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1
De, Gzell Cecelia Elizabeth. "OPTIMISING OUTCOMES IN PATIENTS WITH GLIOBLASTOMA RECEIVING RADIOTHERAPY." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16549.
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More than 1,400 new cases of malignant brain tumours are diagnosed each year in Australia. Glioblastoma, or GBM, remains the most common primary brain tumour in adults and the most devastating. The median age at diagnosis is 61 years and the median survival from diagnosis is only approximately 14 months. The aim of the work presented in this thesis is to optimise radiotherapy protocols in patients with glioblastoma to improve patient outcomes by targeting particular time points along the patients’ treatment journey. After describing the disease and epidemiology of GBM in Chapter 1, Chapter 2 explores the evolution of RT technique in treating this disease throughout the ages. In this disease patients >65 years are considered “elderly” and have a poorer prognosis compared with their younger cohorts. They also represent the majority of patients with GBM as the incidence for this tumour peaks in the sixth and seventh decades. There is currently no internationally accepted standard of care for treating this group. Chapter 3 analyses different RT protocols in this cohort of patients. The remaining chapters examine different aspects of the patient’s post-RT journey. Chapter 4 analyses the phenomenon of pseudoprogression (PsP), a radiological diagnosis of an increase in abnormality on post-RT magnetic resonance imaging (MRI) scan which subsequently improves over time with no change in treatment. This phenomenon is poorly understood and the pathological characteristics are explored. Directly expanding from the work on pseudoprogression, Chapter 5 introduces novel volumetric techniques to analyse post-RT MRI changes and explores whether these impact patients’ survival. Chapter 6 deals with the survivorship issue of a patient’s ability to return to work following RT. As patients are living longer with this disease, and a greater proportion are remaining functionally well until late in the course of the disease, more patients are being offered re-irradiation as part of their salvage treatment. Chapter 7 analyses the evolving role of re-irradiation. RT in addition to surgery remains the cornerstone of treatment of GBM. With ongoing improvements in the technical delivery of RT we expect there to be clinical benefit for patients with reduced short-and late toxicity, if not an improvement in survival. This thesis explores different aspects of the patients’ treatment journey on topics that have previously been poorly understood or novel areas of research.
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RANCATI, SILVIA. "A nanoformulated 11-miRNA pool synergistically modulates GBM cells invasion and in vivo growth." Doctoral thesis, Università degli studi di Genova, 2021. http://hdl.handle.net/11567/1045591.
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Glioblastoma (GBM) is the most common and fatal cancer of the adult brain, with an annual incidence rate of 2-3 per 100 000 (US) and a median survival time around 14 months. GBM is characterized by an infiltrative growth pattern that makes its complete surgical resection arduous. Moreover, the presence of a therapy-refractory cancer stem cell (CSC) component has been linked to the unavoidable insurgence of tumor recurrence experienced by patients.
The failure of current therapeutic standards at completely eradicate this tumor fuels an intense research effort for the identification and development of new therapeutic strategies. To achieve the cure of this malignancy, while preventing its recurrence, the ideal treatment should target both the invasive behavior of GBM and the cancer stem cell population (the latter with so called “differentiation therapy”).
MicroRNAs (endogenous small non-coding RNAs regulating the gene expression at the post transcriptional level) show dysregulated expression in tumors compared to healthy tissues and are involved in several of the “hallmarks of cancer”: hence, they have raised attention for their therapeutic potential. The development of miRNA-based therapies is an expanding field of research: in recent years several formulations entered into clinical trials for treating various malignancies, but none for brain cancers, indicating room for improvement. The functional synergism of multiple, different miRNA, also known as cooperation or convergence, has been proposed as one of the mechanisms that confer robustness to miRNA-mediated regulation of large number of genes, allowing these tiny RNAs to orchestrate essential cellular pathways. MiRNA-based therapies for cancer could benefit from the functional synergism of different miRNAs, especially considering the high intra-tumoral heterogeneity and the number of redundant and compensatory mechanisms of therapy-resistance that characterize refractory tumors as GBM, that are unlikely to be effectively targeted by a single molecule.
Our lab previously identified a “pool” of 11 miRNAs necessary and sufficient to sustain neuronal differentiation of adult neural stem cells in mice by the synergic repression of targets involved in cell morphogenesis and neuron differentiation (Pons-Espinal et al., 2017). This pool is conserved in human and dysregulated in GBM. The molecular and cellular similarities between GBM stem cells (GSC) and neural stem cells (NSC) led to the hypothesis to employ the 11-miRNA pool in GBM, with the originary idea to target the GSC component of this tumor with potential benefit.
Building on the combinatorial nature of the miRNA pathway and on previous results by the host lab, indicating an essential role of the miRNA pool to control NSCs differentiation, the overarching goal of my PhD project was to deploy the 11-miRNA pool in an anticancer therapy against GBM, to test its tumor-suppressive potential and to identify the molecular mechanisms underlying its therapeutic effects. Main results achieved by this work are:
I. The identification of a fundamentally anti-invasive role of the 11 miRNAs, achieved in GBM by synergistic regulation of a wide network of proteins involved in cell-adhesion, cytoskeleton reorganization and extracellular matrix remodeling. Importantly, many of the proteins downregulated by the pool are relevant in GBM pathogenesis and thereby possible targets for future development of conventional drug-based therapies.
II. The development of a delivery strategy that possesses a realistic translational potential, taking the example from clinically approved lipid nanoparticles formulations, considered a leading-edge vector for small RNAs delivery.
III. The demonstration that the functional synergism of the 11-miRNA pool, enhanced in vivo by nano-delivery, is an effective strategy to slow-down the in vivo growth of an aggressive model of human GBM.
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Pavliš, Jaroslav. "Přenos pacientských informací pomoci GSM." Master's thesis, Vysoké učení technické v Brně. Fakulta elektrotechniky a komunikačních technologií, 2008. http://www.nusl.cz/ntk/nusl-217737.
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This diploma thesis is concerned with possibilities of patient data transfer from a pacemaker or implantable cardioverter-defibrillator to physician over GSM. Theoretical part describes options of data transfer in GSM networks, data appropriate for sending and a structure of message is proposed. A device, that is able to send medical data in a form of SMS messages is designed and constructed. The device uses a Freescale MC68HC908GP32 microcontroller, character display with a Hitachi HD44780 controller and a cell phone Sony CMD-J70. The program for microcontroller is written in assembler for HC08. For tabular view of received messages, an application software for PC was created.
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Kober, Sylvia Deborah geb Pflederer [Verfasser]. "Parkinson’s disease patients with heterozygous GBA-mutation : longitudinal phenotyping of motor and non-motor symptoms – more rapid progression compared to Parkinson’s disease patients without GBA-mutation / Sylvia Deborah geb. Pflederer Kober." Tübingen : Universitätsbibliothek Tübingen, 2021. http://d-nb.info/1226756417/34.
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Galper, Jasmin. "Inflammatory and lipid markers in clinical and pre-clinical Parkinson’s disease patients." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/27967.
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Parkinson’s disease (PD) risk gene discoveries have implicated lipids and inflammation in pathology. However, most research to date has been protein-centric. Therefore, the extent of lipid involvement in PD and relationships between inflammatory and lipid pathways are unclear. Research into these areas may provide novel insights into PD pathology, therapeutic targets and biomarkers for an earlier diagnosis and monitoring disease progression in clinical trials.
To investigate lipid dysregulation in PD and in mutation carriers of the PD risk gene LRRK2, untargeted mass spectrometry was performed using serum (N = 221) and cerebrospinal fluid (CSF, N = 88) from controls, pre-clinical and clinical PD LRRK2 G2019S carriers and sporadic PD patients. Findings were then validated in a second cohort (N = 315) using serum from the same groups. Significant lipid alterations were found in mutation carrier and PD patient serum and CSF. Altered lipids implicated sphingolipid metabolism and insulin signalling pathways in PD. Further, altered serum and CSF lipids correlated with cytokines involved in insulin/glucose signalling. Pre-clinical PD biofluid changes suggest that lipids are worthwhile candidates for longitudinal studies assessing whether baseline markers predict PD. Correlation analysis indicated that although serum lipids did not robustly associate with clinical severity, CSF lipids were associated.
Finally, whether mutations in the lipid-related risk gene, GBA, affected inflammatory markers was assessed in plasma (N = 371) from clinical and pre-clinical GBA mutation carriers, sporadic PD patients and controls. Inflammatory markers were overall unchanged in GBA mutation carriers, suggesting these are not promising biomarker candidates.
These findings strongly support a role for lipid dysregulation in PD. These results indicate that lipids are promising candidates to pursue for understanding PD aetiology, as well as potential novel biomarkers for genetic and sporadic PD.
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Hurley, Samantha Jane. "The physico-chemical mechanisms underlying the physiological effects of non-starch polysaccharides: studies in ileostomy patients." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310783.
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RIBOLDI, GIULIETTA. "INTEGRATED GENOMIC ANALYSIS OF ISOLATED CD14+ MONOCYTES IN PATIENTS WITH GBA-RELATED PARKINSON¿S DISEASE." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/827744.
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Background: Genetic mutations of the gene encoding for the beta- glucocerebrosidase (GCase), GBA gene, represent the major genetic risk factor for Parkinson’s disease (PD). The pathogenic mechanisms associated with these mutations and modifiers responsible for the reduced penetrance of this gene are not fully elucidated yet. However, the function of the GBA gene is at the crossroad between the endo-lysosomal pathway and the immune response, which are two main mechanisms involved in PD pathogenesis. Aim: With the present work we aim to characterize the clinical features of a population of patients with PD and healthy controls (CTRL) with and without mutations of the GBA gene and characterize the transcriptomic profiles of purified CD14+ monocytes in order to identify 1) pathogenic mechanisms associated with GBA- PD; 2) potential biomarkers for earlier detection of GBA mutation carriers who will phenoconvert to a disease status; 3) new therapeutic targets for precision medicine approaches.
Material and methods: PD patients and CTRL were enrolled at the Fresco Institute (NYU Langone Health, NY) and Mount Sinai School of Medicine (NY). Demographic information, clinical and family history, as well as motor and non-motor symptoms of PD were collected. DNA and RNA from purified CD14+ monocytes, plasma and peripheral blood mononuclear cells (PBMC) were collected. Genotyping (Illumina Global Screening Array with custom Neurodegenerative disease panel) and RNAseq analysis (60M ribo- depleted, paired-end reads) was performed. Data were analyzed through integrative genomic analysis leveraging different computational methods (differential expression, nested interaction model, outlier detection and trans-eQTLs).
Results: Statistical analysis comparing the clinical phenotypes of 19 PD/GBA+, 37 PD/GBA-, 37 CTRL/GBA-, 9 CTRL/GBA+ showed increased non-motor symptoms in CTRL/GBA+ and increased family history and cognitive impairment in the PD/GBA+ cohort. Integrative genomic analysis of a cohort of 56 PD/GBA-, 66 CTRL/GBA-, 23 PD/GBA+, and 13 CTRL/GBA+ identified a large number of differentially expressed genes and deregulated pathways in the PD/GBA+ compared to CTRL/GBA+ as well as PD/GBA- groups. In particular, PD/GBA+ showed deregulated alpha-synuclein-, amyloid- and aging-related processes compared to PD/GBA-. Compared to CTRL/GBA+, in manifesting carriers there was a deregulation of all the major pathogenic pathways previously associated with PD. Outliers and trans-eQTLs analysis confirmed a prominent involvement of lysosomal, membrane trafficking, and mitochondrial targets, identifying also additional related genes.
Discussion: Clinical and demographic analysis of PD patients and CTRL with and without GBA mutations highlighted characteristic features in the PD/GBA+ and CTRL/GBA+ cohort. Genomic analysis of isolated CD14+ monocytes identified specific molecular targets and deregulated pathways that can help understanding the pathogenic mechanisms associated with GBA mutations in the context of PD.
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Kihlgren, Mona. "Integrity promoting care of demented patients." Doctoral thesis, Umeå universitet, Institutionen för omvårdnad, 1992. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100570.
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The purpose of the thesis was to investigate if integrity promoting care improves functions in demented patients over time. The Erikson (1982) theory of ”eight stages of man” was used as a basis for training of staff in a three-month intervention study (I-VI) at a nursing home ward. A collective living unit where staff had had support in the performance of the delivery of care was also evaluated and compared with a nursing home in a long-term study (VII). Patients, relatives, staff, and the environments were investigated. Cerebrospinal fluid concentrations of somatostatin increased, and reduction of distractability, anxiety and confusion was seen in the intervention group (I) in contrast to controls. In the collective living group (VII) EEG activities indicated a reduction of supposed dementia induced changes. Better motor and social ability, some improved intellectual ability, more alertness and reduced signs of depression were seen (I, II, VII). Patients expressed more autonomy (IV, VII) and initiatives (II-VII) and showed a lot of competence (V) in conversations. Five patients (V) showed patterns of behaviour which seemed to reflect life-long characteristics in spite of their severe dementia. The improvement in the patients' functions can be attributed to the physical environment and the integrity promoting care, since the medical treatment of the patients remained unchanged. In the thesis medical, psychological, and nursing sciences were connected in a complementary process. The results were congruent, and indicate that patients in the care of staff who had had training and support, declined less than controls.S. 1-61: sammanfattning, s. 63-184: 7 uppsatser
digitalisering@umu
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江寶盈 and Po-ying Kong. "Relationship between self-reflection and insight in early psychosis patients using guided illness model questionnaire (GIM) / y Kong Po Ying, Cathy." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/192950.
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Insight impairment is commonly reported in psychosis patients and such impairment leads to poor outcome and it also causes burden to the family and caregivers. It is as yet unclear what causes unawareness of illness therefore it is essential to find out the key element to form this fundamental correlation.
Wiffen and David proposed that self-reflective processing may have similar cognitive mechanisms as theory of mind processing, but this does not imply that the processes cannot be affected independently. Lysaker et al. demonstrated that better meta-cognitive skills, such as the ability to think about one’s own thoughts were related to better insight in schizophrenia patients. An increasing number of studies suggest that patients lacking insight into their own illness, were fully capable of recognizing the illness and symptoms in other patients. This indicated that insight impairment only happened at the self-recognition level.
The ability of integrating information from outside world to the self is seen as a factor in gaining insight, therefore self-reflection ability are commonly seen as key features of awareness of mental illness. Previous studies of chronic schizophrenia patients show that their ability to accept the biological model of their own psychotic symptoms, assessed with Guided Illness Model Questionnaire (GIM) questionnaire, has a positive association with their neuropsychological function and awareness of illness However, it has not been common to use GIM questionnaire in early stage psychosis patients.
This study aims are (1) use Guided Illness Model Questionnaire (GIM) to assess the self-reflection ability of early stage psychosis patients (2) explore the relationship between self-reflection and insight (3) Cognitive functions, particular executive functions, will be evaluated with self-reflection ability and insight. Insight will be measured by scale to assess unawareness of mental disorder (SUMD). Results show self-reflection ability is related with insight impairment and executive function, especially processing speed and attention contributes to self-reflection ability and poor insight. Further investigation reveals that self-reflection ability acts as a mediator for poor insight. This study concludes that executive functioning is the basic-order process for gaining insight and self-reflection could act as higher-order process as mediator for provoking insight for psychosis patients.published_or_final_version
Psychological Medicine
Master
Master of Psychological Medicine
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Toupin, Amanda. "Analyse de biomarqueurs au niveau cellulaire de patients atteints de la maladie de Fabry en utilisant la spectrométrie de masse en tandem." Mémoire, Université de Sherbrooke, 2017. http://hdl.handle.net/11143/11789.
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La maladie de Fabry est une maladie de surcharge lysosomale liée au chromosome X. Elle est causée par une mutation au niveau du gène GLA qui provoque un déficit de l’enzyme α-galactosidase A. Elle entraîne une accumulation de glycosphingolipides tels le globotriaosylcéramide (Gb3), le globotriaosylsphingosine (lyso-Gb3) et galabiosylcéramide (Ga2) ainsi que leurs isoformes/analogues respectifs au niveau des tissus et des liquides biologiques des patients. Les symptômes peuvent se présenter de manière très variable soit par de l’acroparesthésie, des troubles ophtalmologiques, des angiokératomes, des troubles cardiaques, rénaux ou encore neurologiques. Les connaissances au niveau physiopathologique de la maladie de Fabry sont à ce jour, toujours déficientes. Les biomarqueurs analysés ne permettent pas de prédire la sévérité et la progression de la maladie. Afin d’apporter des connaissances plus approfondies à ce niveau, l’objectif principal de cette étude était d’analyser les biomarqueurs au niveau cellulaire pour des patients atteints de la maladie. Les objectifs secondaires étaient: 1) de développer et de valider une méthode en spectrométrie de masse en tandem pour la quantification relative et simultanée de certains biomarqueurs susmentionnés dans les leucocytes, les lymphocytes B et les monocytes de patients Fabry et contrôles sains; 2) d’évaluer les biomarqueurs dans le total des leucocytes, les lymphocytes B, les monocytes, le plasma et l’urine chez les patients Fabry et les contrôles sains appariés selon le sexe et l’âge; et 3) d’établir des corrélations entre la quantité relative de ces biomarqueurs et le génotype des patients traités et non traités. Les résultats de cette étude démontrent qu’il n’y a pas de changements significatifs dans la distribution des groupes d’isoformes/analogues du Gb3 selon le type cellulaire pour les patients et les contrôles. La découverte d’isoformes/analogues méthylés du Gb3 suggère un processus de méthylation qui se produit directement au niveau des cellules sanguines et particulièrement pour les lymphocytes B et les monocytes. Des corrélations face à la quantité de biomarqueurs et le génotype ont été établies. Ces résultats pourraient permettre une meilleure compréhension des processus biochimiques reliés à l’accumulation du Gb3 dans les cellules sanguines.
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Gabes, Michaela [Verfasser], and Christian [Akademischer Betreuer] Apfelbacher. "Patient-reported outcome measures beim Genitourinary Syndrome of Menopause (GSM): systematische Übersichtsarbeit, Validierung des „Day-to-Day Impact of Vaginal Aging (DIVA) Questionnaire“ und Exploration der urologischen Komponente des GSM / Michaela Gabes ; Betreuer: Christian Apfelbacher." Regensburg : Universitätsbibliothek Regensburg, 2021. http://d-nb.info/1233865579/34.
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Ribeiro, Fernandes Hugo José. "Elucidating the role of GBA in the pathology of Parkinson's disease using patient derived dopaminergic neurons differentiated from induced pluripotent stem cells." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:7027574c-dda4-4752-9010-4c573bd0b2aa.
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Heterozygous mutations in the glucocerebrosidase (GBA) gene represent the most common risk factor for Parkinson’s disease (PD), a disease in which midbrain dopaminergic neurons are preferentially vulnerable. However, the mechanisms underlying this association are still unknown, mostly due to the lack of an appropriate model of study. In this thesis, we aimed at elucidating the role of heterozygous GBA mutations in PD using a specific human induced pluripotent stem cell (hiPSC)-based model of disease. First we developed a protocol for the efficient differentiation of hiPSCs into dopaminergic cultures, and extensively characterized the derived dopaminergic neurons which expressed multiple midbrain relevant markers and produced dopamine. Next we screened a clinical cohort of PD patients to identify carriers of GBA mutations of interest. Using for the first time hiPSCs generated from PD patients heterozygous for a GBA mutation (together with idiopathic cases and control individuals) we were able to efficiently derive dopaminergic cultures and identify relevant disease mechanisms. Upon differentiation into dopaminergic neuronal cultures, we observed retention of mutant glucocerebrosidase (GCase) protein in the endoplasmic reticulum (ER) with no change in protein levels, leading to upregulation of ER stress machinery and resulting in increased autophagic demand. At the lysosomal level, we found a reduction of GCase activity in dopaminergic neuronal cultures, and the enlargement of the lysosomal compartment in identified dopaminergic neurons suggesting a decreased capacity for protein clearance. Together, these perturbations of cellular homeostasis resulted in increased release of α-synuclein and could likely represent critical early cellular phenotypes of Parkinson's disease and explain the high risk of heterozygous GBA mutations for PD.
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Schröter, Nils [Verfasser], Nurcan [Gutachter] Üçeyler, and Christoph [Gutachter] Wanner. "Diagnostische Wertigkeit von Gb3-Ablagerungen in der Haut von Patienten mit M. Fabry / Nils Schröter ; Gutachter: Nurcan Üçeyler, Christoph Wanner." Würzburg : Universität Würzburg, 2018. http://d-nb.info/1156534097/34.
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Kämpf, Tanja [Verfasser], and Frank [Akademischer Betreuer] Weidemann. "Definition eines klinisch relevanten Morbus Fabry mit Hilfe des Biomarkers Lyso Gb3 bei Patienten mit einer alpha- Galaktosidase Mutation / Tanja Kämpf. Betreuer: Frank Weidemann." Würzburg : Universitätsbibliothek der Universität Würzburg, 2013. http://d-nb.info/1034813331/34.
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Hohmann, Friedrich Anton [Verfasser], Gerhard [Akademischer Betreuer] Krönke, and Gerhard [Gutachter] Krönke. "Klinische Assoziationen von GBP-1, IFN-α und IFN-γ bei Patienten mit systemischem Lupus erythematodes / Friedrich Anton Hohmann ; Gutachter: Gerhard Krönke ; Betreuer: Gerhard Krönke." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/123889884X/34.
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Vallerand, David. "Etude du stroma de tumeurs mammaires humaines xénogreffées et de modèles transgéniques murins." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T001.
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La progression tumorale est un processus multi-étapes dépendant notamment des interactions entre les cellules cancéreuses et le stroma environnant. Le développement du cancer du sein implique une communication étroite entre les cellules épithéliales mammaires, les cellules inflammatoires, les myofibroblastes et les cellules endothéliales. Ainsi, le microenvironnement tumoral apparaît comme une cible de choix dans le traitement anti-tumoral. L’utilisation de modèles précliniques est une étape clé dans le développement et la validation de nouvelles thérapies. Néanmoins, peu d’études sont disponibles sur le rôle du stroma péri-tumoral dans ces modèles.Dans le but d’étudier le stroma péri-tumoral des modèles précliniques de cancers du sein, nous avons combiné une analyse par cytométrie en flux à une analyse par immunohistochimie afin d’identifier, puis de quantifier, les différentes populations stromales hématopoïétiques (lymphocytes, monocytes/macrophages, polynucléaires) et non hématopoïétiques (myofibroblastes, cellules endothéliales). Vingt et un modèles de xénogreffe de tumeurs humaines de cancers du sein ainsi que 2 modèles transgéniques (MMTV-PyMT et MMTV-ErbB2), ainsi que leurs allogreffes respectives, furent utilisés lors de ce travail.Les analyses des tumeurs humaines et murines ont montré un infiltrat stromal très hétérogène d’une tumeur à l’autre, avec pour composante majoritaire les macrophages. Un infiltrat important en polynucléaires a également été détecté dans les modèles de PDX, caractéristique d’une inflammation locale importante dans ces modèles. L’analyse phénotypique de macrophages a montré une expression variable de marqueurs M1 et M2 dans les modèles de PDX. Les macrophages issus de tumeurs murines transgéniques, spontanées ou allogreffées, présentaient quant à eux un profil majoritairement M1. L’étude transcriptomique de macrophages triés, a permis à la fois de valider les résultats obtenus au niveau protéique mais a également mis en évidence des différences majeures dans l’expression de nombreux gènes, impliqués dans des voies de signalisation variées telles que la croissance tumorale, l’invasion et la métastase.Cette étude nous a permis de mettre en évidence le rôle de la tumeur sur son microenvironnement. En effet, celle-ci est à la fois capable d’attirer un panel de cellules stromales qui lui et propre et ensuite de l’activer de façon spécifiqueTumor development is a multi-step process influencing by interactions between tumor cells and surrounding stroma. Breast cancer development involves a high level of communication between mammary epithelial cells, inflammatory cells, myofibroblasts and endothelial cells. So, the tumoral microenvironment appears as a prime target for anti-tumoral treatment. The use of preclinical models is a critical step in development and validation processes of new therapies. Nevertheless, the role of stroma in these models is poorly understood.In order to evaluate stromal cell populations in breast cancer preclinical models, we combined flow cytometry analysis and immunohistochemistry to identify, and then quantify, various stromal populations as hematopoietic cells (lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes) and non-hematopoietic cells (myofibroblasts, endothelial cells). Twenty-one breast cancer patient-derived xenografts as well as 2 transgenic mouse models (MMTV-PyMT and MMTV-ErbB2), and their respective allografts, were studied.Analysis of human and murine tumors showed a strong heterogeneity between tumors regarding infiltrating stroma-cells, with a high proportion of macrophages. A significant amount of polymorphonuclear leukocytes was also detected in PDXs, indicating a local inflammation in these models. The phenotypic analysis of macrophages showed a variable expression of M1 and M2 markers in PDXs. Macrophages infiltrating transgenic mouse tumors, spontaneous or allografted, were mainly M1. Transcriptomic analyses of sorted macrophages, allowed us to validate previous results but also highlighted major differences in the expression of numerous genes implicated in various pathways as tumor growth, invasion and metastasis.Finally, this study highlighted the impact of tumor cells on their surrounding stroma. Indeed, we demonstrate that cancer cells are able to attract a specific panel of stromal cells and activate them in a specific way
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Skříčková, Alžběta. "Rehabilitační centrum Pasohlávky." Master's thesis, Vysoké učení technické v Brně. Fakulta stavební, 2019. http://www.nusl.cz/ntk/nusl-392069.
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The diploma thesis deals with the design of a rehabilitation center, which is located in the cadastral area of the village Mušov on the border of the village Pasohlávky. It is a two-storey rehabilitation center with a gym and a partial basement. The thesis deepens the initiative of Thermal Pasohlávky, which plans to build a spa resort in the same section, combining elements of spa care, recreation and sports use. The object fulfills the function of a rehabilitation medical facility. The center is designed for up to 50 patients and is functionally divided into three parts. The first part consists of rehabilitation. We will find here several exercise rooms, hydrotherapy, electrotherapy, doctor's office with waiting room and reception. Rehabilitation also includes a gym with access to the terrace and park. On the second floor we can find specialized department of ergotherapy for people with different types of disabilities and second functional part of the bulding designed for staff facilities. It is made up of staffing facilities, dressing rooms, offices and meeting rooms. The third functional part consist from the technical background of the building and is located on the ground floor. The object is designed as a wall system, built from sand-lime bricks km beta Sendvix and insulated with the ETICS thermal insulation made from mineral wool. Horizontal supporting structures are designed as reinforced concrete. The entire building is roofed with a flat roof. Wooden windows and doors are used in the building to fill the holes. Before the building is a parking lot for employees and visitors of the rehabilitation facility. The design respects the principles of barrier-free solutions. The bachelor thesis is elaborated in the form of a project documentation for the execution of the construction.
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Alnaami, Ibrahim. "Evaluation of Concomitant Temozolomide Treatment in Glioblastoma Multiforme Patients in Two Canadian Tertiary Care Centers." Master's thesis, 2010. http://hdl.handle.net/10048/1300.
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The study evaluated the survival of 364 glioblastoma multiforme (GBM) patients who received different modalities of treatment in two Canadian tertiary care centres. Retrospective and prospective databases were utilized to do a retrospective population based cohort study.
The thesis question was among treated GBM patients in Edmonton and Halifax; does the survival rate differ with introduction of concomitant temozolomide and radiation therapy (RT) versus non concomitant treatment?
Our results indicate that concomitant temozolomide with radiation therapy and surgery was associated with longer survival in comparison to radiation therapy with surgery. We also found that age; surgical resection and shorter time to radiation therapy are important factors for longer survival.Clinical epidemiology
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Campos, Valenzuela Jaime Alberto. "Classification of Glioblastoma Multiforme Patients Based on an Integrative Multi-Layer Finite Mixture Model System." Doctoral thesis, 2016. https://tud.qucosa.de/id/qucosa%3A32248.
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Glioblastoma multiforme (GMB) is an extremely aggressive and invasive brain cancer with a median survival of less than one year. In addition, due to its anaplastic nature the histological classification of this cancer is not simple. These characteristics make this disease an interesting and important target for new methodologies of analysis and classification.
In recent years, molecular information has been used to segregate and analyze GBM patients, but generally this methodology utilizes single-`omic' data to perform the classification or multi-’omic’ data in a sequential manner.
In this project, a novel approach for the classification and analysis of patients with GBM is presented. The main objective of this work is to find clusters of patients with distinctive profiles using multi-’omic’ data with a real integrative methodology.
During the last years, the TCGA consortium has made publicly available thousands of multi-’omic’ samples for multiple cancer types. Thanks to this, it was possible to obtain numerous GBM samples (> 300) with data for gene and microRNA expression, CpG sites methylation and copy-number variation (CNV).
To achieve our objective, a mixture of linear models were built for each gene using its expression as output and a mixture of multi-`omic' data as covariates. Each model was coupled with a lasso penalization scheme, and thanks to the mixture nature of the model, it was possible to fit multiple submodels to discover different linear relationships in the same model.
This complex but interpretable method was used to train over \numprint{10000} models. For \texttildelow \numprint{2400} cases, two or more submodels were obtained.
Using the models and their submodels, 6 different clusters of patients were discovered. The clusters were profiled based on clinical information and gene mutations. Through this analysis, a clear separation between the younger patients and with higher survival rate (Clusters 1, 2 and 3) and those from older patients and lower survival rate (Clusters 4, 5 and 6) was found. Mutations in the gene IDH1 were found almost exclusively in Cluster 2, additionally, Cluster 5 presented a hypermutated profile. Finally, several genes not previously related to GBM showed a significant presence in the clusters, such as C15orf2 and CHEK2.
The most significant models for each clusters were studied, with a special focus on their covariants. It was discovered that the number of shared significant models were very small and that the well known GBM related genes appeared as significant covariates for plenty of models, such as EGFR1 and TP53. Along with them, ubiquitin-related genes (UBC and UBD) and NRF1, which have not been linked to GBM previously, had a very significant role.
This work showed the potential of using a mixture of linear models to integrate multi-’omic’ data and to group patients in order to profile them and find novel markers. The resulting clusters showed unique profiles and their significant models and covariates were comprised by well known GBM related genes and novel markers, which present the possibility for new approaches to study and attack this disease. The next step of the project is to improve several elements of the methodology to achieve a more detail analysis of the models and covariates, in particular taking into account the regression coefficients of the submodels.
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Lin, Jian-Yong, and 林建勇. "The correlation and prognostic significance of Foxp3 isoform expression in tumor infiltrating lymphocytes and glioma cells from GBM patients." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/53835870913705937345.
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碩士中國醫藥大學
免疫學研究所碩士班
100
As themost malignant high-grade glioma, prognosis for patients with glioblastoma multiforme (GBM) has only a median survival of 15 month, and 88% mortality within 3 years. Forkhead box protein 3 (Foxp3) is considered to be an important gene for thymically derived and naturally occurring regulatoryTcells (Tregs),whichregulate the immunosuppressive response. Recent studies described the expression of forkhead box P3 (Foxp3) in several tumor cells for providing the possibility of effector T-cell evasion. The present work was to investigate the significance of Foxp3 expression in glioblastoma multiforme (GBM) patients. FOXP3 largely controls the development into Treg cells, and three isoforms Foxp3, Foxp3-WT, FOXP3-△2 and FOXP3-△2△7, have been shown to be expressed in human Treg cells. FOXP3-WT represses NFAT- and NF?羠-mediated gene transcription process , while FOXP3-△2 is involved in repressing the transcriptional activity of the retinoic acid-related orphan receptors alpha (RORα) and gamma-t (RORγt) that regulates the development of antigen-stimulated naive CD4+ T cells into T-helper 17 (Th17) cells . FOXP3-△2△7 has been identified to negatively regulate the function of FOXP3-WT, and FOXP3-△2. We isolated Tregs from infiltrating lymphocytes (TILs) of GBM by FACS analysis. Then, we analyzed the expression of key molecules of Treg function in lymphocytes and tumor cells and correlate with the DC-therapy response of the corresponding patient. Both Tregs and tumor cells express 3 different isoforms of the FOXP3 gene by alternative splicing, one of which represents a naturally occurring dominant negative version of the Foxp3 protein.The proportion of Tregs in CD4+ TILs had been observed the increasing percentage in GBM patients with short survival. However, there was no significant difference in three isoforms of Foxp3 expressed in Tregs comparing with survival of GBM patients. But, three patients with high survival (over 2 years) had shown the expression of dominant negative FOXP3-△2△7 isoform.The differential expression level of Foxp3 isoforms may constitute a potent prognosis factor for GBM patients. Tregs may limit DC-therapy against GBM, while the differential expression of Foxp3 isoforms could provide a basis for the evaluation of the effectiveness of DC-therapy. Functional abrogation of Foxp3 by tuning the splicing preference to its dominant negative isoform may offer an attractive window to inhibit Treg activity.
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Pal, Jagriti. "Elucidating Deregulated Novel Pathways in Glioma through Genetic and Epigenetic Approaches." Thesis, 2016. http://etd.iisc.ac.in/handle/2005/4284.
Full textAbstract:
Malignancy of glial cells is termed as glioma. Gliomas comprise of thirty percent of
all tumors of the central nervous system (CNS) and eighty percent of malignant brain tumors
(Goodenberger and Jenkins, 2012). Astrocytoma, a type of glioma that arise from astrocytes,
is the most common and lethal type of intracranial tumor. It is divided into four groups
according to WHO (2007) classification based on histopathology. Grade I or pilocytic
astrocytoma is benign in nature; however, the other three grades are progressively more
malignant. Grade II or diffused astrocytoma is less aggressive and have a median survival of
5-8 years (Tove et al., 2012); while Grade III or anaplastic astrocytoma and glioblastoma
(GBM) are classified under high grade gliomas with median survival of 2-3 years and 12-15
months respectively (Nuño et al., 2013; Arvold et al., 2014). GBM tumor is fast growing,
highly infiltrative, and treatment refractory. It can be divided into two categories on the basis
of their origin - primary GBM that accounts for 90 percent of GBM cases, manifest de novo
without prior evidence of a pre-existing tumor of lower grade; while secondary GBMs
develop through malignant progression of lower grade astrocytomas. Secondary GBMs
typically exhibit genetic aberrations like TP53 mutation, IDH1 mutation, PTEN mutation,
loss of chromosomal arm 10q etc. Primary GBMs show a whole host of genetic aberrations
including EGFR amplification, PDGFR amplification, mutation in TP53, PTEN, NF1, RB
etc., amplification of MDM2 and MDM4, loss of chromosomal arms 10p and 10q, CDKN2A
and CDKN2B loss (Furnari et al., 2007). With the current treatment modality of GBM that
includes surgical resection followed by radiotherapy and temozolomide chemotherapy, the
median survival achieved till date is only 15 months and in almost all cases, the tumor recurs
(Stupp et al., 2009). The aggressive and recurrent nature of GBM demands further insights
into the molecular pathways deregulated in GBM. The changes that happen within a cell that
lead to malignancy include both genetic and epigenetic alterations. Our objective is to
delineate deregulated pathways in GBM progression and development through screening of
genes via next generation sequencing (NGS) and methylome array. We further strive to
characterize the importance of identified altered molecules and deregulated pathways in the
context of GBM pathogenesis.
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Chang, Chung-Ching, and 張仲晴. "Optimization of Boron Neutron Capture Therapy Treatment Planning System NCTPlan for Patient with GBM." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/74299018315923066315.
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Murphy, Danielle Marie. "Effect of chewing gum on the incidence of plaque accumulation and gingival inflammation in adolescent orthodontic patients a thesis submitted in partial fulfillment ... for the degree of Master of Science (School of Dentistry) ... /." 2002. http://catalog.hathitrust.org/api/volumes/oclc/68962491.html.
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Schröter, Nils. "Diagnostische Wertigkeit von Gb3-Ablagerungen in der Haut von Patienten mit M. Fabry." Doctoral thesis, 2018. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-160552.
Full textAbstract:
In der vorliegenden Arbeit wurde geprüft, ob Gb3 in Hautstanzbiopsien von Patienten mit M. Fabry nachweisbar ist, die Ablagerungen quantifizierbar sind, mit der Krankheitsschwere korrelieren, und ob eine Unterscheidung von Patienten und gesunden Kontrollen anhand der dermalen Gb3-Ablagerungen möglich ist. Es wurden 84 Patienten mit M. Fabry über das FAZiT sowie 27 gesunde Kontrollen zwischen 2008 und 2013 prospektiv rekrutiert und jeweils eine proximale und eine distale Hautbiopsie entnommen. Zusätzlich erfolgten eine Anamnese, eine klinische Untersuchung, eine QST, das Ausfüllen von Fragebögen mit der Fragestellung nach Schmerz und Depression sowie eine Blutentnahme und kardiale Diagnostik. Die Immunfluoreszenz erfolgte mit Antikörpern gegen CD77, einem Marker für Gb3. Es erfolgte die verblindete, semiautomatische Quantifizierung der Gb3 Ablagerungen. Hierzu wurden pro Biopsie drei ROI ausgewählt und die Fläche der ROIs mit Gb3-Ablagerungen in Relation zu der Gesamtfläche der ROIs gesetzt. Für die Auswertung wurden die Patienten sowohl nach Geschlecht als auch nach Krankheitsschwere und einzelnen Symptomen stratifiziert Die Gb3 Ablagerungen ließen sich bevorzugt in Schweißdrüsen und Endothel nachweisen. Es fanden sich jedoch auch größere Mengen an Gb3-Ablagerungen ohne ersichtliches anatomischer Korrelat. Die Gb3-Ablagerungen wurden semiautomatisch quantifiziert. Es konnte nachgewiesen werden, dass männliche Fabry-Patienten eine deutlich größere Menge an Gb3 in den distalen Hautbiopsien zeigen als gesunde Kontrollen, Patienten mit einer eingeschränkten Nierenfunktion hatten eine größere Menge an Gb3-Ablagerungen in der Haut als Patienten mit einer uneingeschränkten Nierenfunktion. Bei Patienten mit einer SFN waren erhöhte dermale Gb3 Mengen vorhanden im Vergleich zu gesunden Kontrollen, bei Patienten ohne eine SFN fand sich dieser Unterschied nicht. Patienten mit einem niedrigen SNAP zeigten im Vergleich zu gesunden Kontrollen eine größere Menge an Gb3 in ihrer distalen Haut, bei Patienten mit einem höheren SNAP fand sich dies nicht. Aus diesen Ergebnissen ergeben sich ein mögliches weiteres Werkzeug sowohl für die Diagnosestellung als auch für das Monitoring der Erkrankung, sowie weiterführend auch ein möglicher Indikator für den Therapieerfolg der ERTFabry disease (FD) is an X-chromosomally linked disease which leads to deposits of globotriaosylceramide 3 (Gb3) in several tissues. The aim of this study was to prove, that these deposits can be shown in the skin of patients with FD via immunofluorescence, that Gb3 deposits can be quantified, that patients with FD have more Gb3-deposits in their skin than healthy controls and that the amount of Gb3 deposits in skin correlates with disease severity. 84 patients were prospectively recruited in the Würzburg Fabry Center for Interdisciplinary Therapy as well as 27 healthy controls. Every patient received a skin biopsy from a proximal and a distal location, a physical examination as well as a thorough anamnesis, filled out questionnaires regarding pain and symptoms hinting for depression and underwent cardiac diagnostics. Immunofluorescence double stains were done for Gb3 and protein-gene-product 9.5 as well as for Gb3 and von Willebrand factor. We quantified the amount of Gb3 semi-automatically in three predetermined regions of interest. We could show, that Gb3 can be visualized and quantified in the skin of patients with FD using immunofluorescence. Furthermore, male patients with FD had a higher Gb3 load in their distal skin than healthy controls (p<0.05). Male patients with FD and an impaired renal function had a higher Gb3 load in their distal skin (p<0.05). Similarly, it was shown, that male patients with a small fiber neuropathy had a higher load of Gb3 in their distal skin than male patients without a small-fiber neuropathy (p<0.05). In conclusion it can be stated, that the quantification of Gb3 via immunofluorescence could be used in the diagnostics of FD and might be of value as a biomarker in the course of the disease
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Raj, Preethi. "The Impact of Gestational Diabetes on Maternal and Cord Blood Lipids Among Prenatal Care Patients in Western Ma." 2012. https://scholarworks.umass.edu/theses/941.
Full textAbstract:
Gestational diabetes mellitus (GDM), a pregnancy-induced metabolic disorder that affects 2-10% of pregnancies poses future risk for diabetes mellitus (DM) and cardiovascular disease in mother and child. However, few prospective studies have examined the effect of GDM on altered maternal and cord blood lipids, specifically HDL, LDL, triglycerides, and total cholesterol, both during and after pregnancy. We have evaluated the association between GDM and lipid metabolism in pregnant mothers and their infants using data from a prospective cohort study conducted at Baystate Medical Center’s Wesson Women and Infant’s Unit. GDM was assessed prenatally by 3-hr GTT blood samples and was confirmed by obstetrician review. Lipids were assessed via fasting and non-fasting blood samples obtained during 3-hr GTTs performed at 24-28 weeks of gestation and 6-8 weeks post-partum. Data for covariates were collected via an interview form administered at the time of recruitment. We used multivariable linear regression to evaluate the association between GDM status and maternal lipids during and after pregnancy as well as cord lipids. These study results inform future research on GDM as a risk factor for future metabolic disorders in mother and child.
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Alão, Mariana Neves Ramalho Ferreira. "Deep and transfer learning approaches for glioblastoma patient survival prediction from pre-treatment MRI." Master's thesis, 2019. http://hdl.handle.net/1822/70817.
Full textAbstract:
Dissertação de mestrado integrado em Engenharia Biomédica (área de especialização em Eletrónica Médica)Glioblastoma Multiforme (GBM) is a harmful brain tumor with a median overall survival (OS) of only fourteen months. Predicting the OS from pre-treatment Magnetic Resonance Imaging (MRI) is intrinsically tricky not only due to the morphologic characteristics of the tumor but also due to the impact of the treatment. In the last years, deep learning began to arouse the interest of the scientific community due to the excellent performances achieved. In the medical imaging field, the convolutional neural networks (CNN) are achieving better performances than the clinicians in several tasks. This dissertation aims to develop a deep learning model for regression to directly predict the OS using pre-treatment MRI scans from patients with glioblastoma. For this, three different approaches were used: the transference of knowledge from a 2D and a 3D CNN and training from scratch on a 3D CNN. The effects of inputting different MRI modalities with different preprocessing techniques, such as the region of interest (ROI) and z-score normalizations, were studied. After a first selection of the top-ranked models based on two distinct criteria, data augmentation was performed. Throughout this work, the approaches were analyzed individually and then compared with each other and with a state-of-the-art approach. Although it was not possible to conclude on the MRI modalities and z-score normalization that benefits the most the OS prediction, a preference for a broader context while training the model was evident. The importance maps from the 3D networks developed showed that the regions considered most important by the network overlap with the ones where the tumor is more frequent. The network with more potential for the OS prediction is the 3D CNN trained from scratch that used FLAIR and tumor segmentation as input, ROI as all image and z-score normalization to all the image. In the end, this model was not able to outperform the state of the art.
O Glioblastoma Multiforme é um tumor cerebral nocivo com uma sobrevida mediana de apenas catorze semanas. Prever o tempo de sobrevida a partir de imagens de ressonância magnética é intrinsecamente difícil, não apenas devido às características morfológicas, mas também devido ao impacto dos tratamentos. Durante os últimos anos, o deep learning começou a despertar o interesse da comunidade científica devido às excelentes performances obtidas. Na área da imagem médica, as redes neuronais convolucionais estão a obter melhores performances que os médicos em diversas tarefas. Esta dissertação tem como objetivo desenvolver um modelo de regressão de deep learning para prever o tempo de sobrevida através de ressonâncias magnéticas pré-tratamento de pacientes com glioblastoma. Para tal, três diferentes abordagens foram utilizadas: a transferência de conhecimento de uma rede neuronal convolucional 2D e de outra 3D e ainda treinar do zero uma rede neuronal convolucional 3D. Os efeitos de introduzir na rede diferentes modalidade de ressonância magnética com diferentes préprocessamentos, tal como a região de interesse considerada ou a normalização padrão efetuada, foram estudados. Após uma primeira seleção dos modelos com melhores métricas baseada em dois critérios distintos foi efetuado o aumento artificial dos dados. Durante este trabalho, as diferentes abordagens foram analisadas individualmente e posteriormente comparadas entre si e com o estado da arte. Embora não seja possível concluir sobre modalidade de ressonância magnética e o tipo de normalização padrão que beneficiam a previsão do tempo de sobrevida, e preferência por um contexto visual mais abrangente foi evidente. Os mapas de importância relativos às redes neuronais 3D mostram que as regiões consideradas mais importantes pela rede coincidem com as que o tumor é mais frequente. A rede que revelou um maior potencial para prever o tempo de sobrevida é a rede neuronal convolutional 3D treinada do zero que utiliza a sequência FLAIR conjugada com a segmentação do tumor como entrada da rede, a região de interesse é toda a imagem e a normalização padrão é efetuada a toda a sequência. Por fim, este modelo não foi capaz de ultrapassar o estado da arte.
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Kämpf, Tanja. "Definition eines klinisch relevanten Morbus Fabry mit Hilfe des Biomarkers Lyso Gb3 bei Patienten mit einer alpha- Galaktosidase Mutation." Doctoral thesis, 2013. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-77819.
Full textAbstract:
Der Morbus Fabry ist eine sehr heterogenetische und heterophänotypische Krankheit. Ursache der Erkrankung liegt in der Mutation des alpha- Galaktosidase Gens. Es kommt zur Akkumulation von Glykosphingolipiden. Man kann den klassischen Typ von mehreren Varianten unterscheiden. Es konnte bisher noch keine Genotyp- Phänotyp Relation hergestellt werden. In unsere Studie wurden 124 Fabry Patienten eingeschlossen. Vier klinische Domänen wurden beurteilt (Herz, Nieren, Nervensystem, Fabry-Symptome). Daneben wurden genetische Analysen und Labortests (inklusive Lyso Gb3) durchgeführt. Die Studie besitzt einen zweiteiligen Aufbau: in die Evaluationsstudie wurden alle bisher bekannten Mutationen eingeschlossen, während die bisher unbekannten Mutationen der Validierungsstudie zugeteilt wurden. Es konnte gezeigt werden, dass mithilfe des Biomarkers Lyso Gb3 die Schwere der Erkrankung vorausgesagt werden kann (insbesondere bei Frauen) und die Diagnostik erleichtert werden kann. Eine bisher unbekannte Mutation kann jetzt viel besser eingeordnet werden, da man mithilfe des Biomarkers Lyso Gb3 zwischen atypischer und klassischer Variante unterscheiden kann und man durch den Biomarker die Krankheitskapazität einer Mutation beurteilen kannFabry disease is a lysosomal storage disorder caused by mutations in the alpha-galactosidase A gene. This leads to a deficiency of alpha-galactosidase A. Therefore globotriaosylceramide accumulate in all tissues containing lysosomes. There is the classical phenotyp and the atypical one. No method to differentiate these variants is available so far. Our study includes 124 Fabry patients. Detailed clinical investigations of the heart, kidneys and the nervous system were made. Apart from that the biomarker lyso-Gb3 was measured in every patient. The study consists of two parts: Part one (evaluation) includes all previously described mutations and part two (validation) all unknown mutations. We could show that the disease-capacity of a mutation can be analyzed by lyso Gb3 and that it is possible to differentiate a classical from an atypical mutation by the biomarker lyso Gb3