ALTERATION OF THE EPHA2/EPHRIN-A SIGNALING AXIS IN PSORIATIC EPIDERMIS

EphA2 is a receptor tyrosine kinase (RTK) that triggers keratinocyte differentiation upon activation and subsequently down-regulation by ephrin-A1 ligand. The objective for this study was to determine if the EphA2/ephrin-A1 signaling axis was altered in psoriasis, an inflammatory skin condition where keratinocyte differentiation is abnormal. Microarray analysis of skin biopsies from psoriasis patients revealed increased mRNA transcripts for several members of this RTK family in plaques, including the EphA1, EphA2 and EphA4 subtypes prominently expressed by keratinocytes. Of these, EphA2 showed the greatest up-regulation, a finding that was confirmed by quantitative RT-PCR, IHC analysis and ELISA. In contrast, psoriatic lesions exhibited reduced ephrin-A ligand immunoreactivity. Exposure of primary keratinocytes induced to differentiated in high calcium or a 3-dimensiosnal raft culture of human epidermis to a combination of growth factors and cytokines elevated in psoriasis increased EphA2 mRNA and protein expression while inducing S100A7 and disrupting differentiation. Pharmacological delivery of a soluble ephrin-A1 peptidomimetic ligand led to a reduction in EphA2 expression and ameliorated proliferation and differentiation in raft cultures exposed to EGF and IL-1α. These findings suggest that ephrin-A1-mediated down-regulation of EphA2 supports keratinocyte differentiation in the context of cytokine perturbation

Atomic force microscopy studies of bioprocess engineering surfaces - imaging, interactions and mechanical properties mediating bacterial adhesion

The detrimental effect of bacterial biofilms on process engineering surfaces is well documented. Thus, interest in the early stages of bacterial biofilm formation; in particular bacterial adhesion and the production of anti-fouling coatings has grown exponentially as a field. During this time, Atomic force microscopy (AFM) has become an essential tool for the evaluation of bacterial adhesion. Due to its versatility AFM offers not only insight into the topographical landscape and mechanical properties of the engineering surfaces, but elucidates, through direct quantification the topographical and biomechnical properties of the foulants The aim of this paper is to collate the current research on bacterial adhesion, both theoretical and practical, and outline how AFM as a technique is uniquely equipped to provide further insight into the nanoscale world at the bioprocess engineering surface

Noninitiation of Tamoxifen in Young Women at High Risk for Breast Cancer

Introduction: Tamoxifen chemoprevention reduces the risk of breast cancer for high-risk patients, but initiation is low among young women. We sought to identify reasons for tamoxifen noninitiation among young high-risk patients. Methods: A retrospective study identified women younger than 46 years who received a high-risk diagnosis (BRCA mutation, lobular carcinoma in situ, atypical ductal hyperplasia/atypical lobular hyperplasia [ADH/ALH], flat epithelial atypia, strong family history), but did not initiate tamoxifen. Excluded were patients who opted for risk-reducing mastectomies, were younger than age 35, received a simultaneous cancer diagnosis, or had a history of tamoxifen use. Patient demographics were identified, along with information regarding discussions about tamoxifen initiation and reasons for noninitiation. Results: We included 67 patients with a median age of 41 years (range 35 to 45 years). The most common high-risk diagnosis was ADH (28.6%). Overall, perception of little benefit for tamoxifen therapy (46%) and lack of provider discussion (35%) were the most common reasons for noninitiation. No specific demographic factors were associated with a patient-provider discussion, but there was an association between ADH/ALH diagnosis and a discussion about tamoxifen (47.6% vs 36.0%, p = 0.02). Among those patients who did have a discussion about tamoxifen and did not initiate the medication, the most common reasons were a perception of little benefit (71%), followed by fertility concerns (22%). Conclusion: A perception of little benefit for treatment and a lack of provider discussion were the most common reasons for tamoxifen noninitiation. Improved strategies for education about the significant benefits of tamoxifen therapy are needed for both high-risk patients and providers

Evidence for Altered Wnt Signaling in Psoriatic Skin

The Wnt gene family encodes a set of highly conserved secreted signaling proteins that have major roles in embryogenesis and tissue homeostasis. Yet the expression of this family of important mediators in psoriasis, a disease characterized by marked changes in keratinocyte growth and differentiation, is incompletely understood. We subjected 58 paired biopsies from lesional and uninvolved psoriatic skin and 64 biopsies from normal skin to global gene expression profiling. WNT5A transcripts were upregulated fivefold in lesional skin, accompanied by increased Wnt-5a protein levels. Notably, WNT5A mRNA was markedly induced by IL-1α, tumor necrosis factor-α, IFN-γ, and transforming growth factor-α in cultured keratinocytes. Frizzled 2 (FZD2) and FZD5, which encode receptors for Wnt5A, were also increased in lesional psoriatic skin. In contrast, expression of WIF1 mRNA, encoding a secreted antagonist of the Wnt proteins, was downregulated >10-fold in lesional skin, along with decreased WNT inhibitory factor (WIF)-1 immunostaining. Interestingly, pathway analysis along with reduced AXIN2 expression and lack of nuclear translocation of β-catenin indicated a suppression of canonical Wnt signaling in lesional skin. The results of our study suggest a shift away from canonical Wnt signaling toward noncanonical pathways driven by interactions between Wnt-5a and its cognate receptors in psoriasis, accompanied by impaired homeostatic inhibition of Wnt signaling by WIF-1 and dickkopf