Stabilisation of MAD2 expression through inhibition of miR-433; A novel mechanism for restoring chemo-responsiveness in ovarian tumours

Epithelial ovarian carcinoma (EOC) is characterised by late diagnosis and recurrences, both of which contribute to the high morbidity and mortality of this cancer. Unfortunately, EOC has an innate susceptibility to become chemo-resistant. Specifically, up to 30% of patients may not respond to current standard chemotherapy (paclitaxel and platinum in combination) and of those who have an initial response, some patients relapse within a few months. Therefore, in order to improve patient outcome it is crucial to establish what factors influence a patients' individualised response to chemotherapy. We analysed MAD2 protein expression in a patient cohort of 35 ovarian tumours and a panel of 5 ovarian cancer cell lines. We have demonstrated that low nuclear MAD2 expression intensity was significantly associated with chemo-resistant ovarian tumours (p=0.0136). Moreover, in vitro studies of the 5 ovarian cancer cell lines revealed that reduced MAD2 expression was associated with paclitaxel resistance. In silico analysis identified a putative miR-433 binding domain in the MAD2 3′UTR and expression profiling of miR-433 in the ovarian cancer cell lines showed that low MAD2 protein expression was associated with high miR-433 levels. In vitro over-expression of miR-433 attenuated MAD2 protein expression with a concomitant increase in cellular resistance to paclitaxel. Over-expression of a morpholino oligonucleotide that blocks miR-433 binding to MAD2 3′UTR stabilised MAD2 protein expression and protects from miR-433 induced degradation. Furthermore, miR-433 expression analysis in 35 ovarian tumour samples revealed that high miR-433 expression was associated with advanced stage presentations (p=0.0236). In conclusion, ovarian tumours that display low nuclear MAD2 intensity are chemo-resistant and stabilising MAD2 expression by antagonising miR-433 activity is a potential mechanism for restoring chemo-responsiveness in these tumours.

Empirical testing of genuine savings as an indicator of weak sustainability: a three-country analysis of long run trends

Genuine Savings has emerged as a widely used indicator of sustainable development. In this paper, we use long -term data stretching back to 1870 to undertake empirical tests of the relationship between Genuine Savings (GS) and future well-being for three countries: Britain, the USA and Germany. Our tests are based on an underlying theoretical relationship between GS and changes in the present value of future consumption. Based on both single country and panel results, we find evidence supporting the existence of javascript:void(0);a cointegrating (long run equilibrium) relationship between GS and future well-being, and fail to reject the basic theoretical result on the relationship between these two macroeconomic variables. This provides some support for the GS measure of weak sustainability.

Best friends and better coping: Facilitating psychological resilience through boys’ and girls’ closest friendships

This is a novel investigation of whether, and how, a single close supportive friendship may facilitate psychological resilience in socio-economically vulnerable British adolescents. A total of 409 adolescents (160 boys, 245 girls, four unknown), aged between 11 and 19 years, completed self-report measures of close friendship quality, psychological resilience, social support, and other resources. Findings revealed a significant positive association between perceived friendship quality and resilience. This relationship was facilitated through inter-related mechanisms of developing a constructive coping style (comprised of support-seeking and active coping), effort, a supportive friendship network, and reduced disengaged and externalising coping. While protective processes were encouragingly significantly present across genders, boys were more vulnerable to the deleterious effects of disengaged and externalizing coping than girls. We suggest that individual close friendships are an important potential protective mechanism accessible to most adolescents. We discuss implications of the resulting Adolescent Friendship and Resilience Model for resilience theories and integration into practice.

Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy:a randomized controlled trial

Background: Small adenomas may be missed during colonoscopy, but chromoscopy has been reported to enhance detection. The aim of this randomized-controlled trial was to determine the effect of total colonic dye spray on adenoma detection during routine colonoscopy.

Methods: Consecutive outpatients undergoing routine colonoscopy were randomized to a dye-spray group (0.1% indigo carmine used to coat the entire colon during withdrawal from the cecum) or control group (no dye).

Results: Two hundred fifty-nine patients were randomized, 124 to the dye-spray and 135 to the control group; demographics, indication for colonoscopy, and quality of the preparation were similar between the groups. Extubation from the cecum took a median of 9:05 minutes (range: 2:4824:44 min) in the dye-spray group versus 4:52 minutes (range: 1:42-15:21 min] in the control group (p <0.0001). The proportion of patients with at least 1 adenoma and the total number of adenomas were not different between groups. However, in the dye-spray group significantly more diminutive adenomas (

Conclusions: Dye-spray increases the detection of small adenomas in the proximal colon and patients with multiple adenomas, but long-term outcomes should be studied to determine the clinical value of these findings.

Action Spectra of P25 TiO2 and a visible light absorbing, carbon-modified titania in the photocatalytic degradation of stearic acid

The photonic efficiencies of films of Evonik (formerly Degussa) P25 TiO2 and carbon-modified TiO2 Kronos VLP 7000 samples are reported as a function of excitation wavelength (300–430 nm; FWHM ∼ 7.5 nm), i.e. the action spectra, for the degradation of stearic acid, a model organic for the photocatalytic destruction of solid surface organic pollutants. For each of these semiconductor photocatalysts, at 365 nm (FWHM = 18 nm), the dependence of the rate of degradation of stearic acid, upon the irradiance, I, is determined and the rate is found to be proportional to I0.65 and I0.82 for P25 and Kronos titania, respectively. Assuming this relationship holds at all wavelengths, the action spectra for two different semiconductor photocatalysts is modified by plotting, (RSA (rate of stearic acid destruction, units: molecules cm−2 s−1)/Iθ) vs. wavelength of excitation (λexcit), and both differ noticeably from those of the original (unmodified) action spectra, which are plots of (RSA/I = photonic efficiency, ξ) vs. λexcit. The shape of the modified action spectrum for P25 TiO2 is consistent with that reported by others for other organic mineralisation reactions and correlates well with diffuse reflectance data for P25 TiO2 (Kubelka–Munk plot), although there is some evidence that the active phase, in the photodegradation of stearic acid, is the anatase form present in P25. The unmodified and modified action spectra of the beige Kronos VLP 7000 TiO2 compound exhibits little or no activity in the visible i.e. (λexcit > 400 nm) and a peak at 350 nm. The Kronos powder contains a yellow/brown conjugated, extractable, organic sensitiser which has been identified by others as the species responsible for its reported photocatalytic visible light activity. But, irradiation of the Kronos powder film, with and without a stearic acid coating, in air, using UVA or visible light, bleaches rapidly (<60 min) most, if not all, of the little colour exhibited by the original Kronos powder. The photobleached form of the Kronos has a similar action spectrum to that of the unbleached form, which, in turn, appears very similar to that of P25 titania, at wavelengths >350 nm. It is proposed that the difference between the Kronos and P25 powder films at wavelengths <350 nm is due to a photodegradation-resistant, previously unidentified (but extractable using MeCN) UV-absorbing organic species in the former which screens the titania particles at these lower wavelengths. The implications of these observations are discussed briefly.

Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials

BACKGROUND: The optimal ways of using aromatase inhibitors or tamoxifen as endocrine treatment for early breast cancer remains uncertain.

METHODS: We undertook meta-analyses of individual data on 31 920 postmenopausal women with oestrogen-receptor-positive early breast cancer in the randomised trials of 5 years of aromatase inhibitor versus 5 years of tamoxifen; of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5; and of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen. Primary outcomes were any recurrence of breast cancer, breast cancer mortality, death without recurrence, and all-cause mortality. Intention-to-treat log-rank analyses, stratified by age, nodal status, and trial, yielded aromatase inhibitor versus tamoxifen first-event rate ratios (RRs).

FINDINGS: In the comparison of 5 years of aromatase inhibitor versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·64, 95% CI 0·52-0·78) and 2-4 (RR 0·80, 0·68-0·93), and non-significantly thereafter. 10-year breast cancer mortality was lower with aromatase inhibitors than tamoxifen (12·1% vs 14·2%; RR 0·85, 0·75-0·96; 2p=0·009). In the comparison of 5 years of aromatase inhibitor versus 2-3 years of tamoxifen then aromatase inhibitor to year 5, recurrence RRs favoured aromatase inhibitors significantly during years 0-1 (RR 0·74, 0·62-0·89) but not while both groups received aromatase inhibitors during years 2-4, or thereafter; overall in these trials, there were fewer recurrences with 5 years of aromatase inhibitors than with tamoxifen then aromatase inhibitors (RR 0·90, 0·81-0·99; 2p=0·045), though the breast cancer mortality reduction was not significant (RR 0·89, 0·78-1·03; 2p=0·11). In the comparison of 2-3 years of tamoxifen then aromatase inhibitor to year 5 versus 5 years of tamoxifen, recurrence RRs favoured aromatase inhibitors significantly during years 2-4 (RR 0·56, 0·46-0·67) but not subsequently, and 10-year breast cancer mortality was lower with switching to aromatase inhibitors than with remaining on tamoxifen (8·7% vs 10·1%; 2p=0·015). Aggregating all three types of comparison, recurrence RRs favoured aromatase inhibitors during periods when treatments differed (RR 0·70, 0·64-0·77), but not significantly thereafter (RR 0·93, 0·86-1·01; 2p=0·08). Breast cancer mortality was reduced both while treatments differed (RR 0·79, 0·67-0·92), and subsequently (RR 0·89, 0·81-0·99), and for all periods combined (RR 0·86, 0·80-0·94; 2p=0·0005). All-cause mortality was also reduced (RR 0·88, 0·82-0·94; 2p=0·0003). RRs differed little by age, body-mass index, stage, grade, progesterone receptor status, or HER2 status. There were fewer endometrial cancers with aromatase inhibitors than tamoxifen (10-year incidence 0·4% vs 1·2%; RR 0·33, 0·21-0·51) but more bone fractures (5-year risk 8·2% vs 5·5%; RR 1·42, 1·28-1·57); non-breast-cancer mortality was similar.

INTERPRETATION: Aromatase inhibitors reduce recurrence rates by about 30% (proportionately) compared with tamoxifen while treatments differ, but not thereafter. 5 years of an aromatase inhibitor reduces 10-year breast cancer mortality rates by about 15% compared with 5 years of tamoxifen, hence by about 40% (proportionately) compared with no endocrine treatment.

FUNDING: Cancer Research UK, Medical Research Council.

In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5' CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (P < 0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score > or =7 (P=0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in early-stage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

Spatial and temporal influences of in-stream factors on the chemistry and epilithic biomasses of upland stream metal deposits

The density and composition of stream bed metal deposits are affected by physical, chemical and biological processes. In this paper we investigate the importance of these processes and their relation to algal and non-photosynthetic detrital (NPD) biomass in a set of upland streams in Northern Ireland. Deposit density and Fe, Mn, Al and P concentrations varied with stream pH across sites but not seasonally. No effects of stream bed erosion or photoreduction were detected on deposit densities. Seasonal variation in stream water metal concentrations was correlated with rainfall. NPD biomass was a significant predictor of both spatial and seasonal variation in deposit concentrations. There were strong, non-linear, relations between NPD biomass and deposit metal concentrations, with Fe and Mn becoming relatively more important and algal biomass declining above threshold deposit/NPD densities. The results suggest that NPD biomass influences deposit density and reduces the biomass of photosynthetic autotrophs above a threshold deposit density.

The International Regulatory Regime on Capital Flows

Capital controls and exchange restrictions are used to restrict international capital flows during economic crises. This paper looks at the legal implications of these restrictions and explores the current international regulatory framework applicable to international capital movements and current payments. It shows how international capital flows suffer from the lack of a comprehensive and coherent regulatory framework that would harmonize the patchwork of
multilateral, regional, and bilateral treaties that currently regulate this issue. These treaties include the Articles of Agreement of the International Monetary Fund (IMF Articles), the General Agreement on Trade in Services (GATS), free-trade agreements, the European Union treaty, bilateral investment treaties, and the Organization for Economic Co-operation and Development (OECD) Code of Liberalization of Capital Movements (OECD Code of Capital Movement). Each
of these instruments regulate differently capital movements with little coordination with other areas of law. This situation sometimes leads to regulatory overlaps and conflict between different sources of law. Given the strong links between capital movements and trade in services, this paper pays particular attention to the rules of the GATS on capital flows and discusses the policy space available in the GATS for restricting capital flows in times of crisis.

EphA2 Expression Is a Key Driver of Migration and Invasion and a Poor Prognostic Marker in Colorectal Cancer

PURPOSE: EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumor initiation, neovascularization, and metastasis in a wide range of epithelial and mesenchymal cancers; however, its role in colorectal cancer recurrence and progression is unclear.

EXPERIMENTAL DESIGN: EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumors (N = 338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive colorectal cancer cell line models.

RESULTS: Colorectal tumors displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III colorectal cancer tissues, in both univariate and multivariate analyses. Preclinically, we found that EphA2 was highly expressed in KRASMT colorectal cancer cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines, and downregulation of EphA2 using RNAi or recombinant EFNA1 suppressed migration and invasion of KRASMT colorectal cancer cells.

CONCLUSIONS: These data show that EpHA2 is a poor prognostic marker in stage II/III colorectal cancer, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. Clin Cancer Res; 22(1); 230-42. ©2015 AACR.

Biometric measurements in highly myopic eyes

Purpose: To assess the repeatability and accuracy of optical biometry (Lenstar LS900 optical low-coherence reflectometry [OLCR] and IOLMaster partial coherence interferometry [PCI]) and applanation ultrasound biometry in highly myopic eyes. Setting: Division of Preventive Ophthalmology, Zhongshan Ophthalmic Center, Guangzhou, China. Design: Comparative evaluation of diagnostic technology. Methods: Biometric measurements were taken in highly myopic subjects with a spherical equivalent (SE) of -6.00 diopters (D) or higher and an axial length (AL) longer than 25.0 mm. Measurements of AL and anterior chamber depth (ACD) obtained by OLCR were compared with those obtained by PCI and applanation A-scan ultrasound. Right eyes were analyzed. Repeatability was evaluated using the coefficient of variation (CoV) and agreement, using Bland-Altman analyses. Results: The mean SE was -11.20 D ± 4.65 (SD). The CoVs for repeated AL measurements using OLCR, PCI, and applanation ultrasound were 0.06%, 0.07%, and 0.20%, respectively. The limits of agreement (LoA) for AL were 0.11 mm between OLCR and PCI, 1.01 mm between OLCR and applanation ultrasound, and 1.03 mm between PCI and ultrasound. The ACD values were 0.29 mm, 0.53 mm, and 0.51 mm, respectively. These repeatability and agreement results were comparable in eyes with extreme myopia (AL ≥27.0 mm) or posterior staphyloma. The mean radius of corneal curvature was similar between OLCR and PCI (7.66 ± 0.24 mm versus 7.64 ± 0.25 mm), with an LoA of 0.12 mm. Conclusion: Optical biometry provided more repeatable and precise measurements of biometric parameters, including AL and ACD, than applanation ultrasound biometry in highly myopic eyes. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. © 2012 ASCRS and ESCRS.

Choice of commuting mode among employees: Do home neighborhood environment, worksite neighborhood environment, and worksite policy and supports matter?

BACKGROUND: Promoting the use of public transit and active transport (walking and cycling) instead of car driving is an appealing strategy to increase overall physical activity.

PURPOSE: To quantify the combined associations between self-reported home and worksite neighborhood environments, worksite support and policies, and employees' commuting modes.

METHOD: Between 2012 and 2013, participants residing in four Missouri metropolitan areas were interviewed via telephone (n = 1,338) and provided information on socio-demographic characteristics, home and worksite neighborhoods, and worksite support and policies. Commuting mode was self-reported and categorized into car driving, public transit, and active commuting. Commuting distance was calculated using geographic information systems. Commuters providing completed data were included in the analysis. Multivariate logistic regression models were used to examine the correlates of using public transit and active commuting.

RESULT: The majority of participants reported commuting by driving (88.9%); only 4.9% used public transit and 6.2% used active modes. After multivariate adjustment, having transit stops within 10-15 minutes walking distance from home (p=0.05) and using worksite incentive for public transit (p<0.001) were associated with commuting by public transit. Commuting distance (p<0.001) was negatively associated with active commuting. Having free or low cost recreation facilities around the worksite (p=0.04) and using bike facilities to lock bikes at the worksite (p<0.001) were associated with active commuting.

CONCLUSION: Both environment features and worksite supports and policies are associated with the choice of commuting mode. Future studies should use longitudinal designs to investigate the potential of promoting alternative commuting modes through worksite efforts that support sustainable commuting behaviors as well as the potential of built environment improvements.