Search

Ovarian cancer is the leading cause of death among all gynecological malignancies due to the development of acquired chemoresistance and disease relapse. Although the role of cancer stem cells (CSCs), a subset of tumor cells with the self-renewal and differentiation capabilities, in therapeutic resistance is beginning to be better understood, the significance of epigenetic regulatory mechanisms responsible for integrating the stemness with drug resistance remain poorly understood. Here we identified that lysine demethylase KDM3A as a critical regulator of ovarian cancer stemness and cisplatin resistance by inducing the expressions of pluripotent molecules Sox2 and Nanog and anti-apoptotic B-cell lymphoma 2 (Bcl-2), respectively. In addition, KDM3A induces ovarian cancer growth while antagonizing cellular senescence by repressing the expression of cyclin-dependent kinase inhibitor, p21Waf1/Cip1. The underlying mechanism of the noted biological processes include KDM3A-mediated stimulation of Sox2 expression, and demethylating p53 protein and consequently, modulating its target genes such as Bcl-2 and p21Waf1/Cip1expression. Consistently, KDM3A depletion inhibited the growth of subcutaneously implanted cisplatin-resistant human ovarian cancer cells in athymic nude mice. Moreover, KDM3A is abundantly expressed and positively correlated with Sox2 expression in human ovarian cancer tissues. In brief, our findings reveal a novel mechanism by which KDM3A promotes ovarian CSCs, proliferation and chemoresistance and thus, highlights the significance of KDM3A as a novel therapeutic target for resistant ovarian cancer.

Correction to: Oncogene (2017) 36, 1537–1545; doi:10.1038/onc.2016.320; published online 3 October 2016 Following the publication of this article the authors note that they inadvertently omitted the correct acknowledgement for the support from the NIH and The Carl and Roberta Deutsch Foundation for the above referenced paper.

Titanium and its alloys are materials that exhibit unique combination of mechanical and physical properties that enable their usage in various fields. In spite of having a lot of advantages, their usage is limited because they are difficult to machine due to their inherent properties of high specific heat capacity, reactivity with tool and low thermal conductivity thereby causing excessive tool wear. To facilitate the process of machining, it becomes necessary to find out and relieve the residual stress caused during machining. Since experiments cannot be performed for each instance, creation of an FE model is desirable. In this paper a finite element analysis (FEA) of the machining of Ti6Al4V for different cutting speeds is presented. A 3D finite element model is developed with the Titanium alloy (Ti6Al4V) as the workpiece and a four flute carbide tip end mill cutter as the tool to predict the residual stress developed within the titanium alloy after machining. The finite element model utilises the Johnson-Cook model to depict the plasticity and the damage criteria and implements the Arbitrary Lagrangian Eulerian (ALE) formulation to increase the accuracy of the model. The FE model has been developed and the findings are presented. The results indicate that residual stresses are maximum at the surface and decrease linearly along the depth and increase as the cutting speed and depth of cut are increased.