| 1. |
- Arvidsson, Yvonne, 1960, et al.
(författare)
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Hypoxia stimulates CXCR4 signalling in ileal carcinoids.
- 2010
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Ingår i: Endocrine-related cancer. - 1479-6821. ; 17:2, s. 303-316
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Tidskriftsartikel (refereegranskat)abstract
- Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. VEGF, CA-IX, HIF-1alpha and HIF-2alpha were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2alpha expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition (EMT) and development was altered including increased expression of the chemokine receptor CXCR4, an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand CXCL12 (SDF-1) activated the MAPK p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1alpha, and HIF-2alpha and CXCR4. Signalling through the CXCL12-CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for this carcinoid tumour disease.
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| 2. |
- Köster, Jan, et al.
(författare)
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The diagnostic utility of DNA copy number analysis of core needle biopsies from soft tissue and bone tumors
- 2022
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Ingår i: Laboratory Investigation. - : Elsevier BV. - 0023-6837. ; 102:8, s. 838-845
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Tidskriftsartikel (refereegranskat)abstract
- Morphologic and immunohistochemical analysis of preoperative core needle biopsies (CNB) is important in the management of patients with soft tissue and bone tumors (STBTs). Most SBTB subtypes have more or less extensive DNA copy number aberrations (CNA), potentially providing useful diagnostic information. To evaluate the technical feasibility of single nucleotide polymorphism (SNP) array analysis and the diagnostic usefulness of the copy number profiles, we studied CNBs from 171 patients with suspected STBTs. SNP array analysis could be performed on 168 (98%) of the samples. The CNA profile was compatible with the CNB diagnosis in 87% of the cases. Discrepant cases were dominated by false-negative results due to nonrepresentative material or contamination with normal cells. 70 genomic profiles were indicative of specific histopathologic tumor entities and in agreement with the corresponding CNB diagnoses in 83%. In 96 of the cases with aberrant CNA profiles, the SNP profiles were of sufficient quality for segmentation, allowing clustering analysis on the basis of the Jaccard similarity index. The analysis of these segment files showed three major CNA clusters, based on the complexity levels and the predominance of gains versus losses. For 43 of these CNB samples, we had SNP array data also from their corresponding surgical samples. In 33 of these pairs, the two corresponding samples clustered next to each other, with Jaccard scores ranging from 0.61 to 0.99 (median 0.96). Also, for those tumor pairs that did not cluster together, the Jaccard scores were relatively high (median 0.9). 10 cases showed discrepant results, mainly due to varying degrees of normal cell contamination or technical issues. Thus, the copy number profile seen in a CNB is typically highly representative of the major cell population in the tumor.
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| 3. |
- Almobarak, Bilal, et al.
(författare)
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Exposure to nonanoic acid alters small intestinal neuroendocrine tumor phenotype
- 2023
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundSmall intestinal neuroendocrine tumors (SI-NET) are highly differentiated and genetically stable malignant tumors, yet they often present with advanced metastatic spread at the time of diagnosis. In contrast to many other types of malignant tumors, primary SI-NET are often asymptomatic and typically smaller in size compared to adjacent lymph node metastases. This study explores the hypothesis that stimulating the chemosensing olfactory receptor 51E1 (OR51E1) decreases SI-NET proliferation suggesting a mechanism that explains a difference in proliferative rate based on tumor location.MethodsClinical data was used to address difference in tumor size depending on location. A SI-NET tissue microarray was used to evaluate expression of OR51E1 and olfactory marker protein (OMP). Primary cultured tumor cells from 5 patients were utilized to determine the effect of OR51E1 agonist nonanoic acid on metabolic activity. The SI-NET cell line GOT1 was used to determine effects of nonanoic acid on the transcriptome as well as long-term effects of nonanoic acid exposure with regards to cell proliferation, serotonin secretion, alterations of the cell-cycle and morphology.ResultsTumor size differed significantly based on location. OR51E1 and OMP were generally expressed in SI-NET. Primary SI-NET cells responded to nonanoic acid with a dose dependent altered metabolic activity and this was replicated in the GOT1 cell line but not in the MCF10A control cell line. Nonanoic acid treatment in GOT1 cells upregulated transcripts related to neuroendocrine differentiation and hormone secretion. Long-term nonanoic acid treatment of GOT1 cells decreased proliferation, induced senescence, and altered cell morphology.ConclusionOur results raise the possibility that exposure of intraluminal metabolites could represent a mechanism determining aspects of the SI-NET tumor phenotype. However, we could not causally link the observed effects of nonanoic acid exposure to the OR51E1 receptor.
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| 4. |
- Arvidsson, Linda, et al.
(författare)
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Managing the Last Move : Older People’s Practical, Relational, and Emotional Work throughout the Transition from Home to a Nursing Home
- 2024
-
Ingår i: Health & Social Care in the Community. - : Hindawi Limited. - 0966-0410 .- 1365-2524. ; 2024, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Moving into a nursing home is a signifcant transition for older people which can be emotional and stressful. Te literature on thedecision to move and subsequent residential stress focuses on the time after admission; however, there is less understanding ofolder people’s management of the process. To fully understand and possibly reduce negative consequences and health-relatedrisks, the aim of this article is to explore how older people manage the transition from home to nursing home. Te study is basedon 21 longitudinal interviews with seven older people during the process of moving. Following Dorothy Smith’s theory of work,the analysis fnds three types of work—practical, relational, and emotional—that older people engage in during the transitionprocess. Te results highlight the importance of considering the entire transition process, not only experiences before or after, ifwe are to reduce the negative, stress-related consequences of relocations of this kind. Te fndings have practical implications forprofessionals in health and social care and point to the need to develop practical, relational, and emotional support for olderpeople throughout the transition process.
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| 5. |
- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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| 6. |
- Broström (red), Tor, et al.
(författare)
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Brandsäkerhet för byggnader med kulturvärden: En kunskapsöversikt
- 2021
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Bok (övrigt vetenskapligt/konstnärligt)abstract
- Abstract [sv] Arbetet med brandsäkerhet för byggnader med kulturvärden kräver anpassade lösningar som också kan tillgodose ett bevarande av byggnaderna och deras kulturvärden. Det finns, utspritt, mycket kunskap och erfarenhet inom det här området både i Sverige och internationellt. För att tillgodose ett behov av samlad kunskap inom detta område initierade Brandforsk en kunskapsöversikt tillsammans med Akademiska hus, Fortifikationsverket, Kammarkollegiet, Kyrkans försäkring, Riksantikvarieämbetet och Statens fastighetsverk. Den här kunskapsöversikten syftar till att sammanställa och presentera den kunskap som finns. Ett kompletterande syfte är att definiera områden där kunskap saknas. Kunskapsöversikten är indelad i sex områden: 2. Skydd mot brands uppkomst 3. Spridning av brand inom byggnad 4. Spridning av brand till byggnad 5. Brandens påverkan på byggnadens stomme 6. Utrymning 7. Räddningstjänstens insats Med utgångspunkt från workshops har en sammanställning av behovsbilden gjorts. Kunskapsöversikten och behovsbilden ligger till grund för en gap-analys vilken pekar på behov av fortsatt forskning och utveckling. Abstract [en] Working with fire safety in historic buildings requires adapted solutions that can also satisfy the preservation of the buildings and their cultural values. There is a lot of knowledge and experience in this area both in Sweden and internationally. In order to make this available to end users, Brandforsk initiated a literature review together with a group of national sponsors. This literature review aims to compile and present the documented knowledge in the field. A complementary purpose is to define knowledge gaps. The review is divided into six areas: 2. Fire prevention 3. Fire spread within buildings 4. Fire spread between structures 5. Structural fire resistance 6. Evacuation 7. Fire and rescue service activities Based on workshops the needs of end users have been compiled. A comparison of the outcome of the review and the end user needs defines a knowledge gap pointing to the need for continued research and development.
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| 7. |
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| 8. |
- Börjesson, Peter, 1980, et al.
(författare)
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The Merits of Situated Evaluation as an Alternative UX Evaluation Method to Understand Appropriation
- 2018
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Ingår i: Interaction Design and Architecture(s). - 2283-2998 .- 1826-9745. ; :37, s. 78-98
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Tidskriftsartikel (refereegranskat)abstract
- Oftentimes, technologies are not used in the ways designers had initially envisioned. Instead, people adapt technologies to their own needs, a phenomenon called ‘appropriation’. Appropriation is an important aspect of User Experience design, related to the situatedness and dynamics of the design, recognizing not only that initial needs and requirements may change over time, but also that a design may change the environment that it was designed for. Appropriation can also contribute to a sense of ownership as people use a design in their own way, sometimes in ways the designer did not intend. However, commonly used User Experience evaluation methods often do not focus on the appropriation process of a technology. Situated Evaluation is an approach that does focus on appropriation, although it has not yet been used extensively in the UX field. In this paper, we therefore present and critically discuss our use of the Situated Evaluation approach for the evaluation of a specific tool that aims to enhance the communication between children, parents, and teaching staff in special education. By presenting this case, we hope to inform other UX researchers and designer about the potential of the approach to understand appropriation is an important factor in UX design.
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| 9. |
- Danielsson, Henrik, et al.
(författare)
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A Systematic Review of Longitudinal Trajectories of Mental Health Problems in Children with Neurodevelopmental Disabilities
- 2024
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Ingår i: Journal of Developmental and Physical Disabilities. - : Springer. - 1056-263X .- 1573-3580. ; 36, s. 203-242
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Forskningsöversikt (refereegranskat)abstract
- To review the longitudinal trajectories - and the factors influencing their development - of mental health problems in children with neurodevelopmental disabilities. Systematic review methods were employed. Searches of six databases used keywords and MeSH terms related to children with neurodevelopmental disabilities, mental health problems, and longitudinal research. After the removal of duplicates, reviewers independently screened records for inclusion, extracted data (outcomes and influencing factors), and evaluated the risk of bias. Findings were tabulated and synthesized using graphs and a narrative. Searches identified 94,662 unique records, from which 49 publications were included. The median publication year was 2015. Children with attention deficit hyperactivity disorder were the most commonly included population in retrieved studies. In almost 50% of studies, trajectories of mental health problems changed by < 10% between the first and last time point. Despite multiple studies reporting longitudinal trajectories of mental health problems, greater conceptual clarity and consideration of the measures included in research is needed, along with the inclusion of a more diverse range of populations of children with neurodevelopmental disabilities.
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| 10. |
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| 11. |
- Hammar, Linus, 1979, et al.
(författare)
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A Probabilistic Model for Hydrokinetic Turbine Collision Risks: Exploring Impacts on Fish
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203 .- 1932-6203. ; 10:3, s. e0117756-
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Tidskriftsartikel (refereegranskat)abstract
- A variety of hydrokinetic turbines are currently under development for power generation in rivers, tidal straits and ocean currents. Because some of these turbines are large, with rapidly moving rotor blades, the risk of collision with aquatic animals has been brought to attention. The behavior and fate of animals that approach such large hydrokinetic turbines have not yet been monitored at any detail. In this paper, we conduct a synthesis of the current knowledge and understanding of hydrokinetic turbine collision risks. The outcome is a generic fault tree based probabilistic model suitable for estimating population-level ecological risks. New video-based data on fish behavior in strong currents are provided and models describing fish avoidance behaviors are presented. The findings indicate low risk for small sized fish. However, at large turbines (≥5 m), bigger fish seem to have high probability of collision, mostly because rotor detection and avoidance is difficult in low visibility. Risks can therefore be substantial for vulnerable populations of large-sized fish, which thrive in strong currents. The suggested collision risk model can be applied to different turbine designs and at a variety of locations as basis for case-specific risk assessments. The structure of the model facilitates successive model validation, refinement and application to other organism groups such as marine mammals.
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| 12. |
- Handlin, Linda, et al.
(författare)
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Effects of Sucking and Skin-to-Skin Contact on Maternal ACTH and Cortisol Levels During the Second Day Postpartum - Influence of Epidural Analgesia and Oxytocin in the Perinatal Period
- 2009
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Ingår i: Breastfeeding Medicine. - : Mary Ann Liebert. - 1556-8253 .- 1556-8342. ; 4:4, s. 207-220
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: In this study we made a detailed analysis of the mothers' release pattern of adreno-corticotropic hormone (ACTH) and cortisol during a breastfeeding session during the second day postpartum and related these patterns to maternal oxytocin levels as well to the duration of sucking and the duration of skin-to-skin contact before sucking the breast. Furthermore, we investigated if epidural analgesia and oxytocin administration during and after labor influenced the release pattern of ACTH and cortisol.Methods: Sixty-three primiparae were included in the study. Fourteen received oxytocin intramuscularly postpartum, nine received oxytocin infusion, 14 received epidural analgesia combined with oxytocin infusion, and six received epidural analgesia alone. Twenty mothers did not receive any of these medical interventions. Blood samples were analyzed for ACTH and cortisol by enzyme-linked immunoassay.Results: Both ACTH and cortisol levels fell significantly during the breastfeeding session. A significant negative relationship was found between oxytocin and ACTH levels, but not between oxytocin and cortisol levels. A contact before onset of sucking was significantly and negatively associated with lower cortisol levels, but not with ACTH levels. Cortisol levels differed significantly between mothers having received epidural analgesia with and without oxytocin.Conclusions: Breastfeeding is associated with a decrease of ACTH and cortisol levels. Skin-to-skin contact contributes to this effect. ACTH correlated negatively with the duration of sucking and median oxytocin levels, whereas cortisol levels correlated inversely with the duration of skin-to-skin contact preceding sucking, suggesting a partial dissociation between the mechanisms regulating ACTH and cortisol release. In addition, medical interventions in connection with birth influence the activity of the hypothalamic-pituitary-adrenal axis 2 days after birth.
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| 13. |
- Harnett, Tove, et al.
(författare)
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Managing the Last Move : Older People’s Practical, Relational, and Emotional Work throughout the Transition from Home to a Nursing Home
- 2024
-
Ingår i: Health & Social Care in the Community. - : Hindawi Limited. - 0966-0410 .- 1365-2524.
-
Tidskriftsartikel (refereegranskat)abstract
- Moving into a nursing home is a significant transition for older people which can be emotional and stressful. The literature on the decision to move and subsequent residential stress focuses on the time after admission; however, there is less understanding of older people’s management of the process. To fully understand and possibly reduce negative consequences and health-related risks, the aim of this article is to explore how older people manage the transition from home to nursing home. The study is based on 21 longitudinal interviews with seven older people during the process of moving. Following Dorothy Smith’s theory of work, the analysis finds three types of work—practical, relational, and emotional—that older people engage in during the transition process. The results highlight the importance of considering the entire transition process, not only experiences before or after, if we are to reduce the negative, stress-related consequences of relocations of this kind. The findings have practical implications for professionals in health and social care and point to the need to develop practical, relational, and emotional support for older people throughout the transition process.
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| 14. |
- Hellsten, Johan, et al.
(författare)
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Electroconvulsive seizures induce angiogenesis in adult rat hippocampus
- 2005
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223. ; 58:11, s. 871-878
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Tidskriftsartikel (refereegranskat)abstract
- Background: Electroconvulsive seizure (ECS)-treatment, a model for electroconvulsive therapy (ECT) has been shown to induce proliferation of endothelial cells in the dentate gyrus (DG) of adult rats. Here we quantified the net angiogenic response after hypoxia a known inducer of aniogenesis. Therefore we also examined the effect of oxygenation on ECS-induced proliferation of endothelial cells. Methods: Total endothelial cell numbers and vessel length were estimated utilizing design based stereological analysis methods. Endothelial cell proliferation in the DG after ECS with or withouy oxygenation was assessed using bromodeoxyuridine. Results: The total number of endothelial cell numbers and vessels lenght was increased. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the DG. Conclusions: ECS-treatment induces a dramatic increase in endothelial cell proliferation leading to a 30% increase in the total numberof endothelial cells. The increase in cell number resulted i na 16% increase in vessel length. These findings raise the possibility that similar vascular growth is induced by clinically administered ECT.
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| 15. |
- Hofving, Tobias, 1989, et al.
(författare)
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SMAD4 haploinsufficiency in small intestinal neuroendocrine tumors
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations at low frequencies with CDKN1B being the most common harboring heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear. Methods: Utilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/− mouse model was used to detect entero-endocrine cell hyperplasia with IHC. Results: Analyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/− mouse model. In addition, patients with low SMAD4 protein expression in primary tumors more often presented with metastatic disease. Conclusions: Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression and spread of metastases. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.
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| 16. |
- Hofving, Tobias, 1989, et al.
(författare)
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The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
- 2018
-
Ingår i: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 25:3, s. 367-380
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Tidskriftsartikel (refereegranskat)abstract
- Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.
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| 17. |
- Hofving, Tobias, et al.
(författare)
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The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines
- 2018
-
Ingår i: Endocrine-Related Cancer. - 1479-6821 .- 1351-0088. ; 25:3, s. 367-380
-
Tidskriftsartikel (refereegranskat)abstract
- Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number rofiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.
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| 18. |
- Karlsson, Linda, et al.
(författare)
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Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases.
- 2024
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Ingår i: Nature Communications. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer's disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.
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| 19. |
- Lemonakis, Konstantinos, et al.
(författare)
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Impact of 1q gains on treatment outcomes of patients with newly diagnosed multiple myeloma in a real-world Swedish population receiving modern treatment
- 2023
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Ingår i: European Journal of Haematology. - 0902-4441. ; 111:3, s. 391-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Amplification of 1q (amp(1q); =4 1q copies) has repeatedly been reported to predict a worse outcome in multiple myeloma (MM), whereas the impact of gain of 1q (gain(1q); three 1q copies) is less clear.Methods: We investigated survival of MM in relation to amp(1q) and gain(1q) by retro-spectively analysing 346 consecutively newly diagnosed MM (NDMM) patients. Of these, 62 (18%) had amp(1q), 97 (28%) gain(1q) and 187 (54%) a normal number of 1q copies (no1q).Results: The patients with amp(1q) had a shorter median progression-free survival than those with gain(1q) or no(1q) (13.1 months, 95% confidence interval [CI] 8.2- 18.1 months vs. 36.1 months, 95% CI 23.1-49.1 months vs. 25.4 months, 95% CI 19.8-31.1 months, p = .005). The 3-year overall survival (OS) was 56% for amp(1q), 76% for gain(1q) and 80% for no1q (p = .003). In the multivariate analysis, the pres-ence of amp(1q) was independently associated with a shorter OS (hazard ratio 1.99, 95% CI 1.03-3.82, p = .039), whereas gain(1q) had no negative effect on survival.Conclusion: Our results thus suggest that amp(1q) should be considered a high-risk abnormality in NDMM and that new treatment strategies should be explored to miti-gate its negative effect on survival.
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| 20. |
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| 21. |
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| 22. |
- Macsari, Istvan, et al.
(författare)
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3-Oxoisoindoline-1-carboxamides : Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na(V)1.7 with Efficacy in Rat Pain Models
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:15, s. 6866-6880
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Tidskriftsartikel (refereegranskat)abstract
- The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.
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| 23. |
- Mubder, Abdalla
(författare)
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Just-in-Time Arrival in Port Calls : Potential and Implementation
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is an urgent need to reduce emissions from maritime transportation to meet environmental targets set by international organizations and governments. To reduce emissions from maritime transportation, technical, market-based, and operational measures can be used. In this thesis, the focus is on operational measures, and in particular Just-in-Time arrival in the port call process. Just-in-Time arrival in the context of port calls refers to maintaining an optimal vessel sailing speed to arrive to the port when the availability of berth and other services are ensured. In earlier studies, the estimated fuel and emission savings potential of Just-in-Time arrival, is promising. Despite the promising potential of Just-in-Time, its implementation remains limited, with few real-world examples. The purpose of this thesis is to explore how to implement Just-in-Time arrival by studying coordination in the port call process.Two research questions were formulated to address the purpose. The first aims to capture the potential benefits of implementing Just-in-Time arrival in port calls and the second aims to address what is required to implement Just-in-Time arrival in port calls. This thesis is based on two studies in the Swedish context. First, a quantitative study, in which Automatic Identification System data in combination with port call statistics and vessel-specific data were used to estimate the fuel and emission savings potential of Just-in-Time arrival. Second, a qualitative single case-study exploring the coordination mechanisms necessary for implementing Just-in-Time arrival in port calls was conducted.The studies show that fuel and emission savings potential of Just-in-Time in previous studies is overestimated due to the assumptions used. Though, the implementation of Just-in-Time has potential to improve port call actors’ resource planning and utilization and increase the competitiveness of ports. This is because Just-in-Time arrival has the potential to aid actors in reaching mandatory emission reduction targets. To implement Just-in-Time arrival, it is necessary to coordinate the plans of actors. The required mechanisms to coordinate planning are pre-booking berth allocation policy and port community systems. The pre-booking policy implies booking time-slots for berths, facilitated by using the port community system. The port community system and the pre-booking policy enable the effective coordination of the planning processes of individual actors enabling Just-in-Time arrival in port calls.
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| 24. |
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| 25. |
- Mårtensson, Jan, et al.
(författare)
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Erfarenhet, kunskap och inställning till prioriteringar : En intervjustudie med personal i primärvården
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Den svenska primärvården med vårdcentraler har utvecklats under en 40-årsperiod. Utvecklingen har delvis varit en anpassning till den alltjämt dominerande specialistvården med anknytning till sjukhusen. I takt med den medicinteknologiska utvecklingen har det också skett en överföring av flera patientgrupper i öppna vårdformer och många av de stora folksjukdomarna utreds och behandlas numera i primärvården. Resurstillskottet till svensk primärvård har i relativa tal varit mindre än det till sjukhusvård under den 40-åriga perioden och det har skapat prioriteringsproblem.Frågor om hur prioriteringar går till och bör gå till blir alltmer aktuella i primärvården i takt med att man upplever att resurserna inte räcker till. Studier och diskussioner om prioriteringar saknas till stor del och det har inte funnits någon vana att hantera prioriteringssituationer inom primärvården. Inte heller har det funnits stöd eller verktyg för att underlätta prioriteringsarbetet för de som arbetar i primärvården.Detta projekt om prioriteringar i primärvård vill belysa hur primärvårdspersonal tänker och agerar i prioriteringsfrågor och hur prioriteringsarbetet sker i praktiken vid ett slumpmässigt urval av landets vårdcentraler. Vi anser därför att resultaten är representativa för svensk primärvård.Projektet utgår från Institutionen för hälsa och samhälle vid Linköpings universitet (Per Carlsson, Eva Arvidsson och Lars Borgquist) i samarbete med Primärvårdens FoU-enhet i Jönköpings läns landsting (Kjell Lindström, Jan Mårtensson och Linda Frank). Arbetet har genomförts med ekonomiskt stöd från forskningsprogrammet Sjukvårdens förändringar, ett samarbete mellan Region Skåne, Västra Götalands Regionen, Landstinget Västmanland, Landstinget i Östergötland, Stockholms läns landsting, Socialstyrelsen och Sveriges Kommuner och Landsting.Tack till alla de personer som medverkat vid intervjuerna, övriga personer i projektet samt anslagsgivaren.
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| 26. |
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| 27. |
- Pullerits, Teet, 1967, et al.
(författare)
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The triad of current asthma, rhinitis and eczema is uncommon among adults: Prevalence, sensitization profiles, and risk factors
- 2021
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Ingår i: Respiratory Medicine. - : Elsevier BV. - 0954-6111 .- 1532-3064. ; 176
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Tidskriftsartikel (refereegranskat)abstract
- Background Coexistence of asthma, rhinitis, and eczema has been studied in children, but data are lacking in adults. As new treatments emerge, epidemiological data on the coexistence are needed. Aims To study the prevalence of concomitant asthma, rhinitis and eczema in the general adult population and among those sensitized to aeroallergens, and to study associations between background characteristics and risks of phenotypes of asthma, rhinitis, and eczema. Methods In the West Sweden Asthma Study, phenotypes and sensitization profiles of 1103 randomly selected adults (16–75 years) were assessed. The methods included measures of serum-IgE and structured interviews on asthma, rhinitis, eczema, their associated symptoms, and relevant risk factors. Results Among all participants and in those sensitized, 2% and 6% had concomitant asthma, rhinitis, and eczema, respectively, and the condition did not differ by age or sex. Corresponding figures for asthma and rhinitis, but not eczema, was 8% and 19%, respectively. Determinants of coexistence of the three conditions were family history of asthma/allergy, body mass index, and occupational exposure to gas, dust and fumes. Allergic sensitization in those with asthma, rhinitis and eczema was found in 78%, in those with asthma and rhinitis but not eczema in 65%, in those with asthma and eczema but not rhinitis in 40%, while only 5% were sensitized among those having asthma only. Conclusions In the general adult population about 2% have concomitant asthma, rhinitis, and eczema. Of sensitized adults, about 6% has coexistence of the three conditions.
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| 28. |
- Ragnarsson, Charlotte, et al.
(författare)
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Constitutional and acquired genetic variants in ARID5B in pediatric B-cell precursor acute lymphoblastic leukemia
- 2024
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Ingår i: Genes Chromosomes and Cancer. - 1045-2257. ; 63:5
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51–67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.
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| 29. |
- (red.) Broström, Tor, 1955-, et al.
(författare)
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Brandsäkerhet för byggnader med kulturvärden : En kunskapsöversikt
- 2021
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Bok (refereegranskat)abstract
- Arbetet med brandsäkerhet för byggnader med kulturvärden kräver anpassade lösningar som också kan tillgodose ett bevarande av byggnaderna och deras kulturvärden. Det finns, utspritt, mycket kunskap och erfarenhet inom det här området både i Sverige och internationellt. För att tillgodose ett behov av samlad kunskap inom detta område initierade Brandforsk en kunskapsöversikt tillsammans med Akademiska hus, Fortifikationsverket, Kammarkollegiet, Kyrkans försäkring, Riksantikvarieämbetet och Statens fastighetsverk. Den här kunskapsöversikten syftar till att sammanställa och presentera den kunskap som finns. Ett kompletterande syfte är att definiera områden där kunskap saknas. Kunskapsöversikten är indelad i sex områden:2. Skydd mot brands uppkomst3. Spridning av brand inom byggnad4. Spridning av brand till byggnad5. Brandens påverkan på byggnadens stomme6. Utrymning7. Räddningstjänstens insatsMed utgångspunkt från workshops har en sammanställning av behovsbilden gjorts. Kunskapsöversikten och behovsbilden ligger till grund för en gap-analys vilken pekar på behov av fortsatt forskning och utveckling.
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| 30. |
- Rezayee, F., et al.
(författare)
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Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia
- 2023
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Ingår i: FRONTIERS IN ONCOLOGY. - : Frontiers Media SA. - 2234-943X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Introduction The suitability of whole-genome sequencing (WGS) as the sole method to detect clinically relevant genomic aberrations in B-cell acute lymphoblastic leukemia (ALL) was investigated with the aim of replacing current diagnostic methods.Methods For this purpose, we assessed the analytical performance of 150 bp paired-end WGS (90x leukemia/30x germline). A set of 88 retrospective B-cell ALL samples were selected to represent established ALL subgroups as well as ALL lacking stratifying markers by standard-of-care (SoC), so-called B-other ALL.Results Both the analysis of paired leukemia/germline (L/N)(n=64) as well as leukemia-only (L-only)(n=88) detected all types of aberrations mandatory in the current ALLTogether trial protocol, i.e., aneuploidies, structural variants, and focal copy-number aberrations. Moreover, comparison to SoC revealed 100% concordance and that all patients had been assigned to the correct genetic subgroup using both approaches. Notably, WGS could allocate 35 out of 39 B-other ALL samples to one of the emerging genetic subgroups considered in the most recent classifications of ALL. We further investigated the impact of high (90x; n=58) vs low (30x; n=30) coverage on the diagnostic yield and observed an equally perfect concordance with SoC; low coverage detected all relevant lesions.Discussion The filtration of the WGS findings with a short list of genes recurrently rearranged in ALL was instrumental to extract the clinically relevant information efficiently. Nonetheless, the detection of DUX4 rearrangements required an additional customized analysis, due to multiple copies of this gene embedded in the highly repetitive D4Z4 region. We conclude that the diagnostic performance of WGS as the standalone method was remarkable and allowed detection of all clinically relevant genomic events in the diagnostic setting of B-cell ALL.
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| 31. |
- Sehgelmeble, Fernando, et al.
(författare)
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Sulfonimidamides as Sulfonamides Bioisosteres : Rational Evaluation through Synthetic, in Vitro, and in Vivo Studies with γ-Secretase Inhibitors
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 396-399
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Tidskriftsartikel (refereegranskat)abstract
- The proof of the pudding: A proof-of-concept study using γ-secretase inhibitors as a model has shown that sulfonimidamides act as bioisosteres for sulfonamides. Detailed in vitro and in vivo profiling reveal that the sulfonimidamide motif imparts desirable properties such as decreased lipophilicity and plasma protein binding, accompanied by increased solubility. Our data support a wider use of this unique functional group in the design of new pharmacologically active agents.
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| 32. |
- Stoustrup, Peter, et al.
(författare)
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Management of orofacial manifestations of juvenile idiopathic arthritis : Interdisciplinary consensus-based recommendations.
- 2023
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Ingår i: Arthritis & Rheumatology. - : John Wiley & Sons. - 2326-5191 .- 2326-5205. ; 75:1, s. 4-14
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Forskningsöversikt (refereegranskat)abstract
- OBJECTIVES: Involvement of the temporomandibular joint (TMJ) is common in juvenile idiopathic arthritis (JIA). TMJ arthritis can lead to orofacial symptoms, dysfunction and dentofacial deformity with negative impact on quality of life. Management involves interdisciplinary collaboration. No current recommendations exist to guide clinical management.OBJECTIVES: 1) To develop consensus-based interdisciplinary recommendations for management of orofacial manifestations of JIA. 2) To create a future research agenda related to management of TMJ arthritis in children with JIA.METHODS: The recommendations were developed using online surveying of relevant stakeholders, systematic literature review, evidence-informed generation of recommendations during two consensus-meetings, and Delphi study iterations involving external experts. The process included disciplines involved in the care of orofacial manifestations of JIA: Pediatric rheumatology, radiology, orthodontics, oral and maxillofacial surgery, orofacial pain specialists and pediatric dentistry. Recommendations were accepted if agreement was >80% during a final Delphi study.RESULTS: Three overarching management principles and 12 recommendations for interdisciplinary management of orofacial manifestations of JIA were outlined. The 12 recommendations pertained to: diagnosis (n=4), treatment of TMJ arthritis (active TMJ inflammation) (n=2), treatment of TMJ dysfunction and symptoms (n=3), treatment of arthritis-related dentofacial deformity (n=2), and other related aspects to JIA (n=1). Additionally, a future interdisciplinary research agenda was developed.CONCLUSIONS: These are the first interdisciplinary recommendations to guide clinical management of TMJ JIA. The 3 overarching principles and 12 recommendations fill an important gap in current clinical practice. They emphasize the importance of an interdisciplinary approach to diagnosis and management of orofacial manifestations of JIA. This article is protected by copyright. All rights reserved.
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| 33. |
- Stoustrup, Peter, et al.
(författare)
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Standardizing Terminology and Assessment for Orofacial Conditions in Juvenile Idiopathic Arthritis : International, Multidisciplinary Consensus-based Recommendations
- 2019
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Ingår i: Journal of Rheumatology. - : Journal Of Rheumatology Publishing Co., Ltd.. - 0315-162X .- 1499-2752. ; 46:5, s. 518-522
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To propose multidisciplinary, consensus-based, standardization of operational terminology and method of assessment for temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA). Methods. Using a sequential expert group-defined terminology and methods-of-assessment approach by (1) establishment of task force, (2) item generation, (3) working group consensus, (4) external expert content validity testing, and (5) multidisciplinary group of experts final Delphi survey consensus. Results. Seven standardized operational terms were defined: TMJ arthritis, TMJ involvement, TMJ arthritis management, dentofacial deformity, TMJ deformity, TMJ symptoms, and TMJ dysfunction. Conclusion. Definition of 7 operational standardized terms provides an optimal platform for communication across healthcare providers involved in JIA-TMJ arthritis management.
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| 34. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
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| 35. |
- Tesi, Bianca, et al.
(författare)
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Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
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Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
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| 36. |
- Van Odijk, Jenny, 1969, et al.
(författare)
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The Use of DAO as a Marker for Histamine Intolerance: Measurements and Determinants in a Large Random Population-Based Survey
- 2023
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Ingår i: Nutrients. - 2072-6643. ; 15:13
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Tidskriftsartikel (refereegranskat)abstract
- Histamine intolerance (HIT) is a common adverse reaction to food where elimination and reintroduction of histamine-rich food is part of the investigation. Analysis of the enzyme diamine oxidase (DAO) is sometimes used as an additional tool for diagnosis. This study aimed to describe the distribution of DAO in a large representative cohort of adults and to determine the association between DAO activity and possible associated factors. The study is based on the population-based West Sweden Asthma Study and includes 1051 subjects. Subjects underwent structured interviews including questions on demography, asthma, allergy symptoms, and lifestyle factors. Subjects were assessed for specific-IgE-antibodies and measurement of DAO activity in serum. Previously suggested cut-off levels for low values (<3 U/mL), normal values (>10 U/mL), and median levels of DAO were used. In the group of 1051 subjects, only a few presented reactions upon histamine intake, whereas 44% presented DAO levels below the suggested normal cut-off levels. BMI and age were shown to have an impact on DAO activity among women with increasing activity of DAO with increasing BMI and age. Among men, only increasing age was seen to have an impact on DAO levels. There was no difference in DAO levels with different sensitization status to common foods or airborne allergens. No association between DAO levels and reported symptoms to histamine-rich foods could be found. In conclusion, the determination of the DAO enzyme needs to be re-evaluated and may not be used as a valuable tool for histamine intolerance using current cut-off values. Further studies are needed to improve the use of DAO as a biomarker for histamine intolerance.
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| 37. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
- 2023
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Ingår i: JCO precision oncology. - : American Society of Clinical Oncology. - 2473-4284. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 38. |
- Wadensten, Elisabeth, et al.
(författare)
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Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer
- 2023
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Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; :7
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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| 39. |
- Woodward, Eleanor L, et al.
(författare)
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Clonal origin and development of high hyperdiploidy in childhood acute lymphoblastic leukaemia
- 2023
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- High hyperdiploid acute lymphoblastic leukemia (HeH ALL), one of the most common childhood malignancies, is driven by nonrandom aneuploidy (abnormal chromosome numbers) mainly comprising chromosomal gains. In this study, we investigate how aneuploidy in HeH ALL arises. Single cell whole genome sequencing of 2847 cells from nine primary cases and one normal bone marrow reveals that HeH ALL generally display low chromosomal heterogeneity, indicating that they are not characterized by chromosomal instability and showing that aneuploidy-driven malignancies are not necessarily chromosomally heterogeneous. Furthermore, most chromosomal gains are present in all leukemic cells, suggesting that they arose early during leukemogenesis. Copy number data from 577 primary cases reveals selective pressures that were used for in silico modeling of aneuploidy development. This shows that the aneuploidy in HeH ALL likely arises by an initial tripolar mitosis in a diploid cell followed by clonal evolution, in line with a punctuated evolution model.
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| 40. |
- Yang, Minjun, et al.
(författare)
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13q12.2 deletions in acute lymphoblastic leukemia lead to upregulation of FLT3 through enhancer hijacking
- 2020
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Ingår i: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 136:8, s. 946-956
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene in 13q12.2 are among the most common driver events in acute leukemia, leading to increased cell proliferation and survival through activation of the phosphatidylinositol 3-kinase/AKT-, RAS/MAPK-, and STAT5-signaling pathways. In this study, we examine the pathogenetic impact of somatic hemizygous 13q12.2 microdeletions in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) using 5 different patient cohorts (in total including 1418 cases). The 13q12.2 deletions occur immediately 59 of FLT3 and involve the PAN3 locus. By detailed analysis of the 13q12.2 segment, we show that the deletions lead to loss of a topologically associating domain border and an enhancer of FLT3. This results in increased cis interactions between the FLT3 promoter and another enhancer located distally to the deletion breakpoints, with subsequent allele-specific upregulation of FLT3 expression, expected to lead to ligand-independent activation of the receptor and downstream signaling. The 13q12.2 deletions are highly enriched in the high-hyperdiploid BCP ALL subtype (frequency 3.9% vs 0.5% in other BCP ALL) and in cases that subsequently relapsed. Taken together, our study describes a novel mechanism of FLT3 involvement in leukemogenesis by upregulation via chromatin remodeling and enhancer hijacking. These data further emphasize the role of FLT3 as a driver gene in BCP ALL.
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| 41. |
- Öfverholm, Ingegerd, et al.
(författare)
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The prognostic impact of IKZF1 deletions and UKALL genetic classifiers in paediatric B-cell precursor acute lymphoblastic leukaemia treated according to NOPHO 2008 protocols
- 2023
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Ingår i: British Journal of Haematology. - : Wiley-Blackwell. - 0007-1048 .- 1365-2141. ; 202:2, s. 384-392
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Tidskriftsartikel (refereegranskat)abstract
- We investigated 390 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) patients treated according to NOPHO ALL 2008, regarding copy number alterations (CNA) of eight loci associated with adverse prognosis, including IKZF1. The impact on outcome was investigated for each locus individually, combined as CNA profiles and together with cytogenetic information. The presence of IKZF1 deletion or a poor-risk CNA profile was associated with poor outcome in the whole cohort. In the standard-risk group, IKZF1-deleted cases had an inferior probability of relapse-free survival (pRFS) (p <= 0.001) and overall survival (pOS) (p <= 0.001). Additionally, among B-other patients, IKZF1 deletion correlated with poor pRFS (60% vs. 90%) and pOS (65% vs. 89%). Both IKZF1 deletion and a poor-risk CNA profile were independent factors for relapse and death in multivariable analyses adjusting for known risk factors including measurable residual disease. Our data indicate that BCP-ALL patients with high-risk CNA or IKZF1 deletion have worse prognosis despite otherwise low-risk features. Conversely, patients with both a good CNA and cytogenetic profile had a superior relapse-free (p <= 0.001) and overall survival (p <= 0.001) in the cohort, across all risk groups. Taken together, our findings highlight the potential of CNA assessment to refine stratification in ALL.
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