Investigation of Cellular and Molecular Responses to Pulsed Focused Ultrasound in a Mouse Model

Continuous focused ultrasound (cFUS) has been widely used for thermal ablation of tissues, relying on continuous exposures to generate temperatures necessary to induce coagulative necrosis. Pulsed FUS (pFUS) employs non-continuous exposures that lower the rate of energy deposition and allow cooling to occur between pulses, thereby minimizing thermal effects and emphasizing effects created by non-thermal mechanisms of FUS (i.e., acoustic radiation forces and acoustic cavitation). pFUS has shown promise for a variety of applications including drug and nanoparticle delivery; however, little is understood about the effects these exposures have on tissue, especially with regard to cellular pro-homing factors (growth factors, cytokines, and cell adhesion molecules). We examined changes in murine hamstring muscle following pFUS or cFUS and demonstrate that pFUS, unlike cFUS, has little effect on the histological integrity of muscle and does not induce cell death. Infiltration of macrophages was observed 3 and 8 days following pFUS or cFUS exposures. pFUS increased expression of several cytokines (e.g., IL-1α, IL-1β, TNFα, INFγ, MIP-1α, MCP-1, and GMCSF) creating a local cytokine gradient on days 0 and 1 post-pFUS that returns to baseline levels by day 3 post-pFUS. pFUS exposures induced upregulation of other signaling molecules (e.g., VEGF, FGF, PlGF, HGF, and SDF-1α) and cell adhesion molecules (e.g., ICAM-1 and VCAM-1) on muscle vasculature. The observed molecular changes in muscle following pFUS may be utilized to target cellular therapies by increasing homing to areas of pathology

Novel role of cPLA2α in membrane and actin dynamics

Actin-directed processes such as membrane ruffling and cell migration are regulated by specific signal transduction pathways that become activated by growth factor receptors. The same signaling pathways that lead to modifications in actin dynamics also activate cPLA2α. Moreover, arachidonic acid, the product of cPLA2α activity, is involved in regulation of actin dynamics. Therefore, it was investigated whether cPLA2α plays a role in actin dynamics, more specifically during growth factor-induced membrane ruffling and cell migration. Upon stimulation of ruffling and cell migration by growth factors, endogenous cPLA2α and its active phosphorylated form were shown to relocate at protrusions of the cell membrane involved in actin and membrane dynamics. Inhibition of cPLA2α activity with specific inhibitors blocked growth factor-induced membrane and actin dynamics, suggesting an important role for cPLA2α in these processes

Cross-Sectional Associations between Body Size, Circulating Sex-Steroid Hormones and IGF Components among Healthy Chinese Women

<div><p>The incidence of breast cancer has increased in Asian countries and rates of hormone receptor (HR) negative breast cancer exceed those of Western countries. Epidemiologic data suggest that the association between body size and BC risk may vary by HR status, and could differ geographically. While body size may influence BC risk by moderating the synthesis and metabolism of circulating sex-steroid hormones, insulin-like growth factor (IGF)-1 and related binding proteins, there is a dearth of literature among Asian women. We aimed to examine these specific associations in a sample of Chinese women. In Sichuan Province 143 women aged ≥40 years were recruited through outpatient services (2011–2012). Questionnaires, anthropometric measurements, and blood samples were utilized for data collection and linear regression was applied in data analyses. Among women <50 years we observed a non-monotonic positive association between body mass index (BMI) and 17β-estradiol, and a reversed J-shaped association between BMI and IGF-1 (<i>p</i> ≤0.05). We observed similar associations between waist-to-hip ratio and these markers. Our finding of augmented IGF-1 among women with low body mass may have implications for understanding breast tumor heterogeneity in diverse populations and should be evaluated in larger prospective studies with cancer outcomes.</p></div