Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways

Purpose Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities. Experimental Design Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers. Results Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing-induced apoptosis. K-Ras-mutated, c-Met-amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing-induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Conclusion Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. ©2011 AACR.

On ‘Activation Workers' Perceptions’ : a reply to Dunn (1)

Andrew Dunn challenges us to include the perspectives of other policy actors in the debate about the merits and limits of activation policies that emphasise greater conditionality for those in receipt of benefits. In his provocative article he focuses on the views and experiences of people who work with unemployed people...

Adapting Lyubashevsky's signature schemes to the ring signature setting

Basing signature schemes on strong lattice problems has been a long standing open issue. Today, two families of lattice-based signature schemes are known: the ones based on the hash-and-sign construction of Gentry et al.; and Lyubashevsky’s schemes, which are based on the Fiat-Shamir framework. In this paper we show for the first time how to adapt the schemes of Lyubashevsky to the ring signature setting. In particular we transform the scheme of ASIACRYPT 2009 into a ring signature scheme that provides strong properties of security under the random oracle model. Anonymity is ensured in the sense that signatures of different users are within negligible statistical distance even under full key exposure. In fact, the scheme satisfies a notion which is stronger than the classical full key exposure setting as even if the keypair of the signing user is adversarially chosen, the statistical distance between signatures of different users remains negligible. Considering unforgeability, the best lattice-based ring signature schemes provide either unforgeability against arbitrary chosen subring attacks or insider corruption in log-sized rings. In this paper we present two variants of our scheme. In the basic one, unforgeability is ensured in those two settings. Increasing signature and key sizes by a factor k (typically 80 − 100), we provide a variant in which unforgeability is ensured against insider corruption attacks for arbitrary rings. The technique used is pretty general and can be adapted to other existing schemes.

Controlling whole blood activation and resultant clot properties by carboxyl and alkyl functional groups on material surfaces : a possible therapeutic approach for enhancing bone healing

Most research virtually ignores the important role of a blood clot in supporting bone healing. In this study, we investigated the effects of surface functional groups carboxyl and alkyl on whole blood coagulation, complement activation and blood clot formation. We synthesised and tested a series of materials with different ratios of carboxyl (–COOH) and alkyl (–CH3, –CH2CH3 and –(CH2)3CH3) groups. We found that surfaces with –COOH/–(CH2)3CH3 induced a faster coagulation activation than those with –COOH/– CH3 and –CH2CH3, regardless of the –COOH ratios. An increase in –COOH ratios on –COOH/–CH3 and –CH2CH3 surfaces decreased the rate of coagulation activation. The pattern of complement activation was entirely similar to that of surface-induced coagulation. All material coated surfaces resulted in clots with thicker fibrin in a denser network at the clot/material interface and a significantly slower initial fibrinolysis when compared to uncoated glass surfaces. The amounts of platelet-derived growth factor-AB (PDGF-AB) and transforming growth factor-b (TGF-b1) released from an intact clot were higher than a lysed clot. The release of PDGF-AB was found to be correlated with the fibrin density. This study demonstrated that surface chemistry can significantly influence the activation of blood coagulation and complement system, resultant clot structure, susceptibility to fibrinolysis as well as release of growth factors, which are important factors determining the bone healing process.

Estrogen receptor β activation impairs mitochondrial oxidative metabolism and affects malignant mesothelioma cell growth in vitro and in vivo

Estrogen receptor (ER)-β has been shown to possess a tumor suppressive effect, and is a potential target for cancer therapy. Using gene-expression meta-analysis of human malignant pleural mesothelioma, we identified an ESR2 (ERβ coding gene) signature. High ESR2 expression was strongly associated with low succinate dehydrogenase B (SDHB) (which encodes a mitochondrial respiratory chain complex II subunit) expression. We demonstrate that SDHB loss induced ESR2 expression, and that activated ERβ, by over-expression or by selective agonist stimulation, negatively affected oxidative phosphorylation compromising mitochondrial complex II and IV activity. This resulted in reduced mitochondrial ATP production, increased glycolysis dependence and impaired cell proliferation. The observed in vitro effects were phenocopied in vivo using a selective ERβ agonist in a mesothelioma mouse model. On the whole, our data highlight an unforeseen interaction between ERβ-mediated tumor suppression and energy metabolism that may be exploited to improve on the therapy for clinical management of malignant mesothelioma.

Different in vitro activation methods for latent transforming growth factors (TGF)–β : considerable exogenous factors to promote higher mesenchymal-origin cell proliferation in a bioprocessing platform

Regenerative medicine includes two efficient techniques, namely tissue-engineering and cell-based therapy in order to repair tissue damage efficiently. Most importantly, huge numbers of autologous cells are required to deal these practices. Nevertheless, primary cells, from autologous tissue, grow very slowly while culturing in vitro; moreover, they lose their natural characteristics over prolonged culturing period. Transforming growth factors-beta (TGF-β) is a ubiquitous protein found biologically in its latent form, which prevents it from eliciting a response until conversion to its active form. In active form, TGF-β acts as a proliferative agent in many cell lines of mesenchymal origin in vitro. This article reviews on some of the important activation methods-physiochemical, enzyme-mediated, non-specific protein interaction mediated, and drug-induced- of TGF-β, which may be established as exogenous factors to be used in culturing medium to obtain extensive proliferation of primary cells.

Chronic activation of the low affinity site of β1-adrenoceptors stimulates haemodynamics but exacerbates pressure-overload cardiac remodelling

Background and Purpose The β1-adrenoceptor has at least two binding sites, high and low affinity sites (β1H and β1L, respectively), which mediate cardiostimulation. While β1H-adrenoceptor can be blocked by all clinically used β-blockers, β1L-adrenoceptor is relatively resistant to blockade. Thus, chronic β1L-adrenoceptor activation may mediate persistent cardiostimulation, despite the concurrent blockade of β1H-adrenoceptors. Hence, it is important to determine the potential significance of β1L-adrenoceptors in vivo, particularly in pathological situations. Experimental Approach C57Bl/6 male mice were used. Chronic (4 or 8 weeks) β1L-adrenoceptor activation was achieved by treatment, via osmotic mini pumps, with (-)-CGP12177 (10 mg·kg−1·day−1). Cardiac function was assessed by echocardiography and micromanometry. Key Results (-)-CGP12177 treatment of healthy mice increased heart rate and left ventricular (LV) contractility. (-)-CGP12177 treatment of mice subjected to transverse aorta constriction (TAC), during weeks 4–8 or 4–12 after TAC, led to a positive inotropic effect and exacerbated fibrogenic signalling while cardiac hypertrophy tended to be more severe. (-)-CGP12177 treatment of mice with TAC also exacerbated the myocardial expression of hypertrophic, fibrogenic and inflammatory genes compared to untreated TAC mice. Washout of (-)-CGP12177 revealed a more pronounced cardiac dysfunction after 12 weeks of TAC. Conclusions and Implications β1L-adrenoceptor activation provides functional support to the heart, in both normal and pathological (pressure overload) situations. Sustained β1L-adrenoceptor activation in the diseased heart exacerbates LV remodelling and therefore may promote disease progression from compensatory hypertrophy to heart failure.

Characterising in situ activation and degradation of hindered amine light stabilisers using liquid extraction surface analysis-mass spectrometry

Changes in the molecular structure of polymer antioxidants such as hindered amine light stabilisers (HALS) is central to their efficacy in retarding polymer degradation and therefore requires careful monitoring during their in-service lifetime. The HALS, bis-(1-octyloxy-2,2,6,6-tetramethyl-4-piperidinyl) sebacate (TIN123) and bis-(1,2,2,6,6-pentamethyl-4-piperidinyl) sebacate (TIN292), were formulated in different polymer systems and then exposed to various curing and ageing treatments to simulate in-service use. Samples of these coatings were then analysed directly using liquid extraction surface analysis (LESA) coupled with a triple quadrupole mass spectrometer. Analysis of TIN123 formulated in a cross-linked polyester revealed that the polymer matrix protected TIN123 from undergoing extensive thermal degradation that would normally occur at 292 degrees C, specifically, changes at the 1- and 4-positions of the piperidine groups. The effect of thermal versus photo-oxidative degradation was also compared for TIN292 formulated in polyacrylate films by monitoring the in situ conversion of N-CH3 substituted piperidines to N-H. The analysis confirmed that UV light was required for the conversion of N-CH3 moieties to N-H - a major pathway in the antioxidant protection of polymers - whereas this conversion was not observed with thermal degradation. The use of tandem mass spectrometric techniques, including precursor-ion scanning, is shown to be highly sensitive and specific for detecting molecular-level changes in HALS compounds and, when coupled with LESA, able to monitor these changes in situ with speed and reproducibility. (C) 2013 Elsevier B. V. All rights reserved.

Desorption electrospray ionisation mass spectrometry of stabilised polyesters reveals activation of hindered amine light stabilisers

The use of hindered amine light stabilizers (HALS) to retard thermo- and photo-degradation of polymers has become increasingly common. Proposed mechanisms of polymer stabilisation involve significant changes to the HALS chemical structure; however, reports of the characterisation of these modified chemical species are limited. To better understand the fate of HALS and determine their in situ modifications, desorption electrospray ionisation mass spectrometry (DESI-MS) was employed to characterise ten commercially available HALS present in polyester-based coil coatings. TINUVIN® 770, 292, 144, 123, 152, and NOR371; HOSTAVIN® 3052, 3055, 3050, and 3058 were separately formulated with a pigmented, thermosetting polyester resin, cured on metal at 262 C and analysed directly by DESI-MS. High-level ab initio molecular orbital theory calculations were also undertaken to aid the mechanistic interpretation of the results. For HALS containing N-substituted piperidines (i.e., N-CH3, N-C(O)CH3, and N-OR) a secondary piperidine (N-H) analogue was detected in all cases. The formation of these intermediates can be explained either through hydrogen abstraction based mechanisms or direct N-OR homolysis with the former dominant under normal service temperatures (ca. 25-80 C), and the latter potentially becoming competitive under the high temperatures associated with curing (ca. 230-260 C). © 2013 Elsevier Ltd. All rights reserved.

Multiple-time signature schemes against adaptive chosen message attacks

Multiple-time signatures are digital signature schemes where the signer is able to sign a predetermined number of messages. They are interesting cryptographic primitives because they allow to solve many important cryptographic problems, and at the same time offer substantial efficiency advantage over ordinary digital signature schemes like RSA. Multiple-time signature schemes have found numerous applications, in ordinary, on-line/off-line, forward-secure signatures, and multicast/stream authentication. We propose a multiple-time signature scheme with very efficient signing and verifying. Our construction is based on a combination of one-way functions and cover-free families, and it is secure against the adaptive chosen-message attack.

Decomposition construction for secret sharing schemes with graph access structures in polynomial time

The purpose of this paper is to describe a new decomposition construction for perfect secret sharing schemes with graph access structures. The previous decomposition construction proposed by Stinson is a recursive method that uses small secret sharing schemes as building blocks in the construction of larger schemes. When the Stinson method is applied to the graph access structures, the number of such “small” schemes is typically exponential in the number of the participants, resulting in an exponential algorithm. Our method has the same flavor as the Stinson decomposition construction; however, the linear programming problem involved in the construction is formulated in such a way that the number of “small” schemes is polynomial in the size of the participants, which in turn gives rise to a polynomial time construction. We also show that if we apply the Stinson construction to the “small” schemes arising from our new construction, both have the same information rate.

Lattice-based threshold changeability for standard shamir sectret-sharing schemes

We consider the problem of increasing the threshold parameter of a secret-sharing scheme after the setup (share distribution) phase, without further communication between the dealer and the shareholders. Previous solutions to this problem require one to start off with a nonstandard scheme designed specifically for this purpose, or to have communication between shareholders. In contrast, we show how to increase the threshold parameter of the standard Shamir secret-sharing scheme without communication between the shareholders. Our technique can thus be applied to existing Shamir schemes even if they were set up without consideration to future threshold increases. Our method is a new positive cryptographic application for lattice reduction algorithms, inspired by recent work on lattice-based list decoding of Reed-Solomon codes with noise bounded in the Lee norm. We use fundamental results from the theory of lattices (geometry of numbers) to prove quantitative statements about the information-theoretic security of our construction. These lattice-based security proof techniques may be of independent interest.

Trust in merged ERP and open data schemes in the “Cloud”

Enterprise resource planning (ERP) systems are rapidly being combined with “big data” analytics processes and publicly available “open data sets”, which are usually outside the arena of the enterprise, to expand activity through better service to current clients as well as identifying new opportunities. Moreover, these activities are now largely based around relevant software systems hosted in a “cloud computing” environment. However, the over 50- year old phrase related to mistrust in computer systems, namely “garbage in, garbage out” or “GIGO”, is used to describe problems of unqualified and unquestioning dependency on information systems. However, a more relevant GIGO interpretation arose sometime later, namely “garbage in, gospel out” signifying that with large scale information systems based around ERP and open datasets as well as “big data” analytics, particularly in a cloud environment, the ability to verify the authenticity and integrity of the data sets used may be almost impossible. In turn, this may easily result in decision making based upon questionable results which are unverifiable. Illicit “impersonation” of and modifications to legitimate data sets may become a reality while at the same time the ability to audit any derived results of analysis may be an important requirement, particularly in the public sector. The pressing need for enhancement of identity, reliability, authenticity and audit services, including naming and addressing services, in this emerging environment is discussed in this paper. Some current and appropriate technologies currently being offered are also examined. However, severe limitations in addressing the problems identified are found and the paper proposes further necessary research work for the area. (Note: This paper is based on an earlier unpublished paper/presentation “Identity, Addressing, Authenticity and Audit Requirements for Trust in ERP, Analytics and Big/Open Data in a ‘Cloud’ Computing Environment: A Review and Proposal” presented to the Department of Accounting and IT, College of Management, National Chung Chen University, 20 November 2013.)

Anionic migration reactions in aromatic systems effected by collisional activation : Deprotonated anilides containing methoxycarbonyl substituents

Long-range cross-ring reactions are of minor importance in the collision-induced mass spectra (MS/MS) of [M - H]- ions of CH2OCO-C6H4-NHCOR systems: e.g. the loss of 'CD3CO2CH3' from CH3OCO-C6H4-(N) over bar COCD3. Major processes involve (i) losses of radicals to form stable radical anions, e.g. loss of a ring hydrogen atom and losses from the ester (CH3 ., CH3O . and . CO2CH3), (ii) losses of neutral molecules from the amide moiety [e.g. CO (R = H) and CH2CO (R = CH3), and proximity effects when the two substituents are ortho [e.g. loss of (CH3OD+CO2) from o-CH3OCO-C6H4 (N) over bar COCD3].

Verifiable multi-secret sharing schemes for multiple threshold access structures

A multi-secret sharing scheme allows several secrets to be shared amongst a group of participants. In 2005, Shao and Cao developed a verifiable multi-secret sharing scheme where each participant’s share can be used several times which reduces the number of interactions between the dealer and the group members. In addition some secrets may require a higher security level than others involving the need for different threshold values. Recently Chan and Chang designed such a scheme but their construction only allows a single secret to be shared per threshold value. In this article we combine the previous two approaches to design a multiple time verifiable multi-secret sharing scheme where several secrets can be shared for each threshold value. Since the running time is an important factor for practical applications, we will provide a complexity comparison of our combined approach with respect to the previous schemes.