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  • 1
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    Online Resource
    AlacatDesignerComputational Design of Peptide Concatamers for Protein Quantitation
    American Chemical Society (ACS) ; 2023
    In:  Journal of Proteome Research Vol. 22, No. 2 ( 2023-02-03), p. 594-604
    Details
    In: Journal of Proteome Research, American Chemical Society (ACS), Vol. 22, No. 2 ( 2023-02-03), p. 594-604
    Type of Medium: Online Resource
    ISSN: 1535-3893 , 1535-3907
    URL: Article
    URL: Article
    DOI: 10.1021/acs.jproteome.2c00608
    DOI: 10.1021/acs.jproteome.2c00608.s001
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2023
    detail.hit.zdb_id: 2065254-9
    SSG: 12
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  • 2
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    Shared Clavulanate and Tazobactam Antigenic Determinants Activate T-Cells from Hypersensitive Patients
    American Chemical Society (ACS) ; 2022
    In:  Chemical Research in Toxicology Vol. 35, No. 11 ( 2022-11-21), p. 2122-2132
    Details
    In: Chemical Research in Toxicology, American Chemical Society (ACS), Vol. 35, No. 11 ( 2022-11-21), p. 2122-2132
    Type of Medium: Online Resource
    ISSN: 0893-228X , 1520-5010
    URL: Article
    DOI: 10.1021/acs.chemrestox.2c00231
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2022
    detail.hit.zdb_id: 2003547-0
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  • 3
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    Investigation of SARS-CoV-2 faecal shedding in the community: a prospective household cohort study (COVID-LIV) in the UK
    Springer Science and Business Media LLC ; 2021
    In:  BMC Infectious Diseases Vol. 21, No. 1 ( 2021-12)
    Details
    In: BMC Infectious Diseases, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: SARS-CoV-2 is frequently shed in the stool of patients hospitalised with COVID-19. The extent of faecal shedding of SARS-CoV-2 among individuals in the community, and its potential to contribute to spread of disease, is unknown. Methods In this prospective, observational cohort study among households in Liverpool, UK, participants underwent weekly nasal/throat swabbing to detect SARS-CoV-2 virus, over a 12-week period from enrolment starting July 2020. Participants that tested positive for SARS-CoV-2 were asked to provide a stool sample three and 14 days later. In addition, in October and November 2020, during a period of high community transmission, stool sampling was undertaken to determine the prevalence of SARS-CoV-2 faecal shedding among all study participants. SARS-CoV-2 RNA was detected using Real-Time PCR. Results A total of 434 participants from 176 households were enrolled. Eighteen participants (4.2%: 95% confidence interval [CI] 2.5–6.5%) tested positive for SARS-CoV-2 virus on nasal/throat swabs and of these, 3/17 (18%: 95% CI 4–43%) had SARS-CoV-2 detected in stool. Two of three participants demonstrated ongoing faecal shedding of SARS-CoV-2, without gastrointestinal symptoms, after testing negative for SARS-CoV-2 in respiratory samples. Among 165/434 participants without SARS-CoV-2 infection and who took part in the prevalence study, none had SARS-CoV-2 in stool. There was no demonstrable household transmission of SARS-CoV-2 among households containing a participant with faecal shedding. Conclusions Faecal shedding of SARS-CoV-2 occurred among community participants with confirmed SARS-CoV-2 infection. However, during a period of high community transmission, faecal shedding of SARS-CoV-2 was not detected among participants without SARS-CoV-2 infection. It is unlikely that the faecal-oral route plays a significant role in household and community transmission of SARS-CoV-2.
    Type of Medium: Online Resource
    ISSN: 1471-2334
    URL: Article
    DOI: 10.1186/s12879-021-06443-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041550-3
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  • 4
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    Activation of Human CD8+ T Cells with Nitroso Dapsone–Modified HLA-B*13:01–Binding Peptides
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 8 ( 2023-04-15), p. 1031-1042
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 8 ( 2023-04-15), p. 1031-1042
    Abstract: Previous studies have shown that cysteine-reactive drug metabolites bind covalently with protein to activate patient T cells. However, the nature of the antigenic determinants that interact with HLA and whether T cell stimulatory peptides contain the bound drug metabolite has not been defined. Because susceptibility to dapsone hypersensitivity is associated with the expression of HLA-B*13:01, we have designed and synthesized nitroso dapsone–modified, HLA-B*13:01 binding peptides and explored their immunogenicity using T cells from hypersensitive human patients. Cysteine-containing 9-mer peptides with high binding affinity to HLA-B*13:01 were designed (AQDCEAAAL [Pep1], AQDACEAAL [Pep2] , and AQDAEACAL [Pep3]), and the cysteine residue was modified with nitroso dapsone. CD8+ T cell clones were generated and characterized in terms of phenotype, function, and cross-reactivity. Autologous APCs and C1R cells expressing HLA-B*13:01 were used to determine HLA restriction. Mass spectrometry confirmed that nitroso dapsone–peptides were modified at the appropriate site and were free of soluble dapsone and nitroso dapsone. APC HLA-B*13:01–restricted nitroso dapsone–modified Pep1- (n = 124) and Pep3-responsive (n = 48) CD8+ clones were generated. Clones proliferated and secreted effector molecules with graded concentrations of nitroso dapsone–modified Pep1 or Pep3. They also displayed reactivity against soluble nitroso dapsone, which forms adducts in situ, but not with the unmodified peptide or dapsone. Cross-reactivity was observed between nitroso dapsone–modified peptides with cysteine residues in different positions in the peptide sequence. These data characterize a drug metabolite hapten CD8+ T cell response in an HLA risk allele–restricted form of drug hypersensitivity and provide a framework for structural analysis of hapten HLA binding interactions.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2200531
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Drug hapten‐specific T‐cell activation: Current status and unanswered questions
    Wiley ; 2021
    In:  PROTEOMICS Vol. 21, No. 17-18 ( 2021-09)
    Details
    In: PROTEOMICS, Wiley, Vol. 21, No. 17-18 ( 2021-09)
    Abstract: Drug haptens are formed from the irreversible, covalent binding of drugs to nucleophilic moieties on proteins, which can warrant adverse reactions in the body including severe delayed‐type, T‐cell mediated, drug hypersensitivity reactions (DHRs). While three main pathways exist for the activation of T‐cells in DHRs, namely the hapten model, the pharmacological interaction model and the altered peptide repertoire model, the exact antigenic determinants responsible have not yet been defined. In recent years, progress has been made using advanced mass spectrometry‐based proteomic methods to identify protein carriers and characterise the structure of drug‐haptenated proteins. Since genome‐wide association studies discovered a link between human leukocyte antigens (HLA) and an individual's susceptibility to DHRs, much effort has been made to define the drug‐associated HLA ligands driving T‐cell activation, including the elution of natural HLA peptides from HLA molecules and the generation of HLA‐binding peptides. In this review, we discuss our current methodology used to design and synthesise drug‐modified HLA ligands to investigate their immunogenicity using T‐cell models, and thus their implication in drug hypersensitivity.
    Type of Medium: Online Resource
    ISSN: 1615-9853 , 1615-9861
    URL: Issue
    URL: Article
    DOI: 10.1002/pmic.v21.17-18
    DOI: 10.1002/pmic.202000267
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2037674-1
    SSG: 12
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  • 6
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    Identification of Flucloxacillin-Haptenated HLA-B*57:01 Ligands: Evidence of Antigen Processing and Presentation
    Oxford University Press (OUP) ; 2020
    In:  Toxicological Sciences Vol. 177, No. 2 ( 2020-10-01), p. 454-465
    Details
    In: Toxicological Sciences, Oxford University Press (OUP), Vol. 177, No. 2 ( 2020-10-01), p. 454-465
    Abstract: Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver reactions. Although expression of human leukocyte antigen (HLA)-B*57:01 increases susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the modification of peptides that are presented by the risk allele. In this study, the binding of flucloxacillin to immune cells was characterized and the nature of the peptides presented by HLA-B*57:01 was analyzed using mass spectrometric-based immunopeptidomics methods. Flucloxacillin modification of multiple proteins was observed, providing a potential source of neoantigens for HLA presentation. Of the peptides eluted from flucloxacillin-treated C1R-B*57:01 cells, 6 putative peptides were annotated as flucloxacillin-modified HLA-B*57:01 peptide ligands (data are available via ProteomeXchange with identifier PXD020137). To conclude, we have characterized naturally processed drug-haptenated HLA ligands presented on the surface of antigen presenting cells that may drive drug-specific CD8+ T-cell responses.
    Type of Medium: Online Resource
    ISSN: 1096-6080 , 1096-0929
    URL: Article
    DOI: 10.1093/toxsci/kfaa124
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1471974-5
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  • 7
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    T cell assays differentiate clinical and subclinical SARS-CoV-2 infections from cross-reactive antiviral responses
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-04-06)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-04-06)
    Abstract: Identification of protective T cell responses against SARS-CoV-2 requires distinguishing people infected with SARS-CoV-2 from those with cross-reactive immunity to other coronaviruses. Here we show a range of T cell assays that differentially capture immune function to characterise SARS-CoV-2 responses. Strong ex vivo ELISpot and proliferation responses to multiple antigens (including M, NP and ORF3) are found in 168 PCR-confirmed SARS-CoV-2 infected volunteers, but are rare in 119 uninfected volunteers. Highly exposed seronegative healthcare workers with recent COVID-19-compatible illness show T cell response patterns characteristic of infection. By contrast, 〉 90% of convalescent or unexposed people show proliferation and cellular lactate responses to spike subunits S1/S2, indicating pre-existing cross-reactive T cell populations. The detection of T cell responses to SARS-CoV-2 is therefore critically dependent on assay and antigen selection. Memory responses to specific non-spike proteins provide a method to distinguish recent infection from pre-existing immunity in exposed populations.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-21856-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2553671-0
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  • 8
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    HLA DRB1*15:01-DQB1*06:02-Restricted Human CD4+ T Cells Are Selectively Activated With Amoxicillin-Peptide Adducts
    Oxford University Press (OUP) ; 2020
    In:  Toxicological Sciences Vol. 178, No. 1 ( 2020-11-01), p. 115-126
    Details
    In: Toxicological Sciences, Oxford University Press (OUP), Vol. 178, No. 1 ( 2020-11-01), p. 115-126
    Abstract: Amoxicillin-clavulanate is the most common cause of idiosyncratic drug-induced liver injury (DILI). Drug-specific CD4+ T cells have been detected in patients with DILI, suggestive of an immune etiology. Furthermore, genetic associations including the human leucocyte antigen (HLA) DRB1*15:01-DQB1*06:02 haplotype influence susceptibility. Amoxicillin forms protein adducts that are postulated to activate T cells, by conjugating with lysine residues. However, a role for such adducts has not been described. This study aimed to (1) investigate whether amoxicillin-modified HLA-DRB1*15:01-DQB1*06:02 binding peptides selectively activate DILI patient T cells and (2) define the nature of the T-cell response with respective to antigen structure. Peptides carrying lysine residues for amoxicillin binding in positions (KP) 2-6 and anchors for the HLA-DRB1*15:01-DQB1*06:02 haplotype were designed. The amoxicillin-modified peptides were characterized by mass spectrometry prior to culturing with patient peripheral blood mononuclear cell. T-cell clones were then tested for specificity with amoxicillin, unmodified- and amoxicillin-modified peptides, and structural variants. Amoxicillin-modified KP-2 and KP-3 peptide-specific CD4+ clones proliferated and secreted interferon gamma (IFN-γ), interleukin (IL)-10, perforin and/or IL-17/IL-22 in a dose-dependent manner and displayed no cross-reactivity with amoxicillin, unmodified peptide or with positional derivatives. The T cells response was HLA class II restricted and the amoxicillin-modified peptides bound selectively to HLA-DRB1*15:01 and/or DQB1*06:02. To conclude, we show that amoxicillin-modified peptides bind to both components of the risk haplotype to stimulate DILI patient T cells and describe the importance of the position of nucleophilic lysine residue in the HLA binding peptide sequence.
    Type of Medium: Online Resource
    ISSN: 1096-6080 , 1096-0929
    URL: Article
    DOI: 10.1093/toxsci/kfaa128
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 1471974-5
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  • 9
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    C1GalT1 expression reciprocally controls tumour cell-cell and tumour-macrophage interactions mediated by galectin-3 and MGL with double impact on cancer development and progression
    Springer Science and Business Media LLC ; 2023
    In:  Cell Death & Disease Vol. 14, No. 8 ( 2023-08-23)
    Details
    In: Cell Death & Disease, Springer Science and Business Media LLC, Vol. 14, No. 8 ( 2023-08-23)
    Abstract: Although most cell membrane proteins are modified by glycosylation, our understanding of the role and actions of protein glycosylation is still very limited. β1,3galactosyltransferase (C1GalT1) is a key glycosyltransferase that controls the biosynthesis of the Core 1 structure of O-linked mucin type glycans and is overexpressed by many common types of epithelial cancers. This study reports that suppression of C1GalT1 expression in human colon cancer cells caused substantial changes of protein glycosylation of cell membrane proteins, many of which were ligands of the galactoside-binding galectin-3 and the macrophage galactose-type lectin (MGL). This led to significant reduction of cancer cell proliferation, adhesion, migration and the ability of tumour cells to form colonies. Crucially, C1GalT1 suppression significantly reduced galectin-3-mediated tumour cell-cell interaction and galectin-3-promoted tumour cell activities. In the meantime, C1GalT1 suppression substantially increased MGL-mediated macrophage-tumour cell interaction and macrophage-tumour cell phagocytosis and cytokine secretion. C1GalT1-expressing cancer cells implanted in chick embryos resulted in the formation of significantly bigger tumours than C1GalT1-suppressed cells and the presence of galectin-3 increased tumour growth of C1GalT1-expressing but not C1GalT1-suppressed cells. More MGL-expressing macrophages and dendritic cells were seen to be attracted to the tumour microenvironment in ME C1galt1 -/- /Erb mice than in C1galt1 f/f /Erb mice. These results indicate that expression of C1GalT1 by tumour cells reciprocally controls tumour cell-cell and tumour-macrophage interactions mediated by galectin-3 and MGL with double impact on cancer development and progression. C1GalT1 overexpression in epithelial cancers therefore may represent a fundamental mechanism in cancer promotion and in reduction of immune response/surveillance in cancer progression.
    Type of Medium: Online Resource
    ISSN: 2041-4889
    URL: Article
    DOI: 10.1038/s41419-023-06082-7
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2541626-1
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  • 10
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    Exosomal Transport of Hepatocyte‐Derived Drug‐Modified Proteins to the Immune System
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Hepatology Vol. 70, No. 5 ( 2019-11), p. 1732-1749
    Details
    In: Hepatology, Ovid Technologies (Wolters Kluwer Health), Vol. 70, No. 5 ( 2019-11), p. 1732-1749
    Abstract: Idiosyncratic drug‐induced liver injury (DILI) is a rare, often difficult‐to‐predict adverse reaction with complex pathomechanisms. However, it is now evident that certain forms of DILI are immune‐mediated and may involve the activation of drug‐specific T cells. Exosomes are cell‐derived vesicles that carry RNA, lipids, and protein cargo from their cell of origin to distant cells, and they may play a role in immune activation. Herein, primary human hepatocytes were treated with drugs associated with a high incidence of DILI (flucloxacillin, amoxicillin, isoniazid, and nitroso‐sulfamethoxazole) to characterize the proteins packaged within exosomes that are subsequently transported to dendritic cells for processing. Exosomes measured between 50 and 100 nm and expressed enriched CD63. Liquid chromatography–tandem mass spectrometry (LC/MS‐MS) identified 2,109 proteins, with 608 proteins being quantified across all exosome samples. Data are available through ProteomeXchange with identifier PXD010760. Analysis of gene ontologies revealed that exosomes mirrored whole human liver tissue in terms of the families of proteins present, regardless of drug treatment. However, exosomes from nitroso‐sulfamethoxazole‐treated hepatocytes selectively packaged a specific subset of proteins. LC/MS‐MS also revealed the presence of hepatocyte‐derived exosomal proteins covalently modified with amoxicillin, flucloxacillin, and nitroso‐sulfamethoxazole. Uptake of exosomes by monocyte‐derived dendritic cells occurred silently, mainly through phagocytosis, and was inhibited by latrunculin A. An amoxicillin‐modified 9‐mer peptide derived from the exosomal transcription factor protein SRY (sex determining region Y)‐box 30 activated naïve T cells from human leukocyte antigen A*02:01–positive human donors. Conclusion: This study shows that exosomes have the potential to transmit drug‐specific hepatocyte‐derived signals to the immune system and provide a pathway for the induction of drug hapten‐specific T‐cell responses.
    Type of Medium: Online Resource
    ISSN: 0270-9139 , 1527-3350
    URL: Article
    DOI: 10.1002/hep.30701
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 1472120-X
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