PRMT2 and RORγ expression are associated with breast cancer survival outcomes

Protein arginine methyltransferases (PRMTs) methylate arginine residues on histones and target transcription factors that play critical roles in many cellular processes, including gene transcription, mRNA splicing, proliferation, and differentiation. Recent studies have linked PRMT-dependent epigenetic marks and modifications to carcinogenesis and metastasis in cancer. However, the role of PRMT2-dependent signaling in breast cancer remains obscure. We demonstrate PRMT2 mRNA expression was significantly decreased in breast cancer relative to normal breast. Gene expression profiling, Ingenuity and protein-protein interaction network analysis after PRMT2-short interfering RNA transfection into MCF-7 cells, revealed that PRMT2-dependent gene expression is involved in cell-cycle regulation and checkpoint control, chromosomal instability, DNA repair, and carcinogenesis. For example, PRMT2 depletion achieved the following: 1) increased p21 and decreased cyclinD1 expression in (several) breast cancer cell lines, 2) decreased cell migration, 3) induced an increase in nucleotide excision repair and homologous recombination DNA repair, and 4) increased the probability of distance metastasis free survival (DMFS). The expression of PRMT2 and retinoid-related orphan receptor-γ (RORγ) is inversely correlated in estrogen receptor-positive breast cancer and increased RORγ expression increases DMFS. Furthermore, we found decreased expression of the PRMT2-dependent signature is significantly associated with increased probability of DMFS. Finally, weighted gene coexpression network analysis demonstrated a significant correlation between PRMT2-dependent genes and cell-cycle checkpoint, kinetochore, and DNA repair circuits. Strikingly, these PRMT2-dependent circuits are correlated with pan-cancer metagene signatures associated with epithelial-mesenchymal transition and chromosomal instability. This study demonstrates the role and significant correlation between a histone methyltransferase (PRMT2)-dependent signature, RORγ, the cell-cycle regulation, DNA repair circuits, and breast cancer survival outcomes.

Democratic systems

Digital signature is a breakthrough of modern cryptographic systems. A (t, n) threshold digital signature allows every set of cardinality t or more (out-of n) co-signers to authenticate a message. In almost all existing threshold digital signatures the threshold parameter t is fixed. There are applications, however, in which the threshold parameter needs to be changed from time to time. This paper considers such a scenario, in order to discuss relevant problems, and proposes a model that solves the related problems.

Efficient one-time proxy signatures

One-time proxy signatures are one-time signatures for which a primary signer can delegate his or her signing capability to a proxy signer. In this work we propose two one-time proxy signature schemes with different security properties. Unlike other existing one-time proxy signatures that are constructed from public key cryptography, our proposed schemes are based one-way functions without trapdoors and so they inherit the communication and computation efficiency from the traditional one-time signatures. Although from a verifier point of view, signatures generated by the proxy are indistinguishable from those created by the primary signer, a trusted authority can be equipped with an algorithm that allows the authority to settle disputes between the signers. In our constructions, we use a combination of one-time signatures, oblivious transfer protocols and certain combinatorial objects. We characterise these new combinatorial objects and present constructions for them.

Efficient extension of standard Schnorr/RSA signatures into Universal Designated-Verifier Signatures

Universal Designated-Verifier Signature (UDVS) schemes are digital signature schemes with additional functionality which allows any holder of a signature to designate the signature to any desired designated-verifier such that the designated-verifier can verify that the message was signed by the signer, but is unable to convince anyone else of this fact. Since UDVS schemes reduce to standard signatures when no verifier designation is performed, it is natural to ask how to extend the classical Schnorr or RSA signature schemes into UDVS schemes, so that the existing key generation and signing implementation infrastructure for these schemes can be used without modification. We show how this can be efficiently achieved, and provide proofs of security for our schemes in the random oracle model.

Parallel authentication and public-key encryption

A parallel authentication and public-key encryption is introduced and exemplified on joint encryption and signing which compares favorably with sequential Encrypt-then-Sign (ɛtS) or Sign-then-Encrypt (Stɛ) schemes as far as both efficiency and security are concerned. A security model for signcryption, and thus joint encryption and signing, has been recently defined which considers possible attacks and security goals. Such a scheme is considered secure if the encryption part guarantees indistinguishability and the signature part prevents existential forgeries, for outsider but also insider adversaries. We propose two schemes of parallel signcryption, which are efficient alternative to Commit-then-Sign-and- Encrypt (Ct&G3&S). They are both provably secure in the random oracle model. The first one, called generic parallel encrypt and sign, is secure if the encryption scheme is semantically secure against chosen-ciphertext attacks and the signature scheme prevents existential forgeries against random-message attacks. The second scheme, called optimal parallel encrypt. and sign, applies random oracles similar to the OAEP technique in order to achieve security using encryption and signature components with very weak security requirements — encryption is expected to be one-way under chosen-plaintext attacks while signature needs to be secure against universal forgeries under random-plaintext attack, that is actually the case for both the plain-RSA encryption and signature under the usual RSA assumption. Both proposals are generic in the sense that any suitable encryption and signature schemes (i.e. which simply achieve required security) can be used. Furthermore they allow both parallel encryption and signing, as well as parallel decryption and verification. Properties of parallel encrypt and sign schemes are considered and a new security standard for parallel signcryption is proposed.

An hybrid approach for efficient multicast stream authentication over unsecured channels

We study the multicast stream authentication problem when an opponent can drop, reorder and inject data packets into the communication channel. In this context, bandwidth limitation and fast authentication are the core concerns. Therefore any authentication scheme is to reduce as much as possible the packet overhead and the time spent at the receiver to check the authenticity of collected elements. Recently, Tartary and Wang developed a provably secure protocol with small packet overhead and a reduced number of signature verifications to be performed at the receiver. In this paper, we propose an hybrid scheme based on Tartary and Wang’s approach and Merkle hash trees. Our construction will exhibit a smaller overhead and a much faster processing at the receiver making it even more suitable for multicast than the earlier approach. As Tartary and Wang’s protocol, our construction is provably secure and allows the total recovery of the data stream despite erasures and injections occurred during transmission.

Threshold MACs

The power of sharing computation in a cryptosystem is crucial in several real-life applications of cryptography. Cryptographic primitives and tasks to which threshold cryptosystems have been applied include variants of digital signature, identification, public-key encryption and block ciphers etc. It is desirable to extend the domain of cryptographic primitives which threshold cryptography can be applied to. This paper studies threshold message authentication codes (threshold MACs). Threshold cryptosystems usually use algebraically homomorphic properties of the underlying cryptographic primitives. A typical approach to construct a threshold cryptographic scheme is to combine a (linear) secret sharing scheme with an algebraically homomorphic cryptographic primitive. The lack of algebraic properties of MACs rules out such an approach to share MACs. In this paper, we propose a method of obtaining a threshold MAC using a combinatorial approach. Our method is generic in the sense that it is applicable to any secure conventional MAC by making use of certain combinatorial objects, such as cover-free families and their variants. We discuss the issues of anonymity in threshold cryptography, a subject that has not been addressed previously in the literature in the field, and we show that there are trade-offis between the anonymity and efficiency of threshold MACs.

Universal designated-verifier signatures

Motivated by privacy issues associated with dissemination of signed digital certificates, we define a new type of signature scheme called a ‘Universal Designated-Verifier Signature’ (UDVS). A UDVS scheme can function as a standard publicly-verifiable digital signature but has additional functionality which allows any holder of a signature (not necessarily the signer) to designate the signature to any desired designated-verifier (using the verifier’s public key). Given the designated-signature, the designated-verifier can verify that the message was signed by the signer, but is unable to convince anyone else of this fact. We propose an efficient deterministic UDVS scheme constructed using any bilinear group-pair. Our UDVS scheme functions as a standard Boneh-Lynn-Shacham (BLS) signature when no verifier-designation is performed, and is therefore compatible with the key-generation, signing and verifying algorithms of the BLS scheme. We prove that our UDVS scheme is secure in the sense of our unforgeability and privacy notions for UDVS schemes, under the Bilinear Diffie-Hellman (BDH) assumption for the underlying group-pair, in the random-oracle model. We also demonstrate a general constructive equivalence between a class of unforgeable and unconditionally-private UDVS schemes having unique signatures (which includes the deterministic UDVS schemes) and a class of ID-Based Encryption (IBE) schemes which contains the Boneh-Franklin IBE scheme but not the Cocks IBE scheme.

Design guidelines for a mobile app for wellbeing of emerging adults

Mental health of young people may be improved through the use of mental health mobile applications,because young people engage with this technology freely. Mental health of young people is improved through the application of positive psychology, studies of which show that regular practice of one’s signature strength increases happiness and wellbeing, while decreasing depression. The issue is how to develop a mobile application intervention so that regular practice of one’s signature strength in novel ways occurs. This research project seeks to develop design guidelines discovered through the application of design thinking, actively working with emerging adults. In addition, this research is framed by the Design Science Research methodology to ensure that the resultant application is relevant and tested rigorously. This paper discusses the theory behind the application and discusses the research methods and research design, and will share the preliminary findings of the discovered design principles.

The effects of low degree alteration on Sm-Nd and U-Pb isotope systematics in Eoarchean basalts from the Doolena Gap and Warralong Greenstone belts, Pilbara Craton, Western Australia

This research led to the discovery of one of the best preserved remnants of the Earth's surficial environment 3.47 billion years ago. These ancient volcanic and sedimentary rocks contain original minerals and textures that are rare in rocks of this age. The research concentrated on chemical analysis of volcanic rocks to differentiate secondary alteration from the primary magmatic signature. This study contributes to our understanding of melting processes and geochemical reservoirs in the early Earth, which is vital for forward modelling of Earth's geodynamic evolution.

Supramolecular organization in fluorene/indenofluorene-oligothiophene alternating conjugated copolymers

A series of conjugated copolymers containing fluorene or indenofluorene units alternating with oligothiophene segments, with potential interest for use as the active layer in field-effect transistors, is investigated. Atomic force microscopy analysis of the morphology of thin deposits shows either the formation of fibrillar structures, which are the signature of long-range π stacking, or the presence of untextured aggregates, resulting from disordered assembly. These morphologies are interpreted in terms of the supramolecular organization of the conjugated chains. Molecular modeling simulations indicate that the commensurability between the lengths of the monomer units and the presence of alkyl side groups are the two key structural factors governing the chain organization into highly ordered assemblies. The most favorable structures are those combining fluorene (indenofluorene) units with unsubstituted bithiophene (terthiophene) segments.

Integrin-linked kinase as a target for ERG-mediated invasive properties in prostate cancer models

Approximately half of prostate cancers (PCa) carry TMPRSS2-ERG translocations; however, the clinical impact of this genomic alteration remains enigmatic. Expression of v-ets erythroblastosis virus E26 oncogene like (avian) gene (ERG) promotes prostatic epithelial dysplasia in transgenic mice and acquisition of epithelial-to-mesenchymal transition (EMT) characteristics in human prostatic epithelial cells (PrECs). To explore whether ERG-induced EMT in PrECs was associated with therapeutically targetable transformation characteristics, we established stable populations of BPH-1, PNT1B and RWPE-1 immortalized human PrEC lines that constitutively express flag-tagged ERG3 (fERG). All fERG-expressing populations exhibited characteristics of in vitro and in vivo transformation. Microarray analysis revealed >2000 commonly dysregulated genes in the fERG-PrEC lines. Functional analysis revealed evidence that fERG cells underwent EMT and acquired invasive characteristics. The fERG-induced EMT transcript signature was exemplified by suppressed expression of E-cadherin and keratins 5, 8, 14 and 18; elevated expression of N-cadherin, N-cadherin 2 and vimentin, and of the EMT transcriptional regulators Snail, Zeb1 and Zeb2, and lymphoid enhancer-binding factor-1 (LEF-1). In BPH-1 and RWPE-1-fERG cells, fERG expression is correlated with increased expression of integrin-linked kinase (ILK) and its downstream effectors Snail and LEF-1. Interfering RNA suppression of ERG decreased expression of ILK, Snail and LEF-1, whereas small interfering RNA suppression of ILK did not alter fERG expression. Interfering RNA suppression of ERG or ILK impaired fERG-PrEC Matrigel invasion. Treating fERG-BPH-1 cells with the small molecule ILK inhibitor, QLT-0267, resulted in dose-dependent suppression of Snail and LEF-1 expression, Matrigel invasion and reversion of anchorage-independent growth. These results suggest that ILK is a therapeutically targetable mediator of ERG-induced EMT and transformation in PCa.

Investigations of dielectric monitoring on an energised transformer oil–paper insulation system

Frequency domain spectroscopy (FDS) is being used to assess the insulation condition of oil–paper power transformers. However, it has to date only been implemented on de-energised transformers, which requires the transformers to be shut down for an extended period and may cause significant costs. To solve this issue, a newly improved monitoring method based on the FDS principle is proposed to implement the dielectric measurement on energised transformers. Moreover, a chirp waveform excitation and its novel processing method are introduced. Compared with the conventional FDS results, dielectric results from the energised insulation system have higher tanδ values because of the increased losses. To further understand the insulation ageing process, the effects of the geometric capacitance are removed from the measured imaginary admittance of the insulation system to enhance the ageing signature. The resulting imaginary admittance is then shown to correlate well with the central time constant in return voltage measurements results. The proposed methods address the issues on techniques used on energised transformers and provide a clue for on-line FDS diagnostic application.

Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)

Selumetinib (AZD6244, ARRY-142886) is a selective, non-ATP-competitive inhibitor of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-1/2. The range of antitumor activity seen preclinically and in patients highlights the importance of identifying determinants of response to this drug. In large tumor cell panels of diverse lineage, we show that MEK inhibitor response does not have an absolute correlation with mutational or phospho-protein markers of BRAF/MEK, RAS, or phosphoinositide 3-kinase (PI3K) activity. We aimed to enhance predictivity by measuring pathway output through coregulated gene networks displaying differential mRNA expression exclusive to resistant cell subsets and correlated to mutational or dynamic pathway activity. We discovered an 18-gene signature enabling measurement of MEK functional output independent of tumor genotype. Where the MEK pathway is activated but the cells remain resistant to selumetinib, we identified a 13-gene signature that implicates the existence of compensatory signaling from RAS effectors other than PI3K. The ability of these signatures to stratify samples according to functional activation of MEK and/or selumetinib sensitivity was shown in multiple independent melanoma, colon, breast, and lung tumor cell lines and in xenograft models. Furthermore, we were able to measure these signatures in fixed archival melanoma tumor samples using a single RT-qPCR-based test and found intergene correlations and associations with genetic markers of pathway activity to be preserved. These signatures offer useful tools for the study of MEK biology and clinical application of MEK inhibitors, and the novel approaches taken may benefit other targeted therapies.

Co-branding strategies for luxury fashion brands : Missoni for Target

Missoni is a luxury Italian knitwear brand that partnered with Target in September 2011 releasing a large, one off, mass-market collection that ranged from apparel to home wares. The collaboration received extensive media coverage and was consequently extremely sought after. The online sales site crashed within hours of opening while shelves were cleared in stores minutes after trading began. Within hours more than 40000 items from the collection were posted for sale online at greatly inflated prices. Evaluation of the case study revealed that sales of the Missoni collection increased following the collaboration and the value of the publicity generated at estimated US$100 million. The lack of available stock, despite the enormous hype created, reinforced Missoni’s luxury image. Missoni was able to gain massive awareness of the brand despite not employing any of its own communication channels in the promotion of the collaboration. However the co-branded collaboration was distinctively Missoni, potentially inciting comparison and confusion with the signature line. Nevertheless, this study shows that co-branding strategies can offer a viable opportunity for luxury brands to increase their market share, while they maintain their market position.