| 1. |
- Williamson, Alice, et al.
(författare)
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Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:6, s. 973-983
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Tidskriftsartikel (refereegranskat)abstract
- Distinct tissue-specific mechanisms mediate insulin action in fasting and postprandial states. Previous genetic studies have largely focused on insulin resistance in the fasting state, where hepatic insulin action dominates. Here we studied genetic variants influencing insulin levels measured 2 h after a glucose challenge in >55,000 participants from three ancestry groups. We identified ten new loci (P < 5 × 10-8) not previously associated with postchallenge insulin resistance, eight of which were shown to share their genetic architecture with type 2 diabetes in colocalization analyses. We investigated candidate genes at a subset of associated loci in cultured cells and identified nine candidate genes newly implicated in the expression or trafficking of GLUT4, the key glucose transporter in postprandial glucose uptake in muscle and fat. By focusing on postprandial insulin resistance, we highlighted the mechanisms of action at type 2 diabetes loci that are not adequately captured by studies of fasting glycemic traits.
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| 2. |
- Winerdal, Malin E., et al.
(författare)
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Urinary Bladder Cancer Tregs Suppress MMP2 and Potentially Regulate Invasiveness
- 2018
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Ingår i: CANCER IMMUNOLOGY RESEARCH. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:5, s. 528-538
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Tidskriftsartikel (refereegranskat)abstract
- Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3+ (FOXP3+) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients (n = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4+FOXP3+ T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC.
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| 3. |
- Moberg, Christina, et al.
(författare)
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De unga gör helt rätt när de stämmer staten
- 2022
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Ingår i: Aftonbladet. - 1103-9000.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- 1 620 forskare och lärare i forskarvärlden: Vi ställer oss bakom Auroras klimatkrav
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| 4. |
- Ahlén Bergman, Emma, et al.
(författare)
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Increased CD4+ T cell lineage commitment determined by CpG methylation correlates with better prognosis in urinary bladder cancer patients
- 2018
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Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083 .- 1868-7075. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Urinary bladder cancer is a common malignancy worldwide. Environmental factors and chronic inflammation are correlated with the disease risk. Diagnosis is performed by transurethral resection of the bladder, and patients with muscle invasive disease preferably proceed to radical cystectomy, with or without neoadjuvant chemotherapy. The anti-tumour immune responses, known to be initiated in the tumour and draining lymph nodes, may play a major role in future treatment strategies. Thus, increasing the knowledge of tumour-associated immunological processes is important. Activated CD4+ T cells differentiate into four main separate lineages: Th1, Th2, Th17 and Treg, and they are recognized by their effector molecules IFN-γ, IL-13, IL-17A, and the transcription factor Foxp3, respectively. We have previously demonstrated signature CpG sites predictive for lineage commitment of these four major CD4+ T cell lineages. Here, we investigate the lineage commitment specifically in tumour, lymph nodes and blood and relate them to the disease stage and response to neoadjuvant chemotherapy.RESULTS: Blood, tumour and regional lymph nodes were obtained from patients at time of transurethral resection of the bladder and at radical cystectomy. Tumour-infiltrating CD4+ lymphocytes were significantly hypomethylated in all four investigated lineage loci compared to CD4+ lymphocytes in lymph nodes and blood (lymph nodes vs tumour-infiltrating lymphocytes: IFNG -4229 bp p < 0.0001, IL13 -11 bp p < 0.05, IL17A -122 bp p < 0.01 and FOXP3 -77 bp p > 0.05). Examination of individual lymph nodes displayed different methylation signatures, suggesting possible correlation with future survival. More advanced post-cystectomy tumour stages correlated significantly with increased methylation at the IFNG -4229 bp locus. Patients with complete response to neoadjuvant chemotherapy displayed significant hypomethylation in CD4+ T cells for all four investigated loci, most prominently in IFNG p < 0.0001. Neoadjuvant chemotherapy seemed to result in a relocation of Th1-committed CD4+ T cells from blood, presumably to the tumour, indicated by shifts in the methylation patterns, whereas no such shifts were seen for lineages corresponding to IL13, IL17A and FOXP3.CONCLUSION: Increased lineage commitment in CD4+ T cells, as determined by demethylation in predictive CpG sites, is associated with lower post-cystectomy tumour stage, complete response to neoadjuvant chemotherapy and overall better outcome, suggesting epigenetic profiling of CD4+ T cell lineages as a useful readout for clinical staging.
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| 5. |
- Haglund, Emma, et al.
(författare)
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Educational needs in patients with spondyloarthritis in Sweden - a mixed-methods study
- 2017
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Ingår i: Bmc Musculoskeletal Disorders. - London : Springer Science and Business Media LLC. - 1471-2474. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a demand for a flexible and individually tailored patient education to meet patients' specific needs and priorities, but this area has seldom been studied in patients with spondyloarthritis (SpA), a family of inflammatory rheumatic diseases. The aim of the present study was to identify needs and priorities in patient education in patients with SpA. A second aim was to investigate patients' experiences and preferences of receiving patient education. Methods: Data collection included a questionnaire survey with the Educational Needs Assessment Tool (ENAT) and interviews, using a mixed-methods design. Patients were identified through a specialist clinic register. Descriptive data are presented as mean with standard deviation, or frequencies. Chi-square test and independent-samples t-test were used for group comparisons. A manifest qualitative conventional content analysis was conducted to explore patients' experiences and needs in patient education, based on two focus groups (n = 6) and five individual interviews. Results: Almost half (43%) of the 183 SpA patients had educational needs, particularly regarding aspects of self-help, feelings, and the disease process. More educational needs were reported by women and in patients with higher disease activity, while duration of disease did not affect the needs. The qualitative analysis highlighted the importance of obtaining a guiding, reliable, and easily available patient education for management of SpA. Individual contacts with healthcare professionals were of importance, but newer media were also requested. Conclusion: There are considerable educational needs in patients with SpA, and education concerning self-help, feelings, and the diseases process were raised as important issues. Healthcare professionals need to consider the importance of presenting varied formats of education based on the experiences and preferences of patients with SpA.
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| 6. |
- Hartana, Ciputra Adijaya, et al.
(författare)
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Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway
- 2018
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Ingår i: PLOS ONE. - : Public Library Science. - 1932-6203. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.
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| 7. |
- Hedlund, Malin, et al.
(författare)
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Type I IFN system activation in newborns exposed to Ro/SSA and La/SSB autoantibodies in utero
- 2020
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Ingår i: RMD Open. - : BMJ. - 2056-5933. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In utero exposure of the fetus to Ro/La autoantibodies may lead to congenital heart block (CHB). In the mother, these autoantibodies are associated with activation of the type I interferon (IFN)-system. As maternal autoantibodies are transferred to the fetus during pregnancy, we investigated whether the type I IFN-system is activated also in newborns of anti-Ro/La positive mothers, and whether fetal IFN activation is affected by maternal immunomodulatory treatment.METHODS: Blood drawn at birth from anti-Ro/La positive mothers, their newborns and healthy control pairs was separated into plasma and peripheral blood mononuclear cells (PBMC). PBMC were analysed directly or cultured. mRNA expression was analysed by microarrays, cell surface markers by flow cytometry, and IFNα levels by immunoassays.RESULTS: We observed increased expression of IFN-regulated genes and elevated plasma IFNα levels not only in anti-Ro/La positive women, but also in their newborns. CD14+ monocytes of both anti-Ro/La positive mothers and their neonates showed increased expression of Sialic acid-binding Ig-like lectin-1, indicating cellular activation. Notably, the IFN score of neonates born to mothers receiving immunomodulatory treatment was similar to that of controls, despite persistent IFN activation in the mothers. In both maternal and neonatal PBMC, IFNα production was induced when cells were cultured with anti-Ro/La positive plasma.CONCLUSIONS: Ro/La autoantibody-exposed neonates at risk of CHB have signs of an activated immune system with an IFN signature. This study further demonstrates that neonatal cells can produce IFNα when exposed to autoantibody-containing plasma, and that maternal immunomodulatory treatment may diminish the expression of IFN-regulated genes in the fetus.
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| 8. |
- Torell, A., et al.
(författare)
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Symptoms of pain, fatigue and self-efficacy in young patients with spondyloarthritis : – a comparison between women and men
- 2017
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Ingår i: Annals of the Rheumatic Diseases. - London : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 76:Suppl. 2, s. 1515-1515
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Tidskriftsartikel (refereegranskat)abstract
- Background; The disease spondyloarthritis (SpA) have often an early onset, and can debuts already in teenagers or young adults. Knowledge of how these patients reporting pain, fatigue and self-efficacy can help to better understand the characteristics of women and men with SpA.Objectives: To study the differences between young women and men with SpA with regards to self-reported questionnaires on pain, fatigue and self-efficacy.A cross sectional population based cohort were used to create a young patients with SpA.Methods: The study is created on a cross-sectional population based cohort of patients with SpA. They were identified through a health care register by searching for ICD-10 codes for SpA between the years 2003-2007, responding to a questionnaire survey in 2009. 201 patients, 18-36, 29% with the diagnosis of ankylosing spondylitis, 39% with psoriatic arthritis, and 32% with undifferentiated spondyloarhtritis form a subgroup of young patients eligible for analysis. The surveys including questions concerning self-reported pain (NRS 0-10 and pain mannequin), fatigue (NRS 0-10), self-efficacy (ASES 10-100, low-high). The pain mannequin was used to categorize patients into groups; non chronic pain, chronic regional pain or chronic generalized pain. Self-reported disease activity (BASDAI 0-10) and health related quality of life (EQ5D, 0-1) were used to describe the group. Characteristic symptoms are reported as mean, standard deviation (SD) and frequencies. Mann- Whitney U test and Chi2 test were used to study gender differences.Results: The mean age (SD) was, 30 (5) years, 60 % were women. The group reported disease activity (BASDAI) of 3.8 (2.3), quality of life 0.75 (0.16), and that they had their diagnosis for 7 (5) years. One third were smokers or former smokers, and 69 % reached WHO’s recommended level of health enhancing physical activity. Women reported higher pain 3.9 (2.4) compared to men 2.9 (2.1), p=0.001. In the group of both women and men 21 % reported regional chronic pain, 41 % generalized chronic pain and the remaining 38 % reported non chronic pain. More women reported regional and generalized chronic pain than men, p=0.026. Women reported more fatigue 5.0 (2.6) compared to men 3.9 (2.7), p=0.003, less self-efficacy for pain 53 (20), compared to men 59 (21), p=0.041 and for symptoms 59 (19) compared to men 65 (20), p=0.045.Conclusion: A significant proportion of both women and men reported symptoms consistent with chronic generalized pain. Women reported generally impaired health compared to men, with a greater percentage with chronic pain, higher rates of pain and fatigue and reduced self-efficacy to manage pain and symptoms. This information could be valuable for clinicians in the care of young patients with SpA.
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| 9. |
- Zirakzadeh, A. Ali, et al.
(författare)
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B cells in tumor draining lymph nodes act asefficient antigen presenting cells in cancer patients
- 2015
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BioMed Central. - 2051-1426. ; 3:Suppl 2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Overall Survival of patients with muscle invasive urothelial bladder cancer MIBC remains around 50% (5 years), albeit some improvements by combining neoadjuvant chemotherapy with radical surgery. Our previous work has demonstrated that in vitro expansions of sentinel node-acquired autologous tumor specific CD4+ T cells are promising for adoptive immunotherapy [1]. In order for naive T helper cells to become activated, they need effective APCs, presenting tumor antigens. In another study, we observed that B cells in cancer patients were tumor antigen experienced and from their phenotypes we suggested a CD4+ T cell dependent anti-tumoral response [2]. In this study, we report a flow cytometric investigation of tumor draining lymph node (sentinel node) derived B cell activation by autologous tumor extract in patients with MIBC.Methods: Sentinel nodes (SNs) from 28 patients with MIBC were detected by a Geiger meter at cystectomy after peritumoral injection with radioactive isotope. Lymphocytes were isolated from freshly received SNs where they were stimulated with autologous tumor extract in a sterile environment. After cultivation for 7 days, the cells were analyzed by multi-color flow cytometry using FASCIA (Flow cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood).Results: Patients displayed an increased B cell activation in SNs after stimulation with autologous tumor extract compared to when SN acquired lymphocytes were stimulated with autologous extract of macroscopically non-malignant bladder. CD4+ T cells from SNs were activated and formed blasts after co-culture with SN acquired B cells in the presence of tumor antigen. However, CD4+ T cells were not activated and did not blast when co-cultured with B cells incubated with HLA-DR-blocking antibodies. This indicates antigen presenting ability of SN acquired B cells.Conclusions: We demonstrate sentinel node acquired B lymphocytes can be activated in culture upon stimulation with autologous tumor extract but not with extract of non-malignant epithelium of the bladder, after 7 days. Lower number of sentinel node acquired CD4+ T cells cultured with HLA-DR blocked CD19+ cells in presence of tumor antigen, indicate functional antigen presenting ability of B cells in sentinel nodes. The role of B cells as APCs in human T cell anti-tumoral response should be further explored, as well as their usefulness in adoptive immunotherapy.
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| 10. |
- Zirakzadeh, A. Ali, et al.
(författare)
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Doxorubicin enhances the capacity of B cells to activate T cells in urothelial urinary bladder cancer
- 2017
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Ingår i: Clinical Immunology. - : Elsevier BV. - 1521-6616 .- 1521-7035. ; 176, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is currently treated by a combination of therapies, including chemotherapy which is believed to suppress the immune system. Combination of immunotherapy and chemotherapy correlates with improved survival but needs careful planning in order to achieve a synergistic effect. In this study, we have demonstrated that doxorubicin treatment of B cells resulted in increased expression of CD86 and concordantly increased CD4(+) T cell activation in the presence of superantigen, an effect that was inhibited by the addition of a CD86 blocking antibody. Furthermore, doxorubicin resulted in decreased expression of the anti-inflammatory cytokines IL-10 and TNF-alpha. Finally, B cells from urinary bladder cancer patients, treated with a neoadjuvant regiment containing doxorubicin, displayed increased CD86-expression. We conclude that doxorubicin induces CD86 expression on B cells and hence enhances their antigen-presenting ability in vitro, a finding verified in patients. Development of tailored time and dose schedules may increase the effectiveness of combining chemotherapy and immunotherapy.
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