Collective invasion induced by an autocrine purinergic loop through connexin-43 hemichannels

Progression of epithelial cancers predominantly proceeds by collective invasion of cell groups with coordinated cell-cell junctions and multicellular cytoskeletal activity. Collectively invading breast cancer cells express the gap junction protein connexin-43 (Cx43), yet whether Cx43 regulates collective invasion remains unclear. We here show that Cx43 mediates gap-junctional coupling between collectively invading breast cancer cells and, via hemichannels, adenosine nucleotide/nucleoside release into the extracellular space. Using molecular interference and rescue strategies, we identify that Cx43 hemichannel function, but not intercellular communication, induces leader cell activity and collective migration through the engagement of the adenosine receptor 1 (ADORA1) and AKT signaling. Accordingly, pharmacological inhibition of ADORA1 or AKT signaling caused leader cell collapse and halted collective invasion. ADORA1 inhibition further reduced local invasion of orthotopic mammary tumors in vivo, and joint up-regulation of Cx43 and ADORA1 in breast cancer patients correlated with decreased relapse-free survival. This identifies autocrine purinergic signaling, through Cx43 hemichannels, as a critical pathway in leader cell function and collective invasion

Positive and negative polar questions in discourse

This paper presents a number of experiments assessing the felicity of positive and negative polar questions in various types of discourse contexts

Automatic detection of the foveal center in optical coherence tomography

We propose a method for automatic detection of the foveal center in optical coherence tomography (OCT). The method is based on a pixel-wise classification of all pixels in an OCT volume using a fully convolutional neural network (CNN) with dilated convolution filters. The CNN-architecture contains anisotropic dilated filters and a shortcut connection and has been trained using a dynamic training procedure where the network identifies its own relevant training samples. The performance of the proposed method is evaluated on a data set of 400 OCT scans of patients affected by age-related macular degeneration (AMD) at different severity levels. For 391 scans (97.75%) the method identified the foveal center with a distance to a human reference less than 750 mum, with a mean (+/- SD) distance of 71 mum +/- 107 mum. Two independent observers also annotated the foveal center, with a mean distance to the reference of 57 mum +/- 84 mum and 56 mum +/- 80 mum, respectively. Furthermore, we evaluate variations to the proposed network architecture and training procedure, providing insight in the characteristics that led to the demonstrated performance of the proposed method

Morphological and topographical appearance of microaneurysms on optical coherence tomography angiography

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RETINAL HYPERREFLECTIVE FOCI IN TYPE 1 DIABETES MELLITUS

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