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Sökning: WFRF:(Nordström MArie C.)

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  • Conti, David, V, et al. (författare)
  • Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
  • 2021
  • Ingår i: Nature Genetics. - : NATURE RESEARCH. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
  • Dadaev, Tokhir, et al. (författare)
  • Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants.
  • 2018
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.
  • Geisler, Christian H., et al. (författare)
  • Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group
  • 2008
  • Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 112:7, s. 2687-2693
  • Tidskriftsartikel (refereegranskat)abstract
    • Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + highdose cytarabine. Responders received highdose chemotherapy with BEAM or BEAC carmustine, etoposide, cytarabine, and melphalan/ cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL- 1 trial, the event- free, overall, and progression- free survival, the duration of molecular remission, and the proportion of PCR- negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression- free survival of MCL and perhaps cure. Registered at www. isrctn. org as # ISRCTN 87866680.
  • Geisler, Christian H., et al. (författare)
  • The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)
  • 2010
  • Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:8, s. 1530-1533
  • Tidskriftsartikel (refereegranskat)abstract
    • Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPI(B) (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPI(B) is feasible.
  • Klasson, Caritha, et al. (författare)
  • Vitamin D and Fatigue in Palliative Cancer : A Cross-Sectional Study of Sex Difference in Baseline Data from the Palliative D Cohort
  • 2021
  • Ingår i: Journal of Palliative Medicine. - 1096-6218 .- 1557-7740. ; 24:3, s. 433-437
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Fatigue is one of the most distressing symptoms in patients with advanced cancer. Previous studies have shown an association between low vitamin D levels and fatigue. Objectives: The aim of this study was to investigate the association between vitamin D levels and self-assessed fatigue in cancer patients admitted to palliative care, with focus on possible sex differences. Design: This is a cross-sectional study. Subjects: Baseline data from 530 screened patients, 265 women and 265 men, from the randomized placebo-controlled trial "Palliative-D" were analyzed. Measurements: Vitamin D status was measured as 25-hydroxyvitamin D (25-OHD) and fatigue was assessed with EORTC-QLQ-PAL15 and with Edmonton Symptom Assessment System (ESAS). Results: In men, there was a significant correlation between 25-OHD and fatigue measured with the "Tiredness question" (Q11) in EORTC-QLQ-PAL15 (p < 0.05), where higher 25-OHD levels were associated with less fatigue. No correlation between 25-OHD and fatigue was seen for women. Fatigue measured with ESAS did not show any significant association with 25-OHD levels neither in men nor in women. Conclusion: Low vitamin D levels were associated with more fatigue in men but not in women. The study underscores the importance of subgroup analysis of men and women when evaluating the effect of vitamin D in clinical trials since the effect may differ between the sexes. The ongoing "Palliative-D study" will reveal whether vitamin D supplementation may counteract fatigue in both men and women.ClinicalTrial.gov: NCT03038516.
  • Sinai, Cave, et al. (författare)
  • Exposure to interpersonal violence and risk of post-traumatic stress disorder among women with borderline personality disorder
  • 2018
  • Ingår i: Psychiatry Research. - : ELSEVIER IRELAND LTD. - 0165-1781 .- 1872-7123. ; 262, s. 311-315
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: This study aims to determine the validity of the Karolinska Interpersonal Violence Scale (KIVS), as a screening tool for PTSD, among women with borderline personality disorder (BPD) and severe suicidal behavior. Method: 106 women with BPD and at least two suicide attempts were assessed with the KIVS for exposure to interpersonal violence as a child and as an adult. The screening ability of the KIVS for the diagnosis of PTSD was analyzed using receiver operating characteristic curve analysis. Results: PTSD diagnosis was valid for 61 (58%) women with BPD. The KIVS exposure of lifetime interpersonal violence, displayed fair accuracy of predicting diagnosis of PTSD (area under the curve 0.79, confidence interval [0.71, 0.88]) and performed well (sensitivity 0.90 and specificity 0.62), with a cut-off score of 4 (range 0-10). Poly-traumatization was not significantly related to PTSD diagnosis as compared to single traumatization, whereas sexual victimization was significantly more prevalent in women with PTSD diagnosis, as compared to other types of traumatic events. Conclusion: A score of 4 or more on the KIVS exposure to interpersonal lifetime violence presents well as a screening instrument for risk of PTSD, among women with BPD.
  • Brose, Ulrich, et al. (författare)
  • Predicting the consequences of species lossusing size-structured biodiversity approaches
  • 2017
  • Ingår i: Biological Reviews. - : Wiley-Blackwell. - 1464-7931 .- 1469-185X. ; 92:2, s. 684-697
  • Forskningsöversikt (refereegranskat)abstract
    • Understanding the consequences of species loss in complex ecological communities is one of the great challenges in current biodiversity research. For a long time, this topic has been addressed by traditional biodiversity experiments. Most of these approaches treat species as trait-free, taxonomic units characterizing communities only by species number without accounting for species traits. However, extinctions do not occur at random as there is a clear correlation between extinction risk and species traits. In this review, we assume that large species will be most threatened by extinction and use novel allometric and size-spectrum concepts that include body mass as a primary species trait at the levels of populations and individuals, respectively, to re-assess three classic debates on the relationships between biodiversity and (i) food-web structural complexity, (ii) community dynamic stability, and (iii) ecosystem functioning. Contrasting current expectations, size-structured approaches suggest that the loss of large species, that typically exploit most resource species, may lead to future food webs that are less interwoven and more structured by chains of interactions and compartments. The disruption of natural body-mass distributions maintaining food-web stability may trigger avalanches of secondary extinctions and strong trophic cascades with expected knock-on effects on the functionality of the ecosystems. Therefore, we argue that it is crucial to take into account body size as a species trait when analysing the consequences of biodiversity loss for natural ecosystems. Applying size-structured approaches provides an integrative ecological concept that enables a better understanding of each species' unique role across communities and the causes and consequences of biodiversity loss.
  • Freischmidt, Axel, et al. (författare)
  • Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia
  • 2015
  • Ingår i: Nature Neuroscience. - 1097-6256 .- 1546-1726. ; 18:5, s. 631-
  • Tidskriftsartikel (refereegranskat)abstract
    • Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.
  • Griffiths, Jennifer R., et al. (författare)
  • The importance of benthic-pelagic coupling for marine ecosystem functioning in a changing world
  • 2017
  • Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 23:6, s. 2179-2196
  • Tidskriftsartikel (refereegranskat)abstract
    • Benthic-pelagic coupling is manifested as the exchange of energy, mass, or nutrients between benthic and pelagic habitats. It plays a prominent role in aquatic ecosystems, and it is crucial to functions from nutrient cycling to energy transfer in food webs. Coastal and estuarine ecosystem structure and function are strongly affected by anthropogenic pressures; however, there are large gaps in our understanding of the responses of inorganic nutrient and organic matter fluxes between benthic habitats and the water column. We illustrate the varied nature of physical and biological benthic-pelagic coupling processes and their potential sensitivity to three anthropogenic pressures - climate change, nutrient loading, and fishing - using the Baltic Sea as a case study and summarize current knowledge on the exchange of inorganic nutrients and organic material between habitats. Traditionally measured benthic-pelagic coupling processes (e.g., nutrient exchange and sedimentation of organic material) are to some extent quantifiable, but the magnitude and variability of biological processes are rarely assessed, preventing quantitative comparisons. Changing oxygen conditions will continue to have widespread effects on the processes that govern inorganic and organic matter exchange among habitats while climate change and nutrient load reductions may have large effects on organic matter sedimentation. Many biological processes (predation, bioturbation) are expected to be sensitive to anthropogenic drivers, but the outcomes for ecosystem function are largely unknown. We emphasize how improved empirical and experimental understanding of benthic-pelagic coupling processes and their variability are necessary to inform models that can quantify the feedbacks among processes and ecosystem responses to a changing world.
  • Sinai, Cave, et al. (författare)
  • Hypothalamic pituitary thyroid axis and exposure to interpersonal violence in childhood among women with borderline personality disorder
  • 2014
  • Ingår i: European Journal of Psychotraumatology. - 2000-8198 .- 2000-8066. ; 5, s. 23911-
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: A relationship between exposure to sexual violence and thyroid hormone alterations has been observed among women with posttraumatic stress disorder (PTSD). Women with borderline personality disorder (BPD) report a high estimate of childhood trauma.OBJECTIVE: The aim of the present study was to assess relationships between thyroid hormone measures and exposure to violence in childhood in women with BPD.METHOD: A total of 92 clinically euthyroid women with BPD (53% with comorbid PTSD) diagnosis and at least two prior suicide attempts were assessed with the Karolinska Interpersonal Violence Scales (KIVS). The KIVS contains four subscales with concrete examples of exposure to violence and expressed violent behavior in childhood (aged 6-14 years) and during adult life (15 years or older). Baseline thyroid function was evaluated by measuring plasma free and bound triiodothyronine (FT3 and T3), thyroxine (FT4 and T4), and thyroid-stimulating hormone (TSH) with immunoassays. The FT3/FT4 ratio was used to estimate peripheral deiodination. Plasma cortisol was also assessed.RESULTS: Sixty-seven percent of patients reported medium high or high level of exposure to interpersonal violence as a child. The FT3/FT4 ratio showed a significant negative correlation with exposure to violence as a child. Patients with PTSD had significantly higher plasma cortisol levels. An ad hoc analysis revealed that the correlation between KIVS exposure to interpersonal violence as a child and FT3/FT4 ratio was significant only in patients with comorbid PTSD. Altered thyroid activity, especially FT3/FT4, levels was associated with exposure to violence in childhood in women with BPD.CONCLUSION: Severe childhood trauma-related stress may promote lasting altered thyroid levels and/or contribute to the development of psychopathology associated with BPD traits or PTSD.
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