S100A4 in cancer metastasis: Wnt signaling-driven interventions for metastasis restriction

The aberrant activity of Wnt signaling is an early step in the transformation of normal intestinal cells to malignant tissue, leading to more aggressive tumors, and eventually metastases. In colorectal cancer (CRC), metastasis accounts for about 90% of patient deaths, representing the most lethal event during the course of the disease and is directly linked to patient survival, critically limiting successful therapy. This review focuses on our studies of the metastasis-inducing gene S100A4, which we identified as transcriptional target of {beta}-catenin. S100A4 increased migration and invasion in vitro and metastasis in mice. In patient CRC samples, high S100A4 levels predict metastasis and reduced patient survival. Our results link pathways important for tumor progression and metastasis: the Wnt signaling pathway and S100A4, which regulates motility and invasiveness. S100A4 suppression by interdicting Wnt signaling has potential for therapeutic intervention. As proof of principle, we applied S100A4 shRNA systemically and prevented metastasis in mice. Furthermore, we identified small molecule inhibitors from high-throughput screens of pharmacologically active compounds employing an S100A4 promoter-driven reporter. Best hits act, as least in part, via intervening in the Wnt pathway and restricted metastasis in mouse models. We currently translate our findings on restricting S100A4-driven metastasis into clinical practice. The repositioned FDA-approved drug niclosamide, targeting Wnt signaling, is being tested in a prospective phase II clinical trial for treatment of CRC patients. Our assay for circulating S100A4 transcripts in patient blood is used to monitor treatment success

Regulation of Kir Channels by Intracellular pH and Extracellular K+: Mechanisms of Coupling

ROMK channels are regulated by internal pH (pHi) and extracellular K+ (K+o). The mechanisms underlying this regulation were studied in these channels after expression in Xenopus oocytes. Replacement of the COOH-terminal portion of ROMK2 (Kir1.1b) with the corresponding region of the pH-insensitive channel IRK1 (Kir 2.1) produced a chimeric channel (termed C13) with enhanced sensitivity to inhibition by intracellular H+, increasing the apparent pKa for inhibition by ∼0.9 pH units. Three amino acid substitutions at the COOH-terminal end of the second transmembrane helix (I159V, L160M, and I163M) accounted for these effects. These substitutions also made the channels more sensitive to reduction in K+o, consistent with coupling between the responses to pHi and K+o. The ion selectivity sequence of the activation of the channel by cations was K+ ≅ Rb+ > NH4+ >> Na+, similar to that for ion permeability, suggesting an interaction with the selectivity filter. We tested a model of coupling in which a pH-sensitive gate can close the pore from the inside, preventing access of K+ from the cytoplasm and increasing sensitivity of the selectivity filter to removal of K+o. We mimicked closure of this gate using positive membrane potentials to elicit block by intracellular cations. With K+o between 10 and 110 mM, this resulted in a slow, reversible decrease in conductance. However, additional channel constructs, in which inward rectification was maintained but the pH sensor was abolished, failed to respond to voltage under the same conditions. This indicates that blocking access of intracellular K+ to the selectivity filter cannot account for coupling. The C13 chimera was 10 times more sensitive to extracellular Ba2+ block than was ROMK2, indicating that changes in the COOH terminus affect ion binding to the outer part of the pore. This effect correlated with the sensitivity to inactivation by H+. We conclude that decreasing pHI increases the sensitivity of ROMK2 channels to K+o by altering the properties of the selectivity filter

Treatment trends for retinopathy of prematurity in the UK:active surveillance study of infants at risk

OBJECTIVES: To estimate the incidence of severe retinopathy of prematurity (ROP) requiring treatment and describe current treatment patterns in the UK. DESIGN: Nationwide population-based case ascertainment study via the British Ophthalmic Surveillance Unit and a national collaborative ROP special interest group. Practitioners completed a standardised case report form (CRF). SETTING: All paediatric ophthalmologists providing screening and/or treatment for retinopathy in the UK were invited to take part. PARTICIPANTS: Any baby with ROP treated or referred for treatment between 1 December 2013 and 30 November 2014, treated with laser, cryotherapy, vascular endothelial growth factor (VEGF) inhibitor or vitrectomy/scleral buckling, or a combination. MAIN OUTCOME MEASURE: Incidence of ROP requiring treatment. RESULTS: We received 370 CRFs; 327 were included. Denominator from epidemiological data: 8112 infants with birth weight of <1500 g. The incidence of ROP requiring treatment was 4% (327/8112, 95% CI 3.6% to 4.5%). Median gestational age was 25 weeks (IQR 24.3–26.1), and median birth weight 706 g (IQR 620–821). Median age at first treatment was 80 days (IQR 71–96). 204 right eyes (62.39%) had type 1 ROP, and 27 (8.26%) had aggressive posterior ROP. Infants were also treated for milder disease: 9 (2.75%) right eyes were treated for type 2 ROP, and 74 (22.63%) for disease milder than type 1 with plus or preplus, which we defined here as ‘type 2 plus’ disease. First-line treatment was diode laser photoablation of the avascular retina in 90.5% and injection of VEGF inhibitor in 8%. CONCLUSIONS: ROP treatment incidence in the UK is 2.5 times higher than previously estimated. 8% of treated infants receive intravitreal VEGF inhibitor, currently unlicensed. Research is needed urgently to establish safety and efficacy of this approach. Earlier treatment and increasing numbers of surviving premature infants require an increase in appropriate eye care facilities and staff. TRIAL REGISTRATION NUMBER: NCT02484989

Проблемы технического нормирования шумовых характеристик текстильных машин

Для целей оценки соответствия шумовых характеристик машин требованиям санитарных норм предложено использовать обобщенные предельно допустимые шумовые характеристики, которые задают предельно допустимые характеристики для близких по типу машин, объединенных в группы с учетом характерной плотности их установки и условий эксплуатации. Для уточненного определения этих характеристик целесообразно использовать методику, учитывающую звукопоглощение и рассеяние шума поверхностью машин, плотность тел рассеяния в поперечном сечении производственного помещения и его акустические и геометрические характеристики.For the purposes of assessing the compliance of noise characteristics of machines with the requirements of sanitary standards, it is suggested to use generalized maximum permissible noise characteristics that set the maximum permissible characteristics for similar machines, grouped together, taking into account the characteristic density of their installation and operating conditions. For an accurate definition of these characteristics, it is advisable to use a technique that takes into account the sound absorption and noise scattering by the machine surface, the density of scattering bodies in the cross section of the production room and its acoustic and geometric characteristics

The poverty of journal publishing

The article opens with a critical analysis of the dominant business model of for-profit, academic publishing, arguing that the extraordinarily high profits of the big publishers are dependent upon a double appropriation that exploits both academic labour and universities’ financial resources. Against this model, we outline four possible responses: the further development of open access repositories, a fair trade model of publishing regulation, a renaissance of the university presses, and, finally, a move away from private, for-profit publishing companies toward autonomous journal publishing by editorial boards and academic associations. </jats:p

Optical Coherence Tomography Findings After Childhood Lensectomy

Purpose: To explore the impact of childhood lensectomy on posterior segment development. / Methods: Cross-sectional observational study at children's eye clinics at a tertiary referral center in London, UK. We included 45 children age 4 to 16 years with healthy eyes and 38 who had undergone lensectomy. We acquired posterior segment optical coherence tomography scans of both eyes. We used parametric and nonparametric tests in SPSS24 for the comparison of parameters between groups and within individuals; a P value less than 0.05 was considered significant. The main outcome measures were foveal pit depth and subfoveal choroidal thickness (CT). Secondary outcomes were inner and outer ring CT and photoreceptor layer parameters, macular and peripapillary retinal nerve fiber layer thickness. / Results: Foveal pit depth and subfoveal CT are significantly reduced in eyes that have undergone lensectomy compared with nonoperated eyes. Inner ring CT and outer ring CT are reduced. Foveal inner retinal layer thickness is increased. Mean inner retinal and outer nuclear layer thickness are not affected. / Conclusions: Childhood lensectomy is associated with a reduction in developmental foveal pit deepening and lack of developmental thickening of the posterior choroid. Mechanical and optical disruption of foveal and subfoveal choroidal development may affect structural foveal development after childhood lensectomy

Fat Mass and Obesity-Associated Gene (FTO) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-infinity; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-infinity; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN. Copyright (C) 2012 S. Karger GmbH, Freibur

Soft Contact Lenses to Optimize Vision in Adults with Idiopathic Infantile Nystagmus: A Pilot Parallel Randomized Controlled Trial

PURPOSE: The optimal management of infantile nystagmus syndrome (INS) is still unclear. Contact lenses (CL) may be superior to glasses in improving visual function in INS but it is not known whether their beneficial effects are due to optical correction alone, or to an additional proprioceptive effect, and whether soft CLs would be as effective as rigid CLs. There is little data on feasibility and and the present study aimed to provide this information. METHODS: We completed a pilot Randomized Control Trial (RCT) at a single tertiary referral centre in London, UK. We enrolled 38 adults with idiopathic INS and randomised them to either plano CL (with corrective spectacles if required) or to corrective CL. CL wear was required for a minimum of 2 weeks. Primary outcome measures were feasibility and safety of CL wear in INS; secondary outcome measures were visual acuity and nystagmus waveform parameters. RESULTS: 27 completed the study (27/38,71%). 4 partcipants withdrew due to difficulty with CL insertion/removal and 7 were lost to follow up. CL tolerability was high (24/27,89%) - 2 found the CLs irritant, and 1 had an exacerbation of allergic eye disease. At two weeks, mean improvement in binocular visual acuity from baseline with plano CLs was 0.07 logMAR (95% confidence interval (CI: 0.03-0.11) and 0.06 logMAR with fully corrective CLs (95% CI:0.02-0.1). Mean improvement in the eXpanded Nystagmus Acuity Function (NAFX, a nystagmus acuity function based on eye movement recording) with plano CLs was -0.04(95% CI: -0.08-0.005) and -0.05 with fully corrective CLs(95% CI: -0.09-0.003). CONCLUSIONS: CLs are well tolerated, with a low risk profile. Whilst our study was not powered to detect significant changes in BCVA and waveform parameters between treatment arms, we observed a trend towards an improvement in visual function at two weeks from baseline with CLs