Integrative analysis identifies the atypical repressor E2F8 as a targetable transcriptional activator driving lethal prostate cancer.

Acquired resistance to androgen receptor (AR)-targeted therapies underscores the need to identify alternative therapeutic targets for treating lethal prostate cancer. In this study, we evaluated the prognostic significance of 1635 human transcription factors (TFs) by analyzing castration-resistant prostate cancer (CRPC) datasets from the West and East Stand Up to Cancer (SU2C) cohorts. Through this screening approach, we identified E2F8, a putative transcriptional repressor, as a TF consistently associated with poorer patient outcomes in both cohorts.

Deciphering and targeting host factors to counteract SARS-CoV-2 and coronavirus infections: insights from CRISPR approaches.

Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses depend on host factors for the process of viral infection and replication. A better understanding of the dynamic interplay between viral pathogens and host cells, as well as identifying of virus-host dependencies, offers valuable insights into disease mechanisms and informs the development of effective therapeutic strategies against viral infections. This review delves into the key host factors that facilitate or hinder SARS-CoV-2 infection and replication, as identified by CRISPR/Cas9-based screening platforms.

Cas13d knockdown of lung protease Ctsl prevents and treats SARS-CoV-2 infection.

SARS-CoV-2 entry into cells requires specific host proteases; however, no successful in vivo applications of host protease inhibitors have yet been reported for treatment of SARS-CoV-2 pathogenesis. Here we describe a chemically engineered nanosystem encapsulating CRISPR-Cas13d, developed to specifically target lung protease cathepsin L (Ctsl) messenger RNA to block SARS-CoV-2 infection in mice. We show that this nanosystem decreases lung Ctsl expression in normal mice efficiently, specifically and safely.

Phosphorylated MED1 links transcription recycling and cancer growth.

Mediator activates RNA polymerase II (Pol II) function during transcription, but it remains unclear whether Mediator is able to travel with Pol II and regulate Pol II transcription beyond the initiation and early elongation steps. By using in vitro and in vivo transcription recycling assays, we find that human Mediator 1 (MED1), when phosphorylated at the mammal-specific threonine 1032 by cyclin-dependent kinase 9 (CDK9), dynamically moves along with Pol II throughout the transcribed genes to drive Pol II recycling after the initial round of transcription. Mechanistically, MED31 mediates the recycling of phosphorylated MED1 and Pol II, enhancing mRNA output during the transcription recycling process.

Nanodiamond autophagy inhibitor allosterically improves the arsenical-based therapy of solid tumors.

Arsenic trioxide (ATO) is a successful chemotherapeutic drug for blood cancers via selective induction of apoptosis; however its efficacy in solid tumors is limited. Here we repurpose nanodiamonds (NDs) as a safe and potent autophagic inhibitor to allosterically improve the therapeutic efficacy of ATO-based treatment in solid tumors. We find that NDs and ATO are physically separate and functionally target different cellular pathways (autophagy vs.

Serum protein corona-responsive autophagy tuning in cells.

Autophagy represents an important cellular response to nanoparticles (NPs), whose modulation holds great promise for developing nanomedicine. Here, we systematically studied cell autophagy responses elicited by the NP-protein corona with diverse protein corona types surrounding NPs with different sizes, shapes, and compositions. We demonstrated that these physicochemical properties of NP-protein coronas exerted a remarkable influence on cell autophagy responses.

One-Shot Immunomodulatory Nanodiamond Agents for Cancer Immunotherapy.

The use of functional nanodiamonds (fNDs) to deliver CpG oligonucleotides (ODNs) for sustained immunostimulation is reported. It is demonstrated that monotherapy using this immunostimulatory agent significantly suppresses the tumor growth in two murine tumor models. This fND-based nanoagent opens new opportunities for immunotherapy, as well as clinical applications of various types of therapeutic nucleic acids.

Fluorescent In Situ Targeting Probes for Rapid Imaging of Ovarian-Cancer-Specific γ-Glutamyltranspeptidase.

γ-Glutamyltranspeptidase (GGT) is a tumor biomarker that selectively catalyzes the cleavage of glutamate overexpressed on the plasma membrane of tumor cells. Here, we developed two novel fluorescent in situ targeting (FIST) probes that specifically target GGT in tumor cells, which comprise 1) a GGT-specific substrate unit (GSH), and 2) a boron-dipyrromethene (BODIPY) moiety for fluorescent signalling. In the presence of GGT, sulfur-substituted BODIPY was converted to amino-substituted BODIPY, resulting in dramatic fluorescence variations.

Size-dependent cytotoxicity of nanocarbon blacks.

In this study, we investigated the toxic effects of nanocarbon blacks (NCBs) with different sizes to mouse macrophage RAW264.7 cells. MTT and fluorescence-based LIVE assays demonstrated that NCBs uptake caused a size and dose-dependent growth inhibition to the cells.