| 1. |
- Isaksson, Hanna, et al.
(författare)
-
High-fiber rye diet increases ileal excretion of energy and macronutrients compared with low-fiber wheat diet independent of meal frequency in ileostomy subjects
- 2013
-
Ingår i: Food & Nutrition Research. - Järfälla : Co-Action Publishing. - 1654-6628 .- 1654-661X. ; 57, s. 18519-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Whole-grain foods and cereal dietary fiber intake is associated with lower body weight. This may partly result from lower energy utilization of high-fiber diets. Objective: In the present study, the impact on ileal excretion of energy and macronutrients in response to a rye bread high-fiber diet compared to a refined wheat low-fiber diet was investigated. Furthermore, the effect of meal frequency on apparent absorption of nutrients was studied for the first time. Design: Ten participants that had undergone ileostomy consumed standardized iso-caloric diets, including low-fiber wheat bread (20 g dietary fiber per day) for 2 weeks followed by high-fiber rye bread (52 g dietary fiber per day) for 2 weeks. The diets were consumed in an ordinary (three meals per day) and a nibbling (seven meals per day) meal frequency in a cross-over design. Ileal effluents were collected during 24 h at the third day of each of the four dietary periods and analyzed for gross energy and nutrient contents. Results: The results showed that intake of rye bread high-fiber diet compared to the refined wheat low-fiber diet caused an increase in ileal excretion of energy and macronutrients. The effect was independent of meal frequency. This suggests that a high intake of rye may result in lower availability of macronutrients for small intestinal digestion and absorption. A regular intake of rye may therefore have implications for weight management.
|
|
| 2. |
- Jacobsson, Hanna, et al.
(författare)
-
Hypoxia-induced secretion stimulates breast cancer stem cell regulatory signalling pathways
- 2019
-
Ingår i: Molecular Oncology. - : Wiley. - 1574-7891 .- 1878-0261. ; 13:8, s. 1693-1705
-
Tidskriftsartikel (refereegranskat)abstract
- It is well known that tumour cells are dependent on communication with the tumour microenvironment. Previously, it has been shown that hypoxia (HX) induces pronounced, diverse and direct effects on cancer stem cell (CSC) qualities in different breast cancer subtypes. Here, we describe the mechanism by which HX-induced secretion influences the spreading of CSCs. Conditioned media (CM) from estrogen receptor (ER)-α-positive hypoxic breast cancer cell cultures increased the fraction of CSCs compared to normal growth conditions, as determined using sets of CSC assays and model systems. In contrast, media from ERα-negative hypoxic cell cultures instead decreased this key subpopulation of cancer cells. Further, there was a striking overrepresentation of JAK-STAT-associated cytokines in both the ERα-positive and ERα-negative linked hypoxic responses as determined by a protein screen of the CM. JAK-STAT inhibitors and knockdown experiments further supported the hypothesis that this pathway is critical for the CSC-activating and CSC-inactivating effects induced by hypoxic secretion. We also observed that the interleukin-6-JAK2-STAT3 axis was specifically central for the ERα-negative hypoxic behaviour. Our results underline the importance of considering breast cancer subtypes in treatments targeting JAK-STAT or HX-associated processes and indicate that HX is not only a confined tumour biological event, but also influences key tumour properties in widespread normoxic microenvironments. © 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.
|
|
| 3. |
- Korhonen, Laura, 1974-, et al.
(författare)
-
Slutrapport. Utvärdering av Barnahus : S2018/00212/FST
- 2019
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- I januari 2018 gav regeringen Barnafrid, nationellt centrum för kunskap om våld mot barn, vid Linköpings universitet, i uppdrag att att utvärdera barnahusverksamheterna i Sverige. I uppdraget (Uppdrag angående utvärdering av barnahus S2018/00212/FST) skriver Socialdepartementet att det är angeläget att den samverkan som sker inom barnahus uppfyller de kriterier som finns för vad som ska känneteckna verksamheterna samt att de nationella riktlinjerna är ändamålsenliga (Rikspolisstyrelsen, 2009). I uppdraget önskades identifiering av goda exempel och eventuella brister i syfte att främja ett kvalitativt och likvärdigt bemötande för brottsutsatta barn. I uppdraget anges vidare att ”en utvärdering belyser kvalitet, behovsuppfyllnad, eventuella skillnader och de konsekvenser sådana skillnader kan få för de barn som utgör målgruppen och kan på så sätt utgöra ett viktigt underlag för berörda myndigheter.” I uppdraget ingår inte att lämna åtgärdsförslag.Inom ramen för utvärderingen besöktes 32 barnahus under september 2018 – februari 2019. Vid varje Barnahus genomfördes gruppintervjuer med Barnahusens samverkansparter och samordnare utifrån en intervjuguide. Intervjuerna har analyserats tematiskt utifrån befintliga nationella riktlinjer och kriterier. Då Barnahusen saknar heltäckande statistik för sina verksamheter baseras utvärderingens resultat på egenrapporterad praxis, med andra ord det samverkansparterna och samordnarna själva uppgav att de gör. Därtill inkom Barnahusen med skriftligt material (aktuella samverkansavtal, lokala riktlinjer och rutiner, verksamhetsberättelser, informationsmaterial med mera) och ledamöter i styrgrupper eller motsvarande ombads besvara en enkät med frågor om det egna Barnahuset.I utvärderingen konstateras att det finns många välfungerande barnahus men att det förekommer regionala skillnader i Barnahusens organisation och verksamhet. 68 kommuner, främst i Norra Sverige, Jämtland, Halland och sydöstra delar av Sverige, står utanför Barnahusverksamheten.De främsta brister som lyfts fram av de intervjuade gäller otydligheter i de nationella riktlinjerna (tex. sekretess och den särskilda företrädarens kompetens och roll) samt tillgång till rättsmedicinsk, barnmedicinsk och barn- och ungdomspsykiatrisk kompetens. Det finns beredskap att ge krisstöd till barnet och hens föräldrar, ibland även till trygghetspersonen, efter barnförhör. Uppgifter om i vilken omfattning krisstöd/ behandling erbjuds saknas i denna utvärdering. Det efterfrågas nationell styrning, översikt av de nationella riktlinjerna i samråd med alla Barnahusens samverkansparter, statistik och certifiering av barnahusen. Det finns även behov av att se över målgruppsdefinitionen och att alla Barnahus arbetar utifrån dessa. Utredningen fann brister särskilt då det gällde barn som som bevittnat våld, internetbrott och i vissa fall hedersrelaterat våld.Ur ett barnperspektiv medför de konstaterade regionala skillnaderna en risk för ett icke likvärdigt bemötande, stöd och skydd. Detta kan yttra sig i form av olikheter bland annat gällande definition av målgrupper för Barnahusen, krisstöd och bedömning av vårdbehov, tillgång till barnmedicinsk och barn- och ungdomspsykiatrisk vård, möjlighet att erbjuda frivilliga hälsokontroller samt att tillgodose syskons behov av stöd och behandling. Läget ter sig problematisk för åldersgruppen 15-18 åringar, som nödvändigtvis inte kommer i kontakt med Barnahus.Sammanfattningsvis kan man konstatera att det har sedan 2013 tillkommit ytterligare ett antal Barnahus samtidigt som de grundläggande problemen som belysts i de tidigare utredningarna kvarstår. Det finns dock utrymme för förbättringar då det gäller det multiprofessionella teamarbetet och det tvärsektionella samarbetet, men de stora utmaningarna finns då det gäller behovet av en enhetlig nationell styrning som slår fast att barn som misstänks vara utsatta för brott ska utredas i en barnvänlig miljö där brörda myndigheter samlas och samverkar under ett tak, och där brottsutredning, skydd, samt fysisk och psykisk hälsa beaktas. Vidare saknas en nationell samordning av verksamheten i Barnahus. Befintlig sekretesslagstiftning försvårar samverkan och gör det svårt för Barnahusen att leva upp till de nationella kriterierna. Lagstiftningen förhindrar även gemensam statistikföring och försvårar därmed uppföljning och planering av verksamheten i Barnahus.Genomförandet av uppdraget har skett i dialog med Polismyndigheten, Åklagarmyndigheten, Socialstyrelsen och Rättsmedicinalverket.Uppdraget ska slutredovisas senast den 31 mars 2019, vilket görs härmed i denna rapport.
|
|
| 4. |
- Landberg, Hanna, et al.
(författare)
-
Comparison and Evaluation of Multiple Users' Usage of the Exposure and Risk Tool : Stoffenmanager 5.1
- 2015
-
Ingår i: Annals of Occupational Hygiene. - : Oxford University Press (OUP). - 0003-4878 .- 1475-3162. ; 59:7, s. 821-835
-
Tidskriftsartikel (refereegranskat)abstract
- Stoffenmanager is an exposure and risk assessment tool that has a control banding part, with risk bands as outcome and a quantitative exposure assessment part, with the 90th percentile of the predicted exposure as a default outcome. The main aim of the study was to investigate whether multiple users of Stoffenmanager came to the same result when modelling the same scenarios. Other aims were to investigate the differences between outcomes of the control banding part with the measured risk quota and to evaluate the conservatism of the tool by testing whether the 90th percentiles are above the measured median exposures. We investigated airborne exposures at companies in four different types of industry: wood, printing, metal foundry, and spray painting. Three scenarios were modelled and measured, when possible, at each company. When modelled, 13 users visited each company on the same occasion creating individual assessments. Consensus assessments were also modelled for each scenario by six occupational hygienists. The multiple users' outcomes were often spread over two risk bands in the control banding part, and the differences in the quantitative exposure outcomes for the highest and lowest assessments per scenario varied between a factor 2 and 100. Four parameters were difficult for the users to assess and had a large impact on the outcome: type of task, breathing zone, personal protection, and control measures. Only two scenarios had a higher measured risk quota than predicted by the control banding part, also two scenarios had slightly higher measured median exposure value than modelled consensus in the quantitative exposure assessment part. Hence, the variability between users was large but the model performed well.
|
|
| 5. |
- Landberg, Hanna E, et al.
(författare)
-
A Study of the Validity of Two Exposure Assessment Tools : Stoffenmanager and the Advanced REACH Tool
- 2017
-
Ingår i: Annals of Work Exposures and Health. - : Oxford University Press. - 2398-7308 .- 2398-7316. ; 61:5, s. 575-588
-
Tidskriftsartikel (refereegranskat)abstract
- The use of exposure modelling tools for estimating chemical airborne exposure has increased since the European Union's REACH legislation for safe use of industrial chemicals came into force. Two tools that European Chemicals Agency recommends are Stoffenmanager® and the Advanced REACH Tool (ART). The aim of this study was to investigate the validity of these two exposure modelling tools by comparing the lack of agreement between estimated and measured exposure. We examined the airborne chemical exposure at companies in seven different types of industries: wood, printing, foundry, spray painting, flour milling, chemical industry, and plastic moulding industry. The inhalable exposure of liquids or powders at two to three situations at each company was modelled with both tools and measured. To study the validity of the tools, the mean differences and precisions (lack of agreement) of exposures from both situations handling liquids and powders were calculated by using the 50th percentile outcome of the tools and the geometric mean of the measured exposure (all data were ln transformed). For Stoffenmanager, the mean difference and precision of the situations concerning liquids were 0.22 ± 1.0 and for powders -0.024 ± 0.66. It was also shown that Stoffenmanager overestimated low exposures and underestimated high exposures. Stoffenmanager showed higher agreement with the measured exposure in the wood and flour mill industries than in foundry and the plastic moulding industry. For ART, the mean difference and precision of liquids were -0.55 ± 0.88 and for powders -1.4 ± 1.6. ART showed lower agreement with the measured exposure in the wood industry.
|
|
| 6. |
- Landberg, Hanna E., et al.
(författare)
-
Evaluation of risk assessment approaches of occupational chemical exposures based on models in comparison with measurements
- 2018
-
Ingår i: Safety Science. - : Elsevier. - 0925-7535 .- 1879-1042. ; 109, s. 412-420
-
Tidskriftsartikel (refereegranskat)abstract
- Risk assessments of chemicals in work places are needed to protect workers' health and safety. Several different strategies can be used for conducting risk assessments. The aim of this study was to investigate approaches to risk assessment of chemicals based on exposure assessment models relative to occupational exposure limits values (OELs) and derived no-effect levels (DNELs) and in comparison with measurements relative to OELs. A second aim was to evaluate the modelled recommended outcome and compare it with measurements of exposure. In this study, 29 situations were assessed with ECETOC TRA, Stoffenmanager (R) 5.1 and ART. Personal exposure measurements were also performed. The percentage of measured exposure exceeding the recommended output was calculated to investigate the level of conservatism. All the modelled exposures were compared with OELs and DNELs where possible, and the GM of the measured exposure was compared with OELs (risk quotas). For ECETOC TRA, 31% of measured exposure exceeded modelled exposure. For Stoffenmanager (R) it was 17% and for ART and ART B it was 3% and 0% respectively. Hence, according to our data, ECETOC TRA is the least conservative. An investigation of the risk quotas showed that ECETOC TRA had 4 false safe situations, meaning the risk was low when the model was used but was high when measurements were used. This may lead to underestimating risks. All models had an elevated proportion, ECETOC TRA and ART the highest, of false unsafe situations meaning the risk was low when measurements were used but high when models were used.
|
|
| 7. |
- Landberg, Hanna, et al.
(författare)
-
Evaluating the Risk Assessment Approach of the REACH Legislation : A Case Study
- 2019
-
Ingår i: Annals of Work Exposures and Health. - : Oxford University Press. - 2398-7308 .- 2398-7316. ; 63:1, s. 68-76
-
Tidskriftsartikel (refereegranskat)abstract
- Risk assessments based on occupational exposure to chemicals have increased since REACH (European regulation on Registration, Evaluation, Authorization, and restriction of Chemicals) came into force. The European Chemicals Agency (ECHA) recommends that chemical exposure could be calculated using exposure models and that parameters used to calculate the exposure scenario (ES) should be communicated in extended safety data sheets (e-SDS) as workplace instructions which downstream users are obligated to follow. We aimed to evaluate REACH's risk assessment approach using the Stoffenmanager((R)) 6.1, the Advanced REACH Tool 1.5 (ART), and the European Centre for Ecotoxicology and Toxicology of Chemicals' targeted risk assessment (ECETOC TRA 3.1) exposure models. We observed 239 scenarios in three companies handling chemicals using 45 e-SDS. Risk characterization ratios (RCRs) were calculated by dividing estimated exposures by derived no-effect levels (DNELs). Observed RCRs were much lower than registered RCRs, indicating lower exposures. However, about 12% of the observed ES still had RCRs > 1, after adjustment for control measures and personal protections described in the ES, when using Stoffenmanager((R)). The ES with observed RCRs > 1 were the same by Stoffenmanager((R)) and ART, but not by ECETOC TRA. Stoffenmanager and ART identified 25 adjusted scenarios with RCR > 1, while ECETOC TRA gave RCR < 1 for the same scenarios. The ES with RCR > 1 were significantly associated to chemicals with higher vapour pressure and lower DNELs than ES with RCR < 1 by Stoffenmanager((R)). The correlations between observed and registered RCRs were lower than those between RCRs calculated from the different models themselves; ECETOC TRA had the lowest correlation with the registered ES. These results put in question the generic ES recommended under the REACH legislation. Downstream users may get better estimates by assessing their own ES, especially for chemicals with low DNELs and high vapour pressure.
|
|
| 8. |
|
|
| 9. |
- Rhost, Sara, et al.
(författare)
-
Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion
- 2018
-
Ingår i: Breast cancer research : BCR. - : Springer Science and Business Media LLC. - 1465-542X. ; 20:1
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS: Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS: In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ERα-negative breast cancer as well as in ERα-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION: The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences.
|
|
| 10. |
- Sandén, Carl, et al.
(författare)
-
Clonal competition within complex evolutionary hierarchies shapes AML over time
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
-
Tidskriftsartikel (refereegranskat)abstract
- Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
|
|
| 11. |
- von Palffy, Sofia, et al.
(författare)
-
The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML
- 2023
-
Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:7, s. 1204-1218
-
Tidskriftsartikel (refereegranskat)abstract
- Mutated Nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in approximately 30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will suffer from relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1)-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we performed an arrayed flow cytometry-based screen directed to 362 cell surface markers. Comparing the cell surface expression on NPM1-mutated AML cells to primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML. By flow cytometry and single cell RNA-sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit NK cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.
|
|
