Autophagy and mitochondrial metabolism: insights into the role and therapeutic potential in chronic myeloid leukaemia

Despite the development of selective BCR‐ABL‐targeting tyrosine kinase inhibitors (TKIs) transforming the management of chronic myeloid leukaemia (CML), therapy‐resistant leukaemic stem cells (LSCs) persist after TKI treatment and present an obstacle to a CML cure. Recently, we and others have made significant contributions to the field by unravelling survival dependencies in LSCs to work towards the goal of eradicating LSCs in CML patients. In this review, we describe these findings focusing on autophagy and mitochondrial metabolism, which have recently been uncovered as two essential processes for LSCs quiescence and survival, respectively. In addition, we discuss the therapeutic potential of autophagy and mitochondrial metabolism inhibition as a strategy to eliminate CML cells in patients where the resistance to TKI is driven by BCR‐ABL‐independent mechanism(s)

Addressing drinking water salinity due to sea water intrusion in Praia de Leste, Parana, by a brackish water desalination pilot plant

Seawater intrusion into the Pombas River, source of freshwater to Praia de Leste on the coast of Parana in Brazil presents a problem to the water utility as most water treatment plants in Brazil are conventional. To find a solution to this problem, a pilot plant (1 m3 /h) consisting of ultrafiltration (UF) followed by reverse osmosis (RO) was developed and evaluated. For testing, brackish water was produced with a concentration of 1,500 ± 100 mg/L of total dissolved solids (TDS), mixing seawater and fresh water. To evaluate the water quality, TDS, electrical conductivity, pH, temperature, apparent color, turbidity, alkalinity, total hardness, calcium, chloride and sulfate were monitored. For operational performance, flowrates, osmotic pressure, filtration rate, recovery rate and mass balance were analyzed. On average, the UF system removed 96.4% of turbidity and 98.6% of apparent color; whereas the RO system removed 99.4% of TDS. The overall average recovery (UF and RO) was 45.81% with average osmotic pressure of 8.21 bar, filtration rate of 30.7 L/h/m2 in the UF system and 21.7 L/h/m2 in the RO system. From a water quality point of view, the system was effective in processing brackish into fresh water of high quality

Natural variation in immune responses to neonatal mycobacterium bovis bacillus calmette-guerin (BCG) vaccination in a cohort of Gambian infants

Background There is a need for new vaccines for tuberculosis (TB) that protect against adult pulmonary disease in regions where BCG is not effective. However, BCG could remain integral to TB control programmes because neonatal BCG protects against disseminated forms of childhood TB and many new vaccines rely on BCG to prime immunity or are recombinant strains of BCG. Interferon-gamma (IFN-) is required for immunity to mycobacteria and used as a marker of immunity when new vaccines are tested. Although BCG is widely given to neonates IFN- responses to BCG in this age group are poorly described. Characterisation of IFN- responses to BCG is required for interpretation of vaccine immunogenicity study data where BCG is part of the vaccination strategy. Methodology/Principal Findings 236 healthy Gambian babies were vaccinated with M. bovis BCG at birth. IFN-, interleukin (IL)-5 and IL-13 responses to purified protein derivative (PPD), killed Mycobacterium tuberculosis (KMTB), M. tuberculosis short term culture filtrate (STCF) and M. bovis BCG antigen 85 complex (Ag85) were measured in a whole blood assay two months after vaccination. Cytokine responses varied up to 10 log-fold within this population. The majority of infants (89-98% depending on the antigen) made IFN- responses and there was significant correlation between IFN- responses to the different mycobacterial antigens (Spearman’s coefficient ranged from 0.340 to 0.675, p=10-6-10-22). IL-13 and IL-5 responses were generally low and there were more non-responders (33-75%) for these cytokines. Nonetheless, significant correlations were observed for IL-13 and IL-5 responses to different mycobacterial antigens Conclusions/Significance Cytokine responses to mycobacterial antigens in BCG-vaccinated infants are heterogeneous and there is significant inter-individual variation. Further studies in large populations of infants are required to identify the factors that determine variation in IFN- responses

Analysis of spatial variability for the development of reduced lead body surface maps

The spatial frequency of measurement points from standard ECG systems lacks accuracy to diagnose local variability in cardiac activity on the torso. Body Surface Mapping (BSM) improves this accuracy, but lacks the simplicity to be implemented in clinic on a regular basis. Reduced-lead BSM system improves applicability, but currently no standardization of lead reduction has been agreed upon. This research investigates the reduction of BSMs based on Lomb-Scargle Spectral Analysis to determine an appropriate electrode positioning through spatial frequency assessment. Based on the measurement of 13 healthy volunteers, a 128 electrode system could be reduced to a 36 electrode system and an 84 electrode system for ventricular and atrial activity measurements, respectively, with up to 10% loss of the full information provided by the original body surface potential map. Further research will investigate the appropriate positions of these electrodes and the effect of lead reduction for various cardiac abnormalities

A novel multivariate STeady-state index during general ANesthesia (STAN)

The assessment of the adequacy of general anesthesia for surgery, namely the nociception/anti-nociception balance, has received wide attention from the scientific community. Monitoring systems based on the frontal EEG/EMG, or autonomic state reactions (e.g. heart rate and blood pressure) have been developed aiming to objectively assess this balance. In this study a new multivariate indicator of patients' steady-state during anesthesia (STAN) is proposed, based on wavelet analysis of signals linked to noxious activation. A clinical protocol was designed to analyze precise noxious stimuli (laryngoscopy/intubation, tetanic, and incision), under three different analgesic doses; patients were randomized to receive either remifentanil 2.0, 3.0 or 4.0 ng/ml. ECG, PPG, BP, BIS, EMG and [Formula: see text] were continuously recorded. ECG, PPG and BP were processed to extract beat-to-beat information, and [Formula: see text] curve used to estimate the respiration rate. A combined steady-state index based on wavelet analysis of these variables, was applied and compared between the three study groups and stimuli (Wilcoxon signed ranks, Kruskal-Wallis and Mann-Whitney tests). Following institutional approval and signing the informed consent thirty four patients were enrolled in this study (3 excluded due to signal loss during data collection). The BIS index of the EEG, frontal EMG, heart rate, BP, and PPG wave amplitude changed in response to different noxious stimuli. Laryngoscopy/intubation was the stimulus with the more pronounced response [Formula: see text]. These variables were used in the construction of the combined index STAN; STAN responded adequately to noxious stimuli, with a more pronounced response to laryngoscopy/intubation (18.5-43.1 %, [Formula: see text]), and the attenuation provided by the analgesic, detecting steady-state periods in the different physiological signals analyzed (approximately 50 % of the total study time). A new multivariate approach for the assessment of the patient steady-state during general anesthesia was developed. The proposed wavelet based multivariate index responds adequately to different noxious stimuli, and attenuation provided by the analgesic in a dose-dependent manner for each stimulus analyzed in this study.The first author was supported by a scholarship from the Portuguese Foundation for Science and Technology (FCT SFRH/BD/35879/2007). The authors would also like to acknowledge the support of UISPA—System Integration and Process Automation Unit—Part of the LAETA (Associated Laboratory of Energy, Transports and Aeronautics) a I&D Unit of the Foundation for Science and Technology (FCT), Portugal. FCT support under project PEst-OE/EME/LA0022/2013.info:eu-repo/semantics/publishedVersio

MYC-microRNA-9-metastasis connection in breast cancer

[Excerpt] Metastasis accounts for more than 90% of cancer patients’ mortality. The metastatic process involves multiple steps [1]. Initially, cancer cells from the primary tumor invade adjacent stroma. To acquire this capacity, cells undergo a process called epithelial-mesenchymal transition (EMT), in which cells in re-sponse to signals from the surrounding stroma, undergo a switch between cell phenotypes and acquire mesenchymal properties and show reduced intercel-lular adhesion, allowing cells to be-come motile. Then cells enter systemic circulation, either through the blood or lymph, and finally extravasate into the parenchyma of distant tissues, where they form micrometastasis and prolifer-ate to form secondary tumors [2]. [...

A platform to guide catheter ablation of persistent atrial fibrillation using dominant frequency mapping

Dominant frequency (DF) mapping has been widely used to study the pathophysiology of atrial fibrillation (AF). In this study, a DF mapping system was developed to guide catheter ablation on electro-physiology (EP) procedures of persistent AF patients. The proposed platform has an automated graphical user interface (GUI) that processes non-contact unipolar electrograms (EGMs) recorded simultaneously by St. Jude Ensite Velocity System and provides 3D representation of the left atrium with DF behaviours and phase analysis

Chromatic Illumination Discrimination Ability Reveals that Human Colour Constancy Is Optimised for Blue Daylight Illuminations

The phenomenon of colour constancy in human visual perception keeps surface colours constant, despite changes in their reflected light due to changing illumination. Although colour constancy has evolved under a constrained subset of illuminations, it is unknown whether its underlying mechanisms, thought to involve multiple components from retina to cortex, are optimised for particular environmental variations. Here we demonstrate a new method for investigating colour constancy using illumination matching in real scenes which, unlike previous methods using surface matching and simulated scenes, allows testing of multiple, real illuminations. We use real scenes consisting of solid familiar or unfamiliar objects against uniform or variegated backgrounds and compare discrimination performance for typical illuminations from the daylight chromaticity locus (approximately blue-yellow) and atypical spectra from an orthogonal locus (approximately red-green, at correlated colour temperature 6700 K), all produced in real time by a 10-channel LED illuminator. We find that discrimination of illumination changes is poorer along the daylight locus than the atypical locus, and is poorest particularly for bluer illumination changes, demonstrating conversely that surface colour constancy is best for blue daylight illuminations. Illumination discrimination is also enhanced, and therefore colour constancy diminished, for uniform backgrounds, irrespective of the object type. These results are not explained by statistical properties of the scene signal changes at the retinal level. We conclude that high-level mechanisms of colour constancy are biased for the blue daylight illuminations and variegated backgrounds to which the human visual system has typically been exposed

Propagation of meandering rotors surrounded by areas of high dominant frequency in persistent atrial fibrillation

Background: Identification of arrhythmogenic regions remains a challenge in persistent atrial fibrillation (persAF). Frequency and phase analysis allows identification of potential ablation targets. Objective: This study aimed to investigate the spatiotemporal association between dominant frequency (DF) and reentrant phase activation areas. Methods: A total of 8 persAF patients undergoing first-time catheter ablation procedure were enrolled. A noncontact array catheter was deployed into the left atrium (LA) and 2048 atrial fibrillation electrograms (AEGs) were acquired for 15 seconds following ventricular far-field cancellation. DF and phase singularity (PS) points were identified from the AEGs and tracked over consecutive frames. The spatiotemporal correlation of high DF areas and PS points was investigated, and the organization index at the core of high-DF areas was compared with that of their periphery. Results: The phase maps presented multiple simultaneous PS points that drift over the LA, with preferential locations. Regions displaying higher PS concentration showed a degree of colocalization with DF sites, with PS and DF regions being neighbors in 61.8% and with PS and DF regions overlapping in 36.8% of the time windows. Sites with highest DF showed a greater degree of organization at their core compared with their periphery. After ablation, the PS incidence reduced over the entire LA (36.2% ± 23.2%, P < .05), but especially at the pulmonary veins (78.6% ± 22.2%, P < .05). Conclusion: Multiple PS points drifting over the LA were identified with their clusters correlating spatially with the DF regions. After pulmonary vein isolation, the PS’s complexity was reduced, which supports the notion that PS sites represent areas of relevance to the atrial substrate