Tight junctions: a barrier to the initiation and progression of breast cancer?

Breast cancer is a complex and heterogeneous disease that arises from epithelial cells lining the breast ducts and lobules. Correct adhesion between adjacent epithelial cells is important in determining the normal structure and function of epithelial tissues, and there is accumulating evidence that dysregulated cell-cell adhesion is associated with many cancers. This review will focus on one cell-cell adhesion complex, the tight junction (TJ), and summarize recent evidence that TJs may participate in breast cancer development or progression. We will first outline the protein composition of TJs and discuss the functions of the TJ complex. Secondly we will examine how alterations in these functions might facilitate breast cancer initiation or progression; by focussing on the regulatory influence of TJs on cell polarity, cell fate and cell migration. Finally we will outline how pharmacological targeting of TJ proteins may be useful in limiting breast cancer progression. Overall we hope to illustrate that the relationship between TJ alterations and breast cancer is a complex one; but that this area offers promise in uncovering fundamental mechanisms linked to breast cancer progression

Which primary care practitioners have poor human papillomavirus (HPV) knowledge? A step towards informing the development of professional education initiatives

Background: Primary care practitioners (PCP) play key roles in cervical cancer prevention. Human papillomavirus (HPV) knowledge is an important influence on PCPs’ cervical cancer prevention-related behaviours. We investigated HPV knowledge, and associated factors, among general practitioners (GPs) and practice nurses. Methods: A survey, including factual questions about HPV infection and vaccination, was mailed to GPs and practice nurses in Ireland. Multivariable logistic regression was used to determine which PCPs had low knowledge (questions correctly answered: infection ≤5/11; vaccination: ≤4/10). Questions least often answered correctly were identified. Results: 697 PCPs participated. For HPV infection, GPs and practice nurses answered a median of nine and seven questions correctly, respectively (p⅓ of PCPs. Conclusions: There are important limitations in HPV infection and vaccination knowledge among PCPs. By identifying factors associated with poor knowledge, and areas of particular uncertainty, these results can inform development of professional education initiatives thereby ensuring women have access to uniformly high-quality HPV-related information and advice

LINVIEW: Incremental View Maintenance for Complex Analytical Queries

Many analytics tasks and machine learning problems can be naturally expressed by iterative linear algebra programs. In this paper, we study the incremental view maintenance problem for such complex analytical queries. We develop a framework, called LINVIEW, for capturing deltas of linear algebra programs and understanding their computational cost. Linear algebra operations tend to cause an avalanche effect where even very local changes to the input matrices spread out and infect all of the intermediate results and the final view, causing incremental view maintenance to lose its performance benefit over re-evaluation. We develop techniques based on matrix factorizations to contain such epidemics of change. As a consequence, our techniques make incremental view maintenance of linear algebra practical and usually substantially cheaper than re-evaluation. We show, both analytically and experimentally, the usefulness of these techniques when applied to standard analytics tasks. Our evaluation demonstrates the efficiency of LINVIEW in generating parallel incremental programs that outperform re-evaluation techniques by more than an order of magnitude.Comment: 14 pages, SIGMO

Breast cancer cell migration is regulated through junctional adhesion molecule-A-mediated activation of Rap1 GTPase

ABSTRACT: INTRODUCTION: The adhesion protein junctional adhesion molecule-A (JAM-A) regulates epithelial cell morphology and migration, and its over-expression has recently been linked with increased risk of metastasis in breast cancer patients. As cell migration is an early requirement for tumor metastasis, we sought to identify the JAM-A signalling events regulating migration in breast cancer cells. METHODS: MCF7 breast cancer cells (which express high endogenous levels of JAM-A) and primary cultures from breast cancer patients were used for this study. JAM-A was knocked down in MCF7 cells using siRNA to determine the consequences for cell adhesion, cell migration and the protein expression of various integrin subunits. As we had previously demonstrated a link between the expression of JAM-A and β1-integrin, we examined activation of the β1-integrin regulator Rap1 GTPase in response to JAM-A knockdown or functional antagonism. To test whether JAM-A, Rap1 and β1-integrin lie in a linear pathway, we tested functional inhibitors of all three proteins separately or together in migration assays. Finally we performed immunoprecipitations in MCF7 cells and primary breast cells to determine the binding partners connecting JAM-A to Rap1 activation. RESULTS: JAM-A knockdown in MCF7 breast cancer cells reduced adhesion to, and migration through, the β1-integrin substrate fibronectin. This was accompanied by reduced protein expression of β1-integrin and its binding partners αV- and α5-integrin. Rap1 activity was reduced in response to JAM-A knockdown or inhibition, and pharmacological inhibition of Rap1 reduced MCF7 cell migration. No additive anti-migratory effect was observed in response to simultaneous inhibition of JAM-A, Rap1 and β1-integrin, suggesting that they lie in a linear migratory pathway. Finally, in an attempt to elucidate the binding partners putatively linking JAM-A to Rap1 activation, we have demonstrated the formation of a complex between JAM-A, AF-6 and the Rap1 activator PDZ-GEF2 in MCF7 cells and in primary cultures from breast cancer patients. CONCLUSIONS: Our findings provide compelling evidence of a novel role for JAM-A in driving breast cancer cell migration via activation of Rap1 GTPase and β1-integrin. We speculate that JAM-A over-expression in some breast cancer patients may represent a novel therapeutic target to reduce the likelihood of metastasis

Evaluating the effectiveness of explanations for recommender systems : Methodological issues and empirical studies on the impact of personalization

Peer reviewedPostprin

Can screening for genetic markers improve peripheral artery bypass patency?

AbstractObjective: Three genetic mutations have been associated with an increased risk of thromboembolic events: factor V Leiden R506Q, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T (MTHFR) mutations. The aim of this study was to determine the effect of these mutations on patency of peripheral bypass procedures and preoperative and postoperative thromboembolic events. Methods: Two hundred forty-four randomly selected volunteers participating in the Veterans Affairs Cooperative Study #362 were tested for factor V Leiden, prothrombin, or MTHFR mutations with polymerase chain reaction. Patients enrolled in the study were randomized to receive aspirin therapy or aspirin and warfarin therapy after a peripheral bypass procedure. The frequencies of preoperative and postoperative thromboembolic events and primary patency (PP), assisted primary patency (APP), and secondary patency (SP) rates were compared among carriers of the various mutations. Results: Fourteen patients (5.7%) were heterozygous for the factor V Leiden mutation, seven (2.9%) were heterozygous for the prothrombin mutation, and 108 (44.6%) were heterozygous and 15 (6.2%) homozygous for the MTHFR mutation. After surgery, patients homozygous for the MTHFR gene mutation had increased graft thrombosis, compared with patients who were heterozygous (33.3% versus 11.1%; P = .01), and lower PP, APP and SP rates (P < .05). Furthermore, patients heterozygous for the MTHFR mutation had fewer graft thromboses (11.1% versus 24.4%; P = .01), fewer below-knee amputations (0.9% versus 7.6%; P = .02), and higher PP, APP, and SP rates (PP, 79.6%; APP, 88.9%; SP, 90.7%; P < .05) compared with wild-type control subjects (PP, 63%; APP, 75.6%; SP, 76.5%; P < .05). Conclusion: Patients with either factor V Leiden or prothrombin mutations were not at an increased risk for postoperative graft occlusion or thromboembolic events. Patients heterozygous for MTHFR mutation had a lower risk of graft thrombosis and higher graft patency rates compared with both homozygous and wild-type control subjects. Patients homozygous for the MTHFR mutation had lower graft patency rates compared with patients who were heterozygous, and a trend was seen toward lower patency rates compared with wild-type control subjects. Therefore, screening for the MTHFR gene mutation before surgery may identify patients at an increased risk of graft thrombosis. (J Vasc Surg 2002;36:1198-206.

Privacy by Design: From Technologies to Architectures (Position Paper)

Existing work on privacy by design mostly focus on technologies rather than methodologies and on components rather than architectures. In this paper, we advocate the idea that privacy by design should also be addressed at the architectural level and be associated with suitable methodologies. Among other benefits, architectural descriptions enable a more systematic exploration of the design space. In addition, because privacy is intrinsically a complex notion that can be in tension with other requirements, we believe that formal methods should play a key role in this area. After presenting our position, we provide some hints on how our approach can turn into practice based on ongoing work on a privacy by design environment