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- Mohammed Taha, Hiba, et al.
(författare)
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The NORMAN Suspect List Exchange (NORMAN-SLE) : facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry
- 2022
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Ingår i: Environmental Sciences Europe. - : Springer. - 2190-4707 .- 2190-4715. ; 34:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The NORMAN Association (https://www.norman-network.com/) initiated the NORMAN Suspect List Exchange (NORMAN-SLE; https://www.norman-network.com/nds/SLE/) in 2015, following the NORMAN collaborative trial on non-target screening of environmental water samples by mass spectrometry. Since then, this exchange of information on chemicals that are expected to occur in the environment, along with the accompanying expert knowledge and references, has become a valuable knowledge base for “suspect screening” lists. The NORMAN-SLE now serves as a FAIR (Findable, Accessible, Interoperable, Reusable) chemical information resource worldwide.Results: The NORMAN-SLE contains 99 separate suspect list collections (as of May 2022) from over 70 contributors around the world, totalling over 100,000 unique substances. The substance classes include per- and polyfluoroalkyl substances (PFAS), pharmaceuticals, pesticides, natural toxins, high production volume substances covered under the European REACH regulation (EC: 1272/2008), priority contaminants of emerging concern (CECs) and regulatory lists from NORMAN partners. Several lists focus on transformation products (TPs) and complex features detected in the environment with various levels of provenance and structural information. Each list is available for separate download. The merged, curated collection is also available as the NORMAN Substance Database (NORMAN SusDat). Both the NORMAN-SLE and NORMAN SusDat are integrated within the NORMAN Database System (NDS). The individual NORMAN-SLE lists receive digital object identifiers (DOIs) and traceable versioning via a Zenodo community (https://zenodo.org/communities/norman-sle), with a total of > 40,000 unique views, > 50,000 unique downloads and 40 citations (May 2022). NORMAN-SLE content is progressively integrated into large open chemical databases such as PubChem (https://pubchem.ncbi.nlm.nih.gov/) and the US EPA’s CompTox Chemicals Dashboard (https://comptox.epa.gov/dashboard/), enabling further access to these lists, along with the additional functionality and calculated properties these resources offer. PubChem has also integrated significant annotation content from the NORMAN-SLE, including a classification browser (https://pubchem.ncbi.nlm.nih.gov/classification/#hid=101).Conclusions: The NORMAN-SLE offers a specialized service for hosting suspect screening lists of relevance for the environmental community in an open, FAIR manner that allows integration with other major chemical resources. These efforts foster the exchange of information between scientists and regulators, supporting the paradigm shift to the “one substance, one assessment” approach. New submissions are welcome via the contacts provided on the NORMAN-SLE website (https://www.norman-network.com/nds/SLE/).
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- Berglund, Åsa M. M., 1978-, et al.
(författare)
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Effects on the food-web structure and bioaccumulation patterns of organic contaminants in a climate-altered Bothnian Sea mesocosms
- 2023
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Ingår i: Frontiers in Marine Science. - : Frontiers Media S.A.. - 2296-7745. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Climate change is expected to alter global temperature and precipitation patterns resulting in complex environmental impacts. The proposed higher precipitation in northern Scandinavia would increase runoff from land, hence increase the inflow of terrestrial dissolved organic matter (tDOM) in coastal regions. This could promote heterotrophic bacterial production and shift the food web structure, by favoring the microbial food web. The altered climate is also expected to affect transport and availability of organic micropollutants (MPs), with downstream effects on exposure and accumulation in biota. This study aimed to assess climate-induced changes in a Bothnian Sea food web structure as well as bioaccumulation patterns of MPs. We performed a mesocosms-study, focusing on aquatic food webs with fish as top predator. Alongside increased temperature, mesocosm treatments included tDOM and MP addition. The tDOM addition affected nutrient availability and boosted both phytoplankton and heterotrophic bacteria in our fairly shallow mesocosms. The increased tDOM further benefitted flagellates, ciliates and mesozooplankton, while the temperature increase and MP addition had minor effect on those organism groups. Temperature, on the other hand, had a negative impact on fish growth and survival, whereas tDOM and MP addition only had minor impact on fish. Moreover, there were indications that bioaccumulation of MPs in fish either increased with tDOM addition or decreased at higher temperatures. If there was an impact on bioaccumulation, moderately lipophilic MPs (log Kow 3.6 - 4.6) were generally affected by tDOM addition and more lipophilic MPs (log Kow 3.8 to 6.4) were generally affected by increased temperature. This study suggest that both increased temperatures and addition of tDOM likely will affect bioaccumulation patterns of MPs in shallow coastal regions, albeit with counteracting effects.
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- Ameline, Baptiste, et al.
(författare)
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Methylation and copy number profiling : emerging tools to differentiate osteoblastoma from malignant mimics?
- 2022
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 35:9, s. 1204-1211
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Tidskriftsartikel (refereegranskat)abstract
- Rearrangements of the transcription factors FOS and FOSB have recently been identified as the genetic driver event underlying osteoid osteoma and osteoblastoma. Nuclear overexpression of FOS and FOSB have since then emerged as a reliable surrogate marker despite limitations in specificity and sensitivity. Indeed, osteosarcoma can infrequently show nuclear FOS expression and a small fraction of osteoblastomas seem to arise independent of FOS/FOSB rearrangements. Acid decalcification and tissue preservation are additional factors that can negatively influence immunohistochemical testing and make diagnostic decision-making challenging in individual cases. Particularly aggressive appearing osteoblastomas, also referred to as epithelioid osteoblastomas, and osteoblastoma-like osteosarcoma can be difficult to distinguish, underlining the need for additional markers to support the diagnosis. Methylation and copy number profiling, a technique well established for the classification of brain tumors, might fill this gap. Here, we set out to comprehensively characterize a series of 77 osteoblastomas by immunohistochemistry, fluorescence in-situ hybridization as well as copy number and methylation profiling and compared our findings to histologic mimics. Our results show that osteoblastomas are uniformly characterized by flat copy number profiles that can add certainty in reaching the correct diagnosis. The methylation cluster formed by osteoblastomas, however, so far lacks specificity and can be misleading in individual cases.
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| 11. |
- Andersson, Åsa, Professor, 1960-, et al.
(författare)
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Serum Protein Response To A Single High-Intensity Interval Training Bout – Comparison Between Individuals With Spondyloarthritis And Healthy Controls
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:Suppl 1, s. 780-781
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Tidskriftsartikel (refereegranskat)abstract
- Axial spondyloarthritis (axSpA) is a chronic inflammatory disease affecting mainly the axial skeleton. To decrease the risk of cardiovascular comorbidity, aerobic training is recommended as a part of disease management in patients with axSpA. High-intensity interval training (HIIT) interventions are, in addition to other recommended treatments, believed to positively affect the disease activity (1). However, the knowledge about the acute effects of HIIT on the inflammatory process at the molecular level is less studied. Understanding the acute HIIT effects on cytokines and additional serum proteins in axSpA is important for further long-term HIIT interventions and recording of the effect of HIIT on the axSpA disease profile.ObjectivesTo study the acute effects on serum proteins, such as cytokines, myokines, and inflammatory- and bone-related proteins, in response to a single bout of HIIT, and to compare the levels between baseline and post-HIIT in patients with axSpA and healthy controls (HC).MethodsThe pilot study included twenty-one participants (10 female, 11 male), mean (SD) age 40 (7) years, ten with axSpA, and eleven age and sex matched HC, who performed a single HIIT on a cycle ergometer consisting of 4x4 minutes interval (90% heart rate, HR-max) with three minutes active rest in between (70% of HR-max). Disease activity (BASDAI, 0-10) in patients with axSpA was 1.6 (0.8). Health status EuroQol (EQ5D, 0-1) were 0.87 (0.11) for axSpA, and 0.93 (0.10) for HC. The groups were well matched with no difference in baseline data for weight, BMI, EQ5D, blood pressure or aerobic capacity.Blood samples were taken before (baseline) and one hour after the single HIIT. The following serum proteins were analyzed on a Luminex MAGPIX System (Luminex corporation, Austin, TX USA): Interleukin (IL)-6, IL-17, IL-18, TNFαAGPIX System (Luminex corporatiosteoprotegerin, osteocalcin, osteopontin, and FGF-23. A three-way analysis of variance (ANOVA) was used to detect differences between groups, between sexes, and before and after a HIIT bout in a 2(group)*2(sex)*2(time) design. For main effects or interactions significant at p≤0.05, simple effect t-tests were used to determine the specific effects.ResultsA group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in the HC, 0.4 pg/ml (SD±0.4) at baseline vs. post-HIIT 1.8 (2.0). The concentration of the cytokines/chemokine IL-17, IL-18, TNFα group main effect (p=0.048) showed that the serum level of IL-6 was increased one hour after the HIIT session primarily in30) in VEGF-A showed that the axSpA group had significantly lower VEGF-A at baseline, 159 pg/ml (138) vs 326 (184) in the control group (which might be due to anti-inflammatory medication). A sex main effect (p=0.029) was observed from baseline to post-HIIT for the bone hormone osteocalcin, with a more pronounced decrease of serum osteocalcin in women with axSpA, 14.0 ng/ml (8.3) vs. post HIIT 13.2 (6.9). Moreover, the level of the multifunctional protein osteopontin was significantly lower (sex main effect, p=0.021) in women, 10.7 ng/ml (7.0) vs. men 20.4 (10.1), post-HIIT.ConclusionThis pilot study shows that one bout of HIIT influences the expression of proteins involved in inflammation and metabolism, and that sex is an important factor in the response to HIIT. The results should be followed up in longer intervention studies including higher numbers of participants.References[1]Sveaas, S. H. et al. (2019). High intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients. British journal of sports medicine, 54(5), 292-297.Disclosure of InterestsÅsa Andersson: None declared, Emma Haglund Consultant of: Novartis, Emma Berthold: None declared, Elisabeth Mogard Consultant of: Novartis, Anna Torell: None declared, M Charlotte Olsson: None declared
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- Gizaw, NY, et al.
(författare)
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PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:49, s. e2116220119-
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Tidskriftsartikel (refereegranskat)abstract
- Rhabdomyosarcoma (RMS) is an aggressive pediatric soft-tissue cancer with features of skeletal muscle. Because of poor survival of RMS patients and severe long-term side effects of RMS therapies, alternative RMS therapies are urgently needed. Here we show that the prospero-related homeobox 1 (PROX1) transcription factor is highly expressed in RMS tumors regardless of their cell type of origin. We demonstrate that PROX1 is needed for RMS cell clonogenicity, growth and tumor formation. PROX1 gene silencing repressed several myogenic and tumorigenic transcripts and transformed the RD cell transcriptome to resemble that of benign mesenchymal stem cells. Importantly, we found that fibroblast growth factor receptors (FGFR) mediated the growth effects of PROX1 in RMS. Because of receptor cross-compensation, paralog-specific FGFR inhibition did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and induced apoptosis. Our findings uncover the critical role of PROX1 in RMS and offer insights into the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in clinical phase I/II trials in other cancer types, our findings provide an alternative option for RMS treatment.
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| 21. |
- Hollender, Juliane, et al.
(författare)
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NORMAN guidance on suspect and non-target screening in environmental monitoring
- 2023
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Ingår i: Environmental Sciences Europe. - : Springer Nature. - 2190-4707 .- 2190-4715. ; 35:1
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Forskningsöversikt (refereegranskat)abstract
- Increasing production and use of chemicals and awareness of their impact on ecosystems and humans has led to large interest for broadening the knowledge on the chemical status of the environment and human health by suspect and non-target screening (NTS). To facilitate effective implementation of NTS in scientific, commercial and governmental laboratories, as well as acceptance by managers, regulators and risk assessors, more harmonisation in NTS is required. To address this, NORMAN Association members involved in NTS activities have prepared this guidance document, based on the current state of knowledge. The document is intended to provide guidance on performing high quality NTS studies and data interpretation while increasing awareness of the promise but also pitfalls and challenges associated with these techniques. Guidance is provided for all steps; from sampling and sample preparation to analysis by chromatography (liquid and gas-LC and GC) coupled via various ionisation techniques to high-resolution tandem mass spectrometry (HRMS/MS), through to data evaluation and reporting in the context of NTS. Although most experience within the NORMAN network still involves water analysis of polar compounds using LC-HRMS/MS, other matrices (sediment, soil, biota, dust, air) and instrumentation (GC, ion mobility) are covered, reflecting the rapid development and extension of the field. Due to the ongoing developments, the different questions addressed with NTS and manifold techniques in use, NORMAN members feel that no standard operation process can be provided at this stage. However, appropriate analytical methods, data processing techniques and databases commonly compiled in NTS workflows are introduced, their limitations are discussed and recommendations for different cases are provided. Proper quality assurance, quantification without reference standards and reporting results with clear confidence of identification assignment complete the guidance together with a glossary of definitions. The NORMAN community greatly supports the sharing of experiences and data via open science and hopes that this guideline supports this effort.
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| 25. |
- Malmborg, Julia, 1988-, et al.
(författare)
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Risk Factors for Persistence and Development of Frequent Musculoskeletal Pain in Adolescent Athletes
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79:Suppl 1, s. 206-206
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity has a positive impact on health, but adolescent athletes often report musculoskeletal pain (MP) which is negative in the aspect of sustaining physical activity over time. There is a lack of longitudinal assessments of MP and potential risk factors, such as timing of physical maturation, in adolescent athletes.Objectives:To identify risk factors associated with the persistence or development of frequent MP at a 2-year follow-up in adolescent sport school students.Methods:Fourteen-year-old sport school students (n=233) were invited to participate in this 2-year longitudinal study. Self-reports of MP was assessed as frequency, distribution, and intensity, and health status by EQ-5D. Physical maturation was calculated by the Mirwald equation (height, weight, and sitting height) (1), and categorized as early (>1 year), average (±1 year), or late (<–1 year). Students were grouped at baseline and follow-up into infrequent (never to monthly) or frequent (weekly to daily) MP groups. Logistic regression analysis was used to study associations between frequent MP at follow-up and baseline variables.Results:131 students (79 boys and 52 girls) were included in the study. Development or persistence of frequent MP at follow-up (n=61) was associated with being a girl, late physical maturation (only boys were categorized as late), non-contact sports participation, frequent MP at baseline, and reporting ≥2 MP sites at baseline. Students with a better health status at baseline were less likely to belong to the frequent MP group at follow-up (Table).Conclusion:Frequent MP is common in sport school students. MP in young athletes may become a future health problem and there is a need for recognition and interventions by coaches and health services to prevent MP from becoming persistent.References:[1]Mirwald, R. L., Baxter-Jones, A. D., Bailey, D. A., & Beunen, G. P. (2002). An assessment of maturity from anthropometric measurements.Med Sci Sports Exerc, 34(4), 689-694.Table.Associations between background variables at baseline and frequent MP at follow-up based on crude logistic regression analysis controlling each variable for sex.Baseline variablesModelInfrequent MP vs. Frequent MPOR(95% CI; p-value)SexBoys1.00Girls2.76(1.34–5.68; p<0.01)Physical maturationAverage (±1 year)1.00Early (>1 year)0.41(0.05–3.65; p=0.42)Late (<–1 year)3.83(1.13–12.95; p=0.03)Sport categoriesContact1.00Non-contact5.16(2.07–12.88; p<0.001)MP groupsInfrequent1.00Frequent2.74(1.31–5.72; p<0.01)MP intensity last week (NRS 0–10, best to worst)1.15(0.98–1.35; p=0.10)Number of MP sites01.0012.32(0.71–7.58; p=0.16)≥22.87(1.32–6.25; p<0.01)EQ-5D (0.00–1.00, worst to best)0.03(0.001–0.58; p=0.02)Disclosure of Interests:None declared
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| 26. |
- Malmborg, Julia S., 1988-, et al.
(författare)
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Musculoskeletal pain and its association with health status, maturity, and sports performance in adolescent sport school students: a 2-year follow-up
- 2022
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Ingår i: Bmc Sports Science Medicine and Rehabilitation. - London : Springer Science and Business Media LLC. - 2052-1847. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Musculoskeletal pain and its risk factors are rarely assessed in studies on adolescent athletes. The aim was to identify risk factors at baseline that were associated with the persistence or development of musculoskeletal pain at a two-year follow-up in adolescent sport school students, and to study cross-sectional associations at follow-up between musculoskeletal pain and sports performance. Methods Sport school students (79 boys and 52 girls, aged 14 years at baseline) were divided into infrequent (never-monthly) or frequent (weekly-almost daily) pain groups, based on frequency of pain using a pain mannequin. Logistic regression analyses were performed to study longitudinal associations between frequent pain at follow-up and baseline variables: pain group, number of regions with frequent pain, health status by EQ-5D, maturity offset (pre, average, or post peak height velocity), and sports (contact or non-contact). Linear regression analyses were used to study cross-sectional associations between pain groups and 20-m sprint, agility T-test, counter-movement jump, and grip strength at follow-up. Results were stratified by sex. Results A higher percentage of girls than boys reported frequent pain at follow-up (62% vs. 37%; p = 0.005). In boys, frequent pain at follow-up was associated with being pre peak height velocity at baseline (OR 3.884, CI 1.146-13.171; p = 0.029) and participating in non-contact sports (OR 3.429, CI 1.001-11.748; p = 0.050). In girls, frequent pain at follow-up was associated with having frequent pain in two or more body regions at baseline (OR 3.600, CI 1.033-12.542; p = 0.044), having a worse health status at baseline (OR 3.571, CI 1.026-12.434; p = 0.045), and participating in non-contact sports (OR 8.282, CI 2.011-34.116; p = 0.003). In boys, frequent pain was associated with worse performances in 20-m sprint and counter-movement jump, but not in agility T-test and grip strength. Conclusions Baseline risk factors for having frequent pain at follow-up were late maturation in boys, frequent pain and worse health status in girls, and participation in non-contact sports in both sexes. Boys with pain performed worse in sports tests. Coaches and school health-care services should pay attention to the risk factors and work towards preventing pain from becoming persistent.
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| 27. |
- Marciniak, Magdalena, et al.
(författare)
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Impact of Stripe Shape on the Reflectivity of Monolithic High Contrast Gratings
- 2021
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Ingår i: ACS Photonics. - : American Chemical Society (ACS). - 2330-4022. ; 8:11, s. 3173-3184
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Tidskriftsartikel (refereegranskat)abstract
- Monolithic high contrast gratings (MHCGs) composed of a one-dimensional grating patterned in a monolithic layer provide up to 100% optical power reflectance and can be fabricated in almost any semiconductor and dielectric material used in modern optoelectronics. MHCGs enable monolithic integration, polarization selectivity, and versatile phase tuning. They can be from 10 to 20 times thinner than distributed Bragg reflectors. The subwavelength dimensions of MHCGs significantly reduce the possibility of ensuring the smoothness of the sidewalls of the MHCG stripes and make precise control of the shape of the MHCG stripe cross-section difficult during the etching process. The question is then whether it is more beneficial to improve the etching methods to obtain a perfect cross-section shape, as assumed by the design, or whether it is possible to find geometrical parameters that enable high optical power reflectance using the shape that a given etching method provides. Here, we present a numerical study supported by the experimental characterization of MHCGs fabricated in various materials using a variety of common surface nanometer-scale shaping methods. We demonstrate that MHCG stripes with an arbitrary cross-section shape can provide optical power reflectance of nearly 100%, which greatly relaxes their fabrication requirements. Moreover, we show that optical power reflectance exceeding 99% with a record spectral bandwidth of more than 20% can be achieved for quasi-Trapezoidal cross-sections of MHCGs. We also show that sidewall corrugations of the MHCG stripes have only a slight impact on MHCG optical power reflectance if the amplitude of the corrugation is less than 16% of the MHCG period. This level of stripe fabrication precision can be achieved using the most current surface etching methods. Our results are significant for the design and production of a variety of photonic devices employing MHCGs. The flexibility with regard to cross-section shape facilitates the reliable fabrication of highly reflective subwavelength grating mirrors. This in turn will enable the manufacture of monolithically integrated high-quality-factor optical micro-and nanocavity devices.
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| 30. |
- Paulsen, Katrine M., et al.
(författare)
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High-throughput sequencing of two European strains of tick-borne encephalitis virus (TBEV), Hochosterwitz and 1993/783
- 2021
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Ingår i: Ticks and Tick-borne Diseases. - : Elsevier. - 1877-959X .- 1877-9603. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Tick-borne encephalitis virus (TBEV) is a medically important arbovirus, widespread in Europe and Asia. The virus is primarily transmitted to humans and animals by bites from ticks and, in rare cases, by consumption of unpasteurized dairy products. The aim of this study was to sequence and characterize two TBEV strains with amplicon sequencing by designing overlapping primers. The amplicon sequencing, via Illumina MiSeq, covering nearly the entire TBEV genome, was successful: We retrieved and characterized the complete polyprotein sequence of two TBEV strains, Hochosterwitz and 1993/783 from Austria and Sweden, respectively. In this study the previous phylogenetic analysis of both strains was confirmed to be of the European subtypes of TBEV (TBEV-Eu) by whole genome sequencing. The Hochosterwitz strain clustered with the two strains KrM 93 and KrM 213 from South Korea, and the 1993/783 strain clustered together with the NL/UH strain from the Netherlands. Our study confirms the suitability and rapidness of the high-throughput sequencing method used to produce complete TBEV genomes from TBEV samples of high viral load giving high-molecular-weight cDNA with large overlapping amplicons.
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| 31. |
- Samuelsson, Christopher Robin, 1989-, et al.
(författare)
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Looking for solutions : students' use of infrared cameras in calorimetry labs
- 2023
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Ingår i: Chemistry Education Research and Practice. - : Royal Society of Chemistry. - 1756-1108 .- 1109-4028. ; :24, s. 299-311
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Tidskriftsartikel (refereegranskat)abstract
- This study adds to the growing body of research on laboratory work. The study involves four pairs of students in a university introductory calorimetry lab of which two pairs, the IR-pairs (infrared camera-pairs), were given access to infrared cameras to use however they liked during their course lab work. Two other pairs, the T-pairs (thermometer-pairs), were not given access to infrared cameras during their course lab work. The IR-pairs were video recorded when they chose to use the IR cameras and the T-pairs were video-recorded during the corresponding sequences. Additionally, all pairs participated in a modified lab after their course lab, in which the pairs had access to IR cameras and were presented with the same phenomena although with equipment modified to better accommodate for the use of IR cameras (thin plastic cups were used instead of calorimeters). Students' practice, communication and reasoning was studied to explore how the IR cameras affect students' activity. The results show that the access to IR cameras led to a reasoning focused on a macroscopic level of chemistry knowledge, involving heat transfer to the surrounding and measurement errors, and that the lab practice of most of the students was continuous (rather than intermittent) when they had access to IR cameras. We conclude by arguing that the access to IR cameras affects students' conceptual and epistemological framing of the lab, i.e. that the students perceive the lab activity differently when they get access to IR cameras (both in a conceptual and epistemological sense). As an implication for teaching, we suggest that giving students access to IR cameras in a chemistry lab may be a way to introduce flexibility in the degree of openness of the lab.
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| 33. |
- Su, YH, et al.
(författare)
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CD11c-CD8 Spatial Cross Presentation: A Novel Approach to Link Immune Surveillance and Patient Survival in Soft Tissue Sarcoma
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Checkpoint inhibitors are slowly being introduced in the care of specific sarcoma subtypes such as undifferentiated pleomorphic sarcoma, alveolar soft part sarcoma, and angiosarcoma even though formal indication is lacking. Proper biomarkers to unravel potential immune reactivity in the tumor microenvironment are therefore expected to be highly warranted. In this study, intratumoral spatial cross presentation was investigated as a novel concept where immune cell composition in the tumor microenvironment was suggested to act as a proxy for immune surveillance. Double immunohistochemistry revealed a prognostic role of direct spatial interactions between CD11c+ antigen-presenting cells (APCs) and CD8+ cells in contrast to each marker alone in a soft tissue sarcoma (STS) cohort of 177 patients from the Karolinska University Hospital (MFS p = 0.048, OS p = 0.025). The survival benefit was verified in multivariable analysis (MFS p = 0.012, OS p = 0.004). Transcriptomics performed in the TCGA sarcoma cohort confirmed the prognostic value of combining CD11c with CD8 (259 patients, p = 0.005), irrespective of FOXP3 levels and in a CD274 (PD-LI)-rich tumor microenvironment. Altogether, this study presents a histopathological approach to link immune surveillance and patient survival in STS. Notably, spatial cross presentation as a prognostic marker is distinct from therapy response-predictive biomarkers such as immune checkpoint molecules of the PD-L1/PD1 pathway.
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| 34. |
- Tay, Apple Hui Min, et al.
(författare)
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A(2B) adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:5, s. e004592-
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Tidskriftsartikel (refereegranskat)abstract
- Background Adenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A(2)ARs. While blockade of the A(2A)ARs subtype effectively rescues lymphocyte activity, with four A(2A)AR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A(2B)AR blockade within cancer immunotherapy. Recent studies suggest the formation of A(2A)AR/A(2B)AR dimers in tissues that coexpress the two receptor subtypes, where the A(2B)AR plays a dominant role, suggesting it as a promising target for cancer immunotherapy. Methods We report the synthesis and functional evaluation of five potent A(2B)AR antagonists and a dual A(2A)AR/A(2B)AR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A(2B)AR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models. Results We provide data for six novel small molecules: five A(2B)AR selective antagonists and a dual A(2A)AR/A(2B)AR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A(2B)AR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A(2A)AR antagonist AZD-4635. We find that A(2B)AR antagonists rescue T and NK cell proliferation, IFN gamma and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules. Conclusions Our results demonstrate that A(2B)AR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A(2B)AR blockade. Inhibition of A(2B)AR signaling restores T cell function and proliferation. Furthermore, A(2B)AR and dual A(2A)AR/A(2B)AR antagonists showed similar or better results than A(2A)AR antagonist AZD-4635 reinforcing the idea of dominant role of the A(2B)AR in the regulation of the immune system.
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| 35. |
- Torell, Anna, 1967-, et al.
(författare)
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Effects of a digital-based high-intensity interval training (HIIT) intervention in individuals with axial spondyloarthritis – a randomized controlled pilot study (RCT)
- 2023
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Ingår i: Annals of the Rheumatic Diseases - The EULAR journal 2023. ; , s. 1049-1049
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Konferensbidrag (refereegranskat)abstract
- Background: Physical exercise is an important treatment for individuals with axial spondyloarthritis (axSpA). Although high-intensity training (HIT) has been shown to reduce disease symptoms and risk of comorbidity without exacerbating disease activity (1), compliance tends to decrease over time. Increased knowledge is needed on how to optimize and tailor individual exercise programs for continued regular exercising and improved health.Objective: To study the effects of HIT on aerobic capacity, body composition, disease activity, physical function, health status and fatigue in individuals with axSpA after a 12-week intervention supported by digital coaching.Methods: Twenty-two individuals (women, n=12), recruited from two rheumatology clinics in southern Sweden, were randomized to a HIT intervention group (HG; n=11) or a control group (CG; n=11). The HG completed three HIT sessions/week, including two interval training sessions (4x4 min), in self-selected activities for 12 weeks. The individuals in the HG were individually coached and had regular support from a physical therapist primarily by digital coaching. The CG continued exercising as usual. Assessment of aerobic capacity (VO2max), body composition (BMI and visceral fat area [cm2]), disease activity (CRP [µg/ml], BASDAI, 0-10 best-worst), physical function (BASFI, 0-10 best-worst), health status (EQ5D, 0-1 worst-best, ASAS health index [ASAS-HI], 0-17 best-worst), and fatigue (fatigue severity scale [FFS], 0-7 best-worst) were sampled at baseline and after 12 weeks. Mean and standard deviation (SD) were used for descriptive statistics. Repeated measures analysis of variance (ANOVA) was used to investigate effect of group (HG*CG) and time (PRE*POST), with a post-hoc analysis using t-tests when ANOVA indicated a significant difference in main effects or interactions. A significance level of p≤0.05 was used. Fisher´s exact test was used to study the effects over time for CRP (as dichotomized variable, > or < 4 µg/ml).Results: Results presented are part of an ongoing RCT based on 19 individuals (women n=11) that have completed the 12-week follow-up analyses. The participants mean (SD) age was 48 (10) years, BMI 25 (4), VO2max 37 (6) mlO2/kg/min, and BASDAI 2.6 (0.3). No differences were present between the HG (n=9) and the CG group (n=10) at baseline for the studied variables. After 12 weeks of HIT an ANOVA interaction (p<0.05 showed that HG increased their VO2max (6.4 [3.6] mlO2/kg/min; p<0.001) but CG did not. For BMI, visceral fat area, disease activity (BASDAI), physical function (BASFI), fatigue (FFS) no differences in main effects or interactions were found (p>0.05). Health status (EQ5D) showed an ANOVA time main effect (p=0.007) where the HG increased their health status (0.10 [0.06] units; p=0.02) after 12-weeks, but CG did not. For health status measured with ASAS-HI no differences between groups were found. For dichotomized CRP-values no differences were found in either of the group’s pre-post. Conclusions: This pilot RCT shows that after 12 weeks of digital-based HIT intervention, the HG increased their aerobic capacity and EQ5D health status compared to CG, while body composition, disease activity, physical function, and fatigue did not show any significant differences between the groups. References(1) Sveaas SH, Bilberg a, Berg IJ, Provan SA, Rollefstad S, Semb AG, et al. high intensity exercise for 3 months reduces disease activity in axial spondyloarthritis (axSpA): a multicentre randomised trial of 100 patients. Br J Sports med. 2019
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- Tsagozis, P, et al.
(författare)
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Sarcoma Tumor Microenvironment
- 2020
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Ingår i: Advances in experimental medicine and biology. - Cham : Springer International Publishing. - 0065-2598. ; 1296, s. 319-348
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Tidskriftsartikel (refereegranskat)
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- Törnblom, M., et al.
(författare)
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Prevalence of Early Symptomatic Knee Osteoarthritis According to Three Clinical Classification Criteria
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80, s. 1330-1330
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Tidskriftsartikel (refereegranskat)abstract
- Knee osteoarthritis (KOA) is a heterogeneous disease. Different classification criteria for symptomatic KOA (SKOA) have been proposed. Determining the prevalence and comparing the different criteria of SKOA in patients with knee pain will serve as a base when studying the predictive ability of these criteria in a longer perspective.Objectives:To study the prevalence of SKOA in individuals with knee pain according to three different classification criteria: the American College of Rheumatology (ACR), (1), the European League Against Rheumatism (EULAR)(2), and the National Institute for Health and Care Excellence (NICE) (3).Methods:Baseline data from an ongoing longitudinal study (HALLOA) including 296 individuals with knee pain, recruited by advertisement, were analysed. The individuals were categorized according to the classification criteria of SKOA (ACR, EULAR and NICE) based on age, clinical examination (crepitation), and self-reported data from KOOS (pain, symptoms, ADL, and sport/recreation), and dichotomized as fulfilling the criteria (SKOA) or not (no SKOA). BMI was measured (kg/m2). Radiographic KOA (RKOA) was assessed according to Ahlbäck criteria (1-5), defined as RKOA with grade 1 or more in at least one knee. Prevalence was calculated (frequencies, %) for each criterion, and Chi-Square test or the Independent-Samples t-test were used for comparisons between individuals fulfilling SKOA or not.Results:The mean age was 52 (min-max 24-73) years, 70% were women and 22% were classified with RKOA. The prevalence of SKOA according to each criterion was 57% (ACR), 51% (EULAR) and 73% (NICE) respectively. In total, 48% had SKOA according to all three criteria and whereof 32% had RKOA, compared to 10% RKOA among individuals with no SKOA. Regardless of the criterion, significantly more individuals classified with SKOA also had RKOA compared to individuals with no SKOA, p<0.001. Those classified as SKOA were significantly older and had higher BMI compared with no SKOA (Table 1).Conclusion:Approximately 50-70% of the individuals with knee pain were classified as having SKOA, where EULAR criteria had the lowest prevalence. A better understanding of early knee pain classification according to different clinical criteria is essential for the ability to capture and follow the long-term prognosis of early SKOA. Further longitudinal studies are needed.References:[1]Altman R et al. Arthritis Rheum. 1986;29(8):1039-49.[2]Zhang W et al. Ann Rheum Dis. 2010;69(3):483-9.[3]Health NIf, Excellence C. UK: National Institute for Clinical Excellence. 2014.Table 1.Comparisons between the ACR, EULAR and NICE criteria of symptomatic knee osteoarthritis, stratified for symptomatic knee osteoarthritis or notACREULARNICETotalOANo OAP-valueOANo OAP-valueOANo OAP-valueN(%)296 (100)170 (57.4)98 (33.1)152 (51.4)114 (38.5)215 (72.6)58 (19.6)Age(Y), Mean (SD)51.6 (8.7)53.3 (7.0)49.0 (10.3)<0.00154.5 (5.1)48.1 (10.8)<0.00154.7 (4.9)40.5 (9.8)<0.001Gender, female (%)208 (70.3)121 (71.2)66 (67.3)0.511108 (58.4)77 (67.5)0.538154 (71.6)36 (62.1)0.160BMI(kg/m2), Mean (SD)26.4 (4.6)26.5 (4.5)25.8 (4.3)0.17926.9 (4.5)25.4 (4.2)0.00526.7 (4.5)24.8 (3.8)0.004RKOA, n (%)64 (21.6) 45 (26.5)12 (12.2)0.00347 (30.9)10 (8.7)<0.00158 (27.0)1 (1.7)<0.001Independent-samples t-test and Chi-2-test. Bold=Significant correlation (p≤0.05). OA = Osteoarthritis. ACR = American College of Rheumatology. EULAR = the European League Against Rheumatism. NICE = the National Institute of Care and Excellence. BMI = Body Mass Index. RKOA = Radiographic Knee Osteoarthritis (Ahlbäck, with grade ≥1 in ≥1 knee).Disclosure of Interests:None declared.
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