Expression of oncogenic HRAS G12V causes defects in control of cell size in NIH 3T3 cells.

Severe defects in control of cell size are closely associated with cancer. However, the mechanisms that drive cell size defects in cancer remain unknown and it is unclear whether they are a direct consequence of signals from primary oncogenic drivers or a secondary consequence of mutations that accumulate during evolution of cancer cells. Here, we report that expression of oncogenic HRAS G12V is sufficient to cause cell size defects in NIH 3T3 cells, which suggests that the cell size defects of cancer cells are a direct consequence of primary oncogenic drivers.

Reversing Cardiac Hypertrophy at the Source Using a Cardiac Targeting Peptide Linked to miRNA106a: Targeting Genes That Cause Cardiac Hypertrophy.

Causes and treatments for heart failure (HF) have been investigated for over a century culminating in data that have led to numerous pharmacological and surgical therapies. Unfortunately, to date, even with the most current treatments, HF remains a progressive disease with no therapies targeting the cardiomyocytes directly. Technological advances within the past two to three years have brought about new paradigms for treating many diseases that previously had been extremely difficult to resolve. One of these new paradigms has been a shift from pharmacological agents to antisense technology (e.g., microRNAs) to target the molecular underpinnings of pathological processes leading to disease onset. Although this paradigm shift may have been postulated over a decade ago, only within the past few years has it become feasible. Here, we show that miRNA106a targets genes that, when misregulated, have been shown to cause hypertrophy and eventual HF. The addition of miRNA106a suppresses misexpressed HF genes and reverses hypertrophy. Most importantly, using a cardiac targeting peptide reversibly linked to miRNA106a, we show delivery is specific to cardiomyocytes.

Cardiac inducing colonies halt fibroblast activation and induce cardiac/endothelial cells to move and expand via paracrine signaling.

Myocardial fibrosis (MF), a common event that develops after myocardial infarction, initially is a reparative process but eventually leads to heart failure and sudden cardiac arrest. In MF, the infarct area is replaced by a collagenous-based scar induced by "excessive" collagen deposition from activated cardiac fibroblasts. The scar prevents ventricular wall thinning; however, over time it expands to noninfarcted myocardium. Therapies to prevent fibrosis include reperfusion, anti-fibrotic agents, and ACE inhibitors. Paracrine factor (PF)/stem cell research has recently gained significance as a therapy. We consistently find that cardiac inducing colonies (CiCs) (derived from human germline pluripotent stem cells) secrete PFs at physiologically relevant concentrations that suppress cardiac fibroblast activation and excessive extracellular matrix protein secretion. These factors also affect human cardiomyocytes and endothelial cells by inducing migration/proliferation of both populations into a myocardial wound model. Finally, CiC factors modulate matrix turnover and proinflammation. Taking the results together, we show that CiCs could help tip the balance from fibrosis toward repair.