Amifostine can differentially modulate DNA double-strand breaks and apoptosis induced by idarubicin in normal and cancer cells

We have previously shown that amifostine differentially modulated the DNA-damaging action of idarubicin in normal and cancer cells and that the presence of p53 protein and oncogenic tyrosine kinases might play a role in this diversity. Aim: To investigate further this effect we have studied the influence of amifostine on idarubicin-induced DNA double-strand breaks (DSBs) and apoptosis. Methods: We employed pulse-field gel electrophoresis () for the detection of DSBs and assessment of their repair in human normal lymphocytes and chronic myelogenous leukaemia K562 cells lacking p53 activity and expressing the BCR/ABL tyrosine kinase. Apoptosis was evaluated by caspase-3 activity assay assisted by the alkaline comet assay and DAPI staining. Results: Idarubicin induced DSBs in a dose-independent manner in normal and cancer cells. Both types of the cells did not repair these lesions in 120 min and amifostine differentially modulated their level — decreased it in the lymphocytes and increased in K562 cells. In contrast to control cells, amifostine potentated apoptotic DNA fragmentation, chromatin condensation and the activity of caspase-3 in leukaemia cells. Conclusion: Amifostine can differentially modulate DSBs and apoptosis induced by idarubicin in normal and cancer cells. It can protect normal cells against drug-induced DNA damage and it can potentate the action of the drug in leukaemic cells. Further studies on link between amifostine-induced modulation of DSBs and apoptosis of cancer cells will bring a deeper insight into molecular mechanism of amifostine action.Ранее нами было показано, что амифостин дифференциально модулирует ДНК-повреждающее действие идарубицина в нормальных и злокачественных клетках, и что наличие белка р53 и онкогенных тирозин киназ может иметь значение для этих различий. Цель: изучить влияние амифостина на идарубицин-опосредованные двухнитевые разрывы ДНК (DSBs) и апоптоз. Методы: мы применили гель-электрофорез в пульсирующем поле (PFGE) для выявления DSBs и изучения их репарации в нормальных лимфоцитах человека и клетках K562 хронической миелоидной лейкемии, у которых р53 неактивен и экспрессирована BCR/ABL-тирозин киназа. Апоптоз оценивали с помощью реактивов для выявления активности каспазы-3, проведения щелочного гель-электрофореза одиночных клеток и DAPI-окрашивания. Результаты: идарубицин вызывает образование DSBs в нормальных и злокачественных клетках независимо от дозы. Оба типа клеток не репарировали эти повреждения за 120 мин, при этом амифостин дифференциально молулировал уровень DSBs — уменьшал в лимфоцитах и увеличивал в K562-клетках. В отличие от контрольных клеток амифостин потенциировал апоптическую фрагментацию ДНК, конденсацию хроматина и активность каспазы-3 в лейкемических клетках. Выводы: амифостин может дифференциально модулировать DSBs и апоптоз, вызванные идарубицином в нормальных и злокачественных клетках. Он может защитить нормальные клетки от повреждения ДНК, вызванного химиопрепаратом, и в то же время потенциировать действие препарата на лейкемические клетки. Дальнейшие исследования связи между вызванной амифостином модуляцией DSBs и апоптоза опухолевых клеток позволит лучше понять молекулярные механизмы действия амифостина

Conformal Invariance, Dark Energy, and CMB Non-Gaussianity

In addition to simple scale invariance, a universe dominated by dark energy naturally gives rise to correlation functions possessing full conformal invariance. This is due to the mathematical isomorphism between the conformal group of certain 3 dimensional slices of de Sitter space and the de Sitter isometry group SO(4,1). In the standard homogeneous isotropic cosmological model in which primordial density perturbations are generated during a long vacuum energy dominated de Sitter phase, the embedding of flat spatial sections in de Sitter space induces a conformal invariant perturbation spectrum and definite prediction for the shape of the non-Gaussian CMB bispectrum. In the case in which the density fluctuations are generated instead on the de Sitter horizon, conformal invariance of the horizon embedding implies a different but also quite definite prediction for the angular correlations of CMB non-Gaussianity on the sky. Each of these forms for the bispectrum is intrinsic to the symmetries of de Sitter space and in that sense, independent of specific model assumptions. Each is different from the predictions of single field slow roll inflation models which rely on the breaking of de Sitter invariance. We propose a quantum origin for the CMB fluctuations in the scalar gravitational sector from the conformal anomaly that could give rise to these non-Gaussianities without a slow roll inflaton field, and argue that conformal invariance also leads to the expectation for the relation n_S-1=n_T between the spectral indices of the scalar and tensor power spectrum. Confirmation of this prediction or detection of non-Gaussian correlations in the CMB of one of the bispectral shape functions predicted by conformal invariance can be used both to establish the physical origins of primordial density fluctuations and distinguish between different dynamical models of cosmological vacuum dark energy.Comment: 73 pages, 9 figures. Final Version published in JCAP. New Section 4 added on linearized scalar gravitational potentials; New Section 8 added on gravitational wave tensor perturbations and relation of spectral indices n_T = n_S -1; Table of Contents added; Eqs. (3.14) and (3.15) added to clarify relationship of bispectrum plotted to CMB measurements; Some other minor modification

Performance of highly sensitive cardiac troponin T assay to detect ischaemia at PET-CT in low-risk patients with acute coronary syndrome: a prospective observational study.

Highly sensitive troponin T (hs-TnT) assay has improved clinical decision-making for patients admitted with chest pain. However, this assay's performance in detecting myocardial ischaemia in a lowrisk population has been poorly documented. To assess hs-TnT assay's performance to detect myocardial ischaemia at positron emission tomography/CT (PET-CT) in low-risk patients admitted with chest pain. Patients admitted for chest pain with a nonconclusive ECG and negative standard cardiac troponin T results at admission and after 6 hours were prospectively enrolled. Their hs-TnT samples were at T0, T2 and T6. Physicians were blinded to hs-TnT results. All patients underwent a PET-CT at rest and during adenosine-induced stress. All patients with a positive PET-CT result underwent a coronary angiography. Forty-eight patients were included. Six had ischaemia at PET-CT. All of them had ≥1 significant stenosis at coronary angiography. Areas under the curve (95% CI) for predicting significant ischaemia at PET-CT using hs-TnT were 0.764 (0.515 to 1.000) at T0, 0.812(0.616 to 1.000) at T2 and 0.813(0.638 to 0.989) at T6. The receiver operating characteristicbased optimal cut-off value for hs-TnT at T0, T2 and T6 needed to exclude significant ischaemia at PET-CT was <4 ng/L. Using this value, sensitivity, specificity, positive and negative predictive values of hs-TnT to predict significant ischaemia were 83%/38%/16%/94% at T0, 100%/40%/19%/100% at T2 and 100%/43%/20%/100% at T6, respectively. Our findings suggest that in low-risk patients, using the hs-TnT assay with a cut-off value of 4 ng/L demonstrates excellent negative predictive value to exclude myocardial ischaemia detection at PET-CT, at the expense of weak specificity and positive predictive value. ClinicalTrials.gov Identifier: NCT01374607

Combined Use of High-Sensitive Cardiac Troponin, Copeptin, and the Modified HEART Score for Rapid Evaluation of Chest Pain Patients.

Clinical short-term risk stratification is a recommended approach in patients with chest pain and possible acute myocardial infarction (AMI) to further improve high safety of biomarker-based rule-out algorithms. The study aim was to assess clinical performance of baseline concentrations of high-sensitivity cardiac troponin T (hs-TnT) and copeptin and the modified HEART score (mHS) in early presenters to the emergency department with chest pain. This cohort study included patients with chest pain with onset maximum of 6 h before admission and no persistent ST-segment elevation on electrocardiogram. hs-TnT, copeptin, and the mHS were assessed from admission data. The diagnostic and prognostic value for three baseline rule-out algorithms: (1) single hs-TnT < 14 ng/l, (2) hs-TnT < 14 ng/l/mHS ≤ 3, and (3) hs-TnT < 14 ng/l/mHS ≤ 3/copeptin < 17.4 pmol/l, was assessed with sensitivity and negative predictive value. Primary diagnostic endpoint was the diagnosis of AMI. Prognostic endpoint was death and/or AMI within 30 days. Among 154 enrolled patients, 44 (29%) were classified as low-risk according to the mHS; AMI was diagnosed in 105 patients (68%). For ruling out AMI, the highest sensitivity and NPV from all studied algorithms were observed for hs-TnT/mHS/copeptin (100%, 95% CI 96.6-100, and 100%, 95% CI 75.3-100). At 30 days, the highest event-free survival was achieved in patients stratified with hs-TnT/mHS/copeptin algorithm (100%) with 100% (95% CI 75.3-100) NPV and 100% (95% CI 96.6-100) sensitivity. The combination of baseline hs-TnT, copeptin, and the mHS has an excellent sensitivity and NPV for short-term risk stratification. Such approach might improve the triage system in emergency departments and be a bridge for inclusion to serial blood sampling algorithms

Multi-laboratory efforts for the standardization of performance assessment of diffuse optics instruments - The BitMap Exercise

A multi-laboratory exercise, involving 29 diffuse optical instruments, aimed at performance assessment of diffuse optics instruments on standardized protocols is presented. The overarching methodology and future actions will also be discussed

A multi-laboratory comparison of photon migration instruments and their performances – the BitMap Exercise

Performance assessment and standardization are indispensable for instruments of clinical relevance in general and clinical instrumentation based on photon migration/diffuse optics in particular. In this direction, a multi-laboratory exercise was initiated with the aim of assessing and comparing their performances. 29 diffuse optical instruments belonging to 11 partner institutions of a European level Marie Curie Consortium BitMap1 were considered for this exercise. The enrolled instruments covered different approaches (continuous wave, CW; frequency domain, FD; time domain, TD and spatial frequency domain imaging, SFDI) and applications (e.g. mammography, oximetry, functional imaging, tissue spectroscopy). 10 different tests from 3 well-accepted protocols, namely, the MEDPHOT2, the BIP3, and the nEUROPt4 protocols were chosen for the exercise and the necessary phantoms kits were circulated across labs and institutions enrolled in the study. A brief outline of the methodology of the exercise is presented here. Mainly, the design of some of the synthetic descriptors, (single numeric values used to summarize the result of a test and facilitate comparison between instruments) for some of the tests will be discussed.. Future actions of the exercise aim at deploying these measurements onto an open data repository and investigating common analysis tools for the whole dataset