20.05.2022

Cannabidiol inhibits SARS-CoV-2 replication through induction of the h... Science Advances, 2022

Abstract The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and ongoing coronavirus disease 2019 (COVID-19) pandemic underscores the need for new treatments. Here, we report that cannabidiol (CBD) inhibits infection of SARS-CoV-2 in cells and mice. CBD and its metabolite 7-OH-CBD, but not THC or other congeneric cannabinoids tested, potently block SARS-CoV-2 replication in lung epithelial cells. CBD acts after viral entry, inhibiting viral gene expression and reversing many effects of SARS-CoV-2 on host gene transcr...

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06.05.2022

Combining selective inhibitors of nuclear export (SINEs) with chimeric... Combining selective inhibitors of nuclear export (SINEs) with chimeric...

Abstract Chimeric antigen receptor (CAR) T cells directed against CD19 (CD19.CAR T cells) have yielded impressive clinical responses in the treatment of patients with lymphoid malignancies. However, resistance and/or relapse can limit treatment outcome. Risk of tumor escape can be reduced by combining treatment strategies. Selective inhibitors of nuclear export (SINEs) directed against nuclear exportin‑1 (XPO1) have demonstrated anti‑tumor efficacy in several hematological malignancies. The aim of the present study was to evaluate the comb...

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28.04.2022

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pa... RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pa...

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in...

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22.04.2022

SARS-CoV-2 variants with reduced infectivity and varied sensitivity to... SARS-CoV-2 variants with reduced infectivity and varied sensitivity to...

Abstract In-depth analysis of SARS-CoV-2 quasispecies is pivotal for a thorough understating of its evolution during infection. The recent deployment of COVID-19 vaccines, which elicit pro- tective anti-spike neutralizing antibodies, has stressed the importance of uncovering and characterizing SARS-CoV-2 variants with mutated spike proteins. Sequencing databases have allowed...

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08.04.2022

The nucleolus functions as a phase-separated protein quality control c... The nucleolus functions as a phase-separated protein quality control c...

Abstract The nuclear proteome is rich in stress-sensitive proteins, which suggests that effective protein quality control mechanisms are in place to ensure conformational maintenance. We investigated the role of the nucleolus in this process. In mammalian tissue culture cells under stress conditions, misfolded proteins entered the granular component (GC) phase of the nucleolus. Transient associations with nucleolar proteins such as NPM1 conferred low mobility to misfolded proteins within the liquid-like GC phase, avoiding irreversible aggr...

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01.04.2022

Mechanosensitive smooth muscle cell phenotypic plasticity emerging fro... Mechanosensitive smooth muscle cell phenotypic plasticity emerging fro...

Abstract THIS WEEK: Reversible differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in vascular biology and disease. Changes in VSMC differentiation correlate with stiffness of the arterial extracellular matrix (ECM), but causal relationships remain unclear. We show that VSMC plasticity is mechanosensitive and that both the de-differentiated and differentiated fates are promoted by the same ECM stiffness. Differential equations developed to model this behavior predicted that a null VSMC state generat...

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25.03.2022

Mapping molecular subtype specific alterations in breast cancer brain... Mapping molecular subtype specific alterations in breast cancer brain...

Abstract The molecular events and transcriptional plasticity driving brain metastasis in clinically relevant breast tumor subtypes has not been determined. Here we comprehensively dissect genomic, transcriptomic and clinical data in patient-matched longitudinal tumor samples, and unravel distinct transcriptional programs enriched in brain metastasis. We report on subtype specific hub genes and functional processes, central to disease-affected networks in brain metastasis. Importantly, in luminal brain metastases we identify homologous recomb...

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18.03.2022

Pharmacologic modulation of RNA splicing enhances anti-tumor immunity Pharmacologic modulation of RNA splicing enhances anti-tumor immunity

Abstract Although mutations in DNA are the best-studied source of neoantigens that determine response to immune checkpoint blockade, alterations in RNA splicing within cancer cells could similarly result in neoepitope production. However, the endogenous

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11.03.2022

Tumor RNA transfected DCs derived from iPS cells elicit cytotoxicity a... Tumor RNA transfected DCs derived from iPS cells elicit cytotoxicity a...

Abstract Significant efficacy of induced pluripotent stem cells (iPSCs) in generating DCs for cancer vaccine therapy was suggested in our previous studies. In clinical application of DC vaccine therapy, however, few DC vaccine systems have shown strong clinical response. To enhance immunogenicity in the DC vaccine, we transfected patient-derived iPSDCs with in vitro transcriptional RNA (ivtRNA), which was obtained from tumors of three patients with colorectal cancer. We investigated iPSDCs-ivtRNA which were induced by transfecting ivtRNA o...

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04.03.2022

Mitochondrial functional and structural impairment is involved in the... Mitochondrial functional and structural impairment is involved in the...

Abstract The therapeutic options for castration-resistant prostate cancer (CRPC) are still limited. Natural bioactive compounds were shown to possess pro-death properties in different tumors. We previously reported that δ-tocotrienol (δ-TT) induces apoptosis, paraptosis and autophagy in CRPC cells. Here, we investigated whether δ-TT might exert its activity by impairing mitochondrial functions. We demonstrated that, in PC3 and DU145 cells, δ-TT impairs mitochondrial respiration and structural dynamics. In both cell...

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