| 1. |
- Staaf, Johan, et al.
(författare)
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Relation between smoking history and gene expression profiles in lung adenocarcinomas
- 2012
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers' lung carcinomas remain to a large extent unclear. Methods: Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets. Results: Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking. Conclusions: Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
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| 2. |
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| 3. |
- Jönsson, Jenny-Maria, et al.
(författare)
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Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome.
- 2014
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Ingår i: Familial Cancer. - : Springer Science and Business Media LLC. - 1389-9600 .- 1573-7292. ; 13:4, s. 537-545
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic ovarian cancers. Lynch syndrome-associated and sporadic ovarian cancers differed by 349 significantly deregulated genes, including PTPRH, BIRC3, SHH and TNFRSF6B. The genes involved were predominantly linked to cell growth, proliferation, and cell-to-cell signaling and interaction. When stratified for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic ovarian cancers point to alternative preferred tumorigenic routes and suggest that genetic discriminators may be relevant for molecular diagnostics and targeted therapeutics.
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| 4. |
- Karlsson, Anna K, et al.
(författare)
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Genome-wide DNA methylation analysis of lung carcinoma reveals one neuroendocrine and four adenocarcinoma epitypes associated with patient outcome.
- 2014
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 20:23, s. 6127-6140
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear. Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), one adenosquamous cancer, five large cell carcinomas, nine large cell neuroendocrine carcinomas (LCNEC), and three small cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathological factors, whole-exome sequencing data, and gene expression profiles. Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathological features such as smoking history, and patient outcome. Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathological characteristics, including patient outcome. This study highlights the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy.
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| 5. |
- Karlsson, Anna K, et al.
(författare)
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Mutational and gene fusion analyses of primary large cell and large cell neuroendocrine lung cancer.
- 2015
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Ingår i: Oncotarget. - 1949-2553. ; 6:26, s. 22028-22037
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Tidskriftsartikel (refereegranskat)abstract
- Large cell carcinoma with or without neuroendocrine features (LCNEC and LC, respectively) constitutes 3-9% of non-small cell lung cancer but is poorly characterized at the molecular level. Herein we analyzed 41 LC and 32 LCNEC (including 15 previously reported cases) tumors using massive parallel sequencing for mutations in 26 cancer-related genes and gene fusions in ALK, RET, and ROS1. LC patients were additionally subdivided into three immunohistochemistry groups based on positive expression of TTF-1/Napsin A (adenocarcinoma-like, n = 24; 59%), CK5/P40 (squamous-like, n = 5; 12%), or no marker expression (marker-negative, n = 12; 29%). Most common alterations were TP53 (83%), KRAS (22%), MET (12%) mutations in LCs, and TP53 (88%), STK11 (16%), and PTEN (13%) mutations in LCNECs. In general, LCs showed more oncogene mutations compared to LCNECs. Immunomarker stratification of LC revealed oncogene mutations in 63% of adenocarcinoma-like cases, but only in 17% of marker-negative cases. Moreover, marker-negative LCs were associated with inferior overall survival compared with adenocarcinoma-like tumors (p = 0.007). No ALK, RET or ROS1 fusions were detected in LCs or LCNECs. Together, our molecular analyses support that LC and LCNEC tumors follow different tumorigenic paths and that LC may be stratified into molecular subgroups with potential implications for diagnosis, prognostics, and therapy decisions.
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| 6. |
- Smirnova, Anna, et al.
(författare)
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Increased apoptosis, reduced Wnt/beta-catenin signaling, and altered tail development in zebrafish embryos exposed to a human-relevant chemical mixture
- 2021
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Ingår i: Chemosphere. - : Elsevier. - 0045-6535 .- 1879-1298. ; 264:1
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Tidskriftsartikel (refereegranskat)abstract
- A wide variety of anthropogenic chemicals is detected in humans and wildlife and the health effects of various chemical exposures are not well understood. Early life stages are generally the most susceptible to chemical disruption and developmental exposure can cause disease in adulthood, but the mechanistic understanding of such effects is poor. Within the EU project EDC-MixRisk, a chemical mixture (Mixture G) was identified in the Swedish pregnancy cohort SELMA by the inverse association between levels in women at around gestational week ten with birth weight of their children. This mixture was composed of mono-ethyl phthalate, mono-butyl phthalate, mono-benzyl phthalate, mono-ethylhexyl phthalate, mono-isononyl phthalate, triclosan, perfluorohexane sulfonate, perfluorooctanoic acid, and perfluorooctane sulfonate. In a series of experimental studies, we characterized effects of Mixture G on early development in zebrafish models. Here, we studied apoptosis and Wnt/beta-catenin signaling which are two evolutionarily conserved signaling pathways of crucial importance during development. We determined effects on apoptosis by measuring TUNEL staining, caspase-3 activity, and acridine orange staining in wildtype zebrafish embryos, while Wnt/beta-catenin signaling was assayed using a transgenic line expressing an EGFP reporter at beta-catenin-regulated promoters. We found that Mixture G increased apoptosis, suppressed Wnt/beta-catenin signaling in the caudal fin, and altered the shape of the caudal fin at water concentrations only 20-100 times higher than the geometric mean serum concentration in the human cohort. These findings call for awareness that pollutant mixtures like mixture G may interfere with a variety of developmental processes, possibly resulting in adverse health effects.
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| 7. |
- Abolfathi, Bela, et al.
(författare)
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The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
- 2018
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Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
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Tidskriftsartikel (refereegranskat)abstract
- The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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| 8. |
- Arildsen, Nicolai Skovbjerg, et al.
(författare)
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Involvement of chromatin remodeling genes and the Rho GTPases RhoB and CDC42 in ovarian clear cell carcinoma
- 2017
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Ingår i: Frontiers in Oncology. - : Frontiers Media SA. - 2234-943X. ; 7:MAY, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Ovarian clear cell carcinomas (OCCCs) constitute a rare ovarian cancer subtype with distinct clinical features, but may nonetheless be difficult to distinguish morphologically from other subtypes. There is limited knowledge of genetic events driving OCCC tumorigenesis beyond ARID1A, which is reportedly mutated in 30-50% of OCCCs. We aimed to further characterize OCCCs by combined global transcriptional profiling and targeted deep sequencing of a panel of well-established cancer genes. Increased knowledge of OCCC-specific genetic aberrations may help in guiding development of targeted treatments and ultimately improve patient outcome. Methods: Gene expression profiling of formalin-fixed, paraffin-embedded (FFPE) tissue from a cohort of the major ovarian cancer subtypes (cohort 1; n = 67) was performed using whole-genome cDNA-mediated Annealing, Selection, extension and Ligation (WG-DASL) bead arrays, followed by pathway, gene module score, and gene ontology analyses, respectively. A second FFPE cohort of 10 primary OCCCs was analyzed by targeted DNA sequencing of a panel of 60 cancer-related genes (cohort 2). Non-synonymous and non-sense variants affecting single-nucleotide variations and insertions or deletions were further analyzed. A tissue microarray of 43 OCCCs (cohort 3) was used for validation by immunohistochemistry and chromogenic in situ hybridization. Results: Gene expression analyses revealed a distinct OCCC profile compared to other histological subtypes, with, e.g., ERBB2, TFAP2A, and genes related to cytoskeletal actin regulation being overexpressed in OCCC. ERBB2 was, however, not overexpressed on the protein level and ERBB2 amplification was rare in the validation cohort. Targeted deep sequencing revealed non-synonymous variants or insertions/deletions in 11/60 cancer-related genes. Genes involved in chromatin remodeling, including ARID1A, SPOP, and KMT2D were frequently mutated across OCCC tumors. Conclusion: OCCCs appear genetically heterogeneous, but harbor frequent alterations in chromatin remodeling genes. Overexpression of TFAP2A and ERBB2 was observed on the mRNA level in relation to other ovarian cancer subtypes. However, overexpression of ERBB2 was not reflected by HER2 amplification or protein overexpression in the OCCC validation cohort. In addition, Rho GTPase-dependent actin organization may also play a role in OCCC pathogenesis and warrants further investigation. The distinct biological features of OCCC discovered here may provide a basis for novel targeted treatment strategies.
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| 9. |
- Bergström, Lena, et al.
(författare)
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Klimatförändringar och biologisk mångfald : Slutsatser från IPCC och IPBES i ett svenskt perspektiv.
- 2020
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- De stora miljö- och samhällsproblemen kommer inte ensamma. De är sammankopplade på olika sätt. Detta innebär utmaningar men ger också möjligheter att utveckla åtgärder och lösningar. Det gäller både för klimatfrågan och frågan om att motverka förlusten av biologisk mångfald och ekosystem. Kunskapens betydelse för att hantera dessa och andra aspekter är ovärderlig, såväl kring specifika frågeställningar som kring omständigheter och förutsättningar för åtgärdsarbetet.Den här kunskapssammanställningen har gjorts av forskare från Lunds universitet och Sveriges lantbruksuniversitet på uppdrag av Naturvårdsverket och SMHI. Forskarna har tagit avstamp i de omfattande kunskapsutvärderingar som gjorts av den mellanstatliga klimatpanelen (IPCC) och den mellanstatliga plattformen för biologisk mångfald (IPBES). Slutsatserna från IPCC och IPBES sätts i ett svenskt perspektiv, bland annat genom utvalda exempel vilka fungerar som aktuella illustrationer av hur klimatförändringar påverkar biologisk mångfald och ekosystem i Sverige.
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| 10. |
- Blanco, Fabiana, et al.
(författare)
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In vivo inhibition of nuclear factor of activated T-cells leads to atherosclerotic plaque regression in IGF-II/LDLR -/-ApoB100/100 mice
- 2018
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Ingår i: Diabetes and Vascular Disease Research. - : SAGE Publications. - 1752-8984 .- 1479-1641. ; 15:4, s. 302-313
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Despite vast clinical experience linking diabetes and atherosclerosis, the molecular mechanisms leading to accelerated vascular damage are still unclear. Here, we investigated the effects of nuclear factor of activated T-cells inhibition on plaque burden in a novel mouse model of type 2 diabetes that better replicates human disease.METHODS & RESULTS: IGF-II/LDLR-/-ApoB100/100mice were generated by crossbreeding low-density lipoprotein receptor-deficient mice that synthesize only apolipoprotein B100 (LDLR-/-ApoB100/100) with transgenic mice overexpressing insulin-like growth factor-II in pancreatic β cells. Mice have mild hyperglycaemia and hyperinsulinaemia and develop complex atherosclerotic lesions. In vivo treatment with the nuclear factor of activated T-cells blocker A-285222 for 4 weeks reduced atherosclerotic plaque area and degree of stenosis in the brachiocephalic artery of IGF-II/LDLR-/-ApoB100/100mice, as assessed non-invasively using ultrasound biomicroscopy prior and after treatment, and histologically after termination. Treatment had no impact on plaque composition (i.e. muscle, collagen, macrophages). The reduced plaque area could not be explained by effects of A-285222 on plasma glucose, insulin or lipids. Inhibition of nuclear factor of activated T-cells was associated with increased expression of atheroprotective NOX4 and of the anti-oxidant enzyme catalase in aortic vascular smooth muscle cells.CONCLUSION: Targeting the nuclear factor of activated T-cells signalling pathway may be an attractive approach for the treatment of diabetic macrovascular complications.
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