Immune-Monitoring
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Immune-Monitoring
Identifying antigen-specific immune cells in infection, neoplasia and auto-immunity
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Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor | Immune-Monitoring | Scoop.it
FoxP3 is a key transcription factor for the development and function of natural CD4+
regulatory T cells (Treg cells). Here we show that human FoxP3+CD4+ T cells were composed
of three phenotypically and functionally distinct subpopulations: CD45RA+FoxP3lo resting
Treg cells (rTreg cells) and CD45RA−FoxP3hi activated Treg cells (aTreg cells), both
of which were suppressive in vitro, and cytokine-secreting CD45RA−FoxP3lo nonsuppressive
T cells. The proportion of the three subpopulations differed between cord blood, aged
individuals, and patients with immunological diseases.
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Dynamic changes in the immunological characteristics of T lymphocytes in surviving patients with severe fever with thrombocytopenia syndrome (SFTS)

•The Fas/FasL pathway may contribute to T lymphocyte apoptosis in SFTS patients.
•Higher T cell proliferation, activation were observed during acute SFTSV infection.
•T cells exhibited higher effector, cytotoxic functions in the acute phase in SFTS.

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Altered circulating T follicular helper cell subsets in patients with psoriasis vulgaris - ScienceDirect

Altered circulating T follicular helper cell subsets in patients with psoriasis vulgaris - ScienceDirect | Immune-Monitoring | Scoop.it
Highlights

The composition of circulating Tfh cells is altered in psoriasis.


The Tfh17 cell subset may be a biomarker for evaluating the severity of psoriasis.


The frequency of Tfh17 cells decreased gradually during the follow-up period.


IL-21R expression on B cells is elevated in patients with psoriasis.
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Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions

Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions | Immune-Monitoring | Scoop.it
T follicular helper (Tfh) cells are pivotal for antibody induction. Streeck and colleagues
show that HIV-specific Tfh cells circulating in the periphery can be identified by
secretion of IL-21 with helper qualities dependent on protein specificity and are
found at increased numbers in the moderately protective HIV vaccine trial (RV144).
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Peptide–MHC Class I Tetramers Can Fail To Detect Relevant Functional T Cell Clonotypes and Underestimate Antigen-Reactive T Cell Populations

Peptide–MHC Class I Tetramers Can Fail To Detect Relevant Functional T Cell Clonotypes and Underestimate Antigen-Reactive T Cell Populations | Immune-Monitoring | Scoop.it
Peptide-MHC (pMHC) multimers, usually used as streptavidin-based tetramers, have transformed the study of Ag-specific T cells by allowing direct detection, phenotyping, and enumeration within polyclonal T cell populations. These reagents are now a standard part of the immunology toolkit and have been used in many thousands of published studies. Unfortunately, the TCR-affinity threshold required for staining with standard pMHC multimer protocols is higher than that required for efficient T cell activation. This discrepancy makes it possible for pMHC multimer staining to miss fully functional T cells, especially where low-affinity TCRs predominate, such as in MHC class II–restricted responses or those directed against self-antigens. Several recent, somewhat alarming, reports indicate that pMHC staining might fail to detect the majority of functional T cells and have prompted suggestions that T cell immunology has become biased toward the type of cells amenable to detection with multimeric pMHC. We use several viral- and tumor-specific pMHC reagents to compare populations of human T cells stained by standard pMHC protocols and optimized protocols that we have developed. Our results confirm that optimized protocols recover greater populations of T cells that include fully functional T cell clonotypes that cannot be stained by regular pMHC-staining protocols. These results highlight the importance of using optimized procedures that include the use of protein kinase inhibitor and Ab cross-linking during staining to maximize the recovery of Ag-specific T cells and serve to further highlight that many previous quantifications of T cell responses with pMHC reagents are likely to have considerably underestimated the size of the relevant populations.
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Malaria-induced interferon-γ drives the expansion of Tbethi atypical memory B cells

Malaria-induced interferon-γ drives the expansion of Tbethi atypical memory B cells | Immune-Monitoring | Scoop.it
Author summary Antibodies are proteins in blood that help kill microbes such as viruses, bacteria and parasites. Antibodies are produced by B cells with the help of T follicular helper (Tfh) cells. Some microbes for which we have no effective vaccines, such as HIV and malaria, establish chronic infections that are not cleared by the immune system. These chronic infections are associated with ‘atypical’ B cells that are less able to produce antibodies. We studied blood samples of malaria-exposed children to understand why normal B cells become atypical B cells. We found that atypical B cells express high levels of T-bet—a protein that is important for determining the fate of other types of immune cells. Children who frequently got malaria had more T-bet expressing B cells than children who rarely got malaria. We also found that malaria parasites cause immune cells to secrete inflammatory substances that cause normal B cells to express T-bet. Similarly, the inflammation-prone Tfh cells that malaria activates, which are relatively poor B cell helpers, also caused normal B cells to express T-bet. This study helps us understand why atypical B cells arise during chronic infections—information that could lead to strategies to improve antibody responses through vaccination.
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Perpetual complexity: predicting human CD8+ T cell responses to pathogenic peptides - Di Carluccio - 2018 - Immunology & Cell Biology - Wiley Online Library

Perpetual complexity: predicting human CD8+ T cell responses to pathogenic peptides - Di Carluccio - 2018 - Immunology & Cell Biology - Wiley Online Library | Immune-Monitoring | Scoop.it
The accurate prediction of human CD8+ T cell epitopes has great potential clinical and translational implications in the context of infection, cancer and autoimmunity. Prediction algorithms have traditionally focused on calculated peptide affinity for the binding groove of MHC-I. However, over the years it has become increasingly clear that the ultimate T cell recognition of MHC-I-bound peptides is governed by many contributing factors within the complex antigen presentation pathway. Recent advances in next-generation sequencing and immunnopeptidomics have increased the precision of HLA-I sub-allele classification, and have led to the discovery of peptide processing events and individual allele-specific binding preferences. Here, we review some of the discoveries that initiated the development of peptide prediction algorithms, and outline some of the current available online tools for CD8+ T cell epitope prediction.
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Activation and Regulation of Blood Vδ2 T Cells Are Amplified by TREM-1+ during Active Pulmonary Tuberculosis

Activation and Regulation of Blood Vδ2 T Cells Are Amplified by TREM-1+ during Active Pulmonary Tuberculosis | Immune-Monitoring | Scoop.it
Triggering receptor expressed on myeloid cells 1 (TREM-1) is a receptor mainly expressed on myeloid cells, and it plays an important role in modulating immune response against infectious agents. The function of TREM-1 on nonmyeloid cells such as Vδ2 T cells has not been characterized, and their role in pulmonary tuberculosis (TB) remains unclear. To assess the expression of TREM-1 on blood Vδ2 T cells from pulmonary TB patients and investigate its mechanism of induction, we exploited flow cytometry analysis to study the expression of TREM-1 on Vδ2 T cells from active pulmonary TB patients and control subjects. In this study we demonstrate that TREM-1 (TREM-1+) is highly expressed on Vδ2 T cells of patients with active pulmonary TB. Unlike TREM-1−–expressing Vδ2 T cells, TREM-1+–producing Vδ2 T cells display APC-like phenotypes. Surprisingly, TREM-1+ signaling promotes the Ag-presenting capability of Vδ2 T cells to induce the CD4+ T cell response. TREM-1+Vδ2 T cells induced the proliferation and differentiation of naive CD4+ T cells, as well as the elimination of intracellular mycobacteria. We identified TREM-1+ (but not TREM-1−) as an Ag-presentation amplifier on human blood Vδ2 T cells, and data shed new light on the regulation of Vδ2 T cells in the phase of innate and adaptive immune responses against Mycobacterium tuberculosis infection. Targeting TREM-1+Vδ2 T cells may be a promising approach for TB therapy.
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High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy

High-dimensional single-cell analysis predicts response to anti-PD-1 immunotherapy | Immune-Monitoring | Scoop.it
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14+CD16−HLA-DRhi monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
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Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy | Immune-Monitoring | Scoop.it
CD8+ T cell-dependent killing of cancer cells requires efficient presentation of tumor antigens by human leukocyte antigen class I (HLA-I) molecules. However, the extent to which patient-specific HLA-I genotype influences response to anti-PD-1 or anti-CTLA-4 is currently unknown. We determined the HLA-I genotype of 1,535 advanced cancer patients treated with immune checkpoint blockade (ICB). Maximal heterozygosity at HLA-I loci ( A , B , and C ) improved overall survival after ICB compared to patients who were homozygous for at least one HLA locus. In two independent melanoma cohorts, patients with the HLA-B44 supertype had extended survival, whereas the HLA-B62 supertype (including HLA-B*15:01) or somatic loss of heterozygosity at HLA-I, was associated with poor outcome. Molecular dynamics simulations of HLA-B*15:01 revealed unique elements that may impair CD8+ T cell recognition of neoantigens. Our results have important implications for predicting response to ICB and for the design of neoantigen-based therapeutic vaccines.
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Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer

Evaluation of PD-L1 expression on vortex-isolated circulating tumor cells in metastatic lung cancer | Immune-Monitoring | Scoop.it
Circulating tumor cell (CTC) PD-L1 levels could aid in screening patients, and could supplement tissue PD-L1 biopsy results by testing PD-L1 expression from disseminated tumor sites. Towards establishing CTCs as a screening tool, we developed a protocol to isolate CTCs at high purity and immunostain for PD-L1. Monitoring of PD-L1 expression on CTCs could be an additional biomarker for precision medicine that may help in determining response to immunotherapies.
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A Macrophage Colony-Stimulating Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence

A Macrophage Colony-Stimulating Factor-Producing γδ T Cell Subset Prevents Malarial Parasitemic Recurrence | Immune-Monitoring | Scoop.it
γδ T cell frequency increases late during mouse and human malaria. Mamedov et al.
show that oligoclonal TRAV15N-1 (Vδ6.3) γδ T cells expand across various tissues and
prevent late-stage parasitemic recurrence. These protective γδ T cells exhibit a distinct
transcriptional profile that includes abundantly expressed M-CSF, which protects against
Plasmodium recurrence.
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One Bug or Another: Promiscuous T Cells Form Lifelong Memory

One Bug or Another: Promiscuous T Cells Form Lifelong Memory | Immune-Monitoring | Scoop.it
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Sensitive and frequent identification of high avidity neo-epitope specific CD8 + T cells in immunotherapy-naive ovarian cancer

Sensitive and frequent identification of high avidity neo-epitope specific CD8 + T cells in immunotherapy-naive ovarian cancer | Immune-Monitoring | Scoop.it
Immunotherapy directed against private tumor neo-antigens derived from non-synonymous somatic mutations is a promising strategy of personalized cancer immunotherapy. However, feasibility in low mutational load tumor types remains unknown. Comprehensive and deep analysis of circulating and tumor-infiltrating lymphocytes (TILs) for neo-epitope specific CD8+ T cells has allowed prompt identification of oligoclonal and polyfunctional such cells from most immunotherapy-naive patients with advanced epithelial ovarian cancer studied. Neo-epitope recognition is discordant between circulating T cells and TILs, and is more likely to be found among TILs, which display higher functional avidity and unique TCRs with higher predicted affinity than their blood counterparts. Our results imply that identification of neo-epitope specific CD8+ T cells is achievable even in tumors with relatively low number of somatic mutations, and neo-epitope validation in TILs extends opportunities for mutanome-based personalized immunotherapies to such tumors.
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JCI Insight - Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus

JCI Insight - Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus | Immune-Monitoring | Scoop.it
B cells play a central role in systemic lupus erythematosus (SLE) pathophysiology but dysregulated pathways leading to a break in B cell tolerance remain unclear. Since Toll-like receptor 9 (TLR9) favors the elimination of autoreactive B cells in the periphery, we assessed TLR9 function in SLE by analyzing the responses of B cells and plasmacytoid dendritic cells (pDCs) isolated from healthy donors and patients after stimulation with CpG, a TLR9 agonist. We found that SLE B cells from patients without hydroxychloroquine treatment displayed defective in vitro TLR9 responses, as illustrated by the impaired upregulation of B cell activation molecules and the diminished production of various cytokines including antiinflammatory IL-10. In agreement with CD19 controlling TLR9 responses in B cells, decreased expression of the CD19/CD21 complex on SLE B cells was detected as early as the transitional B cell stage. In contrast, TLR7 function was preserved in SLE B cells, whereas pDCs from SLE patients properly responded to TLR9 stimulation, thereby revealing that impaired TLR9 function in SLE was restricted to B cells. We conclude that abnormal CD19 expression and TLR9 tolerogenic function in SLE B cells may contribute to the break of B cell tolerance in these patients.
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T follicular helper cells in human autoimmunity - ScienceDirect

T follicular helper cells in human autoimmunity - ScienceDirect | Immune-Monitoring | Scoop.it
Studies with mouse models have established the pathogenic roles of T follicular helper (Tfh) cells in antibody-mediated autoimmune diseases. In contra…
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Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies

Monogenic mutations differentially impact the quantity and quality of T follicular helper cells in human primary immunodeficiencies | Immune-Monitoring | Scoop.it

T follicular helper (Tfh) cells underpin T-cell dependent humoral immunity and the success of most vaccines. Tfh cells also contribute to human immune disorders such as autoimmunity, immunodeficiency and malignancy. 

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T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids

T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids | Immune-Monitoring | Scoop.it
The hallmark function of αβ T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen–presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.
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Atypical memory B cells in human chronic infectious diseases: An interim report - ScienceDirect

Atypical memory B cells in human chronic infectious diseases: An interim report - ScienceDirect | Immune-Monitoring | Scoop.it
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Images in Single cell profiling of peanut-responsive T cells in peanut allergic subjects reveals heterogeneous effector Th2 subsets

Images in Single cell profiling of peanut-responsive T cells in peanut allergic subjects reveals heterogeneous effector Th2 subsets | Immune-Monitoring | Scoop.it
Objectives
Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of individuals with and without peanut allergy (PA).

Methods
We obtained samples from PA individuals, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (CoFAR6). Subjects were confirmed as PA, or if they passed a 1 g peanut challenge they were termed high-threshold (HT). Healthy controls (HC) were also recruited. Peanut-responsive T cells were identified by CD154 expression after 6-18h of stimulation with peanut extract. Cells were analyzed by flow cytometry and single cell RNA sequencing.

Results
PA individuals had tissue and follicle-homing peanut-responsive CD4+ T cells with a heterogeneous pattern of Th2 differentiation, while controls had undetectable T cell responses to peanut. The PA group had a delayed and IL-2-dependent upregulation of CD154 on cells expressing Treg markers, which was absent in HC or HT individuals. Depletion of Tregs in vitro enhanced cytokine production in HC and PA subjects, but cytokines associated with highly differentiated Th2 cells were more resistant to Treg suppression in PA subjects. Analysis of gene expression by single cell RNAseq identified T cells with highly correlated expression of IL4, IL5, IL9, IL13 and the IL-25 receptor IL17RB.

Conclusions
These results demonstrate the presence of highly differentiated Th2 cells producing Th2-associated cytokines with functions beyond IgE-class switch in peanut allergy. A multi-functional Th2 response was more evident than a Treg deficit among peanut-responsive T cells.
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Activated T follicular helper-like cells are released into blood after oral vaccination and correlate with vaccine specific mucosal B-cell memory

Activated T follicular helper-like cells are released into blood after oral vaccination and correlate with vaccine specific mucosal B-cell memory | Immune-Monitoring | Scoop.it
We investigated the frequencies, phenotype and function of circulating Tfh-like CD4+CXCR5+ T cells (cTfh) in adults receiving an oral inactivated enterotoxigenic Escherichia coli vaccine. Subjects were classified as vaccine responders or weak/non-responders based on their intestine-derived antibody-secreting cell (ASC) IgA responses to major vaccine antigens. Oral immunization induced significantly increased proportions of cTfh cells expressing the cTfh activation marker inducible costimulator (ICOS) in ASC responders, but not in weak/non-responders. Vaccination also enhanced the expression of IL-21, Th17 markers and integrin β7 by activated cTfh cells, supporting functionality and gut homing potential. cTfh cells promoted total and vaccine specific IgA production from cocultured B cells. Magnitudes of cTfh responses assessed within a week after primary vaccinations correlated with memory intestine-derived vaccine specific IgA responses 1–2 years later. We conclude that activated ICOS+ Tfh-like cells are mobilized into blood after oral vaccination and may be used as biomarkers of vaccine specific mucosal memory in humans.
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Cancer immunotherapy mystery solved, per new research from IBM

Cancer immunotherapy mystery solved, per new research from IBM | Immune-Monitoring | Scoop.it
IBM, Columbia University and MSKCC published research in Science showing that certain protein molecules contribute to the success of cancer immunotherapies.
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A roadmap towards personalized immunology

A roadmap towards personalized immunology | Immune-Monitoring | Scoop.it
Here, we discuss the recent advances and successful applications in “Omics” data utilization and network analysis on patients’ samples of clinical trials and studies, as well as the major challenges and strategies towards personalized stratification and treatment for infectious or non-communicable inflammatory diseases such as autoimmune diseases or allergies. We provide a roadmap and highlight experimental, clinical, computational analysis, data management, ethical and regulatory issues to accelerate the implementation of personalized immunology.
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The Next Immuno-oncology Frontier?

The Next Immuno-oncology Frontier? | Immune-Monitoring | Scoop.it
Here's some strong evidence for what could be the next wave of immuno-oncology: combining a TLR9 ligand with an OX40 antibody. We're all going to have to get familiar with that sort of talk, so here's what's going on: As those who have worked in inflammation or infectious disease know well, the TLRs (Toll-like
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Frontiers | Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies | Immunology

Frontiers | Protective Cytomegalovirus (CMV)-Specific T-Cell Immunity Is Frequent in Kidney Transplant Patients without Serum Anti-CMV Antibodies | Immunology | Immune-Monitoring | Scoop.it
The absence of anti-CMV IgG is used to classify pre-transplant patients as naïve for CMV infection (CMVneg patients). This study assessed whether pre-transplant CMV-specific T-cell immunity exists in CMVneg patients and whether it protects against CMV-infection after kidney transplantation. The results show that CMV-specific CD137+IFNγ+CD4+ and CD137+IFNγ+CD8+ memory T cells were present in 46% and 39% of CMVneg patients (n=28) although at much lower frequencies compared to CMVpos patients (median 0.01% versus 0.58% for CD4+ and 0.05% versus 0.64% for CD8+ T cells) with a less differentiated CD28-expressing phenotype. In line with these data, CMV-specific proliferative CD4+ and CD8+ T cells were observed in CMVneg patients, which significantly correlated with the frequency of CMV-specific T cells. CMV-specific IgG-antibody secreting cells (ASC) could be detected at low frequency in 36% of CMVneg patients (1 versus 45 ASC/105 cells in CMVpos patients). CMVneg patients with pretransplant CMV-specific CD137+IFNγ+CD4+ T cells had a lower risk to develop CMV-viremia after transplantation with a CMVpos donor kidney (relative risk: 0.43, p=0.03). In conclusion, a solitary CMV-specific T-cell response without detectable anti-CMV antibodies is frequent and clinically relevant as it is associated with protection to CMV-infection following transplantation with a kidney from a CMVpos donor.
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