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| 2. |
- Bernardo, Carina, et al.
(författare)
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Molecular pathology of the non-luminal Ba/Sq-like and Sc/NE-like classes of urothelial tumours : An integrated immunohistochemical analysis
- 2022
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Ingår i: Human Pathology. - : Elsevier BV. - 0046-8177. ; 122, s. 11-24
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Tidskriftsartikel (refereegranskat)abstract
- Several groups have during past years produced molecular classification schemes for bladder cancer. Even though no consensus on how to define a subtype exists, one approach has been to base definitions on how tumours cluster according to their mRNA expression profiles. In many cases, obtained profiles, and thus class defining features, are affected by signals from non-tumour cells within the biopsy. To overcome this issue, we combined gene expression analyses with analyses of the actual tumour cells by extensive immunohistochemistry (IHC). By this approach we were able to define tumour cell phenotypes i.e., subtypes defined by features of the tumour cells only, and adjust mRNA-based algorithms accordingly. In the present investigation we address the non-luminal Basal/Squamous-like (Ba/Sq) and Small cell/Neuroendocrine-like (Sc/NE) categories of tumours defined by mRNA-based classification. We make use of IHC data for 15 proteins, all known to be instrumental for defining molecular subtypes of urothelial carcinoma. We show that the UroB type of tumours, frequently grouped together with Ba/Sq, are different from the Ba/Sq entity at several essential features and is a derivative of Urothelial-like tumours (Uro). We show that the Sc/NE tumours are similar to but represents extreme versions of Genomically Unstable (GU) tumours. We apply clustering to 423 cases representing all subtypes using IHC data for 14 proteins and show that the obtained grouping conforms well with the mRNA-based classification. This work describes in detail the molecular pathology of non-luminal RNA-based bladder cancer subtypes and highlight similarities/dissimilarities suggestive of origin.
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| 3. |
- Bratulic, Sinisa, 1981, et al.
(författare)
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Noninvasive detection of any-stage cancer using free glycosaminoglycans.
- 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. - 0027-8424 .- 1091-6490. ; 119:50
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Tidskriftsartikel (refereegranskat)abstract
- Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (Nurine = 220 cancer vs. 360 healthy) and plasma (Nplasma = 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I; N = 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
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| 4. |
- Cortazar-Chinarro, Maria, et al.
(författare)
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Major Histocompatibility Complex Variation and Haplotype Associated Survival in Response to Experimental Infection of Two Bd-GPL Strains Along a Latitudinal Gradient
- 2022
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Ingår i: Frontiers in Ecology and Evolution. - : Frontiers Media S.A.. - 2296-701X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- While both innate and adaptive immune system mechanisms have been implicated in resistance against the chytrid fungus Batrachochytrium dendrobatidis (Bd), studies on the role of specific MHC haplotypes on Bd infection are rare. Here, we studied variation in MHC Class IIB loci in the common toad Bufo bufo along a latitudinal gradient across Sweden. In general, Swedish toad populations had few MHC Class IIB haplotypes and MHC diversity declined from south (13 haplotypes) to the north (four haplotypes). The low diversity may compromise the ability of northern populations to fight emerging disease, such as Bd. In a laboratory experiment, we infected newly metamorphosed toads with two strains of the Global Pandemic Lineage of the fungus (Bd-GPL) and compared survival with sham controls. Bd-infected toads had lower survival compared to controls. Moreover, survival was dependent on the Bd-strain and northern toads had lower Bd-mediated survival than southern individuals. MHC diversity was lower in northern toads. All northern experimental animals were monomorphic for a single MHC haplotype, whereas we found seven different haplotypes in southern experimental animals. In southern toads, survival was dependent on both Bd-strain and MHC haplotype suggesting differential infection dynamics depending on both Bd-strain and host immune system characteristics.
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| 5. |
- Eriksson, Pontus, et al.
(författare)
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A comparison of rule-based and centroid single-sample multiclass predictors for transcriptomic classification
- 2022
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 38:4, s. 1022-1029
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Gene expression-based multiclass prediction, such as tumor subtyping, is a non-trivial bioinformatic problem. Most classifier methods operate by comparing expression levels relative to other samples. Methods that base predictions on the expression pattern within a sample have been proposed as an alternative. As these methods are invariant to the cohort composition and can be applied to a sample in isolation, they can collectively be termed single sample predictors (SSP). Such predictors could potentially be used for preprocessing-free classification of new samples and be built to function across different expression platforms where proper batch and dataset normalization is challenging. Here we evaluate the behavior of several multiclass single sample predictors based on binary gene-pair rules (k-Top Scoring Pairs, Absolute Intrinsic Molecular Subtyping, and a new Random Forest approach) and compare them to centroids built with centered or raw expression values, with the criteria that an optimal predictor should have high accuracy, overcome differences in tumor purity, be robust across expression platforms, and provide an informative prediction output score.RESULTS: We found that gene-pair based SSPs showed excellent performance on many expression-based classification tasks. The three methods differed in prediction score output, handling of tied scores, and behavior in low purity samples. The k-Top Scoring Pairs and Random Forest approach both achieved high classification accuracy while providing an informative prediction score. Although gene-pair-based SSPs have been touted as being cross-platform compatible (through training on mixed platform data), out-of-the-box compatibility with a new dataset remains a potential issue that warrants cohort-to-cohort verification.AVAILABILITY: Our R package 'multiclassPairs' (https://cran.r-project.org/package=multiclassPairs) (https://doi.org/10.1093/bioinformatics/btab088) is freely available and enables easy training, prediction, and visualization using the gene-pair rule-based Random Forest SSP method and provides additional multiclass functionalities to the switchBox k-Top-Scoring Pairs package.SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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| 6. |
- Ferreira, Alexandra Gabriela, et al.
(författare)
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Restoring tumor immunogenicity with dendritic cell reprogramming
- 2022
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Ingår i: Cancer immunology research. - 2326-6074. ; 10:12 suppl
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Konferensbidrag (refereegranskat)abstract
- Immunotherapy is revolutionizing cancer treatment, but success is limited to a fraction of patients. Tumor immunosurveillance and immunotherapy relies on presentation of tumor-associated antigens by conventional dendritic cells type 1 (cDC1). However, tumors develop mechanisms to avoid immune recognition such as downregulation of antigen presentation and exclusion of cDC1. We have previously demonstrated that enforced expression of the transcription factors PU.1, IRF8 and BATF3 (PIB) imposes the lineage conversion of fibroblasts to cDC1 by direct cell reprogramming. Here, we hypothesize that PIB reprograms cancer cells directly into functional tumor-antigen presenting cells (tumor-APCs) with enhanced immunogenicity. First, we show that enforced expression of PIB in a wide range of murine and human cancer cells from different origins is sufficient to induce surface expression of hematopoietic and DC-lineage specific markers (CD45 and Clec9a). Moreover, reprogramming restored the expression of antigen presentation complexes (MHC-I and MHC-II) and activated the expression of the co-stimulatory molecules CD40, CD80 and CD86, required for productive T cell activation. Transcriptomic analysis using mRNA-sequencing showed that PIB imposes a global cDC1 gene signature and an antigen presentation program in tumor cells as early as day 3 of reprogramming, overriding the original cancer cell program. Furthermore, Assay for Transposase-Accessible Chromatin (ATAC) sequencing analysis revealed that PIB-mediated cDC1 reprogramming elicited rapid epigenetic remodeling followed by gradual rewiring of transcriptional program and stabilization of cDC1 identity. Functionally, tumor-APCs present endogenous antigens on MHC-I, prime naïve CD8+ T and become prone to CD8+ T cell mediated killing. Tumor-APCs secrete pro-inflammatory cytokines (IL-12) and chemoattractants (CXCL10), uptake and process exogenous antigens, phagocyte dead cells, and cross-present exogenous antigens to activate naïve T-cells. In addition, reprogrammed tumor cells harboring TP53, KRAS and PTEN mutations downregulated proliferation and showed impaired tumorigenicity in vitro and in vivo. Importantly, we show that intra-tumoral injection of reprogrammed tumor-APCs elicited tumour growth control in vivo alongside increasing infiltration of CD8+ T and NK cells in B16-OVA tumors. Finally, we showed that our approach can be employed to convert primary cancer cells derived from melanoma, lung, breast, pancreatic, urothelial, and head and neck carcinomas as well as cancer associated fibroblasts. In summary, we provide evidence for the direct reprogramming of tumor cells into immunogenic cDC1-like cells, with restored antigen presentation capacity and the ability to reinstate anti-tumor immunity. Our approach elicits the immune system against cancer and counteract major tumor evasion mechanisms including tumor heterogeneity and impaired antigen presentation, laying the foundation for developing immunotherapeutic strategies based on the cellular reprogramming of human cancer cells.
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| 7. |
- Hurst, Carolyn D., et al.
(författare)
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Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight
- 2021
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Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 2:12
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the molecular determinants that underpin the clinical heterogeneity of non-muscle-invasive bladder cancer (NMIBC) is essential for prognostication and therapy development. Stage T1 disease in particular presents a high risk of progression and requires improved understanding. We present a detailed multi-omics study containing gene expression, copy number, and mutational profiles that show relationships to immune infiltration, disease recurrence, and progression to muscle invasion. We compare expression and genomic subtypes derived from all NMIBCs with those derived from the individual disease stages Ta and T1. We show that sufficient molecular heterogeneity exists within the separate stages to allow subclassification and that this is more clinically meaningful for stage T1 disease than that derived from all NMIBCs. This provides improved biological understanding and identifies subtypes of T1 tumors that may benefit from chemo- or immunotherapy.
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| 8. |
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| 9. |
- Höglund, Mattias, et al.
(författare)
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The Lund taxonomy for bladder cancer classification – from gene expression clustering to cancer cell molecular phenotypes, and back again
- 2023
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 259:4, s. 369-375
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Forskningsöversikt (refereegranskat)abstract
- Treatment of bladder cancer patients depends on precise diagnosis. Molecular subtyping by gene expression profiling may contribute substantially to subclassification of bladder cancer. Several classification systems have been proposed. Most of these base their classification on whole biopsy features, and molecular subtypes are therefore often defined by a combination of features from the cancer cells as well as infiltrating noncancer cells. This makes the link to what is seen at the cancer cell level unclear. The aim of the Lund taxonomy (LundTax) has been to align gene expression-level classification with immunohistochemical classification to identify cancer cell phenotypes independent of infiltration and proliferation. A systematic approach was used in which gene expression clusters were validated and adjusted by immunohistochemistry using markers expressed only by the cancer cells. This review provides a rationale for defining molecular subtypes and a step-by-step description of the development of the LundTax with motivations for each modification and extension. As the cancer cell phenotype defined by gene expression profiling corresponds with the immunohistochemistry of cancer cells, the LundTax represents a harmonization of the gene expression and immunohistochemical levels. Furthermore, the classification system is independent of pathological stage and is, thus, applicable to all urothelial carcinomas. A unified classification system relevant for both the molecular biologist and pathologist will facilitate systematization of current treatment practices, as well as the development of new treatments.
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| 10. |
- Höglund, Mattias
(författare)
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What is a Bladder Cancer Molecular Subtype?
- 2023
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Ingår i: Bladder Cancer. - 2352-3727. ; 9:4, s. 293-298
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND: Several molecular classification systems for bladder cancer have been proposed, but due to differences on how to define molecular subtypes, controversies and misunderstandings have arisen. OBJECTIVE: To discuss different aspects of the molecular classification of bladder cancer and to point to the consequences of using different conceptual approaches. To question some underlying assumptions when defining molecular subtypes. METHODS: To critically reflect on some of the principles and methods used when defining molecular subtypes. RESULTS: Depending on underlying assumptions and aims for the definitions of subtypes, different types of molecular subtypes will be arrived at. CONCLUSION: The underlying assumptions and their consequences must be better clarified when defining molecular subtypes.
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