Hypoxia PET Imaging Identifies Immunosuppressive Tumor Microenvironments and Guides Targeted Evofosfamide Therapy to Rescue Checkpoint Blockade Refractory Tumors
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PROVIDER: PRJNA766674 | ENA |
REPOSITORIES: ENA
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Project description:The results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
2021-09-28 | GSE184863 | GEO
Project description:PurposeHypoxia is a common characteristic of many tumor microenvironments, and it has been shown to promote suppression of antitumor immunity. Despite strong biological rationale, longitudinal correlation of hypoxia and response to immunotherapy has not been investigated.Experimental designIn this study, we probed the tumor and its surrounding microenvironment with 18F-FMISO PET imaging to noninvasively quantify tumor hypoxia in vivo prior to and during PD-1 and CTLA-4 checkpoint blockade in preclinical models of breast and colon cancer.ResultsLongitudinal imaging identified hypoxia as an early predictive biomarker of therapeutic response (prior to anatomic changes in tumor volume) with a decreasing standard uptake value (SUV) ratio in tumors that effectively respond to therapy. PET signal correlated with ex vivo markers of tumor immune response including cytokines (IFNγ, GZMB, and TNF), damage-associated molecular pattern receptors (TLR2/4), and immune cell populations (macrophages, dendritic cells, and cytotoxic T cells). Responding tumors were marked by increased inflammation that were spatially distinct from hypoxic regions, providing a mechanistic understanding of the immune signaling pathways activated. To exploit image-guided combination therapy, hypoxia signal from PET imaging was used to guide the addition of a hypoxia targeted treatment to nonresponsive tumors, which ultimately provided therapeutic synergy and rescued response as determined by longitudinal changes in tumor volume.ConclusionsThe results generated from this work provide an immediately translatable paradigm for measuring and targeting hypoxia to increase response to immune checkpoint therapy and using hypoxia imaging to guide combinatory therapies.
| S-EPMC8776604 | biostudies-literature
Project description:BACKGROUND. Improving and predicting tumor response to immunotherapy remains challenging. Combination therapy with a transforming growth factor β (TGF-β) inhibitor that targets cancer associated fibroblasts (CAFs) is promising to enhance efficacy of cancer immunotherapies. However, the effect of this approach in clinical trials is limited, requiring in vivo methods to better assess tumor responses to combination therapy. METHODS. We measure CAFs in vivo using gallium 68-labeled fibroblast activation protein inhibitor (68Ga-FAPI) for PET/CT imaging to guide TGF-β inhibition and sensitize metastatic colorectal cancer (CRC) to immunotherapy. A total of 131 patients with metastatic CRC underwent 68Ga-FAPI and 18F-fludeoxyglucose (18F-FDG) PET/CT imaging. Fourteen patients underwent surgery after the imaging. Relationship between uptake of 68Ga-FAPI and tumor immunity was analyzed. Mouse cohorts of metastatic CRC were treated with TGF-β receptor (TGF-βR) inhibitor combined with KN046 which blocks PD-L1 and CTLA4, followed with 68Ga-FAPI and 18F-FDG micro-PET/CT imaging to assess tumor responses. RESULTS. Patients with metastatic CRC demonstrated high uptakes of 68Ga-FAPI, along with suppressive tumor immunity and poor prognosis. TGF-βR inhibitor enhanced tumor infiltrating T cells and significantly sensitized metastatic CRC to KN046. 68Ga-FAPI PET/CT imaging accurately monitored the dynamical changes of CAFs and tumor response to combined TGF-βR inhibitor with immunotherapy. CONCLUSION. 68Ga-FAPI PET/CT imaging is powerful in assessing tumor immunity and response to immunotherapy in metastatic CRC. This study supports future clinical application of 68Ga-FAPI PET/CT to stratify and guide patients with CRC for precise TGF-β inhibition plus immunotherapy, recommending 68Ga-FAPI and 18F-FDG dual PET/CT for CRC management.
2023-12-19 | GSE247303 | GEO
Project description:68Ga-FAPI PET imaging assesses tumor immunity and guides TGF-β inhibition to sensitize metastatic colorectal cancer to immunotherapy
| PRJNA1037077 | ENA
Project description:To get further insights on the micro-nanoplastic (MNP) effects on plants, the aim of this study was to: 1) shed light on the transcriptome changes provoked by two different polyethylene terephthalate (PET) MNPs in plant roots; 2) determine their effects on key plant growth parameters in hydroponically-cultivated Arabidopsis thaliana. MNPs of transparent (Tr-PET) and blue (Bl-PET) material caused a significant reduction in root length, while only Bl-PET significantly reduced rosette area. Plant fresh and dry weight did not change, even though various OJIP-test parameters decreased in the presence of MNPs. RNA-seq data showed that Bl-PET and, especially, Tr-PET affected gene expression in comparison to controls. Tr-PET induced starch degradation and isoprenoids, while glycolysis, trehalose metabolism and fermentation were generally repressed. Tr-PET upregulated genes involved in signaling of xenobiotics, whereas Bl-PET scarcely affected root transcriptomic profile, activating few gene categories for abiotic stresses. Regarding hormones, genes involved in ABA response were repressed, while brassinosteroid-related genes were differentially regulated by Tr-PET. Both MNPs, but especially Tr-PET, upregulated major latex protein-related genes. These results allowed to gain insight into the effects of MNP contamination in plant metabolism, identifying targets for biotechnological strategies to enhance plant tolerance and phytoremediation of these xenobiotic agents.
2024-12-31 | E-MTAB-13532 | biostudies-arrayexpress
Project description:The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of cell identity genes and repression of genes encoding lineage-specifying developmental regulators. Here we use large ESC cohesin ChIA-PET datasets and other genomic data to identify the local chromosomal structures at both active and repressed genes across the genome. The results show that super-enhancer driven cell identity genes generally occur within large loops that are connected through CTCF-CTCF interaction sites occupied by cohesin. Smc1 ChIA-PET data from wild type murine embryonic stem cells V6.5 were generated by deep sequencing using Illumina Hi-Seq 2000.
2014-06-27 | E-GEOD-57911 | biostudies-arrayexpress
Project description:Novel PET/CT Imaging Biomarkers of CB-839 in Combination With Panitumumab and Irinotecan in Patients With Metastatic and Refractory RAS Wildtype Colorectal Cancer
| PRJNA1147199 | ENA
Project description:Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these new immuno-modulatory agents is the lack of pharmacodynamic biomarkers indicative of increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe [18F]-fluorothymidine ([18F]FLT). Accordingly, IFN treatment stimulates cancer cell [18F]FLT uptake in the presence of thymidine and this effect is dependent on TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR widely expressed in PDAC, enhances the [18F]FLT avidity of xenograft tumors. Treatment with a small molecule STING agonist triggers IFN signaling-dependent TYMP expression in PDAC cells and enhances both subcutaneous and orthotopic tumor [18F]FLT uptake in vivo following systemic treatment. These findings indicate that [18F]FLT accumulation in tumors is sensitive to IFN signaling and that [18F]FLT PET may serve as a novel pharmacodynamic biomarker for PRR agonist-based immunotherapies in PDAC and possibly other malignancies characterized by elevated STING expression.
2021-08-30 | GSE178901 | GEO
Project description:Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known aboutthe regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1 / neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturationthrough secondary postmitotic regulatoryfactors. The early postnatal switch in Pet-1targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. 5-HT neuron mRNA profiles of E11.5, E15.5, and postnatal (P1-P3) wild type (WT) and Pet-1-/- mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. Myc-tagged Pet-1 ChIP-seq was performed on E12.5 to E14.5 hindbrains and sequencing using NextSeq 500.
2016-01-08 | E-GEOD-74315 | biostudies-arrayexpress
Project description:Polyethylene terephthalate (PET) is one of the most commonly used plastics, utilized in synthetic fibers, water containers, and food packaging. From the 1990s onwards, the demand for PET, and therefore its production, increased exponentially. This increased usage of PET has resulted in a staggering accumulation of undegraded plastic waste. Nearly 80% of the 6300 million tons of plastic waste that had been generated as of 2015 were accumulated in landfills or the natural environment. Moreover, the production of PET relies heavily on non‐renewable fossil fuels, exacerbating environmental concerns over its widespread use. In alignment with principles of environmental sustainability, the biotechnological upcycling of PET has recently emerged as a compelling solution. Since the discovery of PETase, a hydrolase capable of depolymerizing this polyester, enzymatic plastic breakdown is increasingly considered as a promising solution for managing PET waste. This enzyme and its improved derivatives, such as Fast‐PETase, enable the breakdown of PET into bis(2‐41 hydroxyethyl) terephthalate (BHET) and mono(2‐hydroxyethyl) terephthalate (MHET). Subsequently, the enzyme MHETase is responsible for further degradation of MHET into ethylene glycol and terephthalic acid. The metabolic capability of microorganisms to utilize these monomers of PET for growth has been explored in various biotechnological applications, especially in the context of bioremediation and bioconversion processes aimed at transforming plastic waste into useful products using genetically engineered bacteria.
2025-05-23 | PXD060720 | Pride