| 1. |
- Muus, Christoph, et al.
(author)
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Single-cell meta-analysis of SARS-CoV-2 entry genes across tissues and demographics
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:3, s. 546-559
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Journal article (peer-reviewed)abstract
- Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2, TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2, TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2, TMPRSS2 and CTSL. Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2(+)TMPRSS2(+) cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial-macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.
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| 2. |
- Sikkema, Lisa, et al.
(author)
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An integrated cell atlas of the lung in health and disease
- 2023
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In: Nature Medicine. - : Springer Nature. - 1078-8956 .- 1546-170X. ; 29:6, s. 1563-1577
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Journal article (peer-reviewed)abstract
- Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1 + profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.
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| 3. |
- Knuuttila, M., et al.
(author)
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Intratumoral androgen levels are linked to TMPRSS2-ERG fusion in prostate cancer
- 2018
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In: Endocrine-Related Cancer. - : Bioscientifica. - 1351-0088 .- 1479-6821. ; 25:9, s. 807-819
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Journal article (peer-reviewed)abstract
- Intratumoral androgen biosynthesis is one of the mechanisms involved in the progression of prostate cancer, and an important target for novel prostate cancer therapies. Using gas chromatography-tandem mass spectrometry and genome-wide RNA sequencing, we have analyzed androgen concentrations and androgen-regulated gene expression in cancerous and morphologically benign prostate tissue specimens and serum samples obtained from 48 primary prostate cancer patients. Intratumoral dihydrotestosterone (DHT) concentrations were significantly higher in the cancerous tissues compared to benign prostate (P < 0.001). The tissue/serum ratios of androgens were highly variable between the patients, indicating individual patterns of androgen metabolism and/or uptake of androgens within the prostate tissue. An unsupervised hierarchical clustering analysis of intratissue androgen concentrations indicated that transmembrane protease, serine 2/ETS-related gene (TMPRSS2-ERG)-positive patients have different androgen profiles compared to TMPRSS2-ERG- negative patients. TMPRSS2-ERG gene fusion status was also associated with an enhanced androgen-regulated gene expression, along with altered intratumoral androgen metabolism, demonstrated by reduced testosterone concentrations and increased DHT/testosterone ratios in TMPRSS2-ERG-positive tumors. TMPRSS2-ERG-positive and - negative prostate cancer specimens have distinct intratumoral androgen profiles, possibly due to activation of testosterone-independent DHT biosynthesis via the alternative pathway in TMPRSS2-ERG-positive tumors. Thus, patients with TMPRSS2-ERG-positive prostate cancer may benefit from novel inhibitors targeting the alternative DHT biosynthesis.
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| 4. |
- Adam, M., et al.
(author)
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Hydroxysteroid (17 beta) dehydrogenase 13 deficiency triggers hepatic steatosis and inflammation in mice
- 2018
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In: Faseb Journal. - 0892-6638. ; 32:6, s. 3434-3447
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Journal article (peer-reviewed)abstract
- Hydroxysteroid (17(3) dehydrogenases (HSD17Bs) form an enzyme family characterized by their ability to catalyze reactions in steroid and lipid metabolism. In the present study, we characterized the phenotype of HSD17B13-knockout (HSD17B13KO) mice deficient in Hsd1 7b13. In these studies, hepatic steatosis was detected in HSD17B13KO male mice, indicated by histologic analysis and by the increased triglyceride concentration in the liver, whereas reproductive performance and serum steroid concentrations were normal in HSD17B13KO mice. In line with these changes, the expression of key proteins in fatty acid synthesis, such as FAS, acetyl-CoA carboxylase 1, and SCD1, was increased in the HSD17B13KO liver. Furthermore, the knockout liver showed an increase in 2 acylcamitines, suggesting impaired mitochondrial beta-oxidation in the presence of unaltered malonyl CoA and AMPK expression. The glucose tolerance did not differ between wild-type and HSD17B13KO mice in the presence of lower levels of glucose 6-phosphatase in HSD17B13KO liver compared with wild-type liver. Furthermore, microgranulomas and increased portal inflammation together with up-regulation of immune response genes were observed in HSD17B13KO mice. Our data indicate that disruption of Hsdl7b13 impairs hepatic-lipid metabolism in mice, resulting in liver steatosis and inflammation, but the enzyme does not play a major role in the regulation of reproductive functions.
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| 7. |
- Elo, S L, et al.
(author)
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Validity and utilization of epidemiological data: a study of ischaemic heart disease and coronary risk factors in a local population.
- 2009
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In: Public health. - : Elsevier BV. - 1476-5616 .- 0033-3506. ; 123:1, s. 52-7
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To calculate the burden of ischaemic heart disease (IHD) and coronary risk factors in a defined population using data from all public providers of health care, i.e. inpatient and outpatient care in all settings. STUDY DESIGN: Cross-sectional, 1-year retrospective study. METHODS: The main outcome measures were the number of individuals by diagnosis and by care setting, and gender- and age-specific event rates by diagnosis. RESULTS: Less than half of the individuals who visited any care provider for IHD or coronary risk factors were identified in the hospital discharge register. Calculation of the actual burden of disease in the population showed that when hospital discharge data were combined with outpatient data, there were no or slight differences in the age-specific rates of acute myocardial infarction (AMI), while the rates of angina were between two-fold and four-fold higher, and unspecified IHD was between three-fold and ten-fold higher in individuals aged > or =50 years compared with using hospital discharge data alone. The rates of hypertension, diabetes and lipid disorders increased in all age groups when outpatient data were added to hospital discharge data. The differences in the rates were more pronounced in women aged 50-79 years. However, the age-specific rates were higher in men except for hypertension which was higher in older women. CONCLUSION: Data for epidemiological analyses of diseases are often based on hospital discharge data. This study found that hospital discharge data provide limited information on patients treated for IHD and coronary risk factors, except for AMI. These findings suggest that hospital discharge data should be combined with outpatient care data to provide a more comprehensive estimate of the burden of IHD and its risk factors.
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| 8. |
- Elo, T., et al.
(author)
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Ectodysplasin target gene Fgf20 regulates mammary bud growth and ductal invasion and branching during puberty
- 2017
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
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Journal article (peer-reviewed)abstract
- Mammary gland development begins with the appearance of epithelial placodes that invaginate, sprout, and branch to form small arborized trees by birth. The second phase of ductal growth and branching is driven by the highly invasive structures called terminal end buds (TEBs) that form at ductal tips at the onset of puberty. Ectodysplasin (Eda), a tumor necrosis factor-like ligand, is essential for the development of skin appendages including the breast. In mice, Eda regulates mammary placode formation and branching morphogenesis, but the underlying molecular mechanisms are poorly understood. Fibroblast growth factor (Fgf) receptors have a recognized role in mammary ductal development and stem cell maintenance, but the ligands involved are ill-defined. Here we report that Fgf20 is expressed in embryonic mammary glands and is regulated by the Eda pathway. Fgf20 deficiency does not impede mammary gland induction, but compromises mammary bud growth, as well as TEB formation, ductal outgrowth and branching during puberty. We further show that loss of Fgf20 delays formation of Eda-induced supernumerary mammary buds and normalizes the embryonic and postnatal hyperbranching phenotype of Eda overexpressing mice. These findings identify a hitherto unknown function for Fgf20 in mammary budding and branching morphogenesis.
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| 9. |
- Hendi, Arun S., et al.
(author)
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The implications of changing education distributions for life expectancy gradients
- 2021
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In: Social Science and Medicine. - : Elsevier BV. - 0277-9536 .- 1873-5347. ; 272
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Journal article (peer-reviewed)abstract
- Recent research has proposed that shifting education distributions across cohorts are influencing estimates of educational gradients in mortality. We use data from the United States and Finland covering four decades to explore this assertion. We base our analysis around our new finding: a negative logarithmic relationship between relative education and relative mortality. This relationship holds across multiple age groups, both sexes, two very different countries, and time periods spanning four decades. The inequality parameters from this model indicate increasing relative mortality differentials over time. We use these findings to develop a method that allows us to compute life expectancy for any given segment of the education distribution (e.g., education quintiles). We apply this method to Finnish and American data to compute life expectancy gradients that are adjusted for changes in the education distribution. In Finland, these distribution-adjusted education differentials in life expectancy between the top and bottom education quintiles have increased by two years for men, and remained stable for women between 1971 and 2010. Similar distribution-adjusted estimates for the U.S. suggest that educational disparities in life expectancy increased by 3.3 years for non-Hispanic white men and 3.0 years for non-Hispanic white women between the 1980s and 2000s. For men and women, respectively, these differentials between the top and bottom education quintiles are smaller than the differentials between the top and bottom education categories by 18% and 39% in the U.S. and by 39% and 100% in Finland. Had the relative inequality parameters of mortality governing the Finnish and U.S. populations remained constant at their earliest period values, the difference in life expectancy between the top and bottom education quintiles would – because of overall mortality reductions – have declined moderately. The findings suggest that educational expansion may bias estimates of trends in educational differences in life expectancy upwards.
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