Chronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our... Show moreChronic pain is a significant health problem that greatly impacts the quality of life of individual patients and imparts high costs to society. Despite intense research effort and progress in our understanding of the mechanistic and molecular basis of pain, chronic pain remains a significant clinical problem that has few effective therapies Throughout the various chapters we have highlighted some important conceptual and experimental flaws in the way that pain signalling and pharmacological activity are characterised and translated across species and disease conditions. The common denominator of the work presented here is the requirement for accurate characterisation of exposure-response relationships, without which the dose rationale for the progression of a molecule cannot justified, whether drugs are aimed at symptomatic relief, disease modification or prophylaxis. In addition to a comprehensive review of the mechanisms underlying pain signalling and symptoms, the work developed here focuses on three different aspects of research underpinning the use of pharmacokinetic-pharmacodynamic relationships. First, we have explored the requirements for the characterisation of behavioural measures of pain during the early screening of candidate molecules, shedding light onto the shortcomings of experimental protocols commonly used in preclinical research. Then we introduced the prerequisites for the parameterisation of pain behaviour to ensure accurate translation of the pharmacological properties across species as well as for bridging across different phases of development. Lastly, an attempt was made to model clinical response in chronic inflammatory pain and to establish correlations between symptom improvement and the underlying pharmacological effects using biomarkers. In addition our work showed how clinical trial simulations can be used as a design tool, enabling the evaluation of a variety of scenarios that disentangle the contribution of pharmacology from the confounding effects of placebo and disease dynamics. Show less
Over the last decade, a tremendous progress has been made in cardiovascular medicine. The progress includes the treatment of coronary artery disease (CAD) and peripheral artery disease. In CAD,... Show moreOver the last decade, a tremendous progress has been made in cardiovascular medicine. The progress includes the treatment of coronary artery disease (CAD) and peripheral artery disease. In CAD, several advances have been made in the management of patients with acute myocardial infarction (AMI) such as: 1) the importance of networking in the treatment of AMI; 2) perspectives on how to improve the results of primary percutaneous coronary intervention (PCI) procedures including: (i) the administration of a glycoprotein IIb/ IIIa inhibitor (GPI); (ii) strategies for __fighting__ the coronary thrombus during primary PCI; (iii) choice of vascular access site (radial versus femoral artery approach) for primary PCI; (iv) choice of stents (drug eluting versus bare metal stent) for patients with acute ST-segment elevation myocardial infarction (STEMI); and 3) the use of intra-aortic balloon pump (IABP) in acute coronary syndrome (ACS) patients. Another important perspective related to patients with AMI is the utilization of simple, inexpensive but accurate biomarkers with prognostic value such as plasma uric acid concentration and leukocyte count, which are particularly useful in a rural area when other established markers are not available. Show less
Melanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV... Show moreMelanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV exposure, the incidence of melanoma has doubled worldwide over the past three decades (200.000 new cases in 2008). Primary melanomas can be easily treated by surgical resection, leading to a good prognosis for stage I patients. However, metastasized melanoma is almost completely resistant to therapeutic modalities such as radio- and chemotherapy, resulting in a median overall survival of less than one year for this patient group. Despite considerable efforts, for over 20 years there was no melanoma treatment developed that could improve survival of stage IV patients. However, the treatment of unresectable metastasized melanoma has progressed markedly in recent years due to the development of both immunotherapies that stimulate anti-tumor immunity and targeted therapies that block oncogenic proteins. This thesis will focus on pre-clinical work concerning the optimization of melanoma treatment. In detail, it will address for both targeted therapies and immunotherapies factors that play a role in the identification of response-predictive biomarkers, the toxicity of treatments, and the potential efficacy of combination treatments. Show less
Cardiovascular diseases remain the major cause of death throughout the world and can be primarily attributed to atherosclerotic vascular disease leading to stroke and coronary heart disease (CHD).... Show moreCardiovascular diseases remain the major cause of death throughout the world and can be primarily attributed to atherosclerotic vascular disease leading to stroke and coronary heart disease (CHD). Improved primary prevention and the introduction and subsequent optimization of percutaneous coronary interventions (PCI) for myocardial ischemia due to obstructive CHD have significantly improved patient outcome and reduced morbidity and mortality. The insight into disease pathology has however expanded tremendously over the past decade and continuing research has shifted the focus of interest towards post-interventional accelerated atherosclerosis development due to a dysfunctional (auto) immune inflammatory response, responsible for vascular remodeling, re-occlusion and recurrence of symptoms. The aim of this thesis therefore was to investigate the role of the immune system in this pathophysiological process that ultimately results in post-interventional atherosclerotic vascular remodeling and apply this insight for the development of new immune-modulatory therapies in a preclinical setting. Show less
Duchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive... Show moreDuchenne muscular dystrophy (DMD) is the most prevalent neuromuscular disorder, caused by mutations in the DMD gene that prevent synthesis of dystrophin. Fibers that lack dystrophin are sensitive to exercise-induced damage, resulting in progressive muscle wasting, loss of ambulation and premature death. There is no cure, but several therapeutic approaches are clinically tested. At best, these clinical interventions result in the expression of low dystrophin levels. Fortunately, expression of wild type levels is not needed, as both humans and mice expressing ~50% of dystrophin do not show pathology. Detailed studies on which dystrophin levels are needed to prevent pathology and improve muscle function have been performed in this thesis. After the set-up of good outcome measures and serum biomarkers to monitor disease progression, two new innovative mouse models expressing low levels of dystrophin based on skewed X-inactivation were generated. In the mdx-Xist__hs model we observed that <15% dystrophin already improved muscle performance, while histopathology was largely with >15% dystrophin. To protect muscles from exercise-induced damage >22% dystrophin was needed. Dystrophin levels between 3-21% prevent the development of dilated cardiomyopathy in 10 months old mice. Mice lacking both dystrophin and its homologue utrophin, mimic the human phenotype and die before the age of 12 weeks. In these mice, <10% dystrophin improved life expectancy and muscle function while >10% dystrophin was needed to improve histopathology. These findings are encouraging for ongoing and future clinical trails. Show less
Obesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live... Show moreObesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live in lipogenic environment, personal approach in modify obesity may avail. Therefore, understanding how obesity leads to osteoarthritis is needed. The first three chapters of this thesis investigate several aspects of osteoarthritis: what structures are damaged, what factors are associated with worsening of osteoarthritis and how to measure worsening of osteoarthritis. The other four chapters investigate the link between obesity and osteoarthritis. We show that obesity is associated with hand osteoarthritis. Since we do not walk on our hand, there must be another factor than mechanical that cause joint damage in osteoarthritis. One of the factors is adipokines, protein produced mainly by fat tissue. We showed that adiponectin, one of the adipokines, prevents worsening of hand osteoarthritis. We concluded that obesity plays role in osteoarthritis not only due to added mechanical force but also due to added metabolic force (adipokines). These adipokines might be used as target in modifying the effect of obesity on osteoarthritis. However, we still need more studies on how obesity links with osteoarthritis Show less
