Machine learning analysis of metabolomics and neuro-imaging data for Parkinson’s disease

Presentation (2019, January)

Making sense of big data in health research: Towards an EU action plan.

in Genome medicine (2016), 8(1), 71

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation ... [more ▼]

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans. [less ▲]

The mammalian Ste20-like kinase 2 (Mst2) modulates stress-induced cardiac hypertrophy.

in The Journal of biological chemistry (2014), 289(35), 24275-88

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its ... [more ▼]

The Hippo signaling pathway has recently moved to center stage in cardiac research because of its key role in cardiomyocyte proliferation and regeneration of the embryonic and newborn heart. However, its role in the adult heart is incompletely understood. We investigate here the role of mammalian Ste20-like kinase 2 (Mst2), one of the central regulators of this pathway. Mst2(-/-) mice showed no alteration in cardiomyocyte proliferation. However, Mst2(-/-) mice exhibited a significant reduction of hypertrophy and fibrosis in response to pressure overload. Consistently, overexpression of MST2 in neonatal rat cardiomyocytes significantly enhanced phenylephrine-induced cellular hypertrophy. Mechanistically, Mst2 positively modulated the prohypertrophic Raf1-ERK1/2 pathway. However, activation of the downstream effectors of the Hippo pathway (Yes-associated protein) was not affected by Mst2 ablation. An initial genetic study in mitral valve prolapse patients revealed an association between a polymorphism in the human MST2 gene and adverse cardiac remodeling. These results reveal a novel role of Mst2 in stress-dependent cardiac hypertrophy and remodeling in the adult mouse and likely human heart. [less ▲]

Marche et attention sélective chez les personnes âgées

Poster (2014, May)

Un lien entre troubles de la marche, chutes et fonction cognitives (fonctions exécutives et attention), chez les personnes âgées peut être considéré comme établi. En ce qui concerne les paramètres de la ... [more ▼]

Un lien entre troubles de la marche, chutes et fonction cognitives (fonctions exécutives et attention), chez les personnes âgées peut être considéré comme établi. En ce qui concerne les paramètres de la marche, une variabilité du pas élevée et un ralentissement de la vitesse de marche sous condition de double tâche, sont des indicateurs sensibles permettant d’évaluer le risque de chute. La présente étude s´est intéressée aux différences de ces paramètres de marche en fonction de la performance dans un test d´attention sélective. L´échantillon est composé de 33 personnes âgées en long séjour (âge moyen : 83.7, écart-type : 6.2). L´analyse de la marche a été effectué à l´aide du système Gaitrite® qui permet de mesurer e.a. la vitesse, la variabilité de la durée du cycle de marche et la variabilité de la longueur du cycle de marche. L´attention sélective a été mesurée avec un test d´attention sélective adapté aux personnes âgées. Les personnes ont été regroupées sur la base de leur performance dans ce test (temps requis et erreurs commises) afin d´obtenir deux groupes : un groupe plus performant et un groupe moins performant. On a pu observer des différences de marche en fonction de l´attention sélective. Plus précisément, dans le groupe moins performant considérant les erreurs commises lors du test, la variabilité de la longueur du cycle de marche sous condition double tâche était sifnificativement supérieure à celle du groupe plus performant (U = 175.0, p < .05). Ces résultats mettent en évidence les différences dans les paramètres de marche, et le risque de chute associé, en fonction de la capacité d´attention sélective chez les personnes âgées. [less ▲]

Mathematical Histopathology and Systems Pharmacology of Melanoma

Doctoral thesis (2019)

Treated metastatic melanoma often becomes resistant and relapses whereby resistance mechanisms can be found at the level of biochemical, histological, and pharmacological data. By using this data in a ... [more ▼]

Treated metastatic melanoma often becomes resistant and relapses whereby resistance mechanisms can be found at the level of biochemical, histological, and pharmacological data. By using this data in a mathematical form, an integrative understanding of tumour progression can be gained that reveal the functionality of more complex and hidden recurrence mechanisms. The aims of this thesis were - to investigate how a new engineering concept on tumour growth, based on porous media theory, can be leveraged to support medicine and cancer biology research, - to identify suitable tests for cancer growth model validation, - to study how elements of biochemical cancer pathways are linked to the elements of physical growth, and - to establish a pharmacokinetics module for the melanoma cancer drug dabrafenib. The studied engineering concept is qualitatively suitable to represent late-stage metastatic melanoma in irregular fibrous tissue types, whereby all equations are tested for biological relevance and parametrisation. The framework allows modelling of tissue-specific growth, and the thesis shows that the simulated tumour can shift between compact growth with ECM displacement and invasive growth with ECM circumvention as a consequence of cell plasticity/viscosity change. This is unique among continuous models of tumour growth. However, the investigation also shows that the pressure-saturation relationships are not biologically motivated and can be replaced by a swelling polymer model which captures the water absorbing effect of glycans. The thesis addresses a biologically and computationally reasonable strategy to validate the tumour growth model as complete as possible. A suitable way to validate a part of the tumour growth model is using time course data of spheroid growth in hydrogels of different stiffness values. Spheroids generated from the LU451 melanoma cell line mainly grow due to ECM degradation, have a time-variant growth rate increasing with gel rigidity, and the confined environment renders the melanoma cell line drug-resistant upon dabrafenib dose escalation. This setting reveals the interplay between mechanical and biochemical development over time. The dependency between biological elements of cancer pathways and the mechanical elements of the engineering concept on tumour growth were clarified. Therefore, the literature on mechanoregulation has been reviewed and serves as a computational link between systems biology and physical oncology. Finally, the thesis provides preliminary steps and a concept toward a serious interdisciplinary methodology to understand tumour growth, although this cannot be considered a final model for any of the known melanoma growth settings. Additionally, the thesis provides a novel quantitative systems pharmacology approach to consider liver-enzyme-induction and drug-drug-interaction. The finding is that the potent dabrafenib metabolite desmethyl-dabrafenib accumulates with consequential efficacy loss in a confined tumour environment. [less ▲]

Measurement of the nalgesic efects of aspirin with a new experimantal algesimetric procedure

in Pain (1988), 32(2), 215-222

Mechanical strength assessment of a drilled hole in the contralateral cortex at the end of the open wedge for high tibial osteotomy.

in Journal of Experimental Orthopaedics (2017), 4(1),

BACKGROUND: This study aimed to investigate, by means of finite element analysis, the effect of a drill hole at the end of a horizontal osteotomy to reduce the risk of lateral cortex fracture while ... [more ▼]

BACKGROUND: This study aimed to investigate, by means of finite element analysis, the effect of a drill hole at the end of a horizontal osteotomy to reduce the risk of lateral cortex fracture while performing an opening wedge high tibial osteotomy (OWHTO). The question was whether drilling a hole relieves stress and increases the maximum correction angle without fracture of the lateral cortex depending on the ductility of the cortical bone. METHODS: Two different types of osteotomy cuts were considered; one with a drill hole (diameter 5 mm) and the other without the hole. The drill holes were located about 20 mm distally to the tibial plateau and 6 mm medially to the lateral cortex, such that the minimal thickness of the contralateral cortical bone was 5 mm. Based on finite element calculations, two approaches were used to compare the two types of osteotomy cuts considered: (1) Assessing the static strength using local stresses following the idea of the FKM-guideline, subsequently referred to as the "FKM approach" and (2) limiting the total strain during the opening of the osteotomy wedge, subsequently referred to as "strain approach". A critical opening angle leading to crack initiation in the opposite lateral cortex was determined for each approach and was defined as comparative parameter. The relation to bone aging was investigated by considering the material parameters of cortical bones from young and old subjects. RESULTS: The maximum equivalent (von-Mises) stress was smaller for the cases with a drill hole at the end of the osteotomy cut. The critical angle was approximately 1.5 times higher for the specimens with a drill hole compared to those without. This corresponds to an average increase of 50%. The calculated critical angle for all approaches is below 5°. The critical angle depends on the used approach, on patient's age and assumed ductility of the cortical bone. CONCLUSIONS: Drilling a hole at the end of the osteotomy reduces the stresses in the lateral cortex and increases the critical opening angle prior to cracking of the opposite cortex in specimen with small correction angles. But the difference from having a drill hole or not is not so significant, especially for older patients. The ductility of the cortical bone is the decisive parameter for the critical opening angle. [less ▲]

Mechanisms of disease: An introduction to clinical sciences

in Tomlinson, H; Heagerty, AM; Weetman, AP (Eds.) et al Heart Failure (2007)

Medizinische Eingriffe und Operationsstress

in Bengel, J.; Jerusalem, M. (Eds.) Handbuch der Gesundheitspsychologie und Medizinischen Psychologie (2009)

Medroxyprogesterone acetate but not drospirenone ablates the protective function of 17 beta-estradiol in aldosterone salt-treated rats.

in Hypertension (2006), 48(5), 994-1001

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and ... [more ▼]

Controversial results obtained from human and animal studies on the prevention of heart disease by estrogens and progestins warrant a better understanding of nuclear hormone receptor function and interaction. To address this issue and taking into account that effects of synthetic progestins are not only referable to action through the progesterone receptor but may also be mediated by other steroid receptors, we characterized cardiovascular function and inflammatory gene expression in aldosterone salt-treated rats on long-term administration of 17beta-estradiol, medroxyprogesterone acetate, and drospirenone, a new progestogen exhibiting antimineralocorticoid activity. The complex pattern of cardiovascular injury in ovariectomized Wistar rats induced by chronic aldosterone infusion plus a high-salt diet was significantly attenuated in sham-ovariectomized rats and by coadministration of 17beta-estradiol in ovariectomized animals after 8 weeks of continuous treatment. The beneficial role of 17beta-estradiol on blood pressure, cardiac hypertrophy, vascular osteopontin expression, perivascular fibrosis, and impaired NO-dependent relaxation of isolated aortic rings was completely abrogated by coadministration of medroxyprogesterone acetate. In contrast, drospirenone was either neutral or additive to 17beta-estradiol in protecting against aldosterone salt-induced cardiovascular injury and inflammation. The current results support the hypothesis of complex interactions among estrogen, progesterone, glucocorticoid, androgen, and mineralocorticoid receptor signaling in cardiovascular injury and inflammation. Novel progestins, such as drospirenone, confer superior effects compared with medroxyprogesterone acetate in a model of aldosterone-induced heart disease because of its antimineralocorticoid properties. [less ▲]