CYP2D6 variants and the prediction of tamoxifen response in randomized patients: author response

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Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial

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A systematic review of biomarkers for disease progression in Parkinson's disease

Peer reviewedPublisher PD

Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and Validation

Purpose: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. Methods: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates. Results: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifentreated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results

Primary cilia elongation in response to interleukin-1 mediates the inflammatory response

Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50 % increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA

de Sitter Thick Brane Solution in Weyl Geometry

In this paper, we consider a de Sitter thick brane model in a pure geometric Weyl integrable five-dimensional space-time, which is a generalization of Riemann geometry and is invariant under a so-called Weyl rescaling. We find a solution of this model via performing a conformal transformation to map the Weylian structure into a familiar Riemannian one with a conformal metric. The metric perturbations of the model are discussed. For gravitational perturbation, we get the effective modified P$\ddot{\text{o}}$schl-Teller potential in corresponding Schr$\ddot{\text{o}}$dinger equation for Kaluza-Klein (KK) modes of the graviton. There is only one bound state, which is a normalizable massless zero mode and represents a stable 4-dimensional graviton. Furthermore, there exists a mass gap between the massless mode and continuous KK modes. We also find that the model is stable under the scalar perturbation in the metric. The correction to the Newtonian potential on the brane is proportional to $e^{-3 r \beta/2}/r^2$, where $\beta$ is the de Sitter parameter of the brane. This is very different from the correction caused by a volcano-like effective potential.Comment: 24 pages, 13 figures, published versio