken together, our data provide evidence that bile acid metabolism can be modulated by diet and that such modulation may prevent/ameliorate the characteristic features of the metabolic syndrome.
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| 43. |
- Lindstrom, L., et al.
(författare)
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High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia
- 2012
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Ingår i: Alimentary Pharmacology and Therapeutics. - Malden : Wiley. - 0269-2813 .- 1365-2036. ; 35:4, s. 451-457
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Tidskriftsartikel (refereegranskat)abstract
- Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking. Aim To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD. Methods From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia. Results The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo-(n = 50) and UDCA-treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia. Conclusions Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.
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| 44. |
- Munch Roager, Henrik, et al.
(författare)
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Whole grain-rich diet reduces body weight and systemic low-grade inflammation without inducing major changes of the gut microbiome: A randomised cross-over trial
- 2019
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Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 68:1, s. 83-93
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Tidskriftsartikel (refereegranskat)abstract
- Objective T o investigate whether a whole grain diet alters the gut microbiome and insulin sensitivity, as well as biomarkers of metabolic health and gut functionality. Design 60 Danish adults at risk of developing metabolic syndrome were included in a randomised cross-over trial with two 8-week dietary intervention periods comprising whole grain diet and refined grain diet, separated by a washout period of =6 weeks. The response to the interventions on the gut microbiome composition and insulin sensitivity as well on measures of glucose and lipid metabolism, gut functionality, inflammatory markers, anthropometry and urine metabolomics were assessed. Results 50 participants completed both periods with a whole grain intake of 179±50 g/day and 13±10 g/day in the whole grain and refined grain period, respectively. Compliance was confirmed by a difference in plasma alkylresorcinols (p<0.0001). Compared with refined grain, whole grain did not significantly alter glucose homeostasis and did not induce major changes in the faecal microbiome. Also, breath hydrogen levels, plasma short-chain fatty acids, intestinal integrity and intestinal transit time were not affected. The whole grain diet did, however, compared with the refined grain diet, decrease body weight (p<0.0001), serum inflammatory markers, interleukin (IL)-6 (p=0.009) and C-reactive protein (p=0.003). The reduction in body weight was consistent with a reduction in energy intake, and IL-6 reduction was associated with the amount of whole grain consumed, in particular with intake of rye. Conclusion C ompared with refined grain diet, whole grain diet did not alter insulin sensitivity and gut microbiome but reduced body weight and systemic lowgrade inflammation.
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| 45. |
- Strom, Peter, et al.
(författare)
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Artificial intelligence for diagnosis and grading of prostate cancer in biopsies : a population-based, diagnostic study
- 2020
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Ingår i: The Lancet Oncology. - : Elsevier. - 1470-2045 .- 1474-5488. ; 21:2, s. 222-232
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAn increasing volume of prostate biopsies and a worldwide shortage of urological pathologists puts a strain on pathology departments. Additionally, the high intra-observer and inter-observer variability in grading can result in overtreatment and undertreatment of prostate cancer. To alleviate these problems, we aimed to develop an artificial intelligence (AI) system with clinically acceptable accuracy for prostate cancer detection, localisation, and Gleason grading.MethodsWe digitised 6682 slides from needle core biopsies from 976 randomly selected participants aged 50–69 in the Swedish prospective and population-based STHLM3 diagnostic study done between May 28, 2012, and Dec 30, 2014 (ISRCTN84445406), and another 271 from 93 men from outside the study. The resulting images were used to train deep neural networks for assessment of prostate biopsies. The networks were evaluated by predicting the presence, extent, and Gleason grade of malignant tissue for an independent test dataset comprising 1631 biopsies from 246 men from STHLM3 and an external validation dataset of 330 biopsies from 73 men. We also evaluated grading performance on 87 biopsies individually graded by 23 experienced urological pathologists from the International Society of Urological Pathology. We assessed discriminatory performance by receiver operating characteristics and tumour extent predictions by correlating predicted cancer length against measurements by the reporting pathologist. We quantified the concordance between grades assigned by the AI system and the expert urological pathologists using Cohen's kappa.FindingsThe AI achieved an area under the receiver operating characteristics curve of 0·997 (95% CI 0·994–0·999) for distinguishing between benign (n=910) and malignant (n=721) biopsy cores on the independent test dataset and 0·986 (0·972–0·996) on the external validation dataset (benign n=108, malignant n=222). The correlation between cancer length predicted by the AI and assigned by the reporting pathologist was 0·96 (95% CI 0·95–0·97) for the independent test dataset and 0·87 (0·84–0·90) for the external validation dataset. For assigning Gleason grades, the AI achieved a mean pairwise kappa of 0·62, which was within the range of the corresponding values for the expert pathologists (0·60–0·73).InterpretationAn AI system can be trained to detect and grade cancer in prostate needle biopsy samples at a ranking comparable to that of international experts in prostate pathology. Clinical application could reduce pathology workload by reducing the assessment of benign biopsies and by automating the task of measuring cancer length in positive biopsy cores. An AI system with expert-level grading performance might contribute a second opinion, aid in standardising grading, and provide pathology expertise in parts of the world where it does not exist.
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| 46. |
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| 47. |
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| 48. |
- Bacon, Christine D., et al.
(författare)
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Soil fertility and flood regime are correlated with phylogenetic structure of Amazonian palm communities
- 2019
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Ingår i: Annals of Botany. - : Oxford University Press (OUP). - 0305-7364 .- 1095-8290. ; 123:4, s. 641-655
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims Identifying the processes that generate and maintain biodiversity requires understanding of how evolutionary processes interact with abiotic conditions to structure communities. Edaphic gradients are strongly associated with floristic patterns but, compared with climatic gradients, have received relatively little attention. We asked (1) How does the phylogenetic composition of palm communities vary along edaphic gradients within major habitat types? and (2) To what extent are phylogenetic patterns determined by (a) habitat specialists, (b) small versus large palms, and (c) hyperdiverse genera? Methods We paired data on palm community composition from 501 transects of 0.25 ha located in two main habitat types (non-inundated uplands and seasonally inundated floodplains) in western Amazonian rain forests with information on soil chemistry, climate, phylogeny and metrics of plant size. We focused on exchangeable base concentration (cmol(+) kg(-1)) as a metric of soil fertility and a floristic index of inundation intensity. We used a null model approach to quantify the standard effect size of mean phylogenetic distance for each transect (a metric of phylogenetic community composition) and related this value to edaphic variables using generalized linear mixed models, including a term for spatial autocorrelation. Key Results Overall, we recorded 112 008 individuals belonging to 110 species. Palm communities in non-inundated upland transects (but not floodplain transects) were more phylogenetically clustered in areas of low soil fertility, measured as exchangeable base concentration. In contrast, floodplain transects with more severe flood regimes (as inferred from floristic structure) tended to be phylogenetically clustered. Nearly half of the species recorded (44 %) were upland specialists while 18 % were floodplain specialists. In both habitat types, phylogenetic clustering was largely due to the co-occurrence of small-sized habitat specialists belonging to two hyperdiverse genera (Bactris and Geonoma). Conclusions Edaphic conditions are associated with the phylogenetic community structure of palms across western Amazonia, and different factors (specifically, soil fertility and inundation intensity) appear to underlie diversity patterns in non-inundated upland versus floodplain habitats. By linking edaphic gradients with palm community phylogenetic structure, our study reinforces the need to integrate edaphic conditions in eco-evolutionary studies in order to better understand the processes that generate and maintain tropical forest diversity. Our results suggest a role for edaphic niche conservatism in the evolution and distribution of Amazonian palms, a finding with potential relevance for other clades.
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