| 1. |
- Kang, E. Y., et al.
(författare)
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CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study
- 2023
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Ingår i: Cancer. - : Wiley. - 0008-543X .- 1097-0142. ; 129:5, s. 697-713
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Methods: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. Results: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. Conclusion: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
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| 2. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 3. |
- Kang, E. Y., et al.
(författare)
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MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma
- 2022
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 480
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Tidskriftsartikel (refereegranskat)abstract
- Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naive HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naive tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naive HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36-0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
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| 4. |
- Broberg, C. S., et al.
(författare)
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Long-Term Outcomes After Atrial Switch Operation for Transposition of the Great Arteries
- 2022
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Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 80:10, s. 951-963
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Tidskriftsartikel (refereegranskat)abstract
- Background: For patients with d-loop transposition of the great arteries (d-TGA) with a systemic right ventricle after an atrial switch operation, there is a need to identify risks for end-stage heart failure outcomes. Objectives: The authors aimed to determine factors associated with survival in a large cohort of such individuals. Methods: This multicenter, retrospective cohort study included adults with d-TGA and prior atrial switch surgery seen at a congenital heart center. Clinical data from initial and most recent visits were obtained. The composite primary outcome was death, transplantation, or mechanical circulatory support (MCS). Results: From 1,168 patients (38% female, age at first visit 29 ± 7.2 years) during a median 9.2 years of follow-up, 91 (8.8% per 10 person-years) met the outcome (66 deaths, 19 transplantations, 6 MCS). Patients experiencing sudden/arrhythmic death were younger than those dying of other causes (32.6 ± 6.4 years vs 42.4 ± 6.8 years; P < 0.001). There was a long duration between sentinel clinical events and end-stage heart failure. Age, atrial arrhythmia, pacemaker, biventricular enlargement, systolic dysfunction, and tricuspid regurgitation were all associated with the primary outcome. Independent 5-year predictors of primary outcome were prior ventricular arrhythmia, heart failure admission, complex anatomy, QRS duration >120 ms, and severe right ventricle dysfunction based on echocardiography. Conclusions: For most adults with d-TGA after atrial switch, progress to end-stage heart failure or death is slow. A simplified prediction score for 5-year adverse outcome is derived to help identify those at greatest risk.
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| 5. |
- van Dissel, A. C., et al.
(författare)
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End-stage heart failure in congenitally corrected transposition of the great arteries: a multicentre study
- 2023
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Ingår i: European Heart Journal. - 0195-668X. ; 44:34, s. 3278-3291
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims For patients with congenitally corrected transposition of the great arteries (ccTGA), factors associated with progression to end-stage congestive heart failure (CHF) remain largely unclear. Methods This multicentre, retrospective cohort study included adults with ccTGA seen at a congenital heart disease centre. Clinical data from initial and most recent visits were obtained. The composite primary outcome was mechanical circulatory support, heart transplantation, or death. Results From 558 patients (48% female, age at first visit 36 & PLUSMN; 14.2 years, median follow-up 8.7 years), the event rate of the primary outcome was 15.4 per 1000 person-years (11 mechanical circulatory support implantations, 12 transplantations, and 52 deaths). Patients experiencing the primary outcome were older and more likely to have a history of atrial arrhythmia. The primary outcome was highest in those with both moderate/severe right ventricular (RV) dysfunction and tricuspid regurgitation (n = 110, 31 events) and uncommon in those with mild/less RV dysfunction and tricuspid regurgitation (n = 181, 13 events, P < .001). Outcomes were not different based on anatomic complexity and history of tricuspid valve surgery or of subpulmonic obstruction. New CHF admission or ventricular arrhythmia was associated with the primary outcome. Individuals who underwent childhood surgery had more adverse outcomes than age- and sex-matched controls. Multivariable Cox regression analysis identified older age, prior CHF admission, and severe RV dysfunction as independent predictors for the primary outcome. Conclusions Patients with ccTGA have variable deterioration to end-stage heart failure or death over time, commonly between their fifth and sixth decades. Predictors include arrhythmic and CHF events and severe RV dysfunction but not anatomy or need for tricuspid valve surgery.
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| 6. |
- Abreu, Soraia Carvalho, et al.
(författare)
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Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells
- 2020
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Ingår i: American Journal of Physiology: Lung Cellular and Molecular Physiology. - : American Physiological Society. - 1040-0605 .- 1522-1504.
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Tidskriftsartikel (refereegranskat)abstract
- Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.
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| 7. |
- Aurelle, D., et al.
(författare)
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Biodiversity, climate change, and adaptation in the Mediterranean
- 2022
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Ingår i: Ecosphere. - : Wiley. - 2150-8925. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Potential for, and limits to, adaptation to environmental changes are critical for resilience and risk mitigation. The Mediterranean basin is a mosaic of biodiversity-rich ecosystems long affected by human influence, whose resilience is now questioned by climate change. After reviewing the different components of biological adaptation, we present the main characteristics of marine and terrestrial biodiversity in the Mediterranean basin and of the pressures they face. Taking climatic trends into consideration, we discuss the adaptive potential of a range of ecosystems dominated by species without active dispersal. We argue that the high heterogeneity of Mediterranean landscapes and seascapes constitutes a laboratory for the study of adaptation when environmental conditions change rapidly and may provide opportunities for adaptation and adaptability of species and ecosystems. Adaptive management in the Mediterranean can and should harness the nature-based solutions offered by both ecological and evolutionary processes for increasing the resilience of ecosystems to climate change.
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| 8. |
- Biebesheimer, Ellie J., et al.
(författare)
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Asynchronous δ13Ccarb and δ13Corg records during the onset of the Mulde (Silurian) positive carbon isotope excursion from the Altajme core, Gotland, Sweden
- 2021
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Ingår i: Chemical Geology. - : Elsevier BV. - 0009-2541. ; 576
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Tidskriftsartikel (refereegranskat)abstract
- High-resolution paired analyses of δ13Ccarb and δ13Corg from a new drill core from Gotland, Sweden, demonstrate asynchronous positive change in the carbon isotope records during the onset of one of the major Silurian biogeochemical events known as the Mulde Event or “Big Crisis”. The detailed carbon isotope record presented here provides Δ13C (the difference between δ13Ccarb and δ13Corg) and allows the calculation of changes in organic carbon burial (forg) throughout the late Wenlock. The paired data suggest a ~ 38% increase in forg during the peak of the positive δ13Ccarb excursion and the high-resolution record reveals several short-lived inflections in Δ13C that have not been previously identified. When combined with sedimentological and sequence stratigraphic data from multiple paleocontinents, the new data presented here provide strong evidence for a transient global decrease in CO2, in support of previous interpretations of regression and global cooling coinciding with the Mulde Extinction Event.
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| 9. |
- Fazey, Ioan, et al.
(författare)
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Transforming knowledge systems for life on Earth : Visions of future systems and how to get there
- 2020
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Ingår i: Energy Research & Social Science. - : Elsevier. - 2214-6296 .- 2214-6326. ; 70
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Tidskriftsartikel (refereegranskat)abstract
- Formalised knowledge systems, including universities and research institutes, are important for contemporary societies. They are, however, also arguably failing humanity when their impact is measured against the level of progress being made in stimulating the societal changes needed to address challenges like climate change. In this research we used a novel futures-oriented and participatory approach that asked what future envisioned knowledge systems might need to look like and how we might get there. Findings suggest that envisioned future systems will need to be much more collaborative, open, diverse, egalitarian, and able to work with values and systemic issues. They will also need to go beyond producing knowledge about our world to generating wisdom about how to act within it. To get to envisioned systems we will need to rapidly scale methodological innovations, connect innovators, and creatively accelerate learning about working with intractable challenges. We will also need to create new funding schemes, a global knowledge commons, and challenge deeply held assumptions. To genuinely be a creative force in supporting longevity of human and non-human life on our planet, the shift in knowledge systems will probably need to be at the scale of the enlightenment and speed of the scientific and technological revolution accompanying the second World War. This will require bold and strategic action from governments, scientists, civic society and sustained transformational intent.
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| 10. |
- Franklin, Oskar, et al.
(författare)
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Organizing principles for vegetation dynamics
- 2020
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Ingår i: Nature plants. - : Springer Science and Business Media LLC. - 2055-026X .- 2055-0278. ; 6:5, s. 444-453
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Tidskriftsartikel (refereegranskat)abstract
- Plants and vegetation play a critical-but largely unpredictable-role in global environmental changes due to the multitude of contributing processes at widely different spatial and temporal scales. In this Perspective, we explore approaches to master this complexity and improve our ability to predict vegetation dynamics by explicitly taking account of principles that constrain plant and ecosystem behaviour: natural selection, self-organization and entropy maximization. These ideas are increasingly being used in vegetation models, but we argue that their full potential has yet to be realized. We demonstrate the power of natural selection-based optimality principles to predict photosynthetic and carbon allocation responses to multiple environmental drivers, as well as how individual plasticity leads to the predictable self-organization of forest canopies. We show how models of natural selection acting on a few key traits can generate realistic plant communities and how entropy maximization can identify the most probable outcomes of community dynamics in space- and time-varying environments. Finally, we present a roadmap indicating how these principles could be combined in a new generation of models with stronger theoretical foundations and an improved capacity to predict complex vegetation responses to environmental change. Integrating natural selection and other organizing principles into next-generation vegetation models could render them more theoretically sound and useful for earth system applications and modelling climate impacts.
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