Identification of chemokine receptors as potential modulators of endocrine resistance in oestrogen receptor–positive breast cancers

Introduction Endocrine therapies target oestrogenic stimulation of breast cancer (BC) growth, but resistance remains problematic. Our aims in this study were (1) to identify genes most strongly associated with resistance to endocrine therapy by intersecting global gene transcription data from patients treated presurgically with the aromatase inhibitor anastrazole with those from MCF7 cells adapted to long-term oestrogen deprivation (LTED) (2) to assess the clinical value of selected genes in public clinical data sets and (3) to determine the impact of targeting these genes with novel agents. Methods Gene expression and Ki67 data were available from 69 postmenopausal women with oestrogen receptor–positive (ER+) early BC, at baseline and 2 weeks after anastrazole treatment, and from cell lines adapted to LTED. The functional consequences of target genes on proliferation, ER-mediated transcription and downstream cell signalling were assessed. Results By intersecting genes predictive of a poor change in Ki67 with those upregulated in LTED cells, we identified 32 genes strongly correlated with poor antiproliferative response that were associated with inflammation and/or immunity. In a panel of LTED cell lines, C-X-C chemokine receptor type 7 (CXCR7) and CXCR4 were upregulated compared to their wild types (wt), and CXCR7, but not CXCR4, was associated with reduced relapse-free survival in patients with ER+ BC. The CXCR4 small interfering RNA variant (siCXCR4) had no specific effect on the proliferation of wt-SUM44, wt-MCF7 and their LTED derivatives. In contrast, siCXCR7, as well as CCX733, a CXCR7 antagonist, specifically suppressed the proliferation of MCF7-LTED cells. siCXCR7 suppressed proteins associated with G1/S transition and inhibited ER transactivation in MCF7-LTED, but not wt-MCF7, by impeding association between ER and proline-, glutamic acid– and leucine-rich protein 1, an ER coactivator. Conclusions These data highlight CXCR7 as a potential therapeutic target warranting clinical investigation in endocrine-resistant BC

Compact E-Cash and Simulatable VRFs Revisited

Abstract. Efficient non-interactive zero-knowledge proofs are a powerful tool for solving many cryptographic problems. We apply the recent Groth-Sahai (GS) proof system for pairing product equations (Eurocrypt 2008) to two related cryptographic problems: compact e-cash (Eurocrypt 2005) and simulatable verifiable random functions (CRYPTO 2007). We present the first efficient compact e-cash scheme that does not rely on a random oracle. To this end we construct efficient GS proofs for signature possession, pseudo randomness and set membership. The GS proofs for pseudorandom functions give rise to a much cleaner and substantially faster construction of simulatable verifiable random functions (sVRF) under a weaker number theoretic assumption. We obtain the first efficient fully simulatable sVRF with a polynomial sized output domain (in the security parameter).

Additive Combinatorics and Discrete Logarithm Based Range Protocols

We show how to express an arbitrary integer interval $I = [0, H]$ as a sumset $I = \sum_{i=1}^\ell G_i * [0, u - 1] + [0, H']$ of smaller integer intervals for some small values $\ell$, $u$, and $H' < u - 1$, where $b * A = \{b a : a \in A\}$ and $A + B = \{a + b : a \in A \wedge b \in B\}$. We show how to derive such expression of $I$ as a sumset for any value of $1 < u < H$, and in particular, how the coefficients $G_i$ can be found by using a nontrivial but efficient algorithm. This result may be interesting by itself in the context of additive combinatorics. Given the sumset-representation of $I$, we show how to decrease both the communication complexity and the computational complexity of the recent pairing-based range proof of Camenisch, Chaabouni and shelat from ASIACRYPT 2008 by a factor of $2$. Our results are important in applications like e-voting where a voting server has to verify thousands of proofs of e-vote correctness per hour. Therefore, our new result in additive combinatorics has direct relevance in practice

Evaluation of Functional Erythropoietin Receptor Status in Skeletal Muscle In Vivo: Acute and Prolonged Studies in Healthy Human Subjects

BACKGROUND: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased. CONCLUSIONS/SIGNIFICANCE: Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue

Catching MPC Cheaters: Identification and Openability

Secure multi-party computation (MPC) protocols do not completely prevent malicious parties from cheating or disrupting the computation. We augment MPC with three new properties to discourage cheating. First is a strengthening of identifiable abort, called completely identifiable abort, where all parties who do not follow the protocol will be identified as cheaters by each honest party. The second is completely identifiable auditability, which means that a third party can determine whether the computation was performed correctly (and who cheated if it was not). The third is openability, which means that a distinguished coalition of parties can recover the MPC inputs. We construct the first (efficient) MPC protocol achieving these properties. Our scheme is built on top of the SPDZ protocol (Damgard et al., Crypto 2012), which leverages an offline (computation-independent) pre-processing phase to speed up the online computation. Our protocol is optimistic, retaining online SPDZ efficiency when no one cheats. If cheating does occur, each honest party performs only local computation to identify cheaters. Our main technical tool is a new locally identifiable secret sharing scheme (as defined by Ishai, Ostrovsky, and Zikas (TCC 2012)) which we call commitment enhanced secret sharing or CESS. The work of Baum, Damgard, and Orlandi (SCN 2014) introduces the concept of auditability, which allows a third party to verify that the computation was executed correctly, but not to identify the cheaters if it was not. We enable the third party to identify the cheaters by augmenting the scheme with CESS. We add openability through the use of verifiable encryption and specialized zero-knowledge proofs

SWiM: Secure Wildcard Pattern Matching From OT Extension

Suppose a server holds a long text string and a receiver holds a short pattern string. Secure pattern matching allows the receiver to learn the locations in the long text where the pattern appears, while leaking nothing else to either party besides the length of their inputs. In this work we consider secure wildcard pattern matching WPM, where the receiver\u27s pattern is allowed to contain wildcards that match to any character. We present SWiM, a simple and fast protocol for WPM that is heavily based on oblivious transfer (OT) extension. As such, the protocol requires only a small constant number of public-key operations and otherwise uses only very fast symmetric-key primitives. SWiM is secure against semi-honest adversaries. We implemented a prototype of our protocol to demonstrate its practicality. We can perform WPM on a DNA text (4-character alphabet) of length $10^5$ and pattern of length $10^3$ in just over 2 seconds, which is over two orders of magnitude faster than the state-of-the-art scheme of Baron et al. (SCN 2012)