The aim of this thesis was to explore the neuromechanics of recovery of arm-hand function after stroke. A literature review revealed six articles that measured biomechanical and electromyographical... Show moreThe aim of this thesis was to explore the neuromechanics of recovery of arm-hand function after stroke. A literature review revealed six articles that measured biomechanical and electromyographical outcome measures simultaneously, while applying active and passive tasks and multiple movement velocities to separate neural and non-neural contributors to movement disorders after stroke. Therefore, a neuromechanic assessment protocol was developed. Parameters were responsive to clinical status and had good to excellent test-retest reliability. Selective muscle activation was assessed with high measurement reliability and was significantly lower in chronic stroke patients compared to healthy participants. Longitudinally, neuromechanical parameters were combined with data on arm-hand function at six months after stroke. Paresis and diminished modulation of reflexes were associated with poor functional outcome. Changes in tissue properties were represented by a shift in wrist rest angle towards flexion and decline in passive range of motion. Increase in active range of motion and steady rest angle contributed most to prediction of functional outcome. The precision diagnostics provided by a neuromechanical assessment protocol could support clinical decision making and should be used in prediction models and as biomarkers in recovery of arm-hand function after stroke, for example by improving the selection of time-window and patients. Show less
This thesis focused on different aspects of melanoma treatment with immunotherapy and targeted therapy. In chapter 2 we search for biomarkers that could be associated with overall survival in... Show moreThis thesis focused on different aspects of melanoma treatment with immunotherapy and targeted therapy. In chapter 2 we search for biomarkers that could be associated with overall survival in patients treated with ipilimumab. In chapter 3 we describe diarrea, a commonly seen side effect of immunotherapy. Here we show that there is no significant correlation between grade of diarrhea and severity of colitis as seen during endoscopy. Chapters 4 and 5 describe patients with brain metastases and/or leptomeningeal metastases. In chapter 4 we show the difference in overall survival in patients treated with vemurafenib, dabrafenib or the combination of dabrafenib + trametinib. Chapter 5 focusses on the treatment of leptomeningeal metastases. Here a significant difference in overall survival was noted between treated and untreated patients. Furthermore LDH was a predictive biomarker for overall survival. In chapter 6 we show that treating patients with vemurafenib beyond progression of disease has a significant impact on overall survival. Lastly in chapter 7 we review the past, present and future of treating patients with different kinds of cancer with tumor-infiltrating lymphocytes. Show less
Stalenhoef, J.E.; Nieuwkoop, C. van; Wilson, D.C.; Starre, W.E. van der; Delfos, N.M.; Leyten, E.M.S.; ... ; Dissel, J.T. van 2018
This thesis consists of two parts addressing novel imaging technologies to improve the treatment of cancer patients. In part I, the additional value of real time image guidance during surgery is... Show moreThis thesis consists of two parts addressing novel imaging technologies to improve the treatment of cancer patients. In part I, the additional value of real time image guidance during surgery is discussed and the research described in this part of the thesis showed that imaging performed during surgery can be of great value. Nevertheless, the success rate is highly dependent on the choice of imaging modality and biomarker to be targeted. In part II, a necrosis avid probe was successfully evaluated as novel method for early neoadjuvant treatment response monitoring. Show less
Cardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of... Show moreCardiovascular magnetic resonance imaging is an important noninvasive imaging modality for the diagnosis, clinical work‐up and treatment planning in patients suspected for a wide range of cardiovascular pathology. CMR imaging is accurate and reliable, and provides invaluable information to evaluate the cardiovascular system without the need of ionizing radiation. The studies described in this thesis evaluate new CMR imaging techniques in clinical practice and explore the prognostic value of new CMR imaging biomarkers in patients with symptomatic peripheral arterial occlusive disease. New advances and innovations in MR imaging technology improve and further expand the clinical applications of cardiovascular imaging in daily clinical practice. In this thesis, a new, fast free‐breathing 2D delayed‐enhancement MRI sequence is validated and demonstrated to be a reliable tool for detecting myocardial infarction. Furthermore, new technical developments allow single‐injection, three‐station, moving‐table MRA protocol at 3Tesla with similar diagnostic performance when compared to 1.5Tesla. Additionally, submillimeter isotropic voxel acquisition in the lower legs at 1.5Tesla improves the diagnostic accuracy and depicts more open infragenual arterial segments.Additionally, it is demonstrated that new MRI biomarkers as distal aortic pulse wave velocity statistically significantly correlate with stenosis severity in symptomatic patients with peripheral arterial occlusive disease. Finally, we showed that CMR derived biomarkers relating to stenosis severity, aortic stiffness and left ventricular function play a role in prognosis of outcome in patients with symptomatic PAOD. In the future, incorporation of the described new MRI biomarkers in the clinical workup of peripheral arterial occlusive disease may play an important role for full vascular risk assessment and ultimately, patients may benefit in clinical practice. Show less
The work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the... Show moreThe work described in this thesis presents part of a framework that can be used to extract detailed disease biological information from peripheral tissue. This framework is based on the central dogma of biology “DNA to RNA to protein” and on a systems biology approach that aims to produce synergetic data whose disease pathological, prognostic and predictive value is greater than the sum of the individual experiment results. HD patients are often characterized by a multifaceted clinical profile, consisting of several symptoms and variable disease progression rates. Therefore, a systems approach such as the one described above is expected to be the most effective in identifying potential treatments and predictive biomarkers that will be most informative for the different patient subpopulations. Show less
This thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although... Show moreThis thesis demonstrates the application of bioinformatics to investigate the mechanisms that are implicated in Huntington’s Disease (HD). HD is an inherited neurodegenerative disorder and although the cause of the disease is known since 1993 we are still lacking a cure or treatment that can effectively treat the symptoms of HD. In order to tackle such a complicated case study, we followed a multidisciplinary approach to exploit the expertise and knowledge of people with diverse scientific background (chapter 2). This blend of disciplines facilitates constant collaboration between bioinformaticians, wet lab technicians, biologists, computer engineers and data scientists. A collaborative eScience model is proposed as a way to combine state-of-the-art computation analysis and laboratory work (chapter 3). At the same time, we explored methods to preserve the results, materials and methods involved in the experiment to increase the reproducibility and reusability of our research (chapter 4). In chapter 5 we identified disease signatures in blood that are functionally similar to signatures in brain. These are proposed as candidate biomarkers to be used as a monitoring tool for the state of the disease in brain, but also as a means to determine whether a treatment is successful or not. Show less
Globally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued... Show moreGlobally more than 200,000 people develop leprosy every year and 2-3 million people live with leprosy associated disabilities. Despite the availability of multi drug therapy, leprosy has continued affecting many individuals, including children because of the uninterrupted transmission in the population. Untreated multi bacillary cases as well as non-symptomatic M. leprae infected individuals in the population are believed to be the major sources of M. leprae infection and transmission. Leprosy reactions are also the major causes of disabilities. However, no tools are available to predict their occurrence. This thesis focuses on in vitro assessment of recombinant M. leprae proteins and synthetic peptides for their immunogenicity and specificity in populations with different genetic backgrounds by measuring cell mediated immunity and this has shown the presence of potential antigens. Further in depth analysis of the host immune responses against these unique antigens in leprosy patients, their household contacts and healthy endemic controls has led to identification of potential biomarkers with an immense importance in development of diagnostic tools for detection of M. leprae infection and early diagnosis of leprosy reactions. Currently, field friendly tests for early detection are developed at the LUMC using identified M. leprae antigens and host biomarkers with diagnostic potential. Show less
Wijdeven, R.H.; Pang, B.X.; Assaraf, Y.G.; Neefjes, J. 2016