👤 Wendy Broom

First-line immune checkpoint inhibitor (ICI) combinations show responses in subsets of hepatocellular carcinoma (HCC) patients. Nearly half of HCCs are Wnt-active with mutations in CTNNB1 (encoding for β-catenin), AXIN1/2, or APC, and demonstrate heterogeneous and limited benefit to ICI due to an immune excluded tumor microenvironment. We show significant tumor responses in multiple β-catenin-mutated immunocompetent HCC models to a novel siRNA encapsulated in lipid nanoparticle targeting CTNNB1 (LNP-CTNNB1). Both single-cell and spatial transcriptomics reveal cellular and zonal reprogramming, along with activation of immune regulatory transcription factors IRF2 and POU2F1, re-engaged type I/II interferon signaling, and alterations in both innate and adaptive immunity upon β-catenin suppression with LNP-CTNNB1 at early- and advanced-stage disease. Moreover, ICI enhances response to LNP-CTNNB1 in advanced-stage disease by preventing T cell exhaustion and through formation of lymphoid aggregates (LA). In fact, expression of an LA-like gene signature prognosticates survival for patients receiving atezolizumab plus bevacizumab in the IMbrave150 phase III trial and inversely correlates with CTNNB1-mutatational status in this patient cohort. In conclusion, LNP-CTNNB1 is efficacious as monotherapy and in combination with ICI in CTNNB1-mutated HCCs through impacting tumor cell-intrinsic signaling and remodeling global immune surveillance, providing rationale for clinical investigations. Show less

Reverse Cholesterol Transport (RCTr) is the mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam cell formation and the development of atherosclerosis. Exercise affects RCTr, by influencing high-density lipoprotein cholesterol (HDL) through remodeling and by promoting hepatobiliary sterol excretion. The objectives of this systematized review of animal studies is to summarize the literature and provide an overview of the effects of chronic exercise (at least two weeks) on apolipoproteins (Apo A-I, Apo-E), Paraoxonase-1 (PON1), ATP-binding cassette transporters (ABCA1, ABCG1, ABCG4, ABCG5, ABCG8), scavenger receptor class B type I (SR-BI), cholesteryl ester transfer protein (CETP), low-density lipoprotein receptor (LDLr) and cholesterol 7 alpha-hydroxylase (CYP7A1) and Niemann-Pick C1-like 1 (NPC1L1). Three electronic databases (PubMed, Science Direct and Google Scholar) were searched for eligible studies conducted from the earliest available date to August 2018. Most of studies investigate the effects of low to moderate intensity aerobic training on RCTr elements. The majority were on exercised rats undertaking moderate intensity aerobic training. This review highlights that moderate intensity and longer-term training has a greater effect on RCTr elements than low intensity training. There a few studies examining high intensity training which warrants further investigation. Show less

The gene involved in the classical juvenile form of Batten disease, CLN3 has been identified as being highly homologous to the Saccharomyces cerevisiae YHC3 gene. To provide a simple model for the biochemical events underlying this disease, several disruptions have been made in YHC3 in three different S. cerevisiae strains. No obvious growth differences were observed, and neither was the previously reported phenotypic difference between wild-type and yeast disrupted in YHC3. Show less