BRCA1 is a key regulator of breast differentiation through activation of Notch signalling with implications for anti-endocrine treatment of breast cancers

Here, we show for the first time, that the familial breast/ovarian cancer susceptibility gene BRCA1 activates the Notch pathway in breast cells by transcriptional upregulation of Notch ligands and receptors in both normal and cancer cells. We demonstrate through chromatin immunoprecipitation assays that BRCA1 is localized to a conserved intronic enhancer region within the Notch ligand Jagged-1 (JAG1) gene, an event requiring ΔNp63. We propose that this BRCA1/ΔNp63-mediated induction of JAG1 may be important the regulation of breast stem/precursor cells, as knockdown of all three proteins resulted in increased tumoursphere growth and increased activity of stem cell markers such as Aldehyde Dehydrogenase 1 (ALDH1). Knockdown of Notch1 and JAG1 phenocopied BRCA1 knockdown resulting in the loss of Estrogen Receptor-α (ER-α) expression and other luminal markers. A Notch mimetic peptide could activate an ER-α promoter reporter in a BRCA1-dependent manner, whereas Notch inhibition using a γ-secretase inhibitor reversed this process. We demonstrate that inhibition of Notch signalling resulted in decreased sensitivity to the anti-estrogen drug Tamoxifen but increased expression of markers associated with basal-like breast cancer. Together, these findings suggest that BRCA1 transcriptional upregulation of Notch signalling is a key event in the normal differentiation process in breast tissue.

AXL Is a Key Regulator of Inherent and Chemotherapy-Induced Invasion and Predicts a Poor Clinical Outcome in Early-Stage Colon Cancer

Purpose: Despite the use of 5-fluorouracil (5-FU)–based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse.

Experimental Design: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression.

Results: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU–induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues.

Conclusions: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF–targeted therapies have failed.

Editorial: Special Issue on Secure Physical Layer Communications

In wireless networks, the broadcast nature of the propagation medium makes the communication process vulnerable to malicious nodes (e.g. eavesdroppers) which are in the coverage area of the transmission. Thus, security issues play a vital role in wireless systems. Traditionally, information security has been addressed in the upper layers (e.g. the network layer) through the design of cryptographic protocols. Cryptography-based security aims to design a protocol such that it is computationally prohibitive for the eavesdropper to decode the information. The idea behind this approach relies on the limited computational power of the eavesdroppers. However, with advances in emerging hardware technologies, achieving secure communications relying on protocol-based mechanisms alone become insufficient. Owing to this fact, a new paradigm of secure communications has been shifted to implement the security at the physical layer. The key principle behind this strategy is to exploit the spatial-temporal characteristics of the wireless channel to guarantee secure data transmission without the need of cryptographic protocols.

Loss of Synaptic Connectivity, Particularly in Second Order Neurons Is a Key Feature of Diabetic Retinal Neuropathy in the Ins2Akita Mouse

Retinal neurodegeneration is a key component of diabetic retinopathy (DR), although the detailed neuronal damage remains ill-defined. Recent evidence suggests that in addition to amacrine and ganglion cell, diabetes may also impact on other retinal neurons. In this study, we examined retinal degenerative changes in Ins2^Akita diabetic mice. In scotopic electroretinograms (ERG), b-wave and oscillatory potentials were severely impaired in 9-month old Ins2^Akita mice. Despite no obvious pathology in fundoscopic examination, optical coherence tomography (OCT) revealed a progressive thinning of the retina from 3 months onwards. Cone but not rod photoreceptor loss was observed in 3-month-old diabetic mice. Severe impairment of synaptic connectivity at the outer plexiform layer (OPL) was detected in 9-month old Ins2Akita mice. Specifically, photoreceptor presynaptic ribbons were reduced by 25% and postsynaptic boutons by 70%, although the density of horizontal, rod- and cone-bipolar cells remained similar to non-diabetic controls. Significant reductions in GABAergic and glycinergic amacrine cells and Brn3a+ retinal ganglion cells were also observed in 9-month old Ins2^Akita mice. In conclusion, the Ins2^Akita mouse develops cone photoreceptor degeneration and the impairment of synaptic connectivity at the OPL, predominately resulting from the loss of postsynaptic terminal boutons. Our findings suggest that the Ins2^Akita mouse is a good model to study diabetic retinal neuropathy.

How much do you need: a randomised experiment of whether readers can understand the key messages from summaries of Cochrane Reviews, without reading the full review?

Objective: We explored whether readers can understand key messages without having to read the full review, and if there were differences in understanding between various types of summary.
Design: A randomised experiment of review summaries which compared understanding of a key outcome.
Participants: Members of university staff (n = 36).
Setting: Universities on the island of Ireland.
Method: The Cochrane Review chosen examines the health impacts of the use of electric fans during heat waves. Participants were asked their expectation of the effect these would have on mortality. They were then randomly assigned a summary of the review (i.e. abstract, plain language summary, podcast or podcast transcription) and asked to spend a short time reading/listening to the summary. After this they were again asked about the effects of electric fans on mortality and to indicate if they would want to read the full Review.
Main outcome measure: Correct identification of a key review outcome.
Results: Just over half (53%) of the participants identified its key message on mortality after engaging with their summary. The figures were 33% for the abstract group, 50% for both the plain language and transcript groups and 78% for the podcast group.
Conclusions: The differences between the groups were not statistically significant but suggest that the audio summary might improve knowledge transfer compared to written summaries. These findings should be explored further using a larger sample size and with other reviews.

Key Players and Key Groups in Teams

This paper contributes to the literature on centrality measures in economics by defining a team game and identifying the key players and key groups
in the game. We extend the work of Ballester et al. (Econometrica, 2006) by incorporating a network outcome component in the players' payoff functions and prove that there is a unique interior Nash Equilibrium in pure strategies. We develop a team intercentrality measure based on alternative scenarios that capture the externality created by teammates on each player.

Does wave exposure determine the interactive effects of losing key grazers and ecosystem engineers?

The consequences of biodiversity loss in the face of environmental change remain difficult to predict, given the complexity of interactions among species and the context-dependency of their functional roles within ecosystems. Predictions may be enhanced by studies testing how the interactive effects of species loss from different functional groups vary with important environmental drivers. On rocky shores, limpets and barnacles are recognised as key grazers and ecosystem engineers, respectively. Despite the large body of research examining the combined effects of limpet and barnacle removal, it is unclear how their relative importance varies according to wave exposure, which is a dominant force structuring intertidal communities. We tested the responses of algal communities to the removal of limpets and barnacles on three sheltered and three wave-exposed rocky shores on the north coast of Ireland. Limpet removal resulted in a relative increase in microalgal biomass on a single sheltered shore only, but led to the enhanced accumulation of ephemeral macroalgae on two sheltered shores and one exposed shore. On average, independently of wave exposure or shore, ephemeral macroalgae increased in response to limpet removal, but only when barnacles were removed. On two sheltered shores and one exposed shore, however, barnacles facilitated the establishment of fucoid macroalgae following limpet removal. Therefore, at the scale of this study, variability among individual shores was more important than wave exposure per se in determining the effect of limpet removal and its interaction with that of barnacles. Overall, these findings demonstrate that the interactive effects of losing key species from different functional groups may not vary predictably according to dominant environmental factors.

High-Speed Fully Homomorphic Encryption Over the Integers

A fully homomorphic encryption (FHE) scheme is envisioned as a key cryptographic tool in building a secure and reliable cloud computing environment, as it allows arbitrary evaluation of a ciphertext without revealing the plaintext. However, existing FHE implementations remain impractical due to very high time and resource costs. To the authors’ knowledge, this paper presents the first hardware implementation of a full encryption primitive for FHE over the integers using FPGA technology. A large-integer multiplier architecture utilising Integer-FFT multiplication is proposed, and a large-integer Barrett modular reduction module is designed incorporating the proposed multiplier. The encryption primitive used in the integer-based FHE scheme is designed employing the proposed multiplier and modular reduction modules. The designs are verified using the Xilinx Virtex-7 FPGA platform. Experimental results show that a speed improvement factor of up to 44 is achievable for the hardware implementation of the FHE encryption scheme when compared to its corresponding software implementation. Moreover, performance analysis shows further speed improvements of the integer-based FHE encryption primitives may still be possible, for example through further optimisations or by targeting an ASIC platform.