Oxygen Enhanced Optoacoustic Tomography (OE-OT) Reveals Vascular Dynamics in Murine Models of Prostate Cancer

Poor oxygenation of solid tumours has been linked with resistance to chemo- and radio-therapy and poor patient outcomes, hence non-invasive imaging of oxygen supply and demand in tumours could improve disease staging and therapeutic monitoring. Optoacoustic tomography (OT) is an emerging clinical imaging modality that provides static images of endogenous haemoglobin concentration and oxygenation. Here, we demonstrate oxygen enhanced (OE)-OT, exploiting an oxygen gas challenge to visualise the spatiotemporal heterogeneity of tumour vascular function. We show that tracking oxygenation dynamics using OE-OT reveals significant differences between two prostate cancer models in nude mice with markedly different vascular function (PC3 & LNCaP), which appear identical in static OT. LNCaP tumours showed a spatially heterogeneous response within and between tumours, with a substantial but slow response to the gas challenge, aligned with ex vivo analysis, which revealed a generally perfused and viable tumour with marked areas of haemorrhage. PC3 tumours had a lower fraction of responding pixels compared to LNCaP with a high disparity between rim and core response. While the PC3 core showed little or no dynamic response, the rim showed a rapid change, consistent with our ex vivo findings of hypoxic and necrotic core tissue surrounded by a rim of mature and perfused vasculature. OE-OT metrics are shown to be highly repeatable and correlate directly on a per-tumour basis to tumour vessel function assessed ex vivo. OE-OT provides a non-invasive approach to reveal the complex dynamics of tumour vessel perfusion, permeability and vasoactivity in real time. Our findings indicate that OE-OT holds potential for application in prostate cancer patients, to improve delineation of aggressive and indolent disease as well as in patient stratification for chemo- and radio-therapy.We would also like to thank the CRUK Cambridge Institute Core Facilities for their support, including the BRU, Histopathology, Light Microscopy, Biorepository, and Preclinical Imaging. We are grateful for advice from Dr Simon Richardson (Institute of Cancer Research, Sutton, UK) on optimal use of the Oxylite pO2 probe. This work was supported by the EPSRC-CRUK Cancer Imaging Centre in Cambridge and Manchester (C197/A16465), Cancer Research UK (C14303/A17197, C47594/A16267) and the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° FP7-PEOPLE-2013-CIG-630729

Proteomics of Buccal Cavity Mucus in Female Tilapia Fish (Oreochromis spp.): A Comparison between Parental and Non-Parental Fish

Mouthbrooding is an elaborate form of parental care displayed by many teleost species. While the direct benefits of mouthbrooding such as protection and transportation of offsprings are known, it is unclear if mouthbrooding offers additional benefits to embryos during incubation. In addition, mouthbrooding could incur negative costs on parental fish, due to limited feeding opportunities. Parental tilapia fish (Oreochromis spp.) display an elaborated form of parental care by incubating newly hatched embryos in oral buccal cavity until the complete adsorption of yolk sac. In order to understand the functional aspects of mouthbrooding, we undertake a proteomics approach to compare oral mucus sampled from mouthbrooders and non-mouthbrooders, respectively. Majority of the identified proteins have also been previously identified in other biological fluids or mucus-rich organs in different organisms. We also showed the upregulation of 22 proteins and down regulation of 3 proteins in mucus collected from mouthbrooders. Anterior gradient protein, hemoglobin beta-A chain and alpha-2 globin levels were lower in mouthbrooder samples. Mouthbrooder oral mucus collectively showed increase levels of proteins related to cytoskeletal properties, glycolytic pathway and mediation of oxidative stress. Overall the findings suggest cellular stress response, probably to support production of mucus during mouthbrooding phase

Dopamine acting at D1-like, D2-like and α1-adrenergic receptors differentially modulates theta and gamma oscillatory activity in primary motor cortex

The loss of dopamine (DA) in Parkinson’s is accompanied by the emergence of exaggerated theta and beta frequency neuronal oscillatory activity in the primary motor cortex (M1) and basal ganglia. DA replacement therapy or deep brain stimulation reduces the power of these oscillations and this is coincident with an improvement in motor performance implying a causal relationship. Here we provide in vitro evidence for the differential modulation of theta and gamma activity in M1 by DA acting at receptors exhibiting conventional and non-conventional DA pharmacology. Recording local field potentials in deep layer V of rat M1, co-application of carbachol (CCh, 5 μM) and kainic acid (KA, 150 nM) elicited simultaneous oscillations at a frequency of 6.49 ± 0.18 Hz (theta, n = 84) and 34.97 ± 0.39 Hz (gamma, n = 84). Bath application of DA resulted in a decrease in gamma power with no change in theta power. However, application of either the D1-like receptor agonist SKF38393 or the D2-like agonist quinpirole increased the power of both theta and gamma suggesting that the DA-mediated inhibition of oscillatory power is by action at other sites other than classical DA receptors. Application of amphetamine, which promotes endogenous amine neurotransmitter release, or the adrenergic α1-selective agonist phenylephrine mimicked the action of DA and reduced gamma power, a result unaffected by prior co-application of D1 and D2 receptor antagonists SCH23390 and sulpiride. Finally, application of the α1-adrenergic receptor antagonist prazosin blocked the action of DA on gamma power suggestive of interaction between α1 and DA receptors. These results show that DA mediates complex actions acting at dopamine D1-like and D2-like receptors, α1 adrenergic receptors and possibly DA/α1 heteromultimeric receptors to differentially modulate theta and gamma activity in M1

Syndromics: A Bioinformatics Approach for Neurotrauma Research

Substantial scientific progress has been made in the past 50 years in delineating many of the biological mechanisms involved in the primary and secondary injuries following trauma to the spinal cord and brain. These advances have highlighted numerous potential therapeutic approaches that may help restore function after injury. Despite these advances, bench-to-bedside translation has remained elusive. Translational testing of novel therapies requires standardized measures of function for comparison across different laboratories, paradigms, and species. Although numerous functional assessments have been developed in animal models, it remains unclear how to best integrate this information to describe the complete translational “syndrome” produced by neurotrauma. The present paper describes a multivariate statistical framework for integrating diverse neurotrauma data and reviews the few papers to date that have taken an information-intensive approach for basic neurotrauma research. We argue that these papers can be described as the seminal works of a new field that we call “syndromics”, which aim to apply informatics tools to disease models to characterize the full set of mechanistic inter-relationships from multi-scale data. In the future, centralized databases of raw neurotrauma data will enable better syndromic approaches and aid future translational research, leading to more efficient testing regimens and more clinically relevant findings

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Validating novel air pollution sensors to improve exposure estimates for epidemiological analyses and citizen science

Low cost, personal air pollution sensors may reduce exposure measurement errors in epidemiological investigations and contribute to citizen science initiatives. Here we assess the validity of a low cost personal air pollution sensor. Study participants were drawn from two ongoing epidemiological projects in Barcelona, Spain. Participants repeatedly wore the pollution sensor − which measured carbon monoxide (CO), nitric oxide (NO), and nitrogen dioxide (NO2). We also compared personal sensor measurements to those from more expensive instruments. Our personal sensors had moderate to high correlations with government monitors with averaging times of 1-h and 30-min epochs (r ~ 0.38–0.8) for NO and CO, but had low to moderate correlations with NO2 (~0.04–0.67). Correlations between the personal sensors and more expensive research instruments were higher than with the government monitors. The sensors were able to detect high and low air pollution levels in agreement with expectations (e.g., high levels on or near busy roadways and lower levels in background residential areas and parks). Our findings suggest that the low cost, personal sensors have potential to reduce exposure measurement error in epidemiological studies and provide valid data for citizen science studies

Cholinergic blockade and response timing in rats

The effects of central cholinergic blockade on the temporal regulation of behaviour were studied with a two-level DRL schedule. Five-month-old male Wistar rats had to press lever A and then wait for a minimum of 5 s before pressing lever B to obtain the reinforcer (sweetened milk). After a stable baseline performance, subjects were injected in random order with the general cholinergic blocker, scopolamine, 0.15 and 0.5 mg/kg, the peripheral cholinergic blocker, methylscopolamine, 0.15 and 0.5 mg/kg, and a combination of the cholinesterase inhibitor, physostigmine, 0.2 mg/kg, and scopolamine, 0.5 mg/kg. Each drug treatment was separated by 2 days of saline treatment. Results showed that scopolamine at 0.5 mg/kg significantly impaired the temporal regulation of the A-B response sequence: the median A-B inter-response time (IRT) was shortened and the coefficient of variation of the A-B IRT distribution was increased, thus revealing a loss in the sensitivity to time. This disruption of accurate timing behaviour lowered efficiency. The drug changed neither the duration of the B-A interval nor the A-B response rate, but significantly increased the rate of the superfluous B-B sequences. Methylscopolamine was without effects and physostigmine totally or partially reversed all the scopolamine effects. These results suggest that scopolamine at 0.5 mg/kg specifically affected the mechanism(s) underlying response timing, and that the effects were not secondary to changes in activity or motivation. They partly corroborate data obtained in other procedures and support the idea that the central cholinergic system is involved in the temporal regulation of behaviour