Dark production of extracellular superoxide by the coral Porites astreoides and representative symbionts

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Frontiers in Marine Science 3 (2016): 232, doi:10.3389/fmars.2016.00232.The reactive oxygen species (ROS) superoxide has been implicated in both beneficial and detrimental processes in coral biology, ranging from pathogenic disease resistance to coral bleaching. Despite the critical role of ROS in coral health, there is a distinct lack of ROS measurements and thus an incomplete understanding of underpinning ROS sources and production mechanisms within coral systems. Here, we quantified in situ extracellular superoxide concentrations at the surfaces of aquaria-hosted Porites astreoides during a diel cycle. High concentrations of superoxide (~10's of nM) were present at coral surfaces, and these levels did not change significantly as a function of time of day. These results indicate that the coral holobiont produces extracellular superoxide in the dark, independent of photosynthesis. As a short-lived anion at physiological pH, superoxide has a limited ability to cross intact biological membranes. Further, removing surface mucus layers from the P. astreoides colonies did not impact external superoxide concentrations. We therefore attribute external superoxide derived from the coral holobiont under these conditions to the activity of the coral host epithelium, rather than mucus-derived epibionts or internal sources such as endosymbionts (e.g., Symbiodinium). However, endosymbionts likely contribute to internal ROS levels via extracellular superoxide production. Indeed, common coral symbionts, including multiple strains of Symbiodinium (clades A to D) and the bacterium Endozoicomonas montiporae LMG 24815, produced extracellular superoxide in the dark and at low light levels. Further, representative P. astreoides symbionts, Symbiodinium CCMP2456 (clade A) and E. montiporae, produced similar concentrations of superoxide alone and in combination with each other, in the dark and low light, and regardless of time of day. Overall, these results indicate that healthy, non-stressed P. astreoides and representative symbionts produce superoxide externally, which is decoupled from photosynthetic activity and circadian control. Corals may therefore produce extracellular superoxide constitutively, highlighting an unclear yet potentially beneficial role for superoxide in coral physiology and health.This work was supported by a Postdoctoral Fellowship from the Ford Foundation (JD), the National Science Foundation under grants OCE 1225801 (JD) and OCE 1233612 (AA), the Ocean and Climate Change Institute of the Woods Hole Oceanographic Institution (CH), a BIOS Grant in aid award (SM), the Sidney Stern Memorial Trust (CH and AA), as well as an anonymous donor

Species-specific control of external superoxide levels by the coral holobiont during a natural bleaching event

© The Author(s), 2016. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Communications 7 (2016): 13801, doi:10.1038/ncomms13801.The reactive oxygen species superoxide (O2·−) is both beneficial and detrimental to life. Within corals, superoxide may contribute to pathogen resistance but also bleaching, the loss of essential algal symbionts. Yet, the role of superoxide in coral health and physiology is not completely understood owing to a lack of direct in situ observations. By conducting field measurements of superoxide produced by corals during a bleaching event, we show substantial species-specific variation in external superoxide levels, which reflect the balance of production and degradation processes. Extracellular superoxide concentrations are independent of light, algal symbiont abundance and bleaching status, but depend on coral species and bacterial community composition. Furthermore, coral-derived superoxide concentrations ranged from levels below bulk seawater up to ∼120 nM, some of the highest superoxide concentrations observed in marine systems. Overall, these results unveil the ability of corals and/or their microbiomes to regulate superoxide in their immediate surroundings, which suggests species-specific roles of superoxide in coral health and physiology.This work was supported by a Postdoctoral Fellowship from the Ford Foundation (J.M.D.), the National Science Foundation under grants OCE 1225801 (J.M.D.) and OCE 1233612 (A.A.), the Ocean and Climate Change Institute of the Woods Hole Oceanographic Institution (C.M.H.), the Sidney Stern Memorial Trust (C.M.H. and A.A.) and an anonymous donor

The MANGO study: a prospective investigation of oxygen enhanced and blood-oxygen level dependent MRI as imaging biomarkers of hypoxia in glioblastoma

BackgroundGlioblastoma (GBM) is the most aggressive type of brain cancer, with a 5-year survival rate of ~5% and most tumours recurring locally within months of first-line treatment. Hypoxia is associated with worse clinical outcomes in GBM, as it leads to localized resistance to radiotherapy and subsequent tumour recurrence. Current standard of care treatment does not account for tumour hypoxia, due to the challenges of mapping tumour hypoxia in routine clinical practice. In this clinical study, we aim to investigate the role of oxygen enhanced (OE) and blood-oxygen level dependent (BOLD) MRI as non-invasive imaging biomarkers of hypoxia in GBM, and to evaluate their potential role in dose-painting radiotherapy planning and treatment response assessment.MethodsThe primary endpoint is to evaluate the quantitative and spatial correlation between OE and BOLD MRI measurements and [18F]MISO values of uptake in the tumour. The secondary endpoints are to evaluate the repeatability of MRI biomarkers of hypoxia in a test-retest study, to estimate the potential clinical benefits of using MRI biomarkers of hypoxia to guide dose-painting radiotherapy, and to evaluate the ability of MRI biomarkers of hypoxia to assess treatment response. Twenty newly diagnosed GBM patients will be enrolled in this study. Patients will undergo standard of care treatment while receiving additional OE/BOLD MRI and [18F]MISO PET scans at several timepoints during treatment. The ability of OE/BOLD MRI to map hypoxic tumour regions will be evaluated by assessing spatial and quantitative correlations with areas of hypoxic tumour identified via [18F]MISO PET imaging.DiscussionMANGO (Magnetic resonance imaging of hypoxia for radiation treatment guidance in glioblastoma multiforme) is a diagnostic/prognostic study investigating the role of imaging biomarkers of hypoxia in GBM management. The study will generate a large amount of longitudinal multimodal MRI and PET imaging data that could be used to unveil dynamic changes in tumour physiology that currently limit treatment efficacy, thereby providing a means to develop more effective and personalised treatments

Neuroimaging Studies Evaluating Effective Therapies for High-Grade Glioma

High-grade glioma (HGG) is one of the most aggressive types of brain tumours, with a median survival limited to 15 months. The ability to develop new effective therapies for HGG patients has been hampered by the heterogeneous structural and physiological properties of the blood-brain barrier (BBB) in the tumour, which largely influence the efficiency of delivery targeting therapies to the entire population of tumour cells. This thesis focuses on using neuroimaging techniques to investigate how the structural and physiological properties of the BBB in HGG affect the targeted delivery of macromolecular drugs, such as antibodies and nanomedicines. Additionally, this work involves the development of neuroimaging analysis pipelines for evaluating novel strategies for more effective therapies for HGG.The first part of this thesis provides an overview of HGG, discussing the disease’s pathology, current standard of care, limitations in improving overall patient survival and the central role of the BBB in hindering efficient delivery of tumour-targeting drugs. A review of the current strategies for tumour vasculature remodelling to improve drug delivery to brain tumours is presented, together with the evaluation of the role of neuroimaging in the development of biomarkers of BBB disruption and permeability.The second part of the thesis demonstrates how the selection of preclinical animal models of HGG that are able to reproduce the heterogeneous BBB characteristics of HGG patients is key to the clinical translation of new therapies. Contrast enhanced (CE) and dynamic CE (DCE) MRI are used together with histology to show that a patient-derived xenograft model of HGG better reproduces the extent of BBB disruption and permeability of recurrent HGG patients than the currently most widely used cell-line xenograft model, and therefore, is a better preclinical platform for testing novel therapies for HGG. Considerations on the choice of kinetic modelling parameters for BBB permeability assessments and perspectives on the role of comparative oncology for HGG are also discussed.The third part of the thesis focuses on the use of the characterised patient-derived xenograft model of HGG to perform a preclinical trial evaluating the efficiency of MR-guided focused ultrasound (FUS) as a therapeutic strategy to modulate the BBB and enhance delivery of a large tumour-targeting antibody in non-enhancing infiltrating tumour lying behind an intact BBB. In this study, a combination of MRI and PET imaging techniques are used to demonstrate that FUS treatment causes a temporary opening of the BBB that allows for higher accumulation of antibodies into the infiltrating tumour regions. The report of positive preclinical outcomes is followed by a discussion on important considerations for the translation of FUS into clinical trials, with particular focus on the need for standards for the selection of contrast agents and sonication parameters, but also on the potential opportunities that FUS offers to the exploration of immunotherapies for HGG.Finally, the last part of the thesis focuses on the development and testing of a neuroimaging analysis pipeline for the evaluation of outcomes of clinical trials in Neuro-oncology and for the discovery of novel imaging biomarkers for recurrent HGG. This pipeline is tested on a small dataset from a pilot clinical trial investigating the theranostic potential of a PSMA-targeting peptide in patients with recurrent HGG. In particular, the analysis of MRI, PET and CT images is used to assess the ability of the PSMA-targeting peptide to selectively accumulate in the entire tumour mass, and to act as an imaging biomarker with several potential applications for the diagnosis, prognosis and secondary treatment planning of recurrent HGG patients.In summary, this thesis not only highlights the importance of overcoming the limitations posed by the BBB to promote the clinical translation of emerging macromolecular drugs for HGG, but it also unveils the power of neuroimaging as a longitudinal biomarker to evaluate therapeutic strategies and support clinical decision-making

Cold cases e persone scomparse nell'era dei social media: il contributo dell'informatica forense

Il contributo, esito anche di analisi e esperienze sul campo, analizza come i metodi e gli strumenti dell'informatica forense, uniti alle tecnologie disponibili oggi, possano trarre da reperti informatici relativi a casi rimasti insoluti (cold cases), anche risalenti nel tempo, nuovi elementi probatori

Le decisioni nel credito alle Pmi: sono più corrette le informazioni quantitative o relazionali?

Utilizzando un dataset proprietario di linee di credito erogate a piccole-medie imprese (Pmi) tra il 2012 e il 2014, l’obiettivo del paper è capire come l’informazione di tipo hard e soft possa influenzare la correttezza e la probabilità di errore nelle decisioni di affidamento assunte da un campione di banche di credito cooperativo (Bcc). I due tipi di informazione hanno un ruolo complementare nell’influenzare la decisione di prestito finale della banca. L’informazione di tipo quantitativo appare più consistente nel condizionare la correttezza delle decisioni di prestito cosi come quella di evitare gli errori di valutazione. Al contrario, l’informazione di tipo relazionale produce risultati diversi nel tempo e nello spazio. Proprio per questa ragione forme di finanziamento basate sul relationship lending, a seconda del contesto, possono generare decisioni di finanziamento sia corrette sia errate

Le decisioni nel credito alle Pmi: sono più corrette le informazioni quantitative o relazionali?

Riassunto Utilizzando un dataset proprietario di linee di credito erogate a piccole-medie imprese (PMI) tra il 2012 e il 2014, l’obiettivo del paper è capire come l’informazione di tipo hard e soft possa influenzare la correttezza e la probabilità di errore nelle decisioni di affidamento assunte da un campione di banche di credito cooperativo (BCC). I due tipi di informazione hanno un ruolo complementare nell’influenzare la decisione di prestito finale della banca. L’informazione di tipo quantitativo appare più consistente nel condizionare la correttezza delle decisioni di prestito cosi come quella di evitare gli errori di valutazione. Al contrario, l’informazione di tipo relazionale produce risultati diversi nel tempo e nello spazio. Proprio per questa ragione forme di finanziamento basate sul relationship lending, a seconda del contesto, possono generare decisioni di finanziamento sia corrette sia errate. Abstract Using a proprietary database of lending decisions for small and medium-sized enterprises (SMEs), the aim of the paper is to understand how hard and soft information affect the correctness as well as the probability of errors within the loan decisions for a sample of cooperative banks (CBs). The two types of information play a complementary role in defining the bank loan final decision. Hard information appear more consistent in conditioning the correctness of loans decisions as well as to avoid errors. On the contrary, the relationship lending information generates different results over time and across space. In this sense, according to different scenarios, a lending relationship-based technology may generate both correct and wrong loan’s decisions

The potential for remodelling the tumour vasculature in glioblastoma

Despite significant improvements in the clinical management of glioblastoma, poor delivery of systemic therapies to the entire population of tumour cells remains one of the biggest challenges in the achievement of more effective treatments. On the one hand, the abnormal and dysfunctional tumour vascular network largely limits blood perfusion, resulting in an inhomogeneous delivery of drugs to the tumour. On the other hand, the presence of an intact blood-brain barrier (BBB) in certain regions of the tumour prevents chemotherapeutic drugs from permeating through the tumour vessels and reaching the diseased cells. In this review we analyse in detail the implications of the presence of a dysfunctional vascular network and the impenetrable BBB on drug transport. We discuss advantages and limitations of the currently available strategies for remodelling the tumour vasculature aiming to ameliorate the above mentioned limitations. Finally we review research methods for visualising vascular dysfunction and highlight the power of DCE- and DSC-MRI imaging to assess changes in blood perfusion and BBB permeability

Challenges in Glioblastoma Radiomics and the Path to Clinical Implementation

Radiomics is a field of medical imaging analysis that focuses on the extraction of many quantitative imaging features related to shape, intensity and texture. These features are incorporated into models designed to predict important clinical or biological endpoints for patients. Attention for radiomics research has recently grown dramatically due to the increased use of imaging and the availability of large, publicly available imaging datasets. Glioblastoma multiforme (GBM) patients stand to benefit from this emerging research field as radiomics has the potential to assess the biological heterogeneity of the tumour, which contributes significantly to the inefficacy of current standard of care therapy. Radiomics models still require further development before they are implemented clinically in GBM patient management. Challenges relating to the standardisation of the radiomics process and the validation of radiomic models impede the progress of research towards clinical implementation. In this manuscript, we review the current state of radiomics in GBM, and we highlight the barriers to clinical implementation and discuss future validation studies needed to advance radiomics models towards clinical application