2,717 research outputs found

    The medical applications of hyperpolarized Xe and nonproton magnetic resonance imaging

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    Hyperpolarized 129Xe (HP 129Xe) magnetic resonance imaging (MRI) is a relatively young field which is experiencing significant advancements each year. Conventional proton MRI is widely used in clinical practice as an anatomical medical imaging due to its superb soft tissue contrast. HP 129Xe MRI, on the other hand, may provide valuable information about internal organs functions and structure. HP 129Xe MRI has been recently clinically approved for lung imaging in the United Kingdom and the United States. It allows quantitative assessment of the lung function in addition to structural imaging. HP 129Xe has unique properties of anaesthetic, and may transfer to the blood stream and be further carried to the highly perfused organs. This gives the opportunity to assess brain perfusion with HP 129Xe and perform molecular imaging. However, the further progression of the HP 129Xe utilization for brain perfusion quantification and molecular imaging implementation is limited by the absence of certain crucial milestones. This thesis focused on providing important stepping stones for the further development of HP 129Xe molecular imaging and brain imaging. The effect of glycation on the spectroscopic characteristics of HP 129Xe was studied in whole sheep blood with magnetic resonance spectroscopy. An additional peak of HP 129Xe bound to glycated hemoglobin was observed. This finding should be implemented in the spectroscopic HP 129Xe studies in patients with diabetes. [...

    The use of biofluid markers to evaluate the consequences of sport-related subconcussive head impact exposure : a scoping review

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    This review was supported by the University of Stirling (no grant number applies). L.W. also received support as part of Framework 7 programme of the European Union (CENTER-TBI, Grant number: 602150–2). S.M. received research support from the Italian Ministry of Health (GR-2013–02354960).Background Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure. Objective This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research. Methods PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality. Results Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers—such as NfL—appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport. Conclusion Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers’ utility.Publisher PDFPeer reviewe

    Unveiling the frontiers of deep learning: innovations shaping diverse domains

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    Deep learning (DL) enables the development of computer models that are capable of learning, visualizing, optimizing, refining, and predicting data. In recent years, DL has been applied in a range of fields, including audio-visual data processing, agriculture, transportation prediction, natural language, biomedicine, disaster management, bioinformatics, drug design, genomics, face recognition, and ecology. To explore the current state of deep learning, it is necessary to investigate the latest developments and applications of deep learning in these disciplines. However, the literature is lacking in exploring the applications of deep learning in all potential sectors. This paper thus extensively investigates the potential applications of deep learning across all major fields of study as well as the associated benefits and challenges. As evidenced in the literature, DL exhibits accuracy in prediction and analysis, makes it a powerful computational tool, and has the ability to articulate itself and optimize, making it effective in processing data with no prior training. Given its independence from training data, deep learning necessitates massive amounts of data for effective analysis and processing, much like data volume. To handle the challenge of compiling huge amounts of medical, scientific, healthcare, and environmental data for use in deep learning, gated architectures like LSTMs and GRUs can be utilized. For multimodal learning, shared neurons in the neural network for all activities and specialized neurons for particular tasks are necessary.Comment: 64 pages, 3 figures, 3 table

    3D Modelling of Brain Metastasis Microenvironment for Evaluation of Tumour-Stromal Interactions

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    Brain metastases (BM) occur when cancer cells from the primary location spread to the brain through the bloodstream. BM affects approximately 20-40 % of cancer patients, with the majority originating from lung, breast, and skin cancers. If left untreated, the median survival time is usually only one month, and aggressive treatment only extends survival to around four months. Despite the advances in modern medicine, the blood-brain barrier (BBB) poses a significant challenge in treating BM, restricting the entry of approximately 98 % of chemotherapeutic drugs into the brain. Thus, better model systems are needed to understand the complex interplay between cancer cells and normal brain cells. In order to generate novel models, a range of cell lines derived from lung, breast and skin BM were characterized to understand their behaviour in vitro. Subsequently, their distinguishing features were analyzed to identify the most suitable candidates for generating three-dimensional models, which can later be used for drug testing. We found that LBM1, derived from a lung cancer BM, and H16, developed from a melanoma BM, were the best candidates for spheroid formation. The two cell lines underwent treatment with thioridazine, an antipsychotic drug that has been previously tested by our group on various melanoma BM cell lines and demonstrated a significant reduction in their viability. Comparable results were seen with LBM1 and H16 cells. The potential of LBM1- and H16-derived exosomes to serve as imaging agents was also investigated, with focus on iron oxide labelling using carboxyl-coated superparamagnetic iron oxide nanoparticles (SPIONs), through electroporation. To verify the electroporation, further investigation is necessary to confirm the presence of the iron oxide particles within the exosomes. However, dextran-coated SPIONs were successfully internalised by LBM1 cells following 24 h incubation, suggesting its potential labelling attributes and potential uptake by LBM1-derived exosomes. Lastly, LBM1 and H16 cells were injected intracardially into four non-obese diabetic/severe combined immunodeficient (NOD-SCID) mice each for evaluation of their tumourigenic potential. Despite a small sample size, H16-injected mice demonstrated a 23 % increased survival time compared to LBM1-injected mice, but no tumours were observed at week 4. In contrast, 3 out of 4 LBM1-injected mice displayed brain tumours four weeks following injection, thus demonstrating its potential as a model system for future BM research.Masteroppgave i biomedisinBMED395MAMD-MEDB

    Cerebrovascular dysfunction in cerebral small vessel disease

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    INTRODUCTION: Cerebral small vessel disease (SVD) is the cause of a quarter of all ischaemic strokes and is postulated to have a role in up to half of all dementias. SVD pathophysiology remains unclear but cerebrovascular dysfunction may be important. If confirmed many licensed medications have mechanisms of action targeting vascular function, potentially enabling new treatments via drug repurposing. Knowledge is limited however, as most studies assessing cerebrovascular dysfunction are small, single centre, single imaging modality studies due to the complexities in measuring cerebrovascular dysfunctions in humans. This thesis describes the development and application of imaging techniques measuring several cerebrovascular dysfunctions to investigate SVD pathophysiology and trial medications that may improve small blood vessel function in SVD. METHODS: Participants with minor ischaemic strokes were recruited to a series of studies utilising advanced MRI techniques to measure cerebrovascular dysfunction. Specifically MRI scans measured the ability of different tissues in the brain to change blood flow in response to breathing carbon dioxide (cerebrovascular reactivity; CVR) and the flow and pulsatility through the cerebral arteries, venous sinuses and CSF spaces. A single centre observational study optimised and established feasibility of the techniques and tested associations of cerebrovascular dysfunctions with clinical and imaging phenotypes. Then a randomised pilot clinical trial tested two medications’ (cilostazol and isosorbide mononitrate) ability to improve CVR and pulsatility over a period of eight weeks. The techniques were then expanded to include imaging of blood brain barrier permeability and utilised in multi-centre studies investigating cerebrovascular dysfunction in both sporadic and monogenetic SVDs. RESULTS: Imaging protocols were feasible, consistently being completed with usable data in over 85% of participants. After correcting for the effects of age, sex and systolic blood pressure, lower CVR was associated with higher white matter hyperintensity volume, Fazekas score and perivascular space counts. Lower CVR was associated with higher pulsatility of blood flow in the superior sagittal sinus and lower CSF flow stroke volume at the foramen magnum. Cilostazol and isosorbide mononitrate increased CVR in white matter. The CVR, intra-cranial flow and pulsatility techniques, alongside blood brain barrier permeability and microstructural integrity imaging were successfully employed in a multi-centre observational study. A clinical trial assessing the effects of drugs targeting blood pressure variability is nearing completion. DISCUSSION: Cerebrovascular dysfunction in SVD has been confirmed and may play a more direct role in disease pathogenesis than previously established risk factors. Advanced imaging measures assessing cerebrovascular dysfunction are feasible in multi-centre studies and trials. Identifying drugs that improve cerebrovascular dysfunction using these techniques may be useful in selecting candidates for definitive clinical trials which require large sample sizes and long follow up periods to show improvement against outcomes of stroke and dementia incidence and cognitive function

    Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

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    Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma.SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA.See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275.</p

    Combining Tumour-Treating Fields with DNA damage response inhibitors for the improved treatment of glioblastoma

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    Glioblastoma is the most common and deadliest type of primary brain cancer, taking over 2,500 lives each year in the UK. glioblastoma has a median overall survival of 10-16 months, despite treatment consisting of maximal surgical resection followed by chemo- and radio-therapy. glioblastoma survival rates have seen little improvement over the past 40 years and given this devastating prognosis, new treatment options for the management of glioblastoma are urgently needed. Recently, Tumour Treating Fields (TTFields) has emerged as a novel fourth modality for the treatment of high-grade gliomas following its success in clinical trials, where the addition of TTFields to standard care temozolomide was shown to increase median progression-free survival (6.7 versus 4.0 months) and overall survival (20.9 vs 16.0 months) of newly-diagnosed glioblastoma patients compared to temozolomide alone. TTFields are primarily thought to mediate their anti-cancer effects by disrupting tubulin dimer alignment during mitosis, resulting in abnormal chromosomal segregation and mitotic cell death. In addition, recent data suggests that TTFields affect a number of other cellular processes – 1- cell membrane and blood-brain barrier (BBB) permeability, 2- cell migration and invasion, 3- anti�tumour immunity, 4- autophagy, and 5- replication stress and DNA damage repair, the latter of which will be the focus of this project. TTFields has also been shown to downregulate DNA damage response (DDR) proteins and delay the repair of radiotherapy- and chemotherapy-induced DNA lesions, an effect that is thought to be mediated through reduced homologous recombination repair efficiency and induction of a ‘BRCAness’ phenotype. Such vulnerabilities within DNA damage repair pathways provides a rational for the use of TTFields in combinational therapeutic approaches that target the DDR. We therefore aim to assess whether combining TTFields with DDR inhibitors (PARPi, ATMi, ATRi and WEE1i) can enhance the efficacy of TTFields in clinically relevant glioblastoma stem-like cultures (GSCs) using a number of established cell survival assays. Additionally, we aim to investigate the mechanisms by which combination treatments of DDR inhibitors and TTFields affect the DNA damage response. In this thesis we show that combining TTFields with radiation and clinically approved PARP inhibitor therapy leads to significantly increased amounts of DNA damage with concurrent decreased clonogenic survival in GSCs. Furthermore, we have shown similar impressive potency when TTFields treatments are combined with BBB-penetrant ATR inhibitors that are currently being assessed in various global clinical trials for glioblastoma as well as other cancers. Overall, these exciting findings support further assessment of TTFields and DDRi combinations to underpin future clinical trials combining TTFields with clinically approved DDRi to improve outcomes for patients with currently incurable high-grade gliomas

    Optimisation, evaluation and application of cerebrovascular reactivity measurement using magnetic resonance imaging in patients with cerebral small vessel disease

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    Small vessel disease (SVD) is a common cause of strokes and dementia. Currently, there are no treatments; therefore, developing and validating early biomarkers of disease progression and treatment response is important for future drug trials. Though SVD pathogenesis is not well understood, findings from previous studies suggest that blood-brain barrier dysfunction and impaired cerebrovascular reactivity (CVR) contribute to the disease. The latter can be measured in vivo using a vasoactive stimulus in parallel with magnetic resonance imaging (MRI) techniques sensitive to blood flow, such as blood oxygen level dependent (BOLD) contrast, and has frequently been assessed in patients with steno-occlusive diseases. However, it is unclear if the technique is reliable when investigating cerebrovascular health in deep structures of the brain where SVD is prevalent. Therefore, this thesis aimed to assess and optimise the reliability of CVR measurements and deepen our understanding of its role in SVD pathogenesis. A systematic review was performed to provide a detailed overview of CVR MRI methodologies and clinical applications, including SVD, present in the literature, which identified several acquisition and analysis methods, a need for greater standardisation and lack of data on reliability. Specifically in SVD research, there was limited application of CVR MRI in SVD populations, little optimisation and reliability assessment of CVR in deep brain structures relevant to SVD, such as in white and subcortical grey matter. Following those findings, the effects of voxel- and region-based analysis approaches on reliability of CVR estimates were investigated using simulations and test-retest data from healthy volunteers. Voxel-based CVR magnitude estimates in tissues with high noise levels were prone to bias, whereas biases in region-based estimates were independent of noise level, but consistently underestimated CVR magnitude relative to the ground-truth mean. Furthermore, the test-retest study confirmed the repeatability of CVR estimates from a BOLD-CVR experiment with fixed inhaled stimulus, although a systematic, but small, bias was detected due to habituation to the gas challenge. The data from healthy volunteers were further used to conduct a proof-of-concept and investigate the feasibility of extracting cerebral pulsatility from BOLD-CVR data. Small-to-moderate correlations with pulsatility from phase-contrast MRI were found depending on the regions considered. CVR pulsatility was also computed in a small cohort of SVD patients: it was higher than in healthy volunteers, but no associations were found with SVD burden. It was concluded that further optimisation and validation of the technique is needed before being suitable for clinical research. Following the optimisation of the CVR MRI technique, relationships between CVR and SVD neuroimaging features, cognition, stroke severity and outcome were investigated cross-sectionally and longitudinally in a cohort of patients with mild stroke. In the cross-sectional analysis, CVR impairment in normal-appearing and damaged tissues was associated with worse SVD burden and cognition deficit. Furthermore, the longitudinal analysis showed that baseline CVR impairment predicted worsening of white matter hyperintensity and perivascular space volumes after one year. In conclusion, assessment of CVR in the brain and its deeper structures was successfully conducted in healthy volunteers and patients with SVD using MRI. However, this required appropriate optimisation of processing strategy as the latter can affect accuracy of CVR parameters and inter-study comparability. Importantly, applying the technique in a cohort of SVD patients led to the findings that CVR impairment was related to worse SVD burden and is a potential marker of SVD severity and progression
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