Circulating MicroRNAs as Potential Predictors of Anthracycline-Induced Troponin Elevation in Breast Cancer Patients: Diverging Effects of Doxorubicin and Epirubicin

Anthracyclines are anti-neoplastic drugs presenting cardiotoxicity as a side effect. Cardiac troponins (cTn) and echocardiography are currently used to assess cardiac damage and dysfunction, but early biomarkers identifying patients in need of preventive treatments remain a partially met need. Circulating microRNAs (miRNAs) represent good candidates, so we investigated their possible roles as predictors of troponin elevation upon anthracycline treatment. Eighty-eight female breast cancer patients administered with doxorubicin (DOX) or epirubicin (EPI) were divided into four groups basing on drug type and cTn positive (cTn+) or negative (cTn-) levels: DOX cTn-, DOX cTn+, EPI cTn- and EPI cTn+. Blood was collected at baseline, during treatment, and at follow-up. We identified plasma miRNAs of interest by OpenArray screening and single assay validation. Our results showed miR-122-5p, miR-499a-5p and miR-885-5p dysregulation in DOX patients at T0, identifying a signature separating, with good accuracy, DOX cTn- from DOX cTn+. No miRNAs showed differential expression in EPI subjects. Conversely, an anthracycline-mediated modulation (regardless of cTn) was observed for miR-34a-5p, -122-5p and -885-5p. Our study indicates specific circulating miRNAs as possible prediction markers for cardiac troponin perturbation upon anthracycline treatment. Indeed, our findings hint at the possible future use of plasma miRNAs to predict the cardiac responsiveness of patients to different anticancer agents

Clinical outcome of circulating tumor cells in metastatic castration-resistant prostate cancer patients treated with docetaxel: long-term prospective single-centre study

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Nonlinear time-series analysis of Hyperion's lightcurves

Hyperion is a satellite of Saturn that was predicted to remain in a chaotic rotational state. This was confirmed to some extent by Voyager 2 and Cassini series of images and some ground-based photometric observations. The aim of this aticle is to explore conditions for potential observations to meet in order to estimate a maximal Lyapunov Exponent (mLE), which being positive is an indicator of chaos and allows to characterise it quantitatively. Lightcurves existing in literature as well as numerical simulations are examined using standard tools of theory of chaos. It is found that existing datasets are too short and undersampled to detect a positive mLE, although its presence is not rejected. Analysis of simulated lightcurves leads to an assertion that observations from one site should be performed over a year-long period to detect a positive mLE, if present, in a reliable way. Another approach would be to use 2---3 telescopes spread over the world to have observations distributed more uniformly. This may be achieved without disrupting other observational projects being conducted. The necessity of time-series to be stationary is highly stressed.Comment: 34 pages, 12 figures, 4 tables; v2 after referee report; matches the version accepted in Astrophysics and Space Scienc

Diagnostic and Prognostic Utility of Circulating Cytochrome c in Acute Myocardial Infarction

Rationale: In contrast to cardiomyocyte necrosis, which can be quantified by cardiac troponin, functional cardiomyocyte impairment, including mitochondrial dysfunction, has escaped clinical recognition in acute myocardial infarction (AMI) patients. Objective: To investigate the diagnostic accuracy for AMI and prognostic prediction of in-hospital mortality of cytochrome c. Methods and Results: We prospectively assessed cytochrome c serum levels at hospital presentation in 2 cohorts: a diagnostic cohort of patients presenting with suspected AMI and a prognostic cohort of definite AMI patients. Diagnostic accuracy for AMI was the primary diagnostic end point, and prognostic prediction of in-hospital mortality was the primary prognostic end point. Serum cytochrome c had no diagnostic utility for AMI (area under the receiver-operating characteristics curve 0.51; 95% confidence intervals 0.44-0.58; P=0.76). Among 753 AMI patients in the prognostic cohort, cytochrome c was detectable in 280 (37%) patients. These patients had higher in-hospital mortality than patients with nondetectable cytochrome c (6% versus 1%; P<0.001). This result was mainly driven by the high mortality rate observed in ST-segment-elevation AMI patients with detectable cytochrome c, as compared with those with nondetectable cytochrome c (11% versus 1%; P<0.001). At multivariable analysis, cytochrome c remained a significant independent predictor of in-hospital mortality (odds ratio 3.0; 95% confidence interval 1.9-5.7; P<0.001), even after adjustment for major clinical confounders (odds ratio 4.01; 95% confidence interval 1.20-13.38; P=0.02). Conclusions: Cytochrome c serum concentrations do not have diagnostic but substantial prognostic utility in AMI

International study on inter-reader variability for circulating tumor cells in breast cancer

Introduction: Circulating tumor cells (CTCs) have been studied in breast cancer with the CellSearch® system. Given the low CTC counts in non-metastatic breast cancer, it is important to evaluate the inter-reader agreement.Methods: CellSearch® images (N = 272) of either CTCs or white blood cells or artifacts from 109 non-metastatic (M0) and 22 metastatic (M1) breast cancer patients from reported studies were sent to 22 readers from 15 academic laboratories and 8 readers from two Veridex laboratories. Each image was scored as No CTC vs CTC HER2- vs CTC HER2+. The 8 Veridex readers were summarized to a Veridex Consensus (VC) to compare each academic reader using % agreement and kappa (κ) statistics. Agreement was compared according to disease stage and CTC counts using the Wilcoxon signed rank test.Results: For CTC definition (No CTC vs CTC), the median agreement between academic readers and VC was 92% (range 69 to 97%) with a median κ of 0.83 (range 0.37 to 0.93). Lower agreement was observed in images from M0 (median 91%, range 70 to 96%) compared to M1 (median 98%, range 64 to 100%) patients (P < 0.001) and from M0 and <3CTCs (median 87%, range 66 to 95%) compared to M0 and ≥3CTCs samples (median 95%, range 77 to 99%), (P < 0.001). For CTC HER2 expression (HER2- vs HER2+), the median agreement was 87% (range 51 to 95%) with a median κ of 0.74 (range 0.25 to 0.90).Conclusions: The inter-reader agreement for CTC definition was high. Reduced agreement was observed in M0 patients with low CTC counts. Continuous training and independent image review are required

Planck early results V : The Low Frequency Instrument data processing

Peer reviewe

Prevention of congenital malformations and other adverse pregnancy outcomes with 4.0 mg of folic acid : community-based randomized clinical trial in Italy and the Netherlands

Background: In 2010 a Cochrane review confirmed that folic acid (FA) supplementation prevents the first- and second-time occurrence of neural tube defects (NTDs). At present some evidence from observational studies supports the hypothesis that FA supplementation can reduce the risk of all congenital malformations (CMs) or the risk of a specific and selected group of them, namely cardiac defects and oral clefts. Furthermore, the effects on the prevention of prematurity, foetal growth retardation and pre-eclampsia are unclear.Although the most common recommendation is to take 0.4 mg/day, the problem of the most appropriate dose of FA is still open.The aim of this project is to assess the effect a higher dose of peri-conceptional FA supplementation on reducing the occurrence of all CMs. Other aims include the promotion of pre-conceptional counselling, comparing rates of selected CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age, abruptio placentae.Methods/Design: This project is a joint effort by research groups in Italy and the Netherlands. Women of childbearing age, who intend to become pregnant within 12 months are eligible for the studies. Women are randomly assigned to receive 4 mg of FA (treatment in study) or 0.4 mg of FA (referent treatment) daily. Information on pregnancy outcomes are derived from women-and-physician information.We foresee to analyze the data considering all the adverse outcomes of pregnancy taken together in a global end point (e.g.: CMs, miscarriage, pre-eclampsia, preterm birth, small for gestational age). A total of about 1,000 pregnancies need to be evaluated to detect an absolute reduction of the frequency of 8%. Since the sample size needed for studying outcomes separately is large, this project also promotes an international prospective meta-analysis.Discussion: The rationale of these randomized clinical trials (RCTs) is the hypothesis that a higher intake of FA is related to a higher risk reduction of NTDs, other CMs and other adverse pregnancy outcomes. Our hope is that these trials will act as catalysers, and lead to other large RCTs studying the effects of this supplementation on CMs and other infant and maternal outcomes.Trial registration: Italian trial: ClinicalTrials.gov Identifier: NCT01244347.Dutch trial: Dutch Trial Register ID: NTR3161

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries