| 1. |
- Lindahl, Lise M., et al.
(författare)
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STAT5 induces miR-21 expression in cutaneous T cell lymphoma
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:29, s. 45730-45744
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Tidskriftsartikel (refereegranskat)abstract
- In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR- 21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2- induced miR-21 expression in cytokine- independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL.
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| 2. |
- Abrahamsson, Marcus, et al.
(författare)
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Analytical Input to Emergency Preparedness at the Municipal Level – a Case Study
- 2007
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Ingår i: Proceedings of Disaster Recovery and Relief: Current & Future Approaches (TIEMS 2007).
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Konferensbidrag (refereegranskat)abstract
- In this paper an approach for employing risk and vulnerability analyses as the basis for emergency preparedness planning is discussed and exemplified using a case study. The study consisted of three connected parts: a broad scope hazard identification and analysis, an assessment of potential assistance needs should any of the hazards materialise and finally a mapping of actors and dependencies. The case study was conducted as a series of workshops, involving key actors from the studied municipality. Some thirty hazard scenarios, originating from five different categories; accidents, epidemics, infrastructure/utilities breakdown/interruption, criminal activity and socially induced scenarios were identified, described and initially evaluated in terms of possible consequences over a range of predefined attributes. In the next step, an analysis of potential assistance needs that may evolve during the identified scenarios was undertaken. Furthermore, an effort was made to identify municipal actors of central importance in the management of potential emergency scenarios, their respective tasks, resources and dependence on service from various technical infrastructures, other actors etc. Examples from the resulting overview of potential emergency scenarios, generated assistance needs and emergency management actors, tasks, resources and dependencies are presented and discussed, alongside with some implications for societal preparedness activities.
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| 3. |
- Bech-Hanssen, Odd, 1956, et al.
(författare)
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Grading right ventricular dysfunction in left ventricular disease using echocardiography: a proof of concept using a novel multiparameter strategy.
- 2021
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Ingår i: ESC heart failure. - : Wiley. - 2055-5822. ; 8:4, s. 3223-3236
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Tidskriftsartikel (refereegranskat)abstract
- Grading right ventricular dysfunction (RVD) in patients with left ventricular (LV) disease has earned little attention. In the present study, we established an echocardiographic RVD score and investigated how increments of the score correspond to RVD at right heart catheterization.We included 95 patients with LV disease consecutively referred for heart transplant or heart failure work-up with catheterization and echocardiography within 48h. The RVD score (5 points) included well-known characteristics of the development from compensated to decompensated right ventricular (RV) function: pulmonary hypertension, reduced RV strain, RV area dilatation, moderate/severe tricuspid regurgitation, and increased right atrial pressure (RAP) by echocardiography. Comparing three groups with increments of RVD score [1 (mild), 2-3 (moderate), and 4-5 (severe)] showed more advanced RVD with increasing RV end-diastolic pressure (P<0.001) and signs of uncoupling to load (reduced ratio between RV and pulmonary artery elastance, P<0.001) and more spherical RV shape (RV area/length, P<0.001). Receiver operating characteristic curve analysis for detection of severe RV (RAP≥10mmHg) showed for the RVD score an area under the curve of 0.88 compared with 0.69, 0.68, and 0.64 for RV strain, tricuspid annular plane systolic excursion, and fractional area change, respectively. A patient with RVD score≥4 had a 6.7-fold increase in likelihood of severe RVD, and no patient with RVD score≤1 had severe RVD.In this proof of concept study, a novel RVD score outperformed the widely used longitudinal parameters regarding grading of RVD severity, with a potential role for refined diagnosis, follow-up, and prognosis assessment in heart failure patients.
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| 6. |
- Blumel, Edda, et al.
(författare)
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Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4+ T cells in cutaneous T-cell lymphoma
- 2019
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 8:11
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Tidskriftsartikel (refereegranskat)abstract
- Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL.
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| 7. |
- Buus, Terkild Brink, et al.
(författare)
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Single-cell heterogeneity in Sézary syndrome
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:16, s. 2115-2126
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Tidskriftsartikel (refereegranskat)abstract
- Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
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| 8. |
- Fredholm, Angelica, et al.
(författare)
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The practice of thresholds : Autonomy in clinical education explored through variation theory and the threshold concepts framework
- 2020
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Ingår i: Teaching in Higher Education. - : Taylor & Francis. - 1356-2517 .- 1470-1294. ; 25:3, s. 305-320
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Tidskriftsartikel (refereegranskat)abstract
- This paper demonstrates a practical dimension to the discussion about threshold concepts. Threshold concepts have thus far mostly been acknowledged to elucidate learning processes mainly connected to theoretical concepts. By exploring situations that prompted experiences of autonomy and authenticity in clinical learning, findings showed how a practical experience could have the same power to transform thinking and identity as theoretical thresholds and serve as a trigger for transformational learning, therefore making the discussion about ‘practical thresholds' or thresholds in practice possible. The present study explores situations that prompted autonomy and authenticity, and offers context for and substance to these situations by adopting variation theory and the threshold concept framework. In order to learn more about situations that prompt experiences of autonomy and authenticity, and create prerequisites for such experiences, this paper examines how students discern and interpret these situations by analysing them through variation theory and the threshold concept framework.
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| 9. |
- Fredholm, Hanna, et al.
(författare)
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Breast cancer in young women : poor survival despite intensive treatment
- 2009
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Ingår i: PLoS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:11, s. e7695-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Breast cancer is uncommon in young women and correlates with a less favourable prognosis; still it is the most frequent cancer in women under 40, accounting for 30-40% of all incident female cancer. The aim of this study was to study prognosis in young women, quantifying how much stage at diagnosis and management on the one hand, and tumour biology on the other; each contribute to the worse prognosis seen in this age group. METHODOLOGY/PRINCIPAL FINDINGS: In a registry based cohort of women aged 20-69 (n = 22 017) with a primary diagnosis of invasive breast cancer (1992-2005), women aged 20-34 (n = 471), 35-39 (n = 858) and 40-49 (n = 4789) were compared with women aged 50-69 years (n = 15 899). The cumulative 5-year relative survival ratio and the relative excess mortality (RER) were calculated. The cumulative 5-year relative survival ratio was lowest in women aged 20-34. The RER was 2.84 for women aged 20-34 and decreased with increasing age (RER 1.76 and 1.17 for women aged 35-39 and 40-49, respectively). The excess risk was, however, present only in disease stages I and II. For women aged 20-34 with stage I disease RER was 4.63, and 6.70 in the subgroup with tumour size 1-10 mm. The absolute difference in stage I between the youngest and the reference groups amounted to nearly 8%, with a 90% 5-year survival in women aged 20-34. In stages IIa and IIb, the relative excess risk was not as dramatic, but the absolute differences approached 15%. The youngest women with small tumours generally received more aggressive treatment than women in older age groups. CONCLUSIONS: After correction for stage, tumour characteristics and treatment, age remained an independent risk factor for breast cancer death in women <35 years of age. The excess risk for young women was only seen in early stages of disease and was most pronounced in women with small tumours. Young women affected by breast cancer have a high risk of dying compared to their middle-aged counterparts even if diagnosed early and receiving an intense treatment.
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