Immunotherapy Treating GI Cancer
Ontology highlight
ABSTRACT:
DISEASE(S): Cancer
PROVIDER: 2279803 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GHD). We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. These changes reduced the ability of ISCs to differentiate and regenerate ex vivo in serial organoid cultures demonstrating the persistence of the maladaptive impact of an in vivo inflammatory encounter by the ISCs. Thus, inflammation from GI GVHD leaves a memory of its effects on ISCs that persist and are likely to affect their sensitivity to adapt to future stress or challenges.
2024-09-11 | GSE243364 | GEO
Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GVHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. We performed transposase-accessible chromatin sequencing (ATAC-seq) in sorted Lgr5+ISCs harvested from the BALB/c→B6-GFP-Lgr5 model of GVHD.
2024-09-11 | GSE223814 | GEO
Project description:Intestinal stem cells (ISC) encounter inflammatory insults in immune mediated gastro-intestinal (GI) diseases. It remains unknown whether, and how, they adapt, and if the adaptation leaves scars on the ISCs that affects their subsequent regeneration capacity. We investigated the consequences of inflammation on Lgr5+ISCs in well-defined clinically relevant models of gastro-intestinal acute graft-versus-host disease (GI GHD). Utilizing single cell transcriptomics, organoid, metabolic, epigenomic and in vivo models we found that Lgr5+ISCs undergo metabolic changes that lead to accumulation of succinate, which reprograms its epigenome. Single cells were isolated from small intestine crypts from Allo (BALB/c→C57BL/6) or Syn (C57BL/6→C57BL/6) transplant 7 days after bone marrow transplantation (BMT) and analyzed using scRNA-seq.
2024-09-11 | GSE223368 | GEO
Project description:<p>The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products.</p>
| phs001707 | dbGaP
Project description:Plants monitor and integrate temperature, photoperiod and light quality signals to respond to continuous changes in their environment. The GIGANTEA (GI) protein is central in diverse signaling pathways, including photoperiodic, sugar and light signaling pathways, stress responses and circadian clock regulation. Previously, GI was shown to activate expression of the key floral regulators CONSTANS (CO) and FLOWERING LOCUS T (FT) by facilitating degradation of a family of CYCLING DOF FACTOR (CDF) transcriptional repressors. However, whether CDFs are implicated in other processes regulated by GI remains unclear. We investigated the contribution of the GI-CDF module to traits that depend on GI. Transcriptome profiling indicated that mutations in GI and the CDFs have antagonistic effects on expression of a wider set of genes than CO and FT, whilst other genes are regulated by GI independently of the CDFs. Detailed expression studies followed by phenotypic assays showed that the CDFs function downstream of GI to control responses to freezing temperatures and growth, but are not necessary for proper clock function. Thus GI-mediated regulation of CDFs contributes to several processes in addition to flowering, but is not implicated in all of the phenotypes influenced by GI. Seedlings of Col-0, the cdf1-R cdf2-1 cdf3-1 cdf5-1 quadruple mutant, gi-100 and gi-100 cdf1-R cdf2-1 cdf3-1 cdf5-1 quintuple mutant were grown for 10 days under LD conditions (16h light/8h dark). The aerial part of the seedlings was collected at ZT12 and RNA was prepared from three biological replicas
2015-07-31 | E-GEOD-59996 | biostudies-arrayexpress
Project description:Plants monitor and integrate temperature, photoperiod and light quality signals to respond to continuous changes in their environment. The GIGANTEA (GI) protein is central in diverse signaling pathways, including photoperiodic, sugar and light signaling pathways, stress responses and circadian clock regulation. Previously, GI was shown to activate expression of the key floral regulators CONSTANS (CO) and FLOWERING LOCUS T (FT) by facilitating degradation of a family of CYCLING DOF FACTOR (CDF) transcriptional repressors. However, whether CDFs are implicated in other processes regulated by GI remains unclear. We investigated the contribution of the GI-CDF module to traits that depend on GI. Transcriptome profiling indicated that mutations in GI and the CDFs have antagonistic effects on expression of a wider set of genes than CO and FT, whilst other genes are regulated by GI independently of the CDFs. Detailed expression studies followed by phenotypic assays showed that the CDFs function downstream of GI to control responses to freezing temperatures and growth, but are not necessary for proper clock function. Thus GI-mediated regulation of CDFs contributes to several processes in addition to flowering, but is not implicated in all of the phenotypes influenced by GI.
2015-07-31 | GSE59996 | GEO
Project description:Gastrointestinal (GI) B cells and plasma cells (PCs), critical to mucosal homeostasis, play an important role in the host response to HIV-1 infection. Here, high resolution mapping of human B cells and PCs from colon and ileum during both viremic and suppressed HIV-1 infection identified a significant reduction in germinal center (GC) B cells and Follicular Dendritic Cells (FDCs) during HIV-1 viremia. Further, IgA+ PCs, the major cellular output of intestinal GCs were significantly reduced during viremic HIV-1 infection. PC-associated transcriptional perturbations, including type I interferon signaling persisted in antiretroviral therapy (ART) treated individuals, suggesting ongoing disruption of the intestinal immune milieu during ART. GI humoral immune perturbations associated with changes in intestinal microbiome composition and systemic inflammation. Herein, we highlight a key immune defect in the GI mucosa due to HIV-1 viremia, with major implications.
2024-10-28 | GSE272807 | GEO
Project description:GIGANTEA (GI) is an important modulator of plant circadian system. Recent studies have reported that protein GI is localized in both nucleus and cytosol, and nuclear and cytosolic GI exert differential effect on plant circadian clock. We first generated GI-null mutants and transgenic Arabidopsis plants that expressed GI fused to green fluorescent protein gene (GIpro::GI-GFP) and GI-GFP with a nuclear localization signal (GIpro::GI-GFP-NLS) or with a nuclear export signal (GIpro::GI-GFP-NES) under the control of native promoter in GI-null mutants. To investigate differential roles of nuclear and cytosolic GI in regulating plant circadian clock, we performed genome-wide gene expression profiling for wild-type plants and the GI-transgenic plants at morning and evening, and analyzed complementation patterns of gi-2 lesion by nuclear and cytosolic GI. As a result, we identified four complementation patterns representing genes affected by only nuclear GI (GIN) or cytosolic GI (GIC), those by either GIN or GIC, and those by the action of both GIN and GIC. Furthermore, we compared the transgenic plants expressing GIpro::GI-GFP with WT and the other GI-transgenic plants to confirm whether abnormally expressed genes by the gi-2 mutation can be complemented by restoring protein GI. Wild-type plants (Col), GI-null mutants (gi-2), and the other transgenic gi-2 plants expressing GIpro::GI-GFP (called GI plants), GIpro::GI-GFP-NLS (called GI-NLS plants), and GIpro::GI-GFP-NES (called GI-NES plants) were grown for seven days under conditions of 16 h light and 8 h dark (LD) and harvested at 1h (ZT1) and 16 hr (ZT16) after the light is turned on, representing morning and evening, respectively. mRNA levels were measured from three biological replicates of Col, gi-2, GI-NLS, GI-NES, and GI.
2013-09-01 | E-GEOD-47169 | biostudies-arrayexpress
Project description:GIGANTEA (GI) is an important modulator of plant circadian system. Recent studies have reported that protein GI is localized in both nucleus and cytosol, and nuclear and cytosolic GI exert differential effect on plant circadian clock. We first generated GI-null mutants and transgenic Arabidopsis plants that expressed GI fused to green fluorescent protein gene (GIpro::GI-GFP) and GI-GFP with a nuclear localization signal (GIpro::GI-GFP-NLS) or with a nuclear export signal (GIpro::GI-GFP-NES) under the control of native promoter in GI-null mutants. To investigate differential roles of nuclear and cytosolic GI in regulating plant circadian clock, we performed genome-wide gene expression profiling for wild-type plants and the GI-transgenic plants at morning and evening, and analyzed complementation patterns of gi-2 lesion by nuclear and cytosolic GI. As a result, we identified four complementation patterns representing genes affected by only nuclear GI (GIN) or cytosolic GI (GIC), those by either GIN or GIC, and those by the action of both GIN and GIC. Furthermore, we compared the transgenic plants expressing GIpro::GI-GFP with WT and the other GI-transgenic plants to confirm whether abnormally expressed genes by the gi-2 mutation can be complemented by restoring protein GI.
2013-09-01 | GSE47169 | GEO