Effects of Hypoxia and Transferrin on Toxicity and DNA Binding of Ruthenium Antitumor Agents in Hela Cells

Nuclear DNA binding and inhibition of growth of HeLa cells in culture were determined after 24 h incubation with the ruthenium anticancer agents cis-[Cl2(NH3)4Ru]Cl (CCR) and (ImH)trans-[(Im)2Cl4Ru] (ICR) as a function of [Ru], Po2, and added transferrin. Consistent with the “activation-by-reduction” hypothesis, cytotoxicity and DNA binding for both complexes increased under reduced oxygen conditions. Consistent with the “transferrin- transport” hypothesis, inhibition of cell growth also increased with added transferrin for both complexes. Despite their differences in charge, reduction potentials and substitution rates, both complexes behaved remarkably similarly indicating a common mechanism of action for both. Under atmospheric Conditions (Po2 = 159 torr), CCR inhibited HeLa cell growth with IC50 = 3.5 μM, while that for ICR was 2.0 μM. The binding of both complexes to DNA (RuDNA/PDNA) correlated with toxicity and was approximately linear in the concentration of the ruthenium complex in the culture medium, [Ru]. For both complexes, IC50 values decrease and DNA binding increases with decreasing log(Po2). In general, DNA binding at all oxygen pressures for both complexes is in the range of one Ru per 1000-2000 DNA base pairs at [Ru] = IC50

HPC on the Grid: The Theophys Experience

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Anterior Segment-Optical Coherence Tomography features in Blau syndrome.

Blau syndrome (BS) is a rare granulomatous auto-inflammatory disease, characterized by the classic clinical triad of joints, skin and ocular involvements. Ocular manifestation usually consists in a bilateral insidious chronic anterior uveitis with a potential evolution to panuveitis. We describe the case of two siblings, an 8-years old female and a 5-years old male, with a diagnosis of BS, evaluated by Anterior Segment-Optical Coherence Tomography (AS-OCT). In the female patient, slit-lamp examination revealed bilateral anterior granulomatous uveitis and inflammatory sequelae. AS-OCT revealed high intensity reflective layers in the anterior cornea, hyperreflective dots both in the aqueous humor and in the posterior corneal surface. In the male, no signs of inflammation were detected both on slit-lamp examination and AS-OCT scans. AS-OCT is a valuable, non-invasive tool that could improve the diagnosis of ocular involvement, better characterize and follow-up corneal alterations and anterior segment features in pediatric patients with BS

Methodological enhancements in MDO process investigated in the AGILE European project

This paper presents methodological investigations performed in research activities in the field of MDO in overall aircraft design in the ongoing EU funded research project AGILE. AGILE is developing the next generation of aircraft Multidisciplinary Design and Optimization processes, which target significant reductions in aircraft development costs and time to market, leading to cheaper and greener aircraft solutions. The paper introduces the AGILE project structure and describes the achievements of the 1st year (Design Campaign 1) leading to a reference distributed MDO system. A focus is then made on the different novel optimization techniques studied during the 2nd year, all willing to ease the optimization of complex work flows, characterized by high degree of discipline interdependencies, high number of design variables in the context of multi-level and multi-partner collaborative engineering projects. Then the implementation of these methods in the enhanced MDO framework is discussed

Thermosonic inspection of carbon fibre reinforced polymer composites using an airborne haptic ultrasonic phased array

This paper reports the development of a contactless non-destructive evaluation technique using an air-coupled haptic ultrasonic phased array to induce thermosonic frictional heating in damaged carbon fibre reinforced polymer composites. Haptic ultrasonic systems consist of controllable, narrowband, and high-power piezoelectric transducer arrays that are capable of electronically steering and shaping the ultrasonic beam on the surface of test samples. Localised thermal images of the damaged area were observed using an infrared camera. It was found that the intensity of the thermosonic heating reduced with increased distances between the ultrasonic excitation location and the damage. This approach allowed the ultrasonic focal point to be moved across the sample to identify the areas of damage, without moving either the array or the infrared camera, thus significantly decreasing the time needed for inspection

Withaferin A activates TRIM16 for its anti‐cancer activity in melanoma

Although selective BRAF inhibitors and novel immunotherapies have improved short-term treatment responses in metastatic melanoma patients, acquired resistance to these therapeutics still represent a major challenge in clinical practice. In this study, we evaluated the efficacy of Withaferin A (WFA), derived from the medicinal plant Withania Somnifera, as a novel therapeutic agent for the treatment of melanoma. WFA showed selective toxicity to melanoma cells compared to non-malignant cells. WFA induced apoptosis, significantly reduced cell proliferation and inhibited migration of melanoma cells. We identified that repression of the tumour suppressor TRIM16 diminished WFA cytotoxicity, suggesting that TRIM16 was in part responsible for the cytotoxic effects of WFA in melanoma cells. Together our data indicates that WFA has potent cytopathic effects on melanoma cells through TRIM16, suggesting a potential therapeutic application of WFA in the disease

Antiphospholipid antibodies and heart failure with preserved ejection fraction. The multicenter athero-aps study

Background. The prevalence of heart failure with preserved ejection fraction (HFpEF) in patients with antiphospholipid syndrome (APS) is unknown. Methods. A prospective multicenter cohort study including 125 patients was conducted: 91 primary APS (PAPS), 18 APS-SLE, and 16 carriers. HFpEF was diagnosed according to the 2019 European Society of Cardiology criteria: patients with ≥5 points among major and minor functional and morphological criteria including NT-ProBNP > 220 pg/mL, left atrial (LA) enlargement, increased left ventricular filling pressure. Results. Overall, 18 (14.4%) patients were diagnosed with HFpEF; this prevalence increased from 6.3% in carriers to 13.2% in PAPS and 27.8% in APS-SLE. Patients with HFpEF were older and with a higher prevalence of hypertension and previous arterial events. At logistic regression analysis, age, arterial hypertension, anticardiolipin antibodies IgG > 40 GPL (odds ratio (OR) 3.43, 95% confidence interval (CI) 1.09–10.77, p = 0.035), anti β-2-glycoprotein-I IgG > 40 GPL (OR 5.28, 1.53– 18.27, p = 0.009), lupus anticoagulants DRVVT > 1.25 (OR 5.20, 95% CI 1.10–24.68, p = 0.038), and triple positivity (OR 3.56, 95% CI 1.11–11.47, p = 0.033) were associated with HFpEF after adjustment for age and sex. By multivariate analysis, hypertension (OR 19.49, 95% CI 2.21–171.94, p = 0.008), age (OR 1.07, 95% CI 1.00–1.14, p = 0.044), and aβ2GPI IgG > 40 GPL (OR 8.62, 95% CI 1.23–60.44, p = 0.030) were associated with HFpEF. Conclusion. HFpEF is detectable in a relevant proportion of APS patients. The role of aPL in the pathogenesis and prognosis of HFpEF needs further investigation.publishersversionpublishe

A precise measurement of the non‐leptonic weak decay parameters α and ϕ in the spin 3/2 decay ω−→Λ0+K−

Experiment E800 at Fermilab using the E800 spectrometer has made a precise measurement of the non‐leptonic weak decay parameters for the spin 3/2 decay, Ω−→Δ°+K−. The paratmeters determined are αδαΩ=0.0126±0.0042, αΩ=0.0196±0.0066, and ϕπ=−3.4°±10.3°. This measurement of αΩ is nearly four times more precise than the previous world average value of −0.026±0.026 and shows this parameter to be inconsistent with zero. Also, E800 has made the first measurement of ϕΩ. (AIP) © 1995 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87479/2/692_1.pd

A precision measurement of the Ω− magnetic moment

The structure of baryons can be probed at long range by measuring their magnetic moments. The particulary simple valence quark structure (three strange quarks with their spins aligned) of the Ω− should make a precise measurments its magnetic moment a useful test of models of baryon structure. The only previous measurement of the Ω− magnetic moment to a precision of 10%, could not clearly differentiate between these models. © 1995 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/87480/2/478_1.pd