Matrix metalloproteinase-induced epithelial-mesenchymal transition: tumor progression at Snail's pace.

Matrix metalloproteinases (MMPs) are enzymes that digest components of the extracellular matrix (ECM) as well as cell surface receptors for soluble factors and junctional proteins involved in cell-cell and cell-ECM interactions. MMPs are involved in many physiological processes that require tissue remodeling but are also expressed in nearly all tumors, where they stimulate tumor growth, invasion, and metastasis. Previous studies have shown that expression of stromelysin-1/MMP-3 in the mammary glands of transgenic mice causes the production of invasive carcinomas; our recent investigations provide insight into how MMPs can promote the development of such tumors. We show that exposing mouse mammary epithelial cells to MMP-3 stimulates epithelial-mesenchymal transition (EMT), a phenotypic alteration in which epithelial cells acquire invasive mesenchymal characteristics. EMT is a necessary component of embryonic development, but acquisition of EMT characteristics by cancer cells facilitates invasion and metastasis. MMP-3-induced EMT involves induction of Snail, a transcription factor long studied for its role in physiological EMT but which is increasingly recognized as a factor involved in tumor progression and malignancy. In this review, we examine how MMPs and Snail function in tumor progression and how identification of an MMP-Snail signaling axis provides insight into new anticancer therapeutic strategies.

Smarter hospital communication: secure smartphone text messaging improves provider satisfaction and perception of efficacy, workflow.

BACKGROUND: Though current hospital paging systems are neither efficient (callbacks disrupt workflow), nor secure (pagers are not Health Insurance Portability and Accountability Act [HIPAA]-compliant), they are routinely used to communicate patient information. Smartphone-based text messaging is a potentially more convenient and efficient mobile alternative; however, commercial cellular networks are also not secure. OBJECTIVE: To determine if augmenting one-way pagers with Medigram, a secure, HIPAA-compliant group messaging (HCGM) application for smartphones, could improve hospital team communication. DESIGN: Eight-week prospective, cluster-randomized, controlled trial SETTING: Stanford Hospital INTERVENTION: Three inpatient medicine teams used the HCGM application in addition to paging, while two inpatient medicine teams used paging only for intra-team communication. MEASUREMENTS: Baseline and post-study surveys were collected from 22 control and 41 HCGM team members. RESULTS: When compared with paging, HCGM was rated significantly (P < 0.05) more effective in: (1) allowing users to communicate thoughts clearly (P = 0.010) and efficiently (P = 0.009) and (2) integrating into workflow during rounds (P = 0.018) and patient discharge (P = 0.012). Overall satisfaction with HCGM was significantly higher (P = 0.003). 85% of HCGM team respondents said they would recommend using an HCGM system on the wards. CONCLUSIONS: Smartphone-based, HIPAA-compliant group messaging applications improve provider perception of in-hospital communication, while providing the information security that paging and commercial cellular networks do not.

Genetic variation in DNA repair pathways and risk of non-Hodgkin's lymphoma.

Molecular and genetic evidence suggests that DNA repair pathways may contribute to lymphoma susceptibility. Several studies have examined the association of DNA repair genes with lymphoma risk, but the findings from these reports have been inconsistent. Here we provide the results of a focused analysis of genetic variation in DNA repair genes and their association with the risk of non-Hodgkin's lymphoma (NHL). With a population of 1,297 NHL cases and 1,946 controls, we have performed a two-stage case/control association analysis of 446 single nucleotide polymorphisms (SNPs) tagging the genetic variation in 81 DNA repair genes. We found the most significant association with NHL risk in the ATM locus for rs227060 (OR = 1.27, 95% CI: 1.13-1.43, p = 6.77×10(-5)), which remained significant after adjustment for multiple testing. In a subtype-specific analysis, associations were also observed for the ATM locus among both diffuse large B-cell lymphomas (DLBCL) and small lymphocytic lymphomas (SLL), however there was no association observed among follicular lymphomas (FL). In addition, our study provides suggestive evidence of an interaction between SNPs in MRE11A and NBS1 associated with NHL risk (OR = 0.51, 95% CI: 0.34-0.77, p = 0.0002). Finally, an imputation analysis using the 1,000 Genomes Project data combined with a functional prediction analysis revealed the presence of biologically relevant variants that correlate with the observed association signals. While the findings generated here warrant independent validation, the results of our large study suggest that ATM may be a novel locus associated with the risk of multiple subtypes of NHL.

Matrix metalloproteinase-induced fibrosis and malignancy in breast and lung.

Fibrosis is a pathological condition in which tissue structure is disrupted by production of excess extracellular matrix (ECM), and chronic tissue fibrosis is associated with tumor development. Myofibroblasts are the principal mediators of fibrosis, producing abundant ECM as well as inflammatory and angiogenic factors. Myofibroblasts are also abundant in tumor stroma, where they facilitate tumor growth and progression. Matrix metalloproteinases (MMPs), enzymes that degrade and remodel the ECM, are believed to play a critical role in the development of fibrotic tissue, though the mechanism by which this occurs is unclear. Expression of MMP-3 in mammary epithelial cells of transgenic mice stimulates development of fibrosis and subsequent tumor formation. We have recently determined that exposure of mammary epithelial cells to MMP-3 induces a specialized form of epithelial-mesenchymal transition in which the cells acquire myofibroblast-like characteristics and that this process is dependent upon the generation of cellular reactive oxygen species (ROS). New data from culture models in which MMPs are inducibly expressed in human lung cell lines, and transgenic mouse models in which MMPs are inducibly expressed in lung alveolar epithelial cells, suggest that similar processes likely exist in the lung.