| 1. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 2. |
- Coustenis, A., et al.
(författare)
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TandEM : Titan and Enceladus mission
- 2009
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Ingår i: Experimental astronomy. - : Springer Science and Business Media LLC. - 0922-6435 .- 1572-9508. ; 23:3, s. 893-946
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Tidskriftsartikel (refereegranskat)abstract
- TandEM was proposed as an L-class (large) mission in response to ESA's Cosmic Vision 2015-2025 Call, and accepted for further studies, with the goal of exploring Titan and Enceladus. The mission concept is to perform in situ investigations of two worlds tied together by location and properties, whose remarkable natures have been partly revealed by the ongoing Cassini-Huygens mission. These bodies still hold mysteries requiring a complete exploration using a variety of vehicles and instruments. TandEM is an ambitious mission because its targets are two of the most exciting and challenging bodies in the Solar System. It is designed to build on but exceed the scientific and technological accomplishments of the Cassini-Huygens mission, exploring Titan and Enceladus in ways that are not currently possible (full close-up and in situ coverage over long periods of time). In the current mission architecture, TandEM proposes to deliver two medium-sized spacecraft to the Saturnian system. One spacecraft would be an orbiter with a large host of instruments which would perform several Enceladus flybys and deliver penetrators to its surface before going into a dedicated orbit around Titan alone, while the other spacecraft would carry the Titan in situ investigation components, i.e. a hot-air balloon (MontgolfiSre) and possibly several landing probes to be delivered through the atmosphere.
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| 3. |
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| 4. |
- Kurki, MI, et al.
(författare)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Tidskriftsartikel (refereegranskat)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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| 5. |
- Yamauchi, M., et al.
(författare)
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Plasma-neutral gas interactions in various space environments : Assessment beyond simplified approximations as a Voyage 2050 theme
- 2022
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Ingår i: Experimental astronomy. - : Springer Nature. - 0922-6435 .- 1572-9508.
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Tidskriftsartikel (refereegranskat)abstract
- In the White Paper, submitted in response to the European Space Agency (ESA) Voyage 2050 Call, we present the importance of advancing our knowledge of plasma-neutral gas interactions, and of deepening our understanding of the partially ionized environments that are ubiquitous in the upper atmospheres of planets and moons, and elsewhere in space. In future space missions, the above task requires addressing the following fundamental questions: (A) How and by how much do plasma-neutral gas interactions influence the re-distribution of externally provided energy to the composing species? (B) How and by how much do plasma-neutral gas interactions contribute toward the growth of heavy complex molecules and biomolecules? Answering these questions is an absolute prerequisite for addressing the long-standing questions of atmospheric escape, the origin of biomolecules, and their role in the evolution of planets, moons, or comets, under the influence of energy sources in the form of electromagnetic and corpuscular radiation, because low-energy ion-neutral cross-sections in space cannot be reproduced quantitatively in laboratories for conditions of satisfying, particularly, (1) low-temperatures, (2) tenuous or strong gradients or layered media, and (3) in low-gravity plasma. Measurements with a minimum core instrument package (< 15 kg) can be used to perform such investigations in many different conditions and should be included in all deep-space missions. These investigations, if specific ranges of background parameters are considered, can also be pursued for Earth, Mars, and Venus.
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| 6. |
- Heinosalo, T., et al.
(författare)
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Secreted frizzled-related protein 2 (SFRP2) expression promotes lesion proliferation via canonical WNT signaling and indicates lesion borders in extraovarian endometriosis
- 2018
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Ingår i: Human Reproduction. - : Oxford University Press (OUP). - 0268-1161 .- 1460-2350. ; 33:5, s. 817-831
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: What is the role of SFRP2 in endometriosis? SUMMARY ANSWER: SFRP2 acts as a canonical WNT/CTNNBI signaling agonist in endometriosis, regulating endometriosis lesion growth and indicating endometriosis lesion borders together with CTNNBI (also known as beta catenin). WHAT IS KNOWN ALREADY: Endometriosis is a common, chronic disease that affects women of reproductive age, causing pain and infertility, and has significant economic impact on national health systems. Despite extensive research, the pathogenesis of endometriosis is poorly understood, and targeted medical treatments are lacking. WNT signaling is dysregulated in various human diseases, but its role in extraovarian endometriosis has not been fully elucidated. STUDY DESIGN, SIZE, DURATION: We evaluated the significance of WNT signaling, and especially secreted frizzled-related protein 2 (SFRP2), in extraovarian endometriosis, including peritoneal and deep lesions. The study design was based on a cohort of clinical samples collected by laparoscopy or curettage and questionnaire data from healthy controls and endometriosis patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Global gene expression analysis in human endometrium ( n = 104) and endometriosis (n = 177) specimens from 47 healthy controls and 103 endometriosis patients was followed by bioinformatics and supportive qPCR analyses. Immunohistochemistry, Western blotting, primary cell culture and siRNA knockdown approaches were used to validate the findings. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 220 WNT signaling and CTNNBI target genes analysed, 184 genes showed differential expression in extraovarian endometriosis (P < 0.05) compared with endometrium tissue, including SFRP2 and CTNNI. Menstrual cycle-dependent regulation of WNT genes observed in the endometrium was lost in endometriosis lesions, as shown by hierarchical clustering. Immunohistochemical analysis indicated that SFRP2 and CTNNBI are novel endometriosis lesion border markers, complementing immunostaining for the known marker CD10 (also known as MME). SFRP2 and CTNNBI localized similarly in both the epithelium and stroma of extraovarian endometriosis tissue, and interestingly, both also indicated an additional distant lesion border, suggesting that WNT signaling is altered in the endometriosis stroma beyond the primary border indicated by the known marker CD10. SFRP2 expression was positively associated with pain symptoms experienced by patients (P < 0.05), and functional loss of SFRP2 in extraovarian endometriosis primary cell cultures resulted in decreased cell proliferation (P < 0.05) associated with reduced CTNNBI protein expression (P = 0.05). LIMITATIONS REASONS FOR CAUTION: SFRP2 and CTNNBI improved extraovarian endometriosis lesion border detection in a relatively small cohort (n = 20), although larger studies with different endometriosis subtypes in variable cycle phases and under hormonal medication are required. WIDER IMPLICATIONS OF THE FINDINGS: The highly expressed SFRP2 and CTNNBI improve endometriosis lesion border detection, which can have clinical implications for better visualization of endometriosis lesions over CD10. Furthermore, SFRP2 acts as a canonical WNT/CTNNBI signaling agonist in endometriosis and positively regulates endometriosis lesion growth, suggesting that the WNT pathway may be an important therapeutic target for endometriosis.
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| 7. |
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| 8. |
- Lammer, H., et al.
(författare)
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Geophysical and Atmospheric Evolution of Habitable Planets
- 2010
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Ingår i: Astrobiology. - : Mary Ann Liebert Inc. - 1531-1074 .- 1557-8070. ; 10:1, s. 45-68
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Tidskriftsartikel (refereegranskat)abstract
- The evolution of Earth-like habitable planets is a complex process that depends on the geodynamical and geophysical environments. In particular, it is necessary that plate tectonics remain active over billions of years. These geophysically active environments are strongly coupled to a planet's host star parameters, such as mass, luminosity and activity, orbit location of the habitable zone, and the planet's initial water inventory. Depending on the host star's radiation and particle flux evolution, the composition in the thermosphere, and the availability of an active magnetic dynamo, the atmospheres of Earth-like planets within their habitable zones are differently affected due to thermal and nonthermal escape processes. For some planets, strong atmospheric escape could even effect the stability of the atmosphere.
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| 9. |
- Pollinger, F., et al.
(författare)
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The European GeoMetre project : developing enhanced large-scale dimensional metrology for geodesy
- 2023
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Ingår i: Applied Geomatics. - : Springer Science and Business Media Deutschland GmbH. - 1866-9298 .- 1866-928X. ; 15:2, s. 371-381
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Tidskriftsartikel (refereegranskat)abstract
- We provide a survey on the joint European research project “GeoMetre”, which explores novel technologies and their inclusion to existing surveying strategies to improve the traceability of geodetic reference frames to the SI definition of the metre. This work includes the development of novel distance meters with a range of up to 5 km, the realisation of optical multilateration systems for large structure monitoring at an operation distance of 50 m and beyond, and a novel strategy for GNSS-based distance determination. Different methods for refractivity compensation, based on classical sensors, on dispersion, on spectroscopic thermometry, and on the speed of sound to reduce the meteorological uncertainties in precise distance measurements, are developed further and characterised. These systems are validated at and applied to the novel European standard baseline EURO5000 at the Pieniny Kippen Belt, Poland, which was completely refurbished and intensely studied in this project. We use our novel instruments for a reduced uncertainty of the scale in the surveillance networks solutions for local tie measurements at space-geodetic co-location stations. We also investigate novel approaches like close-range photogrammetry to reference point determination of space-geodetic telescopes. Finally, we also investigate the inclusion of the local gravity field to consider the deviations of the vertical in the data analysis and to reduce the uncertainty of coordinate transformations in this complex problem.
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| 10. |
- Christ, T. W., et al.
(författare)
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"Being a Risk" or "Being at Risk": Factors Shaping Negotiation of Concerns of Radicalization within Multiagency Collaboration in the Nordic Countries
- 2024
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Ingår i: Democracy & Security. - 1741-9166 .- 1555-5860. ; 20:1, s. 1-24
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Tidskriftsartikel (refereegranskat)abstract
- Multiagency collaboration between state and municipal actors such as schools, social services and the police is at the core of the Nordic countries' approach to preventing radicalization and violent extremism. Yet, assessment of reported concerns of radicalization differs across countries. This qualitative study analyze how professionals negotiate assessments to identify factors that shape whether a concern of radicalization develops into a perception of risk. We argue that differences in structural factors and "institutional logics" in addition to trustful relations between practitioners at the local level affect collaboration and shape the perception of the task when the assessments of concrete concerns are negotiated.
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| 11. |
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| 12. |
- Fortner, Renée T, et al.
(författare)
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Human Chorionic Gonadotropin Does Not Correlate with Risk for Maternal Breast Cancer : Results from the Finnish Maternity Cohort
- 2017
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 77:1, s. 134-141
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Tidskriftsartikel (refereegranskat)abstract
- Human chorionic gonadotropin (hCG) is necessary for the maintenance of early pregnancy and promotes normal breast cell differentiation. Administered hCG reduces risk of carcinogen-induced breast cancer in animal models, and higher circulating hCG concentrations were associated with significantly lower long-term risk of breast cancer in a prior nested case-control study. In this study, we investigated early-pregnancy hCG concentrations and subsequent breast cancer risk. We conducted a nested case-control study with 1,191 cases and 2,257 controls (matched on age and date at blood collection) in the Finnish Maternity Cohort, a cohort with serum samples from 98% of pregnancies registered in Finland since 1983. This study included women with a serum sample collected early (<140 days gestation) in their first pregnancy resulting in a live, term birth. Breast cancer cases were identified via the Finnish Cancer Registry. Age at breast cancer diagnosis ranged from 22 to 58 years (mean: 41 years). hCG was measured using a solid-phase competitive chemiluminescence assay. Odds ratios (OR) were calculated using conditional logistic regression. We observed no association between hCG and breast cancer risk, overall [Quartile 4 vs. 1, OR, 1.14; 95% confidence interval (CI), 0.94-1.39], by estrogen and progesterone receptor status, or by ages at first-term birth or diagnosis. Associations did not differ by time between pregnancy and diagnosis (e.g., <5 years, ORQ4 vs. Q1, 1.10; 95% CI, 0.64-1.89; ≥15 years, ORQ4 vs. Q1, 1.36; 95% CI, 0.86-2.13; pheterogeneity = 0.62). This large prospective study does not support an inverse relationship between early pregnancy serum hCG concentrations and breast cancer risk.
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| 13. |
- Gizaw, NY, et al.
(författare)
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PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:49, s. e2116220119-
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Tidskriftsartikel (refereegranskat)abstract
- Rhabdomyosarcoma (RMS) is an aggressive pediatric soft-tissue cancer with features of skeletal muscle. Because of poor survival of RMS patients and severe long-term side effects of RMS therapies, alternative RMS therapies are urgently needed. Here we show that the prospero-related homeobox 1 (PROX1) transcription factor is highly expressed in RMS tumors regardless of their cell type of origin. We demonstrate that PROX1 is needed for RMS cell clonogenicity, growth and tumor formation. PROX1 gene silencing repressed several myogenic and tumorigenic transcripts and transformed the RD cell transcriptome to resemble that of benign mesenchymal stem cells. Importantly, we found that fibroblast growth factor receptors (FGFR) mediated the growth effects of PROX1 in RMS. Because of receptor cross-compensation, paralog-specific FGFR inhibition did not mimic the effects of PROX1 silencing, whereas a pan-FGFR inhibitor ablated RMS cell proliferation and induced apoptosis. Our findings uncover the critical role of PROX1 in RMS and offer insights into the mechanisms that regulate RMS development and growth. As FGFR inhibitors have already been tested in clinical phase I/II trials in other cancer types, our findings provide an alternative option for RMS treatment.
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| 14. |
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| 15. |
- Huhtaniemi, R., et al.
(författare)
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Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts
- 2018
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 188:12, s. 2890-2901
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Tidskriftsartikel (refereegranskat)abstract
- The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P4 and in a further reduction in the low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor–dependent growth of CRPC. © 2018 American Society for Investigative Pathology
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| 16. |
- Huhtaniemi, R., et al.
(författare)
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High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice
- 2022
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:5
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Tidskriftsartikel (refereegranskat)abstract
- Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.
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| 17. |
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| 18. |
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Kauppila, JH, et al.
(författare)
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Cohort profile: gastric cancer in the population-based, Finnish National Esophago-Gastric Cancer Cohort (FINEGO) Study
- 2020
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:10, s. e039574-
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Tidskriftsartikel (refereegranskat)abstract
- The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established with the aim of identifying factors that could contribute to improved outcomes in oesophago-gastric cancer. The aim of this study is to describe the patients with gastric cancer included in FINEGO.ParticipantsA total of 10 457 patients with gastric cancer or tumour diagnosis in the Finnish Cancer Registry or the Finnish Patient Registry during 1987–2016 were included in the cohort, with follow-up from Causes of Death Registry until 31 December 2016. All of the participants were at least 18 years of age, and had undergone either resectional or endoscopic mucosal surgery with curative or palliative intent.Findings to dateOf the 10 457 patients, 90.1% were identified to have cancer in both cancer and patient registries. In all, the median age was 70 at the time of surgery, 54.5% of the patients were men and 64.4% had no comorbidities. Education data were available for 31.1% of the patients, of whom the majority had had <12 years of formal education. Of the 7798 with cancer staging data available, 41.1% had a local cancer. Adenocarcinoma was the most common (94.2%) histological type. Almost all patients underwent open gastrectomy and 214% in hospitals with annual volume of more than 30 gastrectomies per year. A total of 8561 deaths occurred during the study period, of which 6474 were due to oesophago-gastric cancers. The 5-year survival was 34.6% and 5-year cancer-specific survival was 39.7%.Future plansThe data in FINEGO can be currently used for registry-based research but is being expanded by data extraction from patient records and scanning of histological samples from the Finnish biobanks. Initially, we are planning on studies on the national trends in treatment and mortality, and studies on the demographic factors and their influence on survival.
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| 23. |
- Knuuttila, M., et al.
(författare)
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Castration Induces Up-Regulation of Intratumoral Androgen Biosynthesis and Androgen Receptor Expression in an Orthotopic VCaP Human Prostate Cancer Xenograft Model
- 2014
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 0002-9440. ; 184:8, s. 2163-2173
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Tidskriftsartikel (refereegranskat)abstract
- Androgens are key factors involved in the development and progression of prostate cancer (PCa), and PCa growth can be suppressed by androgen deprivation therapy. In a considerable proportion of men receiving androgen deprivation therapy, however, PCa progresses to castration-resistant PCa (CRPC), making the development of efficient therapies challenging. We used an orthotopic VCaP human PCa xenograft model to study cellular and molecular changes in tumors after androgen deprivation therapy (castration). Tumor growth was monitored through weekly serum prostate-specific antigen measurements, and mice with recurrent tumors after castration were randomized to treatment groups. Serum prostate-specific antigen concentrations showed significant correlation with tumor volume. Castration-resistant tumors retained concentrations of intratumoral androgen (androstenedione, testosterone, and 5 alpha-dihydrotestosterone) at Levels similar to tumors growing in intact hosts. Accordingly, castration induced up-regulation of enzymes involved in androgen synthesis (CYP17A1, AKR1C3, and HSD17B6), as well as expression of full-length androgen receptor (AR) and AR splice variants (AR-V1 and AR-V7). Furthermore, AR target gene expression was maintained in castration-resistant xenografts. The AR antagonists enzalutamide (MDV3100) and ARN-509 suppressed PSA production of castration-resistant tumors, confirming the androgen dependency of these tumors. Taken together, the findings demonstrate that our VCaP xenograft model exhibits the key characteristics of clinical CRPC and thus provides a valuable tool for identifying druggable targets and for testing therapeutic strategies targeting AR signaling in CRPC.
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| 24. |
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| 25. |
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| 26. |
- Mandt, K. E., et al.
(författare)
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RPC observation of the development and evolution of plasma interaction boundaries at 67P/Churyumov-Gerasimenko
- 2016
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 462, s. S9-S22
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Tidskriftsartikel (refereegranskat)abstract
- One of the primary objectives of the Rosetta Plasma Consortium, a suite of five plasma instruments on-board the Rosetta spacecraft, is to observe the formation and evolution of plasma interaction regions at the comet 67P/Churyumov-Gerasimenko (67P/CG). Observations made between 2015 April and 2016 February show that solar wind-cometary plasma interaction boundaries and regions formed around 2015 mid-April and lasted through early 2016 January. At least two regions were observed, separated by an ion-neutral collisionopause boundary. The inner region was located on the nucleus side of the boundary and was characterized by low-energy water-group ions, reduced magnetic field pileup and enhanced electron densities. The outer region was located outside of the boundary and was characterized by reduced electron densities, water-group ions that are accelerated to energies above 100 eV and enhanced magnetic field pileup compared to the inner region. The boundary discussed here is outside of the diamagnetic cavity and shows characteristics similar to observations made on-board the Giotto spacecraft in the ion pileup region at 1P/Halley. We find that the boundary is likely to be related to ion-neutral collisions and that its location is influenced by variability in the neutral density and the solar wind dynamic pressure.
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| 27. |
- Nilsson, Hans, et al.
(författare)
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Evolution of the ion environment of comet 67P/Churyumov-Gerasimenko
- 2015
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 583
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Tidskriftsartikel (refereegranskat)abstract
- Context. The Rosetta spacecraft is escorting comet 67P/Churyumov-Gerasimenko from a heliocentric distance of >3.6 AU, where the comet activity was low, until perihelion at 1.24 AU. Initially, the solar wind permeates the thin comet atmosphere formed from sublimation. Aims. Using the Rosetta Plasma Consortium Ion Composition Analyzer (RPC-ICA), we study the gradual evolution of the comet ion environment, from the first detectable traces of water ions to the stage where cometary water ions accelerated to about 1 keV energy are abundant. We compare ion fluxes of solar wind and cometary origin. Methods. RPC-ICA is an ion mass spectrometer measuring ions of solar wind and cometary origins in the 10 eV-40 keV energy range. Results. We show how the flux of accelerated water ions with energies above 120 eV increases between 3.6 and 2.0 AU. The 24 h average increases by 4 orders of magnitude, mainly because high-flux periods become more common. The water ion energy spectra also become broader with time. This may indicate a larger and more uniform source region. At 2.0 AU the accelerated water ion flux is frequently of the same order as the solar wind proton flux. Water ions of 120 eV-few keV energy may thus constitute a significant part of the ions sputtering the nucleus surface. The ion density and mass in the comet vicinity is dominated by ions of cometary origin. The solar wind is deflected and the energy spectra broadened compared to an undisturbed solar wind. Conclusions. The flux of accelerated water ions moving from the upstream direction back toward the nucleus is a strongly nonlinear function of the heliocentric distance.
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| 28. |
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| 29. |
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| 30. |
- Orsini, S., et al.
(författare)
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Inner southern magnetosphere observation of Mercury via SERENA ion sensors in BepiColombo mission
- 2022
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mercury’s southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury’s magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.
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| 31. |
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| 32. |
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| 33. |
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| 34. |
- Soderstrom, HK, et al.
(författare)
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Cohort profile: a nationwide population-based retrospective assessment of oesophageal cancer in the Finnish National Esophago-Gastric Cancer Cohort (FINEGO)
- 2020
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Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:10, s. e039575-
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Tidskriftsartikel (refereegranskat)abstract
- The Finnish National Esophago-Gastric Cancer Cohort (FINEGO) was established to combine the available registry data with detailed patient information to form a comprehensive, retrospective, population-based research platform of surgically treated oesophageal and gastric cancer in Finland. This cohort profile describes the 2045 surgically treated patients with oesophageal cancer included in the FINEGO cohort.ParticipantsRegistry data were collected from the National Cancer, Patient, Education and Death Registries from 1 January 1987 to 31 December 2016. All patients over 18 years of age, who had either curative surgery, palliative surgery or salvage surgery for primary cancer in the oesophagus are included in this study.Findings to date2045 patients had surgery for oesophageal cancer in the selected time period. 67.2% were man, and the majority had only minor comorbidities. The proportions of adenocarcinomas and squamous cell carcinomas were 43.1% and 44.4%, respectively, and 12.5% had other or missing histology. Only about 23% of patients received neoadjuvant therapy. Oesophagectomy was the treatment of choice and most patients were treated at low-volume centres, but median annual hospital volume increased over time. Median overall survival was 23 months, 5-year survival for all patients in the cohort was 32.9% and cancer-specific survival was 36.5%.Future plansEven though Finland only has a population of 5.5 million, surgery for oesophageal carcinoma has not been centralised and therefore previously reported results have mostly been small, single-centre cohorts. Because of FINEGO, we now have a population-based, unselected cohort of surgically treated patients, enabling research on national trends over time regarding oesophageal cancer, including patient characteristics, tumour histology, stage and neoadjuvant treatment, surgical techniques, hospital volumes and patient mortality. Data collection is ongoing, and the cohort will be expanded to include more detailed data from patient records and national biobanks.
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| 35. |
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| 36. |
- Aho, Sonja, et al.
(författare)
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Impact of Primary Tumor Location on Demographics, Resectability, Outcomes, and Quality of Life in Finnish Metastatic Colorectal Cancer Patients (Subgroup Analysis of the RAXO Study)
- 2024
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The location of the primary tumor in the right colon, left colon, or rectum affects the efficacy of biological drugs used in the treatment of metastatic colorectal cancer, but how? We examined how the primary tumor location affects disease characteristics, treatability, quality of life, and outcome in a real-life study population of 1080 Finnish patients in the RAXO study. The primary tumor location correlates with the location of metastases, the frequency of gene mutations, how often metastases can be operated upon, long-term survival after curative surgery or palliative chemotherapy, and the quality of life during the disease trajectory. The primary tumor location is a helpful surrogate for clinicians working with metastatic colorectal cancer patients in estimating the clinical course of the disease. This study cannot identify the reasons for the associations, i.e., whether it is the primary location per se, the different mutations, or other reasons.Abstract The primary tumor location (PTL) is associated with the phenotype, metastatic sites, mutations, and outcomes of metastatic colorectal cancer (mCRC) patients, but this has mostly been studied according to sidedness (right vs. left sided). We studied right colon vs. left colon vs. rectal PTL in a real-life study population (n = 1080). Health-related quality of life (HRQoL) was assessed multi-cross-sectionally with QLQ-C30, QLQ-CR29, EQ-5D, and 15D. A chi-square, Kaplan-Meier, and Cox regression were used to compare the groups. The PTL was in the right colon in 310 patients (29%), the left colon in 396 patients (37%), and the rectum in 375 patients (35%). The PTL was associated with distinct differences in metastatic sites during the disease trajectory. The resectability, conversion, and resection rates were lowest in the right colon, followed by the rectum, and were highest in the left colon. Overall survival was shortest for right colon compared with left colon or rectal PTL (median 21 vs. 35 vs. 36 months), with the same trends after metastasectomy or systemic therapy only. PTL also remained statistically significant in a multivariable model. The distribution of symptoms varied according to PTL, especially between the right colon (with general symptoms of metastases) and rectal PTL (with sexual- and bowel-related symptoms). mCRC, according to PTL, behaves differently regarding metastatic sites, resectability of the metastases, outcomes of treatment, and HRQoL.
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| 37. |
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| 38. |
- Alho, Markku, et al.
(författare)
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Hybrid modeling of cometary plasma environments : II. Remote-sensing of a cometary bow shock
- 2019
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 630
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Tidskriftsartikel (refereegranskat)abstract
- Context. The ESA Rosetta probe has not seen direct evidence of a fully formed bow shock at comet 67P/Churyumov–Gerasimenko (67P). Ion spectrometer measurements of cometary pickup ions measured in the vicinity of the nucleus of 67P are available and may contain signatures of the large-scale plasma environment.Aims. The aim is to investigate the possibility of using pickup ion signatures to infer the existence or nonexistence of a bow shock-like structure and possibly other large-scale plasma environment features.Methods. A numerical plasma model in the hybrid plasma description was used to model the plasma environment of a comet. Simulated pickup ion spectra were generated for different interplanetary magnetic field conditions. The results were interpreted through test particle tracing in the hybrid simulation solutions.Results. Features of the observed pickup ion energy spectrum were reproduced, and the model was used to interpret the observation to be consistent with a shock-like structure. We identify (1) a spectral break related to the bow shock, (2) a mechanism for generating the spectral break, and (3) a dependency of the energy of the spectral break on the interplanetary magnetic field magnitude and bow shock standoff distance.
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| 39. |
- Andersson, Charlotte, et al.
(författare)
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Enhanced Ribosome and tRNA Contents in Escherichia coli Expressing a Truncated Vitreoscilla Hemoglobin Mutant Analyzed by Flow Field-Flow Fractionation
- 2003
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Ingår i: Biotechnology Letters. - 1573-6776. ; 25:18, s. 1499-1504
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Tidskriftsartikel (refereegranskat)abstract
- The ribosome and tRNA levels of Escherichia coli cells, transformed with a native or mutated Vitreoscilla hemoglobin genes (vhb), were investigated using asymmetrical flow field-flow fractionation (AFFFF). Mutagenesis of vhb by error-prone PCR was carried out to alter the growth behavior of microaerobically cultivated native VHb-expressing E. coli. A VHb mutant, pVMT1, was identified, which was able to reach a remarkably high final A600 of 15, the value of which being 160% higher than that of a VHb control carrying pVHb8 (A600 5.8). AFFFF revealed that cells expressing mutant vhbs showed up to a doubling in the number of active 70S ribosomes cell-1, an almost 3-fold increase in the number of tRNAs cell-1, and up to a 26% increase in the mass fraction of active 70S ribosomes.
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| 40. |
- Andersson, Charlotte I J, et al.
(författare)
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Error-prone PCR of Vitreoscilla hemoglobin (VHb) to support the growth of microaerobic Escherichia coli
- 2000
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Ingår i: Biotechnology and Bioengineering. - 0006-3592. ; 70:4, s. 55-446
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Tidskriftsartikel (refereegranskat)abstract
- Expression of the gene encoding bacterial hemoglobin (VHb) from Vitreoscilla has been previously used to improve recombinant cell growth and enhance product formation under microaerobic conditions. It is very likely that the properties of VHb are not optimized for foreign hosts; therefore, we used error-prone PCR to generate a number of randomly mutated vhb genes to be expressed and studied in Escherichia coli. In addition, the mutated VHb proteins also contained an extension of eight residues (MTMITPSF) at the amino terminus. VHb mutants were screened for improved growth properties under microaerobic conditions and 15 clones expressing mutated hemoglobin protein were selected for further characterization and cultivated in a microaerobic bioreactor to analyze the physiological effects of novel VHb proteins on cell growth. The expression of four VHb mutants, carried by pVM20, pVM50, pVM104, and pVM134, were able to enhance microaerobic growth of E. coli by approximately 22%, 155%, 50%, and 90%, respectively, with a concomitant decrease of acetate excretion into the culture medium. The vhb gene in pVM20 contains two mutations substituting residues Glu19(A17) and Glu137(H23) to Gly. pVM50 expresses a VHb protein carrying two mutations: His36(C1) to Arg36 and Gln66(E20) to Arg66. pVM104 and pVM134 express VHb proteins carrying the mutations Ala56(E10) to Gly and Ile24(B5) to Thr, respectively. Our experiments also indicate that the positive effects elicited by mutant VHb-expression from pVM20 and pVM50 are linked to the peptide tail. Removal of the N-terminal sequence reduced cell growth approximately 23% and 53%, respectively, relative to wild-type controls. These results clearly demonstrate that it is possible to obtain mutated VHb proteins with improved characteristics for improving microaerobic growth of E. coli by using combined mutation techniques, addition of a peptide tail, and random error-prone PCR.
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| 41. |
- Blomberg, Lars G., et al.
(författare)
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MEFISTO - An electric field instrument for BepiColombo/MMO
- 2006
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Ingår i: Advances in Space Research. - : Elsevier BV. - 0273-1177 .- 1879-1948. ; 38:4, s. 672-679
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Tidskriftsartikel (refereegranskat)abstract
- MEFISTO, together with the companion instrument WPT, are planning the first-ever in situ measurements of the electric field in the magnetosphere of planet Mercury. The instruments have been selected by JAXA for inclusion in the BepiColombo/MMO payload, as part of the Plasma Wave Investigation coordinated by Kyoto University. The magnetosphere of Mercury was discovered by Mariner 10 in 1974 and will be studied further by Messenger starting in 2011. However, neither spacecraft did or will measure the electric field. Electric fields are crucial in the dynamics of a magnetosphere and for the energy and plasma transport between different regions within the magnetosphere as well as between the magnetosphere and the surrounding regions. The MEFISTO instrument will be capable of measuring electric fields from DC to 3 MHz, and will thus also allow diagnostics of waves at all frequencies of relevance to the Hermean magnetosphere. MEFISTO is a double-probe electric field instrument. The double-probe technique has strong heritage and is well proven on missions such as Viking, Polar, and Cluster. For BepiColombo, a newly developed deployment mechanism is planned which reduces the mass by a factor of about 5 compared to conventional mechanisms for 15 in long booms. We describe the basic characteristics of the instrument and briefly discuss the new developments made to tailor the instrument to flight in Mercury orbit.
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| 42. |
- Bösl, Korbinian, et al.
(författare)
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Common Nodes of Virus-Host Interaction Revealed Through an Integrated Network Analysis
- 2019
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.
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| 43. |
- Carlsson, Ella, et al.
(författare)
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Mass composition of the escaping plasma at Mars
- 2006
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Ingår i: Icarus. - : Elsevier BV. - 0019-1035 .- 1090-2643. ; 182:2, s. 320-328
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Tidskriftsartikel (refereegranskat)abstract
- Data from the Ion Mass Analyzer (IMA) sensor of the ASPERA-3 instrument suite on Mars Express have been analyzed to determine the mass composition of the escaping ion species at Mars. We have examined 77 different ion-beam events and we present the results in terms of flux ratios between the following ion species: CO2+/O+ and O-2(+)/O+. The following ratios averaged over all events and energies were identified: CO2+/O+ = 0.2 and O-2(+)/O+ = 0.9. The values measured are significantly higher, by a factor of 10 for O-2(+)/O+, than a contemporary modeled ratio for the maximum fluxes which the martian ionosphere can supply. The most abundant ion species was found to be O+, followed by O-2(+) and CO2+. We estimate the loss of CO2+ to be 4.0 x 10(24) s(-1) (0.29 kg s(-1)) by using the previous measurements of Phobos-2 in our calculations. The dependence of the ion ratios in relation to their energy ranges we studied, 0.3-3.0 keV, indicated that no clear correlation was found.
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| 44. |
- Facsko, G., et al.
(författare)
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One year in the Earth's magnetosphere : A global MHD simulation and spacecraft measurements
- 2016
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Ingår i: Space Weather. - 1542-7390. ; 14:5, s. 351-367
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Tidskriftsartikel (refereegranskat)abstract
- The response of the Earth's magnetosphere to changing solar wind conditions is studied with a 3-D Magnetohydrodynamic (MHD) model. One full year (155 Cluster orbits) of the Earth's magnetosphere is simulated using Grand Unified Magnetosphere Ionosphere Coupling simulation (GUMICS-4) magnetohydrodynamic code. Real solar wind measurements are given to the code as input to create the longest lasting global magnetohydrodynamics simulation to date. The applicability of the results of the simulation depends critically on the input parameters used in the model. Therefore, the validity and the variance of the OMNIWeb data are first investigated thoroughly using Cluster measurement close to the bow shock. The OMNIWeb and the Cluster data were found to correlate very well before the bow shock. The solar wind magnetic field and plasma parameters are not changed significantly from the L-1 Lagrange point to the foreshock; therefore, the OMNIWeb data are appropriate input to the GUMICS-4. The Cluster SC3 footprints are determined by magnetic field mapping from the simulation results and the Tsyganenko (T96) model in order to compare two methods. The determined footprints are in rather good agreement with the T96. However, it was found that the footprints agree better in the Northern Hemisphere than the Southern one during quiet conditions. If the B-y is not zero, the agreement of the GUMICS-4 and T96 footprint is worse in longitude in the Southern Hemisphere. Overall, the study implies that a 3-D MHD model can increase our insight of the response of the magnetosphere to solar wind conditions.
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| 45. |
- Fortner, Renée T, et al.
(författare)
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Early pregnancy sex steroids and maternal breast cancer : a nested case-control study
- 2014
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 74:23, s. 6958-6967
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Tidskriftsartikel (refereegranskat)abstract
- Pregnancy, parity, and circulating steroid hormone levels are associated with risk of breast cancer, but little is known about hormone concentrations during pregnancy and subsequent breast cancer risk. We evaluated early pregnancy (<140 days gestation) serum estradiol, estrone, progesterone, and testosterone and breast cancer risk in a nested case-control study in the Finnish Maternity Cohort. The cohort includes 98% of pregnancies registered in Finland since 1983. Individuals with samples collected in the first pregnancy leading to a live birth were eligible. Breast cancer cases (n = 1,199) were identified through linkage with the Finnish Cancer Registry; 2,281 matched controls were selected using incidence density sampling. ORs were calculated using conditional logistic regression. Hormone concentrations were not associated with breast cancer overall. Estradiol was positively associated with risk of breast cancer diagnosed age <40 [4th vs. 1st quartile OR 1.60 (1.07-2.39); Ptrend = 0.01], and inversely associated with breast cancer diagnosed at age ≥40 [4th vs. 1st quartile OR 0.71 (0.51-1.00); Ptrend = 0.02]. Elevated concentrations of the steroid hormones were associated with increased risk of estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors in women age <40 at diagnosis. We observed no association between steroid hormones and ER(+)/PR(+) disease. These data suggest a positive association between high concentrations of early pregnancy steroid hormones and risk of ER(-)/PR(-) breast cancer in women diagnosed age <40, and an inverse association for overall breast cancer diagnosed age ≥40. Further research on pregnancy hormones and risk of steroid receptor-negative cancers is needed to further characterize this association.
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| 46. |
- Frey, Alexander D., et al.
(författare)
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Globin-expression postpones onset of stationary phase specific gene expression in Escherichia coli
- 2007
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Ingår i: Journal of Biotechnology. - : Elsevier BV. - 1873-4863 .- 0168-1656. ; 129:3, s. 461-471
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Tidskriftsartikel (refereegranskat)abstract
- We have analyzed gene expression of Escherichia coli MG1655 expressing native and engineered bacterial globin proteins, in order to identify the molecular mechanisms leading to the improved phenotypical traits relative to control cells under oxygen-limited conditions. Regulated expression of hemoglobin and flavohemoglobin proteins postponed the onset of rpoS expression relative to plasmid bearing control cells. This change in expression pattern coincided with the expression pattern of stationary-phase specific genes including sigma(S)-dependent and sigma(S)-independent genes. Furthermore, several genes known to affect rpoS transcription, rpoS mRNA stability and sigma(S) turnover were regulated in such a manner as to ultimately lower the cellular level of sigma(S) in all globin-expressing strains. In a strain harboring an rpoS-lacZ fusion, lacZ expression correlated with acetate accumulation, a metabolite that is known to activate rpoS transcription, but not with growth. Therefore, we hypothesize that reduced excretion of acetate in globin expressing cells prevents induction of stationary phase specific genes. Additionally, several genes responding to carbon starvation (e.g. csrAB, cstA, sspA) were expressed at lower levels in globin-expressing cells. These findings are in good agreement with previous reports showing a more efficient energy household, i.e. also reduced glucose consumption, in hemoglobin- and flavohemoglobin-expressing cells relative to controls. (c) 2007 Elsevier B.V. All rights reserved.
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| 47. |
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| 48. |
- Iurchenkova, Anna A., 1997-, et al.
(författare)
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Relationships between polypyrrole synthesis conditions, its morphology and electronic structure with supercapacitor properties measured in electrolytes with different ions and pH values
- 2021
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Ingår i: Electrochimica Acta. - : Elsevier. - 0013-4686 .- 1873-3859. ; 391
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Tidskriftsartikel (refereegranskat)abstract
- Despite a large number of articles about synthesis methods, structure, morphology and electrochemical properties of polypyrrole, none of these works reports the relationships between polypyrrole synthetic conditions, the electronic states of atoms in the polymer chains and its electrochemical properties in various electrolytes. Our work is dedicated to filling part of this gap. This work is focused on the effect of the synthetic medium used for polypyrrole synthesis on their atomic and electronic structure and morphology as well as investigation of the influence of these on the electrochemical characteristics of polypyrrole in aqueous electrolytes with different ions and pH values within a supercapacitor setup. It is shown that synthetic medium does not affect polymer particle shapes but changes particle sizes. Using oxygen functional groups containing synthetic medium based on water and ethanol leads to a decrease in C:N ratio, increase in C:O ratio, increase in the concentration of positively charged nitrogen-species and formation of linear-structured polymer chains. Contrary, acetonitrile-based synthetic medium without oxygen-containing functional groups leads to an increase in C:N ratio and concentration of neutrally charged nitrogen species, decrease in C:O ratio and formation of branched-structured polymer chains. Electrochemical properties of polypyrrole depend on the nature of the electrolyte, then nitrogen species and oxygen-containing functional groups in polypyrrole structure, and the size of polypyrrole particles. The favorable electrolyte for using polypyrrole in supercapacitors is neutral. The specific capacitance of polypyrrole produced in acetonitrile is shown to reach the value of ~ 385 F g −1 which is stable for more than 10,000 cycles in 1M KCl aqueous solution.
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| 49. |
- Joensuu, Heikki, et al.
(författare)
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Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial.
- 2016
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 34:3, s. 244-250
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Tidskriftsartikel (refereegranskat)abstract
- Three years of adjuvant imatinib therapy are recommended for patients with GI stromal tumor (GIST) with high-risk features, according to survival findings in the Scandinavian Sarcoma Group XVIII/AIO (Arbeitsgemeinschaft Internistische Onkologie) trial. To investigate whether the survival benefits have persisted, we performed the second planned analysis of the trial.
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| 50. |
- Joensuu, Heikki, et al.
(författare)
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Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib : An exploratory analysis of a randomized clinical trial
- 2017
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Ingår i: JAMA Oncology. - : American Medical Association (AMA). - 2374-2437. ; 3:5, s. 602-609
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: Little is known about whether the duration of adjuvant imatinib influences the prognostic significance of KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PDGFRA) mutations. OBJECTIVE: To investigate the effect of KIT and PDGFRA mutations on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) treated with surgery and adjuvant imatinib. DESIGN, SETTING, AND PARTICIPANTS: This exploratory study is based on the Scandinavian Sarcoma Group VIII/Arbeitsgemeinschaft Internistische Onkologie (SSGXVIII/AIO) multicenter clinical trial. Between February 4, 2004, and September 29, 2008, 400 patients who had undergone surgery for GISTs with a high risk of recurrence were randomized to receive adjuvant imatinib for 1 or 3 years. Of the 397 patients who provided consent, 341 (85.9%) had centrally confirmed, localized GISTs with mutation analysis for KIT and PDGFRA performed centrally using conventional sequencing. During a median follow-up of 88 months (completed December 31, 2013), 142 patients had GIST recurrence. Data of the evaluable population were analyzed February 4, 2004, through December 31, 2013. MAIN OUTCOMES AND MEASURES: The main outcome was RFS. Mutations were grouped by the gene and exon. KIT exon 11 mutations were further grouped as deletion or insertion-deletion mutations, substitution mutations, insertion or duplication mutations, and mutations that involved codons 557 and/or 558. RESULTS: Of the 341 patients (175 men and 166 women; median age at study entry, 62 years) in the 1-year group and 60 years in the 3-year group), 274 (80.4%) had GISTs with a KIT mutation, 43 (12.6%) had GISTs that harbored a PDGFRA mutation, and 24 (7.0%) had GISTs that were wild type for these genes. PDGFRA mutations and KIT exon 11 insertion or duplication mutations were associated with favorable RFS, whereas KIT exon 9 mutations were associated with unfavorable outcome. Patients with KIT exon 11 deletion or insertion-deletion mutation had better RFS when allocated to the 3-year group compared with the 1-year group (5-year RFS, 71.0% vs 41.3%; P < .001), whereas no significant benefit from the 3-year treatment was found in the other mutational subgroups examined. KIT exon 11 deletion mutations, deletions that involved codons 557 and/or 558, and deletions that led to pTrp557-Lys558del were associated with poor RFS in the 1-year group but not in the 3-year group. Similarly, in the subset with KIT exon 11 deletion mutations, higher-than-the-median mitotic counts were associated with unfavorable RFS in the 1-year group but not in the 3-year group. CONCLUSIONS AND RELEVANCE: Patients with KIT exon 11 deletion mutations benefit most from the longer duration of adjuvant imatinib. The duration of adjuvant imatinib modifies the risk of GIST recurrence associated with some KIT mutations, including deletions that affect exon 11 codons 557 and/or 558.
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