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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
151

Charakterisierung des zirkulierenden FAPalpha in humanem Plasma bei Patienten mit akutem Koronarsyndrom / Circulating FAP alpha in acute coronary syndrome

Habbaba, Yasmin January 2014 (has links) (PDF)
FAPα ist ein Membranglykoprotein mit Dipeptidyl-Peptidase- und Typ I Kollagenase-Aktivität, das eine wichtige Rolle im Rahmen des Gewebeumbaus und der Angiogenese spielt. Die Expression von FAPα wurde für eine Reihe von Geweben gezeigt. So konnte bereits gezeigt werden, dass FAPα nach Myokardinfarkt auf humanen kardialen Fibroblasten (HCF) verstärkt exprimiert wird. Ausgehend von der Erkenntnis, dass eine im Blut zirkulierende Form von FAPα, APCE, gefunden wurde, sollte in der vorliegenden Arbeit eine mögliche Assoziation des in HCF exprimierten FAPα mit dem zirkulierenden APCE untersucht werden. Hierfür wurden ebenfalls die Signalwege, die zur Induktion von FAPα führen, näher untersucht. Im Rahmen der vorliegenden Arbeit konnte gezeigt werden, dass das von humanen kardialen Fibroblasten exprimierte FAPα ebenfalls im Zellkulturüberstand nachgewiesen werden kann. Wie bereits beschrieben, führte eine Stimulation mit TGFβ1 zur Expression von FAPα. Diese ist abhängig von Smad-3 und konnte durch Zugabe des Inhibitors SB431542 blockiert werden. Auch Smad-2 scheint die FAPα-Expression zu beeinflussen. Ein Effekt von EGR-1, CTGF und TNFα auf die FAPα-Expression konnte hingegen nicht nachgewiesen werden. Darüber hinaus wurde im Rahmen der vorliegenden Arbeit ein ELISA zur Messung von humanem FAPα im Plasma erstmalig etabliert. In der Evaluation des ELISA wurden die Grenzwerte für die Detektion und Quantifizierung bestimmt, die Intra- und Intervariabilität des ELISAs berechnet und die Linearität der Wiederfindung von humanem rekombinantem FAPα bewertet, sowie die Stabilität von FAPα nach mehrfachen Einfrier-Auftau-Zyklen und nach der Lagerung bei verschiedenen Temperaturen evaluiert. Da hier nur kommerziell erwerbliche Materialien verwendet wurden, ist eine Anwendung durch Dritte leicht durchführbar. Es wurde weiterhin eine klinische Studie zur Messung der FAPα-Plasmaspiegel in 101 gesunden Blutspendern und 407 Patienten mit akutem Koronarsyndrom (ACS) sowie von 25 Patienten mit stabiler koronarer Herzerkrankung (KHK) durchgeführt. Hierbei konnten erstmals Referenzwerte für zirkulierendes FAPα im Plasma beschrieben werden. Die FAPα-Plasmaspiegel der gesunden Kontrollgruppe unterschieden sich nicht von denen der Patienten mit stabiler KHK. Bei Patienten mit akutem Koronarsyndrom war die FAPα-Konzentration im Vergleich mit den FAPα-Plasmaspiegeln der Kontrollgruppe hingegen signifikant erniedrigt. Auch zeigte sich bei den Patienten mit FAPα-Spiegeln im kleinsten Quartil eine erhöhte Mortalität. Die biologische Funktion von FAPα bzw. dessen mögliche Pathophysiologie im Rahmen eines ACS sowie die mit niedrigen FAPα-Spiegeln assoziierte Mortalität sind noch unklar und bleiben Gegenstand der weiteren Forschung. / FAPα is a membrane protein with dipeptidyl-peptidase and type-I-collagenase activity involved in angiogenesis and tissue repair. A number of cells and tissues including human cardiac fibroblasts (HCF) after myocardial infarction express FAPα. Due to the recent discovery of a circulating form of FAPα, APCE, a possible association between the cell-bound form of FAPα and APCE was studied in HCF. Furthermore, the signaling pathways that lead to an induction of FAPα were analyzed. It could be demonstrated that HCF shed FAPα, which can be detected in the cell culture supernatant. Moreover, in accordance with earlier results, FAPα expression is induced by TGFβ1. This is dependent on Smad-3 and could be blocked by the inhibitor SB431542. Additionally, Smad-2, but not EGR-1, CTGF or TNFα are involved in FAPα expression. Within this work an ELISA for the quantification of FAPα in human plasma was established and the limits of detection and quantification, the intra- and interassay variability and the linearity of recovery of human FAPα were determined. Furthermore, the stability of FAPα after multiple thaw-freeze-cycles or different storage conditions was evaluated. Because of the exclusive use of commercially available products, others could easily repeat this ELISA. FAPα plasma concentrations in 101 healthy blood donors, 407 patients with acute coronary syndrome (ACS) and in 25 patients with stable coronary artery disease were quantified by ELISA. This is the first time reference values for FAPα plasma levels could be derived. There was no significant difference between healthy donors and patients with stable coronary artery disease. However, compared to the healthy control group, FAPα levels were significantly lower in patients with ACS. Importantly, ACS patients with FAPα levels in the lowest quartile showed an increased mortality. The biological function of FAPα and its possible pathophysiological role in ACS are still unclear and remain the object of future studies.
152

ADN circulant nucléaire et mitochondrial et étude de l'influence de l'hypoxie sur leur libération / Nuclear and Mitochondrial circulating DNA and study of the influence of hypoxia on their release

Otandault Aviviani, Amaelle Cherone 10 July 2019 (has links)
Plusieurs travaux s’accordent sur le fait que l’analyse de l’ADN circulant (ADNcir) est un outil à fort potentiel diagnostic, pronostic, théranostic et de suivi en oncologie clinique. Cependant, le manque de standardisation des procédures pré-analytiques, des connaissances approfondies des structures des ADNcir ainsi que les facteurs influençant la dynamique de son relargage constituent des obstacles à son transfert en pratique clinique. C’est dans ce contexte que nous avons choisi d’approfondir l’étude des structures des ADNcir d’origines nucléaire et mitochondriale, évaluer leur utilité clinique en oncologie et étudier l’effet de l’hypoxie sur leur libération. A partir d’une technique de qPCR optimisée et validée cliniquement pour l’analyse des ADN circulants, nous avons quantifié les ADN extracellulaires d’origines nucléaire et mitochondriale dans des milieux de culture cellulaire et dans des plasmas humains et murins.Nos données ont révélé l’influence des procédures pré-analytiques sur la quantification de l’ADN circulant en fonction de l’origine. En effet, nous montrons que la préparation du plasma par séparation en ficoll diminue de manière significative la quantification de l’ADNcir d’origine mitochondriale sans influencer la quantification de l’ADNcir d’origine nucléaire, ce qui suggère la présence de structures de densité différente contenant de l’ADN mitochondrial dans le plasma. D’autre part, j’ai contribué à l’évaluation d’un test de dépistage du cancer basé sur l’analyse de l’ADNcir nucléaire et mitochondrial mise au point au laboratoire. Nos résultats préliminaires montrent de façon significative la capacité diagnostic de ce test sur des cohortes de patients atteints de cancers colorectal (n = 127) versus des individus sains (n = 91) (AUC = 0,8657 ; p < 0,0001).Nous montrons in vitro que l’hypoxie module de manière différente le relargage des ADN extracellulaires en fonction de leur origine, et notamment que l’ADN extracellulaire d’origine mitochondriale semble être régulé négativement en condition hypoxique. In vivo, l’hypoxie entraîne une augmentation de la libération de l’ADNcir d’origine nucléaire (p=0,002), mais pas d’origine mitochondriale, dans le plasma de souris greffées avec des cellules tumorales de cancer de poumon.Pour conclure, les travaux réalisés au cours de cette thèse mettent en lumière : (i) l’intérêt de la mise en place de procédures pré-analytiques standardisées pour la compréhension des origines et structures des ADNcir ; (ii) le fort potentiel diagnostic de l’analyse de l’ADNcir en oncologie ; (iii) et l’influence de l’hypoxie sur le relargage de l’ADN circulant. / Different studies converge on the diagnostic, theragnostic and prognostic properties of circulating DNA analysis (cirDNA) in clinical oncology. There remain various obstacles, however, to its transfer to clinical practice. These include the lack of standardization of pre-analytical procedures, and limited knowledge of cirDNA structures and of the factors influencing the dynamics of their release. In this context, we studied the structures of cirDNA of nuclear and mitochondrial origins, evaluated their diagnostic potential, and then evaluated the effect of hypoxia on their release. Using an optimized qPCR technique previously validated in clinical studies for the analysis of cirDNA, we quantified extracellular DNA of nuclear and mitochondrial origins in cell culture medium and in human and mouse plasma.Our data also revealed the influence of pre-analytical procedures on the quantification of cirDNA, depending on its origin. Indeed, we showed that plasma preparation with Ficoll separation significantly reduces the quantification of mitochondrial cirDNA without influencing the quantification of nuclear cirDNA.In addition, we evaluated the value of nuclear and mitochondrial cirDNA analysis in a cancer-screening test developed in the laboratory. Our preliminary results demonstrated a significant discrimination between colorectal cancer patients (n=127) and healthy individuals (n=91) (AUC=0.8657; p<0.0001).We demonstrated that in vitro hypoxia modulates the release of extracellular DNA in different ways, depending on its origin, and showed that extracellular DNA of mitochondrial origin is negatively regulated. By contrast, we demonstrated in vivo that hypoxia leads to a greater release of nuclear cirDNA (p=0.002), but not of mitochondrial cirDNA, as compared to normoxia. These experiments were performed using the plasma of mice grafted with lung cancer tumor cells.In conclusion, the work carried out for this thesis highlights: (i) the importance of setting up standardized pre-analytical procedures when investigating the origins and structures of cirDNA; (ii) the strong diagnostic potential of cirDNA analysis in oncology and (iii) the influence of hypoxia on the release of cirDNA.
153

Putative Biomarker neuropsychiatrischer Entwicklungskomorbiditäten beim Deletionssyndrom 22q11.2 / Potential biomarkers of neuropsychiatric comorbidities in 22q11.2 Deletion Syndrome

Holweck, Julia January 2022 (has links) (PDF)
Vom Deletionssyndrom 22q11.2 Betroffene sind einem überdurchschnittlich hohen Risiko ausgesetzt im Entwicklungsverlauf psychisch zu erkranken. Häufige Störungsbilder sind unter anderem ADHS, Angsterkrankungen, affektive Störungen, Erkrankungen aus dem schizophrenen Formenkreis und Morbus Parkinson. Ziel der Studie war es, phänotypische Auffälligkeiten beim DS22q11 zu identifizieren, die dabei helfen könnten, Hochrisikogruppen innerhalb des Syndroms frühzeitig identifizieren zu können und in Form von Biomarkern messbar sind. Hierzu wurden die bereits in Forschung und teilweise auch in der Klinik etablierten Verfahren der transkraniellen Sonographie und der standardisierten Riechtestung eingesetzt. / Individuals affected with 22q11.2 Deletion Syndrome (22q11.2DS) are at an above average risk to develop neuropsychiatric disorders (such as attention-deficit/hyperactivity disorder, anxiety disorders, affective disorders, schizophrenia and Parkinson's disease). The aim of this study is to identify phenotypical characteristics in 22q11.2DS to help point out high-risk groups within the syndrome and then be measured as biomarkers. To achieve this, we performed transcranial sonography and olfactory testing which are known to be established clinical and research methods.
154

Overcoming frataxin gene silencing in Friedreich’s ataxia with small molecules: studies on cellular and animal models

Rai, Myriam 05 January 2010 (has links)
Friedreich’s ataxia (FRDA) is an inherited recessive disorder characterized by progressive neurological disability and heart disease. It is caused by a pathological intronic hyperexpansion of a GAA repeat in the FXN gene, encoding the essential mitochondrial protein frataxin. At the homozygous state, the GAA expansion induces a heterochromatin state with decreased histone acetylation and increased methylation, resulting in a partial deficiency of frataxin expression. This was established in cells from FRDA patients. We showed that the same chromatin changes exist in a GAA based mouse model, KIKI, generated in our laboratory. Furthermore, treatment of KIKI mice with a novel Histone Deacetylase Inhibitor (HDACi), 106, a pimelic diphenylamide that increases frataxin levels in FRDA cell culture, restored frataxin levels in the nervous system and heart of KIKI mice and induced histone hyperacetylation near the GAA repeat. As shown by microarrays, most of the differentially expressed genes in KIKI were corrected towards wild type. In an effort to improve the pharmacological profile of compound 106, we synthesized more compounds based on its structure and specificity. We characterized two of these compounds in FRDA patients’ peripheral blood lymphocytes and in the KIKI mouse model. We observed a sustained frataxin upregulation in both systems, and, by following the time course of the events, we concluded that the effects of these compounds last longer than the time of direct exposure to HDACi. Our results support the pre-clinical development of a therapeutic approach based on pimelic diphenylamide HDACis for FRDA. Laboratory tools to follow disease progression and assess drug efficacy are needed in a slowly progressive neurodegenerative disease such as FRDA. We used microarrays to characterize the gene expression profile in peripheral lymphocytes from FRDA patients, carriers and controls. We identified gene expression changes in heterozygous, clinically unaffected GAA expansion carriers, suggesting that they present a biochemical phenotype, consistent with data from animal models of frataxin deficiency. We identified a subset of genes changing in patients as a result of pathological frataxin deficiency establishing robust gene expression changes in peripheral lymphocytes. These changes can be used as a biomarker to monitor disease progression and potentially assess drug efficacy. To this end, we used he same methodology to characterize the gene expression profiles in peripheral lymphocytes after treatment with pimelic diphenylamide HDACi. This treatment had relevant effects on gene expression on peripheral patients’ blood lymphocytes. It increased frataxin levels in a dose-dependent manner, and partially rescued the gene expression phenotype associated with frataxin deficiency in the tested cell model, thus providing the first application of a biomarker gene set in FRDA.
155

Model-based Biomarker Detection and Systematic Analysis in Translational Science

Sun, Youting 2012 May 1900 (has links)
This dissertation is concerned with the application of mathematical modeling and statistical signal processing into the rapidly expanding fields of proteomics and genomics. The research is guided by a translational goal which drives the problem formalization and experimental design, and leads to optimization, prediction and control of the underlying system. The dissertation is comprised of three interconnected subjects. In the first part of the dissertation, two Bayesian peptide detection algorithms are proposed to optimize the feature extraction step, which is the most fundamental step in mass spectrometry-based proteomics. The algorithms are designed to tackle data processing challenges that are not satisfactorily addressed by existing methods. In contrast to most existing methods, the proposed algorithms perform deisotoping and deconvolution of mass spectra simultaneously, which enables better identification of weak peptide signals. Unlike greedy template-matching algorithms, the proposed methods have the capability to handle complex spectra where features overlap. The proposed methods achieve better sensitivity and accuracy compared to many popular software packages such as msInspect. In the second part of the dissertation, we consider modeling and assessing the entire mass spectrometry-based proteomic data analysis pipeline. Different modules are identified and analyzed, resulting in a framework that captures key factors in system performance. The effects of various model parameters on protein identification rates and quantification errors, differential expression results, and classification performance are examined. The proposed pipeline model can be used to aid experimental design, pinpoint critical bottlenecks, optimize the work flow, and predict biomarker discovery results. Finally, the same system methodology is extended to analyze the work flow in DNA microarray experiments. A model-based approach is developed to explore the relationship among microarray data properties, missing value imputation, and sample classification in a complicated data analysis pipeline. The situations when it is suitable to apply missing value imputation are identified and recommendations regarding imputation are provided. In addition, a missing value rate-related peaking phenomenon is uncovered.
156

Molecular Characterisation and Prognostic Biomarker Discovery in Human Non-Small Cell Lung Cancer

Edlund, Karolina January 2012 (has links)
Non-small cell lung cancer (NSCLC) constitutes a clinically, histologically, and genetically heterogeneous disease entity that represents a major cause of cancer-related death. Early-stage patients, who undergo surgery with curative intent, experience high recurrence rates and the effect of adjuvant treatment is modest. Prognostic biomarkers would be of particular relevance to guide intensified treatment depending on expected outcome and moreover often infer a biological role in tumourigenesis. This thesis presents a translational study approach to establish a well-characterised NSCLC frozen-tissue cohort and to obtain a profile of each specimen with regard to genome-wide copy number alterations, global gene expression levels and somatic mutations in selected cancer-related genes. Furthermore, the generation of a formalin-fixed, paraffin-embedded tissue microarray enabled validation of findings on the protein level using immunohistochemistry. The comprehensive molecular characterisation, combined with data on clinical parameters, enabled the analysis of biomarkers linked to disease outcome. In Paper I, single nucleotide polymorphism arrays were applied to assess copy number alterations in NSCLC and associations with overall survival in adenocarcinoma and squamous cell carcinoma were described. In Paper II, we evaluated expression levels of selected stromal proteins in NSCLC using immunohistochemistry and the adhesion molecule CD99 was identified as an outcome-related biomarker in two independent cohorts. Paper III presents a strategy for prognostic biomarker discovery based on gene expression profiling, meta-analysis, and validation of protein expression on tissue microarrays, and suggests the putative tumour suppressor CADM1 as a candidate biomarker. In Paper IV, we propose a prognostic role for tumour-infiltrating IGKC-expressing plasma cells in the local tumour microenvironment, indicating an involvement of the humoral immune response in anti-tumor activity. In Paper V, we combined next-generation deep sequencing with statistical analysis of the TP53 database to define novel parameters for database curation. In summary, this thesis exemplifies the benefits of a translational study approach, based on a comprehensive tumour characterisation, and describes molecular markers associated with clinical outcome in NSCLC.
157

Proteomic Analysis of Urinary Bladder Cancer : Aiming for Novel Biomarkers

Lindén, Mårten January 2013 (has links)
Urinary bladder cancer is a heterogeneous disease appearing in different forms, e.g. non-muscle invasive and muscle invasive. For all variants, the expression of proteins is interesting to analyze for diagnostic, predictive, prognostic and drug targeting purposes, since it reflects the altered gene expression causing the cancer. Since urothelial cells of the bladder are in direct contact with urine it is likely that this body fluid contains cancer-related proteins. In Paper I, unbiased analysis of proteins in urine from urinary bladder cancer patients and controls, using label-free quantification by mass spectrometry, was applied and four interesting proteins APOE, FGB, LRG and SERPINA1 were selected and further analyzed with western and dot blot. In Paper II, two more proteins, POLR1E and TOP2A, were validated as relevant proteins in bladder cancer urine. In Paper III and IV, the proteins GAL1 and STMN1 were investigated for their prognostic and therapeutic target potential in bladder cancer. In Paper II, III and IV, the expression of seven of the proteins were analyzed on tissue microarrays representing tumour tissue from 360 patients with different tumour stages. For the proteins identified by the urine screening approach, their protein expressions were confirmed in bladder cancer tissue. The expression level in tissue of five of the proteins, APOE, FGB, POLR1E (Paper II), GAL1 (Paper III) and STMN1 (Paper IV), increased with tumour stage, showing diagnostic relevance and three of the proteins, SERPINA1 (Paper II), STMN1 (Paper IV) and GAL1 (Paper III) had prognostic potential in urinary bladder cancer. In addition, GAL1 and STMN1 were demonstrated to be highly expressed in metastatic disease and inhibition of STMN1 reduced cell growth (Paper III and IV), indicating that these proteins are promising drug targets in urinary bladder cancer. In conclusion, the approach of this thesis has generated several candidate protein biomarkers in urine and tissue, validated with independent methods, which have the potential to improve the care for bladder cancer patients.
158

Molecular Imaging and Sensing Using Plasmonic Nanoparticles

Crow, Matthew James January 2010 (has links)
<p>Noble metal nanoparticles exhibit unique optical properties that are beneficial to a variety of applications, including molecular imaging. The large scattering cross sections of nanoparticles provide high contrast necessary for biomarkers. Unlike alternative contrast agents, nanoparticles provide refractive index sensitivity revealing information regarding the local cellular environment. Altering the shape and composition of the nanoparticle shifts the peak resonant wavelength of scattered light, allowing for implementation of multiple spectrally distinct tags. In this project, nanoparticles that scatter in different spectral windows are functionalized with various antibodies recognizing extra-cellular receptors integral to cancer progression. A hyperspectral imaging system is developed, allowing for visualization and spectral characterization of cells labeled with these conjugates. Various molecular imaging and microspectroscopy applications of plasmonic nanoparticles are then investigated. First, anti-EGFR gold nanospheres are shown to quantitatively measure receptor expression with similar performance to fluorescence assays. Second, anti-EGFR gold nanorods and novel anti-IGF-1R silver nanospheres are implemented to indicate local cellular refractive indices. Third, because biosensing capabilities of nanoparticle tags may be limited by plasmonic coupling, polarization mapping is investigated as a method to discern these effects. Fourth, plasmonic coupling is tested to monitor HER-2 dimerization. Experiments reveal the interparticle conformation of proximal HER-2 bound labels, required for plasmonic coupling-enhanced dielectric sensing. Fifth, all three functionalized plasmonic tags are implemented simultaneously to indicate clinically relevant cell immunophenotype information and changes in the cellular dielectric environment. Finally, flow cytometry experiments are conducted utilizing the anti-EGFR nanorod tag to demonstrate profiling of receptor expression distribution and potential increased multiplexing capability.</p> / Dissertation
159

Proteins as Biomarkers to Characterize Bacteria and Distinguish Cancer Cell

Lo, Li-Hua 23 June 2003 (has links)
none
160

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Lo, Li-hua 26 March 2009 (has links)
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