Mesenchymal Cells Support the Oncogenicity and Therapeutic Response of the Hedgehog Pathway in Triple-Negative Breast Cancer

The paracrine interaction between tumor cells and adjacent stroma has been associated with the oncogenic activity of the Hedgehog (Hh) pathway in triple-negative breast tumors. The present study developed a model of paracrine Hh signaling and examined the impact of mesenchymal cell sources and culture modalities in the oncogenicity of the Hh pathway in breast tumor cells. Studies consisted of tumor cell monocultures and co-cultures with cancer-associated and normal fibroblasts, tumor cells that undergo epithelial–mesenchymal transition (EMT), or adipose-derived mesenchymal stem cells (ADMSCs). Hh ligand and pathway inhibitors, GANT61 and NVP-LDE225 (NVP), were evaluated in both cell cultures and a mouse xenograft model. Results in monocultures show that tumor cell viability and Hh transcriptional activity were not affected by Hh inhibitors. In co-cultures, down-regulation of GLI1, SMO, and PTCH1 in the stroma correlated with reduced tumor growth rates in xenografted tumors and cell cultures, confirming a paracrine interaction. Fibroblasts and EMT cells supported Hh transcriptional activity and enhanced tumor cell growth. Mixed and adjacent culture modalities indicate that tumor growth is supported via fibroblast-secreted soluble factors, whereas enriched tumor stemness requires close proximity between tumor and fibroblasts. Overall this study provides a tumor–mesenchymal model of Hh signaling and highlights the therapeutic value of mesenchymal cells in the oncogenic activity of the Hh pathway.</jats:p

Hypertension prevalence, awareness, treatment and control among older people in Latin America, India and China: a 10/66 cross-sectional population-based survey

Objectives To estimate the prevalence, social patterning, treatment and control of hypertension among older people in the 10/66 Dementia Research Group developing country sites. Methods Cross-sectional surveys of SBP, hypertension, and hypertension awareness, treatment and control among 17 014 people aged 65 years and over in eight urban and four rural sites in Latin America, India and China. Results Hypertension prevalence was higher in urban (range 52.6-79.8%) than rural sites (range 42.6-56.9%), and lower in men than women [pooled prevalence ratio 0.89, 95% confidence interval (CI) 0.85-0.93]. Educational attainment was positively associated with hypertension in rural and least-developed sites. Age-standardized morbidity ratios, compared to USA (100), were higher in urban sites in Cuba (105), Dominican Republic (109), and Venezuela (107), similar in Puerto Rico (105), urban Mexico (99) and urban India (101), and lower in urban (75) and rural (61) Peru, rural Mexico (81), urban (91) and rural (84) China and rural India (65). In most Latin American centres, and urban China just over one-third of those with hypertension were controlled (BP&lt;140/90). Control was poor in rural China (2%), urban India (12%) and rural India (9%). The proportion controlled, not compositional factors (age, sex, education and obesity), explained most of the between-site variation in SBP. Conclusion Uncontrolled hypertension is common among older people in developing countries, and may rise further during the demographic and health transitions. It is a major determinant of population SBP level. Strengthening primary care to improve hypertension management is necessary for primary prevention. J Hypertens 30:177-187 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams &amp; Wilkins.Peripheral Vascular DiseaseSCI(E)SSCI21ARTICLE1177-1873

Cell damage produced by magnetic fluid hyperthermia on microglial BV2 cells

We present evidence on the effects of exogenous heating by water bath (WB) and magnetic hyperthermia (MHT) on a glial micro-tumor phantom. To this, magnetic nanoparticles (MNPs) of 30-40 nm were designed to obtain particle sizes for maximum heating efficiency. The specific power absorption (SPA) values (f = 560 kHz, H = 23.9 kA/m) for as prepared colloids (533-605 W/g) dropped to 98-279 W/g in culture medium. The analysis of the intracellular MNPs distribution showed vesicle-trapped MNPs agglomerates spread along the cytoplasm, as well as large (~0.5-0.9 μm) clusters attached to the cell membrane. Immediately after WB and MHT (T = 46 °C for 30 min) the cell viability was ≈70% and, after 4.5 h, decreased to 20-25%, demonstrating that metabolic processes are involved in cell killing. The analysis of the cell structures after MHT revealed a significant damage of the cell membrane that is correlated to the location of MNPs clusters, while local cell damage were less noticeable after WB without MNPs. In spite of the similar thermal effects of WB and MHT on the cell viability, our results suggest that there is an additional mechanism of cell damage related to the presence of MNPs at the intracellular space.This work was supported by the Spanish Ministerio de Economia y Competitividad (MINECO) through project MAT2016-78201-P. We are indebted to Dr. M. López Fanarraga for her advice with the BV2 cell line used here, to Dr. B. Sanz for helping with the in vitro experimental design, and to Dr. R. Fernandez-Pacheco for his support regarding STEM imaging. Authors would like to acknowledge the use of Servicio General de Apoyo a la Investigación (SAI-UZ), Servicios Científico Técnicos CIBA-IACS-UZ and Laboratorio de Microscopias Avanzadas for technical support.Peer reviewe