Molecular Imaging of Brain Tumours

This chapter is a review of the most common radiotracers currently used in clinical brain tumour imaging, and an update of future potentially useful radiotracers for imaging brain tumours with positron emission tomography (PET). It will focus mainly on glioma—the most common type of primary brain tumour—and intracranial metastases, as the cause of the majority of morbidity and mortality in neurooncology. Emerging data support the use of somatostatin analogue PET in the treatment planning and surveillance of meningiomas. There is currently a limited role of PET in other non-glial brain neoplasms including neuronal tumours, pineal and pituitary tumours, germ cell tumours and embryonal tumours (PNET, neuroblastoma). Finally, the newest hybrid imaging modality of PET/MRI and the promise it holds for obtaining state-of-the-art structural and functional imaging data simultaneously, are concisely reviewed

Chronic mild stress and deficits in the rodent brain: A preliminary examination of neuroinflammation-induced cognitive and behavioral changes in rats

This pilot study investigated the effects of chronic mild stress on a variety of cognitive and behavioral tasks in Sprague-Dawley rats. Our study consisted of two cohorts, one housed individually and one housed in dyad pairs, stressed over six weeks. We then examined the rat’s weight, sucrose preference, forced swim behaviors, and performance on maze-based cognitive tasks. Tests were conducted to examine whether chronic stress was sufficient to induce inflammation in the brain that would result in significant deficits. Results will be compared with analysis of the brains post-mortem to examine potential neurobiological correlates in regions of the rodent brain

Tissue engineering of the human atrium : approaching mechanisms of genesis and control of atrial fibrillation

Cardiovascular disease is prevalent across the western world and is a major cause of morbidity and mortality, accounting for approximately a third of all fatalities. Investigating the heart by simulating its electrophysiology via the aid of mathematical models has advanced significantly over the past 60 years and is now a well established field. While much of the research focus is placed on the ventricles, the study of the atria is in comparison neglected. Therefore this Thesis is focused on the genesis and maintenance of atrial fibrillation (AF). A series of case studies are performed whereby established biophysically detailed mathematical models are implemented and modified to incorporate electrophysical alterations of atrial cells resulting from a variety of external conditions. The opening section of this Thesis is dedicated to developing a background to the field, including a discussion into the clinical aspect of the diagnosis and management of AF. The suitability of two atrial cell models is discussed and the development of single cell, 1D, 2D, and 3D multi-scale simulation protocols are described in detail. In addition measurements taken to quantify the arrhythmogenic properties of the cells susceptibility to AF are outlined. The second section is focused on the incorporation of conditions thought to enhance atrial tissues ability to initiate and maintain the genesis of AF. Included is a case study into the missence S140G gene mutation, and elevated physiological levels of the hormone Homocystein. The third section investigates the effectiveness of well established and widely used pharmacological treatments such as Beta-Blockers. In addition possible avenues of investigations for the development of atrial specific drugs are explored. These include blocking of the ultra rapid potassium channel and a more novel target for therapy via the targeting of 5HT4 receptors; which is transcribed solely in the atria and alters the electrophysical properties of the L-type Calcium current. The final part of this Thesis is dedicated to the development of a 2D atrial sheet model which includes electrical and spatial heterogeneities via the inclusion of multiple cell types and basic fiber orientation respectively. This allows for an investigation into the role that heterogeneities play in role genesis and maintenance of AF. The main finding of this Thesis is that alterations to the electrophysiology of atrial cells, due to external factors, can be successfully simulated via the implementation of mathematically detailed atrial cell models. It is concluded that simulations of the KENQ1 mutation and elevated levels of Homocystein successfully reproduce conditions which increase the onset of AF. Established treatments such as Beta-Blockers are found to have limited effectiveness. Possible theoretical treatments, such as the blocking of IKur, are found to provide a small amount of therapeutic benefit. In contrast, investigations into the effects of Serotonin were inconclusive. The study into the 2D atria indicated the importance that heterogeneities play in atria. The conclusions show that models provide a powerful tool when investigating how changes to electrophysiology of cells are manifested at a multi-scale level. The models also have their limitations and require further advancement to improve their accuracy.EThOS - Electronic Theses Online ServiceEPSRCGBUnited Kingdo

Studying Ion Channel Dysfunction and Arrythmogenesis in the Human Atrium: A Computational Approach

Non

Kepler-424 b: A "lonely" hot Jupiter that found a companion

Peer reviewedFinal Accepted Versio

The effect of stimulus strength on binocular rivalry rate in healthy individuals: Implications for genetic, clinical and individual differences studies

Binocular rivalry (BR) occurs when conflicting images concurrently presented to corresponding retinal locations of each eye stochastically alternate in perception. Anomalies of BR rate have been examined in a range of clinical psychiatric conditions. In particular, slow BR rate has been proposed as an endophenotype for bipolar disorder (BD) to improve power in large-scale genome-wide association studies. Examining the validity of BR rate as a BD endophenotype however requires large-scale datasets (n = 1000 s to 10,000 s), a standardized testing protocol, and optimization of stimulus parameters to maximize separation between BD and healthy groups. Such requirements are indeed relevant to all clinical psychiatric BR studies. Here we address the issue of stimulus optimization by examining the effect of stimulus parameter variation on BR rate and mixed-percept duration (MPD) in healthy individuals. We aimed to identify the stimulus parameters that induced the fastest BR rates with the least MPD. Employing a repeated-measures within-subjects design, 40 healthy adults completed four BR tasks using orthogonally drifting grating stimuli that varied in drift speed and aperture size. Pairwise comparisons were performed to determine modulation of BR rate and MPD by these stimulus parameters, and individual variation of such modulation was also assessed. From amongst the stimulus parameters examined, we found that 8 cycles/s drift speed in a 1.5 degrees aperture induced the fastest BR rate without increasing MPD, but that BR rate with this stimulus configuration was not substantially different to BR rate with stimulus parameters we have used in previous studies (i.e., 4 cycles/s drift speed in a 1.5 degrees aperture). In addition to contributing to stimulus optimization issues, the findings have implications for Levelt's Proposition IV of binocular rivalry dynamics and individual differences in such dynamics

Implementation of marine CO2 removal for climate mitigation: The challenges of additionality, predictability, and governability

Achieving net zero CO2 emissions requires gigatonne-scale atmospheric CO2 removal (CDR) to balance residual emissions that are extremely difficult to eliminate. Marine CDR (mCDR) methods are seen increasingly as potentially important additions to a global portfolio of climate policy actions. The most widely considered mCDR methods are coastal blue carbon and seaweed farming that primarily depend on biological manipulations; ocean iron fertilisation, ocean alkalinity enhancement, and direct ocean capture that depend on chemical manipulations; and artificial upwelling that depends on physical manipulation of the ocean system. It is currently highly uncertain which, if any, of these approaches might be implemented at sufficient scale to make a meaningful contribution to net zero. Here, we derive a framework based on additionality, predictability, and governability to assess implementation challenges for these mCDR methods. We argue that additionality, the net increase of CO2 sequestration due to mCDR relative to the baseline state, will be harder to determine for those mCDR methods with relatively large inherent complexity, and therefore higher potential for unpredictable impacts, both climatic and non-climatic. Predictability is inherently lower for mCDR methods that depend on biology than for methods relying on chemical or physical manipulations. Furthermore, predictability is lower for methods that require manipulation of multiple components of the ocean system. The predictability of an mCDR method also affects its governability, as highly complex mCDR methods with uncertain outcomes and greater likelihood of unintended consequences will require more monitoring and regulation, both for risk management and verified carbon accounting. We argue that systematic assessment of additionality, predictability, and governability of mCDR approaches increases their chances of leading to a net climatic benefit and informs political decision-making around their potential implementation

A diagnostic autoantibody signature for primary cutaneous melanoma

Melanoma is an aggressive form of skin cancer that is curable by surgical excision in the majority of cases, if detected at an early stage. To improve early stage melanoma detection, the development of a highly sensitive diagnostic test is of utmost importance. Here we aimed to identify antibodies to a panel of tumour associated antigens that can differentiate primary melanoma patients and healthy individuals. A total of 245 sera from primary melanoma patients and healthy volunteers were screened against a high-throughput microarray platform containing 1627 functional proteins. Following rigorous statistical analysis, we identified a combination of 10 autoantibody biomarkers that, as a panel, displays a sensitivity of 79%, specificity of 84% and an AUC of 0.828 for primary melanoma detection. This melanoma autoantibody signature may prove valuable for the development of a diagnostic blood test for routine population screening that, when used in conjunction with current melanoma diagnostic techniques, could improve the early diagnosis of this malignancy and ultimately decrease the mortality rate of patients

Phenome-wide association study (PheWAS) of colorectal cancer risk SNP effects on health outcomes in UK Biobank

BACKGROUND: Associations between colorectal cancer (CRC) and other health outcomes have been reported, but these may be subject to biases, or due to limitations of observational studies. METHODS: We set out to determine whether genetic predisposition to CRC is also associated with the risk of other phenotypes. Under the phenome-wide association study (PheWAS) and tree-structured phenotypic model (TreeWAS), we studied 334,385 unrelated White British individuals (excluding CRC patients) from the UK Biobank cohort. We generated a polygenic risk score (PRS) from CRC genome-wide association studies as a measure of CRC risk. We performed sensitivity analyses to test the robustness of the results and searched the Danish Disease Trajectory Browser (DTB) to replicate the observed associations. RESULTS: Eight PheWAS phenotypes and 21 TreeWAS nodes were associated with CRC genetic predisposition by PheWAS and TreeWAS, respectively. The PheWAS detected associations were from neoplasms and digestive system disease group (e.g. benign neoplasm of colon, anal and rectal polyp and diverticular disease). The results from the TreeWAS corroborated the results from the PheWAS. These results were replicated in the observational data within the DTB. CONCLUSIONS: We show that benign colorectal neoplasms share genetic aetiology with CRC using PheWAS and TreeWAS methods. Additionally, CRC genetic predisposition is associated with diverticular disease