Antiproliferative effect of gold(I) compound auranofin through inhibition of STAT3 and telomerase activity in MDA-MB 231 human breast cancer cells

Signal transducer and activator of transcription 3 (STAT3) andtelomerase are considered attractive targets for anticancertherapy. The in vitro anticancer activity of the gold(I) compoundauranofin was investigated using MDA-MB 231 human breastcancer cells, in which STAT3 is constitutively active. In cellculture, auranofin inhibited growth in a dose-dependent manner,and N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygenspecies (ROS), markedly blocked the effect of auranofin.Incorporation of 5-bromo-2’-deoxyuridine into DNA andanchorage-independent cell growth on soft agar were decreasedby auranofin treatment. STAT3 phosphorylation and telomeraseactivity were also attenuated in cells exposed to auranofin, butNAC pretreatment restored STAT3 phosphorylation andtelomerase activity in these cells. These findings indicate thatauranofin exerts in vitro antitumor effects in MDA-MB 231 cellsand its activity involves inhibition of STAT3 and telomerase.Thus, auranofin shows potential as a novel anticancer drug thattargets STAT3 and telomerase. [BMB Reports 2013; 46(1): 59-64

Bubble formation in globe valve and flow characteristics of partially filled pipe water flow

Air bubble entrainment is a phenomenon that can significantly reduce the efficiency of liquid motion in piping systems. In the present study, the bubble formation mechanism in a globe valve with 90% water fraction flow is explained by visualization study and pressure oscillation analysis. The shadowgraph imaging technique is applied to illustrate the unsteady flow inside the transparent valve. This helps to study the effect of bubbles induced by the globe valve on pressure distribution and valve flow coefficient. International Society of Automation (ISA) recommends locations for measuring pressure drop of the valve to determine its flow coefficient. This paper presents the comparison of the pressures at different locations along with the upstream and the downstream of the valve with the values at recommended positions by the ISA standard. The results show that in partially filled pipe flow, the discrepancies in pressure between different measurement locations in the valve downstream are significant at valve openings less than 30%. The aerated flow induces the oscillation in pressure and flow rate, which leads to the fluctuation in the flow coefficient of the valve. The flow coefficients have a linear relationship with the Reynolds number. For the same increase of Reynolds number, the flow coefficients grow faster with larger valve openings and level off at the opening of 50%

Pericoronary fat attenuation index in computed tomography angiography is associated with mortality in end-stage renal disease

Background An increased pericoronary fat attenuation index (FAI) on computed tomography angiography (CTA) is associated with increased all-cause and cardiac mortality in the general population. However, the ability of pericoronary FAI to predict long-term outcomes in chronic kidney disease (CKD) patients is unknown. Methods In this single-center retrospective longitudinal cohort study, we assessed the utility of CTA-based pericoronary FAI measurement to predict mortality of CKD patients, including those with end-stage renal disease (ESRD). Mapping and analysis of pericoronary FAI involved three major proximal coronary arteries. The prognostic value of pericoronary FAI for long-term mortality was assessed with multivariable Cox regression models. Results Among 268 CKD participants who underwent coronary CTA, 209 participants with left anterior descending artery (LAD) FAI measurements were included. The pericoronary FAI measured at the LAD was not significantly associated with adjusted risk of all-cause mortality (hazard ratio [HR], 2.08; 95% confidence interval [CI], 0.94–3.51) in any CKD group. However, ESRD patients with elevated pericoronary FAI values had a greater adjusted risk of all-cause mortality compared with the low-FAI group (HR, 2.26; 95% CI, 1.11–4.61). Conclusion The pericoronary FAI measured at the LAD predicted long-term mortality in patients with ESRD, which could provide an opportunity for early primary intervention in ESRD patients

Clinical outcomes of spontaneous bacterial peritonitis due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species: A retrospective matched case-control study

<p>Abstract</p> <p>Background</p> <p>Clinical outcomes of spontaneous bacterial peritonitis (SBP) due to extended-spectrum β-lactamase-producing <it>Escherichia coli </it>and <it>Klebsiella </it>species (ESBL-EK) have not been adequately investigated.</p> <p>Methods</p> <p>We conducted a retrospective matched case-control study to evaluate the outcomes of SBP due to ESBL-EK compared with those due to non-ESBL-EK. Cases were defined as patients with liver cirrhosis and SBP due to ESBL-EK isolated from ascites. Control patients with liver cirrhosis and SBP due to non-ESBL-EK were matched in a 3:1 ratio to cases according to the following five variables: age (± 5 years); gender; species of infecting organism; Child-Pugh score (± 2); Acute Physiological and Chronic Health Evaluation II score (± 2). 'Effective initial therapy' was defined as less than 72 hours elapsing between the time of obtaining a sample for culture and the start of treatment with an antimicrobial agent to which the EK was susceptible. Cephalosporin use for ESBL-EK was considered 'ineffective', irrespective of the minimum inhibitory concentration. ESBL production was determined according to the Clinical and Laboratory Standards Institute guidelines on stored isolates.</p> <p>Results</p> <p>Of 1026 episodes of SBP in 958 patients from Jan 2000 through Dec 2006, 368 (35.9%) episodes in 346 patients were caused by SBP due to EK, isolated from ascites. Of these 346 patients, twenty-six (7.5%) patients with SBP due to ESBL-EK were compared with 78 matched controls. Treatment failure, evaluated at 72 hours after initial antimicrobial therapy, was greater among the cases (15/26, 58% <it>vs</it>. 10/78, 13%, <it>P </it>= .006); 30-day mortality rate was also higher than in the controls (12/26, 46% <it>vs</it>. 11/78, 15%, <it>P </it>= .001). When the case were classified according to the effectiveness of the initial therapy, 'ineffective initial therapy' was associated with higher 30-day mortality rate (11/18, 61% <it>vs</it>. 1/8, 13%, <it>P </it>= .036).</p> <p>Conclusion</p> <p>SBP due to ESBL-EK had poorer outcomes than SBP due to non-ESBL-EK. Ineffective initial therapy seems to be responsible for the higher rate of treatment failure and mortality in SBP due to ESBL-EK.</p

Stochastic Particle Flow for Nonlinear High-Dimensional Filtering Problems

A series of novel filters for probabilistic inference that propose an alternative way of performing Bayesian updates, called particle flow filters, have been attracting recent interest. These filters provide approximate solutions to nonlinear filtering problems. They do so by defining a continuum of densities between the prior probability density and the posterior, i.e. the filtering density. Building on these methods' successes, we propose a novel filter. The new filter aims to address the shortcomings of sequential Monte Carlo methods when applied to important nonlinear high-dimensional filtering problems. The novel filter uses equally weighted samples, each of which is associated with a local solution of the Fokker-Planck equation. This hybrid of Monte Carlo and local parametric approximation gives rise to a global approximation of the filtering density of interest. We show that, when compared with state-of-the-art methods, the Gaussian-mixture implementation of the new filtering technique, which we call Stochastic Particle Flow, has utility in the context of benchmark nonlinear high-dimensional filtering problems. In addition, we extend the original particle flow filters for tackling multi-target multi-sensor tracking problems to enable a comparison with the new filter

Imidazole propionate ameliorates atopic dermatitis-like skin lesions by inhibiting mitochondrial ROS and mTORC2

BackgroundImidazole propionate (IMP) is a histidine metabolite produced by some gut microorganisms in the human colon. Increased levels of IMP are associated with intestinal inflammation and the development and progression of cardiovascular disease and diabetes. However, the anti-inflammatory activity of IMP has not been investigated. This study aimed to elucidate the role of IMP in treating atopic dermatitis (AD). MethodsTo understand how IMP mediates immunosuppression in AD, IMP was intraperitoneally injected into a Dermatophagoides farinae extract (DFE)/1-chloro-2,4 dinitrochlorobenzene (DNCB)-induced AD-like skin lesions mouse model. We also characterized the anti-inflammatory mechanism of IMP by inducing an AD response in keratinocytes through TNF-α/IFN-γ or IL-4 stimulation. ResultsContrary to the prevailing view that IMP is an unhealthy microbial metabolite, we found that IMP-treated AD-like skin lesions mice showed significant improvement in their clinical symptoms, including ear thickness, epidermal and dermal thickness, and IgE levels. Furthermore, IMP antagonized the expansion of myeloid (neutrophils, macrophages, eosinophils, and mast cells) and Th cells (Th1, Th2, and Th17) in mouse skin and prevented mitochondrial reactive oxygen species production by inhibiting mitochondrial energy production. Interestingly, we found that IMP inhibited AD by reducing glucose uptake in cells to suppress proinflammatory cytokines and chemokines in an AD-like in vitro model, sequentially downregulating the PI3K and mTORC2 signaling pathways centered on Akt, and upregulating DDIT4 and AMPK. DiscussionOur results suggest that IMP exerts anti-inflammatory effects through the metabolic reprogramming of skin inflammation, making it a promising therapeutic candidate for AD and related skin diseases