Molecular imaging of metabolism in cancer metastasis

Cancer progression is characterised by extensive metabolic reprogramming. Renewed enthusiasm in this field has been sparked in part by the realisation that metabolic pathways, oncogenes and tumour suppressors are intimately linked and regulate tumour growth and metastasis through complex reciprocal interactions. The identification of key pathways and enzymes regulating metabolism in cancer cells provides new opportunities for cancer therapy. This has motivated the development of several specific inhibitors targeting metabolic pathways and their therapeutic evaluation in pre-clinical models or in cancer patients. The unravelling of metabolic pathways associated with cancer progression has also highlighted the extensive metabolic heterogeneity that exists between, and within, each cancer type as well as between metastatic sites. The translation of these findings into personalised therapy remains a considerable challenge. To this end, the use of positron emission tomography to non-invasively visualise tumour metabolism is likely to facilitate the implementation of and assessment of new targeted therapies. Here, we briefly review the key metabolic changes associated with cancer progression and discuss recent advances in the field of positron emission tomography for metabolic imaging of cancer and their potential to improve the clinical management of cancer patients

Fabry disease and the heart: a comprehensive review

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations of the GLA gene that result in a deficiency of the enzymatic activity of α-galactosidase A and consequent accumulation of glycosphingolipids in body fluids and lysosomes of the cells throughout the body. GB3 accumulation occurs in virtually all cardiac cells (cardiomyocytes, conduction system cells, fibroblasts, and endothelial and smooth muscle vascular cells), ultimately leading to ventricular hypertrophy and fibrosis, heart failure, valve disease, angina, dysrhythmias, cardiac conduction abnormalities, and sudden death. Despite available therapies and supportive treatment, cardiac involvement carries a major prognostic impact, representing the main cause of death in FD. In the last years, knowledge has substantially evolved on the pathophysiological mechanisms leading to cardiac damage, the natural history of cardiac manifestations, the late-onset phenotypes with predominant cardiac involvement, the early markers of cardiac damage, the role of multimodality cardiac imaging on the diagnosis, management and follow-up of Fabry patients, and the cardiac efficacy of available therapies. Herein, we provide a comprehensive and integrated review on the cardiac involvement of FD, at the pathophysiological, anatomopathological, laboratory, imaging, and clinical levels, as well as on the diagnosis and management of cardiac manifestations, their supportive treatment, and the cardiac efficacy of specific therapies, such as enzyme replacement therapy and migalastat

Understanding inflammation requires neuroscience

Inflammation and its resolution are processes subject to neural regulation (1). The best-characterized immune-regulating reflex is the “inflammatory reflex”, in which the efferent branch of the vagus nerve plays a central role in regulating cytokine-release in the periphery. This neural pathway is fundamental to maintaining host homeostasis and preventing potentially damaging inflammation (1–3) . Hence, this biology has already been exploited in several clinical trials regarding potentially new therapies for chronic inflammatory diseases (4–6). Of note, cardiovascular disease (CVD) represents the first cause of death worldwide, and its most common manifestation is atherosclerosis which is an inflammatory disease (7,8) . Little is known about the neural control of inflammation in this pathology. Atherosclerotic plaques are not innervated (9) , and neurotransmitter signaling in atherosclerosis has not been investigated. The 1998 Nobel Prize for “nitric oxide (NO) as a signaling molecule in the cardiovascular system” reveals the importance of the neurotransmitter acetylcholine (ACh) for regulation of vascular relaxation (10). ACh is also a key component of the inflammatory reflex, in which cholinergic signals regulate the course of inflammation. In the inflammatory reflex, ACh is produced by nerves and by acetyl-cholinesterase (ChAT)+ T cell under the control of the nervous system, and interacts with alpha 7 nicotinic acetylcholine receptor subunit (α7nAChR)-expressing macrophages (MΦ) (11) . Most of the current knowledge on the inflammatory reflex was obtained from numerous experiments performed in animals, mice in primis. Much is still unclear about the details of neural regulation of inflammation and its resolution, and understanding these mechanisms in detail will require further experimental studies. At the same time, it is also important to translate these findings to human pathophysiology, and investigate whether it may inform the design of therapeutic strategies for treatment of inflammatory diseases. This thesis addresses several aspects of this biology: In Project I, we discovered that human ChAT+ T cells participate in cholinergic regulation of vascular function and are found in blood collected from patients in circulatory distress. In Project II, we found components of neurotransmitter signaling in human atherosclerosis, observed an association between low glutamate-receptor expression and adverse clinical events, and found that glutamate signaling regulates smooth muscle cell phenotypic modulation. In Project III, we describe an effective and simple method to electrically stimulate the cervical vagus nerve in mice for the study of experimental inflammation. In Project IV, we provide evidence that electrical activation of the cervical vagus nerve accelerates inflammation resolution in mice through a cholinergic mechanism that involves synthesis of specialized pro-resolving mediators. Technological limitations in vagus nerve stimulation methods for mice has hampered mechanistic studies of peripheral nerve activation in chronic diseases. Hence, the understanding of mechanisms of vagus nerve regulation of inflammation in chronic diseases is yet incomplete. To solve this, in Project V we used a novel approach and developed noninvasive activation of peripheral nerves using temporally-interfering electrical fields. This technology attempts to address methodological shortcoming of “traditional” electrical vagus nerve stimulation (VNS) and enable studies of VNS in genetic mouse models of chronic inflammatory diseases and beyond. In summary, this thesis studies aspects of neural signaling in inflammation and reveal new details on glutamatergic and cholinergic signals in inflammation and vascular pathophysiology. The work also contributes new methodology which we postulate will be helpful in further understanding of the neural signals that regulate inflammation and for clinical translation of discoveries in this field

Fusing organisational change and leadership into a practical roadmap for South African organisations

The intention of this study was theory creation in the field of organisational change, directed towards the creation of a conceptual change framework. A qualitative research approach was followed and a grounded theory methodology adopted. This study involved a theoretical investigation of organisational change and leadership within South African organisations, although insights gained could be transferred across contexts or settings. The primary aim was to create a practical change framework to ensure sustainable organisational change. Secondly, to determine the impact of leadership on successful organisational change. Thirdly, to establish whether any fundamental elements can be identified as essential for inclusion in such a change framework. Fourthly, to identify non-negotiable success factors that can ensure successful change. Fifthly, to determine the human elements that should be included in order to minimise negative outcomes such as resistance and noncompliance. The final aim was to ascertain what meta-insights can be gained from organisational change and leadership. The research findings concluded that the first perception when speaking about change is fear, anxiety and increased stress, resulting in impaired functioning. Organisations struggle to handle increased stress levels during periods of change and require improved methods of dealing with stress to ensure optimal individual functioning. Only through reduced stress levels will individuals be able to engage with organisational change initiatives. Alternative intervention technologies were suggested which could assist the individual change journey through reduced stress and/or increased consciousness. These alternative intervention technologies were suggested because of the paucity of current literature. It practically aids organisations on how to deal with the stress dilemma. This research introduced the concepts of anti-leader and anti-manager. These concepts depict the negative characteristics of leadership and management which invariably increases individual stress levels. Emotions elicited by the anti-leader and/or anti-manager could potentially split, divide and fragment a workforce. The ideal organisational approach should be designed by the people, be inclusive of all, involve, empower and allow individuals to make the required decisions. As organisational change can only be effected through individual change, this thesis places the individual in the centre. Without individual change, vicissitude and sustainable organisational change become highly unlikely.Graduate School of Business LeadershipDB