| 1. |
- Bedran, Georges, et al.
(författare)
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The Immunopeptidome from a Genomic Perspective : Establishing the Noncanonical Landscape of MHC Class I–Associated Peptides
- 2023
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Ingår i: Cancer immunology research. - 2326-6066. ; 11:6, s. 742-762
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Tidskriftsartikel (refereegranskat)abstract
- Tumor antigens can emerge through multiple mechanisms, including translation of noncoding genomic regions. This noncanonical category of tumor antigens has recently gained attention; however, our understanding of how they recur within and between cancer types is still in its infancy. Therefore, we developed a proteogenomic pipeline based on deep learning de novo mass spectrometry (MS) to enable the discovery of noncanonical MHC class I–associated peptides (ncMAP) from noncoding regions. Considering that the emergence of tumor antigens can also involve posttranslational modifications (PTM), we included an open search component in our pipeline. Leveraging the wealth of MS-based immunopeptidomics, we analyzed data from 26 MHC class I immunopeptidomic studies across 11 different cancer types. We validated the de novo identified ncMAPs, along with the most abundant PTMs, using spectral matching and controlled their FDR to 1%. The noncanonical presentation appeared to be 5 times enriched for the A03 HLA supertype, with a projected population coverage of 55%. The data reveal an atlas of 8,601 ncMAPs with varying levels of cancer selectivity and suggest 17 cancer-selective ncMAPs as attractive therapeutic targets according to a stringent cutoff. In summary, the combination of the open-source pipeline and the atlas of ncMAPs reported herein could facilitate the identification and screening of ncMAPs as targets for T-cell therapies or vaccine development.
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| 2. |
- Rohmer, Laurence, et al.
(författare)
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Comparison of Francisella tularensis genomes reveals evolutionary events associated with the emergence of human pathogenic strains
- 2007
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Ingår i: Genome Biology. - : BioMed Central. - 1465-6906 .- 1474-760X. ; 8:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Francisella tularensis subspecies tularensis and holarctica are pathogenic to humans, whereas the two other subspecies, novicida and mediasiatica, rarely cause disease. To uncover the factors that allow subspecies tularensis and holarctica to be pathogenic to humans, we compared their genome sequences with the genome sequence of Francisella tularensis subspecies novicida U112, which is nonpathogenic to humans. RESULTS: Comparison of the genomes of human pathogenic Francisella strains with the genome of U112 identifies genes specific to the human pathogenic strains and reveals pseudogenes that previously were unidentified. In addition, this analysis provides a coarse chronology of the evolutionary events that took place during the emergence of the human pathogenic strains. Genomic rearrangements at the level of insertion sequences (IS elements), point mutations, and small indels took place in the human pathogenic strains during and after differentiation from the nonpathogenic strain, resulting in gene inactivation. CONCLUSION: The chronology of events suggests a substantial role for genetic drift in the formation of pseudogenes in Francisella genomes. Mutations that occurred early in the evolution, however, might have been fixed in the population either because of evolutionary bottlenecks or because they were pathoadaptive (beneficial in the context of infection). Because the structure of Francisella genomes is similar to that of the genomes of other emerging or highly pathogenic bacteria, this evolutionary scenario may be shared by pathogens from other species.
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| 3. |
- Schvartz, D., et al.
(författare)
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The Human Diabetes Proteome Project (HDPP) : The 2014 update
- 2015
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Ingår i: Translational Proteomics. - : Elsevier BV. - 2212-9626. ; 8-9, s. 1-7
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Tidskriftsartikel (refereegranskat)abstract
- Diabetes is an increasing worldwide problem leading to major associated health issues and increased health care costs. In 2012, 9.3% of the American population was affected by diabetes, according to the American Diabetes Association, with 1.7 million of new cases since during the year (www.diabetes.org). Proteome initiatives can provide a deeper understanding of the biology of this disease and help develop more effective treatments. The collaborative effort of the Human Diabetes Proteome Project (HDPP) brings together a wide variety of complementary resources to increase the existing knowledge about both type 1 and type 2 diabetes and their related complications. The goals are to identify proteins and protein isoforms associated with the pathology and to characterize underlying disease-related pathways and mechanisms. Moreover, a considerable effort is being made on data integration and network biology. Sharing these data with the scientific community will be an important part of the consortium. Here we report on: the content of the HDPP session held at the 12th HUPO meeting in Yokohama; recent achievements of the consortium; discussions of several HDPP workshops; as well as future HDPP directions as discussed at the 13th HUPO congress in Madrid, with a special attention given to the lists of prioritized, diabetes-related proteins and the proteomic means to study them.
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| 4. |
- Urban-Wojciuk, Zuzanna, et al.
(författare)
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The Role of TLRs in Anti-cancer Immunity and Tumor Rejection
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 10
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Forskningsöversikt (refereegranskat)abstract
- In recent years, a lot of scientific interest has focused on cancer immunotherapy. Although chronic inflammation has been described as one of the hallmarks of cancer, acute inflammation can actually trigger the immune system to fight diseases, including cancer. Toll-like receptor (TLR) ligands have long been used as adjuvants for traditional vaccines and it seems they may also play a role enhancing efficiency of tumor immunotherapy. The aim of this perspective is to discuss the effects of TLR stimulation in cancer, expression of various TLRs in different types of tumors, and finally the role of TLRs in anti-cancer immunity and tumor rejection.
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| 5. |
- Hajjar, Adeline M, et al.
(författare)
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Lack of in vitro and in vivo recognition of Francisella tularensis subspecies lipopolysaccharide by Toll-like receptors.
- 2006
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 74:12, s. 6730-8
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Tidskriftsartikel (refereegranskat)abstract
- Francisella tularensis is an intracellular gram-negative bacterium that is highly infectious and potentially lethal. Several subspecies exist of varying pathogenicity. Infection by only a few organisms is sufficient to cause disease depending on the model system. Lipopolysaccharide (LPS) of gram-negative bacteria is generally recognized by Toll-like receptor 4 (TLR4)/MD-2 and induces a strong proinflammatory response. Examination of human clinical F. tularensis isolates revealed that human virulent type A and type B strains produced lipid A of similar structure to the nonhuman model pathogen of mice, Francisella novicida. F. novicida LPS or lipid A is neither stimulatory nor an antagonist for human and murine cells through TLR4 or TLR2. It does not appear to interact with TLR4 or MD-2, as it is not an antagonist to other stimulatory LPS. Consistent with these observations, aerosolization of F. novicida LPS or whole bacteria induced no inflammatory response in mice. These results suggest that poor innate recognition of F. tularensis allows the bacterium to evade early recognition by the host innate immune system to promote its pathogenesis for mammals.
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| 6. |
- Pacheco, Benny, et al.
(författare)
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Identification of the active site of DS-epimerase 1 and requirement of N-glycosylation for enzyme function.
- 2009
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 284:3, s. 1741-1747
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Tidskriftsartikel (refereegranskat)abstract
- Dermatan sulfate is a highly sulfated polysaccharide and has a variety of biological functions in development and disease. Iduronic acid domains in dermatan sulfate, which are formed by the action of two DS-epimerases, have a key role in mediating these functions. We have identified the catalytic site and three putative catalytic residues in DS-epimerase 1, His205, Tyr261 and His450, by tertiary structure modeling and amino acid conservation to heparinase II. These residues were systematically mutated to alanine or more conserved residues, which resulted in complete loss of epimerase activity. Based on these data, and the close relationship between lyase and epimerase reactions, we propose a model where His450 functions as a general base abstracting the C5-proton from glucuronic acid. Subsequent cleavage of the glycosidic linkage by Tyr261 generates a 4,5-unsaturated hexuronic intermediate, which is protonated at the C5-carbon by His205 from the side of the sugar plane opposite to the side of previous proton abstraction. Concomitant recreation of the glycosidic linkage ends the reaction generating iduronic acid. In addition, we show that proper N-glycosylation of DS-epimerase 1 is required for enzyme activity. This study represents the first description of the structural basis for epimerization by a glycosaminoglycan epimerase.
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