RanGTPase : a candidate for myc-mediated cancer progression

Background Ras-related nuclear protein (Ran) is required for cancer cell survival in vitro and human cancer progression, but the molecular mechanisms are largely unknown. Methods We investigated the effect of the v-myc myelocytomatosis viral oncogene homolog (Myc) on Ran expression by Western blot, chromatin immunoprecipitation, and luciferase reporter assays and the effects of Myc and Ran expression in cancer cells by soft-agar, cell adhesion, and invasion assays. The correlation between Myc and Ran and the association with patient survival were investigated in 14 independent patient cohorts (n = 2430) and analyzed with Spearman's rank correlation and Kaplan-Meier plots coupled with Wilcoxon-Gehan tests, respectively. All statistical tests were two-sided. Results Myc binds to the upstream sequence of Ran and transactivates Ran promoter activity. Overexpression of Myc upregulates Ran expression, whereas knockdown of Myc downregulates Ran expression. Myc or Ran overexpression in breast cancer cells is associated with cancer progression and metastasis. Knockdown of Ran reverses the effect induced by Myc overexpression in breast cancer cells. In clinical data, a positive association between Myc and Ran expression was revealed in 288 breast cancer and 102 lung cancer specimens. Moreover, Ran expression levels differentiate better or poorer survival in Myc overexpressing breast (χ2 = 24.1; relative risk [RR] = 9.1, 95% confidence interval [CI] = 3.3 to 24.7, P <. 001) and lung (χ2 = 6.04; RR = 2.8, 95% CI = 1.2 to 6.3; P =. 01) cancer cohorts. Conclusions Our results suggest that Ran is required for and is a potential therapeutic target of Myc-driven cancer progression in both breast and lung cancers. © 2013 The Author.

Targeting amino acid transport in metastatic castration-resistant prostate cancer : effects on cell cycle, cell growth, and tumor development

Background L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth. Methods We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided. Results LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4–7 months of neoadjuvant hormone therapy (4–7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4–mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo. Conclusion Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.

A systemic view of innovation adoption in the Australian beef industry

Significant investments in developing technological innovations have been made in the Australian beef industry but with low adoption rates. By modelling the key variables and their interactions in the innovation adoption process, this research seeks to demonstrate the complexity and dynamics of the process. This research uses causal loop modelling and develops a holistic model of the current innovation adoption system in the Australian beef industry to show the complexity of dynamic interactions among multiple variables. It is suggested that innovation adoption is such an extremely complex issue, and we need to shift our views on this issue from a paradigm of linear thinking to systems thinking. Innovation adoption is more likely to be enhanced based on a full understanding of the complexity and dynamics of the system as a whole. The paper demonstrates to practitioners and developers of innovation the multiple variables and interactions impacting innovation adoption.

Vascular remodeling in the internal mammary artery graft and association with in situ endothelin-1 and receptor expression

BACKGROUND: The vasoconstricting peptide endothelin-1 (ET-1) has been associated with atherosclerotic cardiovascular disease, vascular smooth muscle cell (VSMC) growth stimulation, and intimal thickening. ET-1 binds 2 receptor subtypes, endothelin A and B, and the ETA receptor mediates vasoconstriction and VSMC growth. This study aims to quantitatively assess arterial remodeling variables and compare them with changes in ET-1, ETA, and ETB expression in the internal mammary artery (IMA). METHODS AND RESULTS: Specimens from 55 coronary artery disease (CAD) patients (45 men, 10 women; mean age 65 years) and 14 control IMA specimens (from 7 men and 7 women; mean age 45 years) were collected. IMA cross sections were assessed by histochemical and immunohistochemical staining methods to quantify the levels of medionecrosis, fibrosis, VSMC growth, ET-1, ETA, ETB, and macrophage infiltration. The percentage area of medionecrosis in the patients was almost double that in the controls (31.85+/-14.52% versus 17.10+/-9.96%, P=0.0006). Total and type 1 collagen was significantly increased compared with controls (65.8+/-18.3% versus 33.7+/-13.7%, P=0.07, and 14.2+/-10.0% versus 4.8+/-2.8%, P=0.01, respectively). Despite ACE and/or statin therapy, ET-1 expression and cell cycling were significantly elevated in the patient IMAs relative to the controls (46.27+/-18.46 versus 8.56+/-8.42, P=0.0001, and 37.29+/-12.88 versus 11.06+/-8.18, P=0.0001, respectively). ETA and ETB staining was elevated in the patient vessels (46.88+/-11.52% versus 18.58+/-7.65%, P=0.0001, and 42.98+/-7.08% versus 34.73+/-5.20%, P=0.0067, respectively). A mild presence of macrophages was noted in all sections. CONCLUSIONS: Elevated distribution of collagen indicative of fibrosis coupled with increased cell cycling and high levels of ET-1 and ETA expression in the absence of chronic inflammation suggests altered IMA VSMC regulation is fundamental to the remodeling process.

Interleukin-1β stimulates human renal fibroblast proliferation and matrix protein production by means of a transforming growth factor-β-dependent mechanism

One of the hallmarks of progressive renal disease is the development of tubulointerstitial fibrosis. This is frequently preceded by macrophage infiltration, raising the possibility that macrophages relay fibrogenic signals to resident tubulointerstitial cells. The aim of this study was to investigate the potentially fibrogenic role of interleukin-1beta (IL-1beta), a macrophage-derived inflammatory cytokine, on cortical fibroblasts (CFs). Primary cultures of human renal CFs were established and incubated for 24 hours in the presence or absence of IL-1beta. We found that IL-1beta significantly stimulated DNA synthesis (356.7% +/- 39% of control, P <.003), fibronectin secretion (261.8 +/- 11% of control, P <.005), collagen type 1 production, (release of procollagen type 1 C-terminal-peptide, 152.4% +/- 26% of control, P <.005), transforming growth factor-beta (TGF-beta) secretion (211% +/- 37% of control, P <.01), and nitric oxide (NO) production (342.8% +/- 69% of control, P <.002). TGF-beta (1 ng/mL) and the phorbol ester phorbol 12-myristate 13-acetate (PMA, 25 nmol/L) produced fibrogenic effects similar to those of IL-1beta. Neither a NO synthase inhibitor (N(G)-methyl-l-arginine, 1 mmol/L) nor a protein kinase C (PKC) inhibitor (bis-indolylmaleimide 1, 1 micromol/L) altered the enhanced level of fibronectin secretion or DNA synthesis seen in response to IL-1beta treatment. However, addition of a TGF-beta-neutralizing antibody significantly reduced IL-1beta-induced fibronectin secretion (IL-1beta + IgG, 262% +/- 72% vs IL-1beta + alphaTGF-beta 156% +/- 14%, P <.02), collagen type 1 production (IL-1beta + IgG, 176% +/- 28% vs IL-1beta + alphaTGF-beta, 120% +/- 14%, P <.005) and abrogated IL-1beta-induced DNA synthesis (245% +/- 49% vs 105% +/- 21%, P <.005). IL-1beta significantly stimulated CF DNA synthesis and production of fibronectin, collagen type 1, TGFbeta, and NO. The fibrogenic and proliferative action of IL-1beta on CF appears not to involve activation of PKC or production of NO but is at least partly TGFbeta-dependent.

French version of the Family Attitude Scale : psychometric properties and relation of attitudes to the respondent's psychiatric status

The Family Attitude Scale (FAS) is a self-report measure of critical or hostile attitudes and behaviors towards another family member, and demonstrates an ability to predict relapse in psychoses. Data are not currently available on a French version of the scale. The present study developed a French version of the FAS, using a large general population sample to test its internal structure, criterion validity and relationships with the respondents' symptoms and psychiatric diagnoses, and examined the reciprocity of FAS ratings by respondents and their partners. A total of 2072 adults from an urban population undertook a diagnostic interview and completed self-report measures, including an FAS about their partner. A subset of participants had partners who also completed the FAS. Confirmatory factor analyses revealed an excellent fit by a single-factor model, and the FAS demonstrated a strong association with dyadic adjustment. FAS scores of respondents were affected by their anxiety levels and mood, alcohol and anxiety diagnoses, and moderate reciprocity of attitudes and behaviors between the partners was seen. The French version of the FAS has similarly strong psychometric properties to the original English version. Future research should assess the ability of the French FAS to predict relapse of psychiatric disorders.

Fasting increases serum bilirubin levels in clinically normal, healthy males but not females : a retrospective study from phase I clinical trial participants

Aim: To examine if fasting affects serum bilirubin levels in clinical healthy males and females. Methods: We utilised retrospective data from phase 1 clinical trials where blood was collected in either a fed or fasting state at screening and pre-dosing time points and analysed for total bilirubin levels as per standard clinical procedures. Participants were clinically healthy males (n = 105) or females (n = 30) aged 18 to 48 inclusive who participated in a phase 1 clinical trial in 2012 or 2013. Results: We found a statistically significant increase in total serum bilirubin levels in fasting males as compared to non-fasting males. The fasting time correlated positively with increased bilirubin levels. The age of the healthy males did not correlate with their fasting bilirubin level. We found no correlation between fasting and bilirubin levels in clinically normal females. Conclusions: The recruitment and screening of volunteers for a clinical trial is a time-consuming and expensive process. This study clearly demonstrates that testing for serum bilirubin should be conducted on non-fasting male subjects. If fasting is required, then participants should not be excluded from a trial based on an elevated serum bilirubin that is deemed non-clinically significant.

Inhibition of homogenous formation of calcium carbonate by poly (acrylic acid). The effect of molar mass and end-group functionality

The ability of poly(acrylic acid) (PAA) with different end groups and molar masses prepared by Atom Transfer Radical Polymerization (ATRP) to inhibit the formation of calcium carbonate scale at low and elevated temperatures was investigated. Inhibition of CaCO3 deposition was affected by the hydrophobicity of the end groups of PAA, with the greatest inhibition seen for PAA with hydrophobic end groups of moderate size (6–10 carbons). The morphologies of CaCO3 crystals were significantly distorted in the presence of these PAAs. The smallest morphological change was in the presence of PAA with long hydrophobic end groups (16 carbons) and the relative inhibition observed for all species were in the same order at 30 °C and 100 °C. As well as distorting morphologies, the scale inhibitors appeared to stabilize the less thermodynamically favorable polymorph, vaterite, to a degree proportional to their ability to inhibit precipitation.

Investigation of brain derived neurotrophic factor (BDNF) gene variants in migraine

A number of observations have suggested that brain derived neurotrophic factor (BDNF) plays a role in migraine pathophysiology. This study investigates whether variants in the BDNF gene are associated with migraine in an Australian case-control population. Background. Brain derived neurotrophic factor (BDNF) has an important role in neural growth, development and survival in the central nervous system and is an important modulator of central and peripheral pain responses. Variants in BDNF, in particular the functional Val66Met polymorphism (rs6265), have been found to be associated with a number of psychiatric disorders, cognitive function and obesity. As BDNF has been found to be differentially expressed in a number of aspects related to migraine, we tested for association between single nucleotide polymorphisms (SNPs) in BDNF and migraine. Methods. Five SNPs in the BDNF locus (rs1519480, rs6265, rs712507, rs2049046 and rs12273363) were genotyped initially in a cohort of 277 migraine cases, including 172 diagnosed with migraine with aura (MA) and 105 with migraine without aura (MO), and 277 age- and sex-matched controls. Three of these SNPs (rs6265, rs2049046 and rs12273363) were subsequently genotyped in a second cohort of 580 migraineurs, including 473 diagnosed with MA and 105 with O, and 580 matched controls. Results. – BDNF SNPs rs1519480, rs6265, rs712507 and rs12273363 were not significantly associated with migraine. However, rs2049046 showed a significant association with migraine, and in particular, MA in the first cohort. In the second cohort, although an increase in the rs2049046 T-allele frequency was observed in migraine cases, and in both MA and MO subgroups, it was not significantly different from controls. Analysis of data combined from both cohorts for rs2049046 showed significant differences in the genotypic and allelic distributions for this marker in both migraine and the MA sub-group. Conclusion. This study confirmed previous studies that the functional BDNF SNP rs6265 (Val66Met) is not associated with migraine. However, we found that rs2049046, which resides at the 5’ end of 3 one the BDNF transcripts, may be associated with migraine, suggesting that further investigations of this SNP may be warranted.

Outdoor flight testing of a pole inspection UAV incorporating high-speed vision

We present a pole inspection system for outdoor environments comprising a high-speed camera on a vertical take-off and landing (VTOL) aerial platform. The pole inspection task requires a vehicle to fly close to a structure while maintaining a fixed stand-off distance from it. Typical GPS errors make GPS-based navigation unsuitable for this task however. When flying outdoors a vehicle is also affected by aerodynamics disturbances such as wind gusts, so the onboard controller must be robust to these disturbances in order to maintain the stand-off distance. Two problems must therefor be addressed: fast and accurate state estimation without GPS, and the design of a robust controller. We resolve these problems by a) performing visual + inertial relative state estimation and b) using a robust line tracker and a nested controller design. Our state estimation exploits high-speed camera images (100Hz) and 70Hz IMU data fused in an Extended Kalman Filter (EKF). We demonstrate results from outdoor experiments for pole-relative hovering, and pole circumnavigation where the operator provides only yaw commands. Lastly, we show results for image-based 3D reconstruction and texture mapping of a pole to demonstrate the usefulness for inspection tasks.

Experiential role of artefacts in cooperative design

The role of material artefacts in supporting distributed and co-located work practices has been well acknowledged within HCI and CSCW research. In this paper, we show that in addition to their ecological, coordinative and organizational support, artefacts also play an 'experiential' role. In this case, artefacts not only improve efficiency or have a purely functional role (e.g. allowing people to complete tasks quickly), but the materiality, use and manifestations of these artefacts bring quality and richness to people's performance and help them make better sense of their everyday lives. In a domain such as industrial design, such artefacts play an important role for supporting creativity and innovation. Based on our ethnographic fieldwork on understanding cooperative design practices of industrial design students and researchers, we describe several experiential practices that are supported by design-related artefacts such as sketches, drawings, physical models and explorative prototypes -- used and developed in designers' everyday work. Our main intention in carrying out this kind of research is to develop technologies to support designers' everyday practices. We believe that with the emergence of ubiquitous computing, there is a growing need to focus on the personal, social and creative side of people's everyday experiences. By focusing on the experiential practices of designers, we can provide a much broader view in the design of new interactive technologies.

Academics in the policy process : engagement with Australian media policy inquiries 2011-2013

This paper critically evaluates the series of inquires that the Australian Labor government undertook during 2011-2013 into reform of Australian media, communications and copyright laws. One important driver of policy reform was the government’s commitment to building a National Broadband Network (NBN), and the implications this had for existing broadcasting and telecommunications policy, as it would constitute a major driver of convergence of media and communications access devices and content platforms. These inquiries included: the Convergence Review of media and communications legislation; the Australian Law Reform Commission (ALRC) review of the National Classification Scheme; and the Independent Media Inquiry (Finkelstein Review) into Media and Media Regulation. One unusual feature of this review process was the degree to which academics were involved in the process, not simply as providers of expert opinion, but as review chairs seconded from their universities. This paper considers the role played by activist groups in all of these inquiries and their relationship to the various participants in the inquiries, as well as the implications of academics being engaged in such inquiries, not simply as activist-scholars, but as those primarily responsible for delivering policy review outcomes. The paper draws upon the concept of "policy windows" in order to better understand the context in which the inquiries took place, and their relative lack of legislative impact.

Fragmentation pathways of 2,3-dimethyl-2,3-dinitrobutane cations in the gas phase

2,3-Dimethyl-2,3-dinitrobutane (DMNB) is an explosive taggant added to plastic explosives during manufacture making them more susceptible to vapour-phase detection systems. In this study, the formation and detection of gas-phase \[M+H](+), \[M+Li](+), \[M+NH(4)](+) and \[M+Na](+) adducts of DMNB was achieved using electrospray ionisation on a triple quadrupole mass spectrometer. The \[M+H](+) ion abundance was found to have a strong dependence on ion source temperature, decreasing markedly at source temperatures above 50 degrees C. In contrast, the \[M+Na](+) ion demonstrated increasing ion abundance at source temperatures up to 105 degrees C. The relative susceptibility of DMNB adduct ions toward dissociation was investigated by collision-induced dissociation. Probable structures of product ions and mechanisms for unimolecular dissociation have been inferred based on fragmentation patterns from tandem mass (MS/MS) spectra of source-formed ions of normal and isotopically labelled DMNB, and quantum chemical calculations. Both thermal and collisional activation studies suggest that the \[M+Na](+) adduct ions are significantly more stable toward dissociation than their protonated analogues and, as a consequence, the former provide attractive targets for detection by contemporary rapid screening methods such as desorption electrospray ionisation mass spectrometry. Copyright (C) 2009 Commonwealth of Australia. Published by John Wiley & Sons, Ltd.

Threshold privacy preserving keyword searches

We consider the following problem: users of an organization wish to outsource the storage of sensitive data to a large database server. It is assumed that the server storing the data is untrusted so the data stored have to be encrypted. We further suppose that the manager of the organization has the right to access all data, but a member of the organization can not access any data alone. The member must collaborate with other members to search for the desired data. In this paper, we investigate the notion of threshold privacy preserving keyword search (TPPKS) and define its security requirements. We construct a TPPKS scheme and show the proof of security under the assumptions of intractability of discrete logarithm, decisional Diffie-Hellman and computational Diffie-Hellman problems.

Generation and characterization of ionic and neutral dihydroxy boron B(OH)(2)(+/0) in the gas phase

The dicoordinated borinium ion, dihydroxyborinium, B(OH)(2)(+) is generated from methyl boronic acid CH3B(OH)(2) by dissociative electron ionization and its connectivity confirmed by collisional activation. Neutralization-reionization (NR) experiments on this ion indicate that the neutral B(OH)(2) radical is a viable species in the gas phase. Both vertical neutralization of B(OH)(2)(+) and reionization of B(OH)(2) in the NR experiment are, however, associated with particularly unfavorable Franck-Condon factors. The differences in adiabatic and vertical electron transfer behavior can be traced back to a particular pi stabilization of the cationic species compared to the sp(2)-type neutral radical. Thermochemical data on several neutral and cationic boron compounds are presented based on calculations performed at the G2 level of theory.