Background: The remarkable success of clinical trials in mineralocorticoid receptor (MR) inhibition in heart failure has driven research on the physiological and pathological role(s) of nonepithelial MR expression. MR is widely expressed in the cardiovascular system and is a major determinant of endothelial function, smooth muscle tone, vascular remodeling, fibrosis, and blood pressure. An important new dimension is the appreciation of the role MR plays in immune cells and target organ damage in the heart, kidney and vasculature, and in the development of insulin resistance. Summary: The mechanism for MR activation in tissue injury continues to evolve with the evidence to date suggesting that activation of MR results in a complex repertoire of effects involving both macrophages and T cells. MR is an important transcriptional regulator of macrophage phenotype and function. Another important feature of MR activation is that it can occur even with normal or low aldosterone levels in pathological conditions. Tissue-specific conditional models of MR expression in myeloid cells, endothelial cells, smooth muscle cells and cardiomyocytes have been very informative and have firmly demonstrated a critical role of MR as a key pathophysiologic variable in cardiac hypertrophy, transition to heart failure, adipose inflammation, and atherosclerosis. Finally, the central nervous system activation of MR in permeable regions of the blood-brain barrier may play a role in peripheral inflammation. Key Message: Ongoing clinical trials will help clarify the role of MR blockade in conditions, such as atherosclerosis and chronic kidney disease.

The degree of heterogeneity among cancer stem cells (CSC) remains ill-defined and may hinder effective anti-CSC therapy. Evaluation of oral cancers for such heterogeneity identified two compartments within the CSC pool. One compartment was detected using a reporter for expression of the H3K4me3 demethylase JARID1B to isolate a JARID1Bhigh fraction of cells with stem cell-like function. JARID1Bhigh cells expressed oral CSC markers including CD44 and ALDH1 and showed increased PI3-kinase (PI3K) pathway activation. They were distinguished from a fraction in a G0-like cell cycle state characterized by low reactive oxygen species and suppressed PI3K/AKT signaling. G0-like cells lacked conventional CSC markers but were primed to acquire stem cell-like function by upregulating JARID1B, which directly mediated transition to a state expressing known oral CSC markers. The transition was regulated by PI3K signals acting upstream of JARID1B expression, resulting in PI3K inhibition depleting JARID1Bhigh cells but expanding the G0-like subset. These findings define a novel developmental relationship between two cell phenotypes that may jointly contribute to CSC maintenance. Expansion of the G0-like subset during targeted depletion of JARID1Bhigh cells implicates it as a candidate therapeutic target within the oral CSC pool.

<p>Characterization of G0-like OSCC cells (S1); Characterization of JARID1Bhigh OSCC cells (S2); Functional analysis of JARID1Bhigh OSCC cells (S3); Molecular analysis of G0-like and JARID1Bhigh OSCC cells (S4); Characterization of G0-like and EGFPhigh fractions under normal and JARID1B-depleted conditions (S5); Activation and inhibition of PI3K-Akt signaling pathway in OSCC cells (S6).</p>

<p>Top (most significant) 200 up-regulated gene sets enriched in JARID1Bhigh vs. G0-like LNT14 cells.</p>

<p>Primary antibodies used.</p>

<p>Differentially expressed genes in JARID1Bhigh vs. bulk LNT14 cells.</p>

<p>Top (most significant) 200 up-regulated gene sets enriched in G0-like cells vs. bulk population.</p>

<p>QRT-PCR primer sequences.</p>