| 1. |
- Trkulja, C. L., et al.
(författare)
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Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:16
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Tidskriftsartikel (refereegranskat)abstract
- Several important drug targets, e.g., ion channels and G protein-coupled receptors, are extremely difficult to approach with current antibody technologies. To address these targets classes, we explored kinetically controlled proteases as structural dynamics-sensitive druggability probes in native-state and disease-relevant proteins. By using low-Reynolds number flows, such that a single or a few protease incisions are made, we could identify antibody binding sites (epitopes) that were translated into short-sequence antigens for antibody production. We obtained molecular-level information of the epitope-paratope region and could produce high-affinity antibodies with programmed pharmacological function against difficult-to-drug targets. We demonstrate the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies, and apoptosis-inducing antibodies selectively mediating cytotoxicity in KRAS-mutated cells. It is our hope that this platform will widen the scope of antibody therapeutics for the benefit of patients.
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| 2. |
- Western, Benedikte, et al.
(författare)
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Dropout from exercise trials among cancer survivors—An individual patient data meta-analysis from the POLARIS study
- 2024
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Ingår i: Scandinavian Journal of Medicine and Science in Sports. - Chichester, West Sussex : Wiley-Blackwell Publishing Inc.. - 0905-7188 .- 1600-0838. ; 34:2, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. Methods: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. Results: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2, performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. Conclusions: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects. © 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.
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| 3. |
- Nilsson, M., et al.
(författare)
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Mortality after surgery for primary hyperparathyroidism : results from a nationwide cohort
- 2021
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Ingår i: The British journal of surgery. - : Oxford University Press (OUP). - 1365-2168 .- 0007-1323. ; 108:7, s. 858-863
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Contemporary patients with primary hyperparathyroidism are often diagnosed with mildly raised serum calcium levels. Previous studies have reported increased mortality in patients with primary hyperparathyroidism. This retrospective cohort study aimed to examine whether contemporary patients operated for primary hyperparathyroidism have higher mortality than the general population, and whether mortality in these patients is associated with serum calcium concentration, adenoma weight or multiglandular disease. METHODS: Patients from a Swedish national cohort consisting of patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery 2003-2013, were matched with population controls. The National Patient Register, the Swedish Cause of Death Register, and socioeconomic data were cross-linked. End of follow-up was 10 years after surgery, 31 December 2015, or emigration. Mortality was analysed by standardized mortality ratio, Kaplan-Meier survival estimates, and univariable and multivariable Cox regression. Multiple imputation by chained equations was performed on missing data. RESULTS: After exclusions, there were 5009 patients with primary hyperparathyroidism and 14 983 controls. Multivariable Cox regression analysis adjusted for age, sex, Charlson Co-morbidity Index, marital status, level of education, disposable income, and period of surgery showed lower mortality in patients than controls (hazard ratio (HR) 0.83, 95 per cent c.i. 0.75 to 0.92). In univariable Cox regression of mortality in patients, serum calcium concentration (mmoles per litre) was associated with mortality (HR 2.20, 1.53 to 3.16). This association remained in multivariable Cox regression after multiple imputation (HR 1.79, 1.19 to 2.70). CONCLUSION: Mortality was not increased in patients operated for primary hyperparathyroidism compared with controls in a contemporary setting. Preoperative serum calcium concentration might, however, influence survival.
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| 4. |
- Bybrant, M. C., et al.
(författare)
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Celiac disease can be predicted by high levels of tissue transglutaminase antibodies in children and adolescents with type 1 diabetes
- 2021
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 22:3, s. 417-424
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Children with type 1 diabetes (T1D) are not included in guidelines regarding diagnosis criteria for celiac disease (CD) without a diagnostic biopsy, due to lack of data. We explored whether tissue transglutaminase antibodies (anti-tTG) that were >= 10 times the upper limit of normal (10x ULN) predicted CD in T1D. Methods Data from the Swedish prospective Better Diabetes Diagnosis study was used, and 2035 children and adolescents with T1D diagnosed between 2005-2010 were included. Of these, 32 had been diagnosed with CD before T1D. The children without CD were repeatedly screened for CD using anti-tTG antibodies of immunoglobulin type A. In addition, their human leukocyte antigen (HLA) were genotyped. All children with positive anti-tTG were advised to undergo biopsy. Biopsies were performed on 119 children and graded using the Marsh-Oberhuber classification. Results All of the 60 children with anti-tTG >= 10x ULN had CD verified by biopsies. The degree of mucosal damage correlated with anti-tTG levels. Among 2003 screened children, 6.9% had positive anti-tTG and 5.6% were confirmed CD. The overall CD prevalence, when including the 32 children with CD before T1D, was 7.0% (145/2035). All but one of the children diagnosed with CD had HLA-DQ2 and/or DQ8. Conclusions As all screened children and adolescents with T1D with tissue transglutaminase antibodies above 10 times the positive value 10x ULN had CD, we propose that the guidelines for diagnosing CD in screened children, when biopsies can be omitted, should also apply to children and adolescents with T1D as a noninvasive method.
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| 5. |
- Dekov, V.M., et al.
(författare)
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Mineralogy, geochemistry and microbiology insights into precipitation of stibnite and orpiment at the Daiyon-Yonaguni Knoll (Okinawa Trough) hydrothermal barite deposits
- 2022
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Ingår i: Chemical Geology. - Amsterdam : Elsevier. - 0009-2541 .- 1872-6836. ; 610, s. 121092-121092
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Tidskriftsartikel (refereegranskat)abstract
- Samples of active chimneys, chimney flanges and massive sulfides from the Daiyon-Yonaguni Knoll hydrothermal field are composed of major barite and minor stibnite and orpiment. Barite is inferred to precipitate from focused-discharge fluids composed of >40% hydrothermal end-member fluid at T = 100-240°C, whereas the stibnite and orpiment are later and lower temperature precipitates. The hydrothermal fluids from this field were subject of sub-seafloor boiling and phase separation and, consequently, are brine-rich depleted in volatile and enriched in non-volatile elements. Boiling and phase separation exerted major control on the rare earth elements (REE) partitioning in the vent fluids: high-chlorinity high-temperature fluids were enriched in light REE and low-chlorinity low-temperature fluids were enriched in heavy REE. Y/Ho molar ratio and Ce anomaly of the vent fluids suggest that the seawater has not completely reacted with the basement rocks and has not equilibrated with them. The trace element concentrations in the hydrothermal deposits suggest a complex interplay among hydrothermal, hydrogenetic and microbial processes. Sulfur isotope composition of the sulfides suggests that the sulfide S is a mixture of both basement rock and seawater S with a higher proportion of the basement rock S. The sulfate dissolved in the fluids was subjected to reduction during a slow mixing of hydrothermal fluid and seawater within the chimney walls of the Tiger and Abyss vents and this resulted in a heavy S-isotope composition of the vent fluid sulfate. Lead isotope composition of the hydrothermal deposits indicates mixing relationships suggesting that Pb and potentially other metals with similar geochemical behavior were derived from two or three sources. The Pb isotopes in the hydrothermal deposits imply that an enriched source, either sediments or extended continental lithosphere, and a depleted source, potentially back-arc mafic volcanics, are present in the area of Daiyon-Yonaguni Knoll. Filamentous orpiment found in the deposits is supposed to be either heavily mineralized fungal hyphae or pure abiogenic biomorphs. Presence of carbonaceous matter on and around the orpiment filaments suggests for microbial activity during filament formation. The filaments experienced temperature of 209.1±37.1°C which falls within the temperature range of the Daiyon-Yonaguni Knoll vent fluids. Stability phase diagrams modeling reveals that the stability of stibnite does not depend on the vent fluid chlorinity, but depends on the vent fluid temperature: the area of stibnite stability increases with decreasing vent fluid temperature and results in stibnite precipitation at low log10a of Sb2S42- and less reduced environment (Eh still <0). Orpiment is stable in a wide range of log10a of H2AsO4-, in reduced conditions and at high S activity. Barite is stable in wide range of log10a of Ba2+ and precipitates in slightly reduced to slightly oxic conditions.
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| 6. |
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| 7. |
- Haugaard-Kedström, Linda M., et al.
(författare)
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A High-Affinity Peptide Ligand Targeting Syntenin Inhibits Glioblastoma
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:3, s. 1423-1434
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Tidskriftsartikel (refereegranskat)abstract
- Despite the recent advances in cancer therapeutics, highly aggressive cancer forms, such as glioblastoma (GBM), still have very low survival rates. The intracellular scaffold protein syntenin, comprising two postsynaptic density protein-95/discslarge/zona occludens-1 (PDZ) domains, has emerged as a novel therapeutic target in highly malignant phenotypes including GBM. Here, we report the development of a novel, highly potent, and metabolically stable peptide inhibitor of syntenin, KSL-128114, which binds the PDZ1 domain of syntenin with nanomolar affinity. KSL-128114 is resistant toward degradation in human plasma and mouse hepatic microsomes and displays a global PDZ domain selectivity for syntenin. An X-ray crystal structure reveals that KSL128114 interacts with syntenin PDZ1 in an extended noncanonical binding mode. Treatment with KSL-128114 shows an inhibitory effect on primary GBM cell viability and significantly extends survival time in a patient-derived xenograft mouse model. Thus, KSL-128114 is a novel promising candidate with therapeutic potential for highly aggressive tumors, such as GBM.
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| 9. |
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| 10. |
- Kalén, Anton, et al.
(författare)
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The Role of Domain-Specific and Domain-General Cognitive Functions and Skills in Sports Performance: A Meta-Analysis
- 2021
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Ingår i: Psychological Bulletin. - Washington, DC : American Psychological Association (APA). - 0033-2909 .- 1939-1455. ; 147:12, s. 1290-1308
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Tidskriftsartikel (refereegranskat)abstract
- Cognition plays a key role in sports performance. This meta-analytic review synthesizes research that examined the relationship between cognitive functions, skills, and sports performance. We identified literature by searching Cochrane Library, APA PsycINFO, PubMed, and Web of Science. We included studies conducted on competitive athletes, assessed cognitive prerequisites, and included performance measures related to the sport. Of the 9,433 screened records, 136 reports were included, containing 142 studies, 1,227 effect sizes, and 8,860 participants. Only 11 studies used a prospective study design. The risk of bias was assessed using the Risk of Bias Assessment Tool for Nonrandomized Studies. The multilevel meta-analysis showed a medium effect size for the overall difference in cognitive functions and skills, with higher skilled athletes scoring better than lower skilled athletes (Hedges' g = 0.59, 95% CI [0.49, 0.69]). The moderator analysis showed larger effect size for tests of cognitive decision-making skills (g = 0.77, 95% CI [0.6, 0.94]) compared to basic (g = 0.39, 95% CI [0.21, 0.56]) and higher cognitive functions (g = 0.44, 95% CI [0.26, 0.62]), as well as larger effect for sport-specific task stimuli compared to general ones. We report that higher skilled athletes perform better on cognitive function tests than lower skilled athletes. There was insufficient evidence to determine whether cognitive functions and skills can predict future sport performance. We found no evidence to support claims that tests of general cognitive functions, such as executive functioning, should be used by practitioners for talent identification or player selection. Public Significance Statement This meta-analysis indicates that testing cognitive functions or skills using sport-specific stimuli has the potential to differentiate between elite and nonelite athletes. There is, however, no evidence for the usefulness of using general, non-sport-specific cognitive function tests to predict future sport performance.
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