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1.
  • Aine, Mattias, et al. (författare)
  • Biological determinants of bladder cancer gene expression subtypes.
  • 2015
  • Ingår i: Scientific Reports. - Nature Publishing Group. - 2045-2322. ; 5
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular stratification of tumors by gene expression profiling has been applied to a large number of human malignancies and holds great promise for personalized treatment. Comprehensive classification schemes for urothelial carcinoma have been proposed by three separate groups but have not previously been evaluated simultaneously in independent data. Here we map the interrelations between the proposed molecular subtypes onto the intrinsic structure of a rich independent dataset and show that subtype stratification within each scheme can be explained in terms of a set of common underlying biological processes. We highlight novel biological and genomic drivers of urothelial carcinoma molecular subtypes and show that tumors carrying genomic aberrations characteristic of distinct molecular pathways converge on a common top level phenotype corresponding to the two major molecular subtypes of non-muscle invasive disease.
2.
  • Aine, Mattias, et al. (författare)
  • Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.
  • 2015
  • Ingår i: Genome Medicine. - BioMed Central (BMC). - 1756-994X. ; 7:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors.
3.
  • Aine, Mattias, et al. (författare)
  • On Molecular Classification of Bladder Cancer: Out of One, Many.
  • 2015
  • Ingår i: European Urology. - Elsevier. - 1873-7560. ; 68:6, s. 921-923
  • Tidskriftsartikel (refereegranskat)abstract
    • Comparative analysis showed that bladder cancer classification systems identify overlapping subtypes but at different levels. Muscle-invasive bladder cancer shows remarkable heterogeneity, and six subtypes were identified that differ in transcriptional networks, marker profiles, and expression of actionable targets.
4.
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5.
  • Choi, Woonyoung, et al. (författare)
  • Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.
  • 2017
  • Ingår i: European urology. - 1873-7560. ; 72:3, s. 354-365
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties.The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes.We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers.The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors.The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations.Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer.
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6.
  • Choi, Woonyoung, et al. (författare)
  • Genetic Alterations in the Molecular Subtypes of Bladder Cancer : Illustration in the Cancer Genome Atlas Dataset
  • 2017
  • Ingår i: European Urology. - Elsevier. - 0302-2838. ; 72:3, s. 354-365
  • Forskningsöversikt (refereegranskat)abstract
    • Context: Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. Objective: The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. Evidence: We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. Evidence synthesis: The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. Conclusions: The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Patient summary: Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer. We analyzed the prevalence of the most common genomic alterations in the bladder cancer molecular subtypes. The results have important implications for our understanding of bladder cancer etiology and the development of molecular subtype-specific therapies.
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7.
8.
  • Eriksson, Pontus, et al. (författare)
  • Molecular subtypes of urothelial carcinoma are defined by specific gene regulatory systems.
  • 2015
  • Ingår i: BMC Medical Genomics. - BioMed Central (BMC). - 1755-8794. ; 8:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Molecular stratification of bladder cancer has revealed gene signatures differentially expressed across tumor subtypes. While these signatures provide important insights into subtype biology, the transcriptional regulation that governs these signatures is not well characterized.
9.
  • Hedegaard, Jakob, et al. (författare)
  • Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma
  • 2016
  • Ingår i: Cancer Cell. - Cell Press. - 1535-6108. ; 30:1, s. 27-42
  • Tidskriftsartikel (refereegranskat)abstract
    • Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous disease with widely different outcomes. We performed a comprehensive transcriptional analysis of 460 early-stage urothelial carcinomas and showed that NMIBC can be subgrouped into three major classes with basal- and luminal-like characteristics and different clinical outcomes. Large differences in biological processes such as the cell cycle, epithelial-mesenchymal transition, and differentiation were observed. Analysis of transcript variants revealed frequent mutations in genes encoding proteins involved in chromatin organization and cytoskeletal functions. Furthermore, mutations in well-known cancer driver genes (e.g., TP53 and ERBB2) were primarily found in high-risk tumors, together with APOBEC-related mutational signatures. The identification of subclasses in NMIBC may offer better prognostication and treatment selection based on subclass assignment.
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10.
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