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Takala, H. (Heikki). "Biomarkers in esophageal cancer". Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514298400.
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Abstract Mediators of epithelial permeability, angiogenesis and invasion may serve as prognostic indicators and targets for therapies in esophageal cancer (EC). The expressions of claudins, hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor-A (VEGF), nitric oxide synthases (iNOS, eNOS, nNOS) and toll-like receptor 9 (TLR9) were evaluated by immunohistochemistry in EC. The results were compared with clinicopathological variables, tumor proliferation and apoptosis. All of the claudins were expressed in most of the cancers. Esophageal adenocarcinomas (EAC) displayed more often increased claudin 3 and 5 expression than esophageal squamous cell carcinomas (ESCC). Loss of claudin 3 expression associated with distant metastases in EC and a tendency in this direction was also observed for claudin 4. Cancers with stronger claudin 4 expression showed increased apoptosis in both EAC and ESCC. HIF-1α was present in most of the ECs and like iNOS more often in ESCC than in EAC. Strong HIF-1α expression tended to associate with positive VEGF immunostaining. In ESCC, both strong HIF-1α expression and VEGF positivity tended to associate with increased microvessel density (MVD). In EAC, tumors showing VEGF positivity associated with increased MVD outside the tumor. Patients with strong HIF-1α expression had more often distant metastases than other patients in EC. There was no VEGF expression in normal esophageal mucosa and T3-4 tumors tended to be more often VEGF positive than T1-2 tumors. The expression of TLR9 was more intensive in dysplasia than in normal epithelium and ESCC and abundant TLR9 expression could serve as a marker of squamous cell high grade dysplasia. Intensive TLR9 expression was associated with higher grade tumors and the presence of nodal and distant metastases in ESCC. EC and its progression may be related to increased angiogenesis regulated by VEGF and HIF-1α. In EC, claudin expression varies along with the histology of the tumor. Claudin expression may be associated with apoptosis or proliferation and contribute to tumor behavior. An association was detected between moderate to strong expression of claudin 3 and a high TLR9 histoscore in ESCC. Altered expression of claudin 3 may result to upregulation of endosomal TLR9. TLR9 may serve as a marker for squamous cell dysplasia and ESCC progressionTiivistelmä Solukerrosten läpäisevyyttä, verisuonten uudismuodostusta ja kasvainsolujen liikkuvuutta säätelevät tekijät voivat toimia ruokatorvisyövän ennustetekijöinä ja hoidon kohteina. Tässä tutkimuksessa selvitettiin klaudiinien, hypoksia-indusoituvan tekijän 1α (HIF-1α), verisuonen endoteelin kasvutekijän A (VEGF), kolmen typpioksidisyntaasin (iNOS, eNOS ja nNOS) sekä tollin kaltaisen reseptorin 9 (TLR9) ilmentymistä ja merkitystä ruokatorvisyövässä immunohistokemiallisin menetelmin. Tuloksia arvioitiin suhteessa proliferaatioon ja apoptoosiin. Useimmat syöpäkasvaimet ilmensivät jokaista tutkittua klaudiinia. Ruokatorven rauhassyövässä ilmeni levyepiteelisyöpää useammin klaudiineja 3 ja 5. Klaudiinin 3 vähäinen ilmentyminen oli yhteydessä etäpesäkkeiseen tautiin. Sama suuntaus näkyi klaudiinin 4 kohdalla. Apoptoosia todettiin enemmän kasvaimissa, jotka ilmensivät muita enemmän klaudiini 4:ä. Useimmat syöpäkasvaimet ilmensivät HIF-1α:a. Sekä iNOS että HIF-1α ilmentyivät runsaammin levyepiteeli- kuin rauhassyövässä. Tutkimus viittasi yhteyteen voimakkaan HIF-1α:n ilmentymisen ja VEGF:n ilmentymisen välillä. Voimakas HIF-1α:n ilmentyminen ja VEGF:n ilmentyminen vaikuttivat liittyvän ruokatorven levyepiteelisyövän uudissuonituksen lisääntymiseen. Rauhassyövän lisääntynyt uudissuonitus kasvaimen ulkopuolella saattaa liittyä VEGF:n ilmentymiseen. Potilailla, joiden kasvaimissa HIF-1α:n ilmentyminen oli voimakasta, todettiin etäpesäkkeitä muita useammin. VEGF:a ei todettu normaalissa limakalvossa, ja sen ilmentyminen vaikutti olevan yleisempää syvälle kasvavissa kuin pinnallisissa syövissä. TLR9 ilmentyi voimakkaammin levyepiteelin dysplasiassa kuin normaalissa tai kasvainepiteelissä. Huonosti erilaistuvissa ja levinneissä kasvaimissa TLR9 ilmentyi voimakkaammin kuin muissa kasvaimissa. Ruokatorvisyövän synty ja eteneminen voivat liittyä HIF:n ja VEGF:n säätelemään verisuonten uudismuodostukseen. Klaudiinit saattavat vaikuttaa syövän käyttäytymiseen myös apoptoosin ja proliferaation kautta. Tutkimuksessa todettiin yhteys lisääntyneen klaudiinin 3 ilmentymisen ja voimakkaasti ilmentyvän TLR9:n välillä. Muutos klaudiinin 3 ilmentymisessä saattaa lisätä levyepiteelin läpäisevyyttä johtaen TLR9:n aktivoitumiseen. TLR9 voi vaikuttaa ruokatorven levyepiteelin dysplasian ja syövän syntyyn sekä toimia vaikean dysplasian ja aggressiivisen levyepiteelisyövän merkkiaineena
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Blyth, Alison. "Lipid biomarkers in speleothems". Thesis, University of Newcastle Upon Tyne, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435638.
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Scott-Fordsmand, Janeck James. "Biomarkers of soil contamination". Thesis, University of Reading, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265176.
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Hasan, Nazeeha. "Biomarkers for ischaemic stroke". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/27254.
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Background: Current diagnostic, prognostic and risk stratification tools are inadequate for effective ischaemic stroke management. Hypothesising that -omics approaches can be used to detect novel candidate biomarkers for ischaemic stroke, this thesis aimed to evaluate the current status of biomarkers for ischaemic stroke and develop strategies for biomarker discovery. Methods: Systematic literature review and individual patient data meta-analyses were performed to assess current candidate biomarkers associated with ischaemic stroke. Proteomic SELDI-TOF MS profiling was undertaken to identify novel blood-based protein biomarkers for the diagnosis of acute ischaemic stroke, consisting of a pilot study and a subsequent well-powered discovery study of 104 patients. In an integrative genomics study, transcriptomics data from carotid endarterectomy samples was combined with a genome-wide association study meta-analysis and subjected to functional enrichment analysis to detect differential gene expression or alternative splicing profiles that may be under the control of a genetic variant. Results: Systematic review and meta-analysis concluded that no current candidate biomarkers could be recommended for routine clinical practice, supporting the pursuit of novel biomarkers for ischaemic stroke and informing the design of subsequent experimental studies. SELDI-TOF MS detected two plasma protein ions, m/z 3699 and m/z 6640, which could differentiate between acute cerebral ischaemia and stroke mimics. Protein ion m/z 6640, identified as ApoC 1, highlighted the role of lipid dysregulation and was postulated to be a novel candidate biomarker for acute cerebral ischaemia. Integrative genomics provided evidence for the genetic regulation of cytoskeletal organisation and extracellular matrix remodelling processes in carotid disease. The LTBP4 gene was found to be a candidate risk biomarker for ischaemic stroke by predicting plaque instability and rupture. Conclusions: This work provides workflows for successful biomarker discovery using innovative -omics approaches, highlights key pathogenic pathways and identifies novel candidate biomarkers for ischaemic stroke diagnosis and risk stratification.
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Alhilal, Maryam. "Biomarkers of fat intake". Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/biomarkers-of-fat-intake(32ce2b69-77d6-4cc8-93d7-2d9c38b6f9d4).html.
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The thesis reviews the previous use of biomarkers of fatty acid intake and concludes that there is a lack of supporting evidence from large randomized controlled trials (RCT) of sufficient duration for their use to be justified. The hypothesis that fatty acid biomarkers are robust indices of the intake certain fatty acids was tested by the analysis of blood samples from three large and long-term RCTs where dietary intake had been well controlled and compared with a control treatment. Erythrocyte lipid fatty acid composition was unable to detect changes in saturated fatty acid (SFA) or oleic acid intake. Plasma total lipids and phospholipids SFA were also poor indicators of SFA intake. The intake of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) could be predicted from the proportions in plasma and erythrocytes. Principal components analysis appeared to be a valid data reduction technique to measure changes in fatty acid patterns. A co-twin study design conducted in 570 female participants enrolled in the St Thomas‟ Twins Study investigated the heritability of fatty acid biomarkers (adipose tissue and plasma). For most fatty acids, environmental factors (dietary intake) were dominant, but in the case of arachidonic acid, 65% of the variance was explained by additive genetic factors. Investigations subsequently explored the effects of variations in single nucleotide polymorphisms (SNP) in the fatty acid desaturase (FADS) genes on the fatty acid composition of the biomarkers. Polymorphism in FADS1 rs174537 explained some of this variation. Carriage of the minor allele of rs174537 SNP also influenced the proportions of n-6 LC-PUFA in an RCT. Further research is suggested to identify what appeared to be a FADS1/FADS2 haplotype predicting lower levels of LC-PUFA, which might be of public health significance. In conclusion, plasma fatty acid composition can be recommended to elucidate the potential relationships between polyunsaturated, trans-unsaturated and branched chain fatty acid intake and non-communicable diseases.
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Esteves, Eduardo Jorge Mónica. "Biomarkers in Ovis aries". Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/14034.
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Mestrado em Biologia Molecular e CelularFerramentas que armazenem e procedam à catalogação das proteínas identificadas em proteomas resultantes de amostras de tecidos diversos recolhidos a partir de indivíduos representativos de situações fisiológicas e patológicas, constituem instrumentos poderosos para a integração da informação já publicada. Muita informação sobre os mecanismos moleculares subjacentes a patologias pode hoje ser gerada a partir de estratégias bioinformáticas. No âmbito de projetos anteriormente desenvolvidos foi construída uma base de dados, o OralOme. O presente trabalho tem como objetivo a criação de uma base de dados, o OvinOme, aplicando a mesma metodologia desenvolvida para saúde humana, agora para o armazenamento e catalogação de proteínas identificadas a partir dos proteomas parciais de Ovis aries. A criação desta ferramenta bioinformática contribuirá para o desenvolvimento de métodos de diagnóstico em vida, capazes de detetar as principais patologias que grassam nos rebanhos de ovelhas Serra da Estrela. O desenvolvimento da base de dados passa pelo compilar manual das proteínas identificadas pelos vários estudos publicados relativamente a Ovis aries, anotando toda a informação relativa à caracterização do individuo dador da amostra, tipo de amostra biológica, técnicas utilizadas para a identificação das proteínas e toda a informação conhecida relativa a cada proteína catalogada. O desenvolvimento de um método de diagnóstico em vida passa pela concepção de protocolos de colheita, armazenamento e caracterização da qualidade da amostra. Assim no âmbito de presente trabalho foi também objectivo o desenvolvimento de toda a estratégia para recolha de amostras de saliva em ovinos, transporte, armazenamento e avaliação da qualidade da amostra. A criação de um banco de saliva de rebanhos de ovelhas Serra da Estrela será um objectivo a cumprir em termos de futuro, visando o estabelecimento do diagnóstico precoce utilizando a saliva como fluído para avaliação de proteínas que identifiquem cada patologia, determinadas por análise in silico recorrendo á ferramenta bioinformática OvinOme desenvolvida no âmbito do presente trabalho.
Tools that store and proceed to the cataloging of proteins identified in proteomes derived from samples of various tissues collected from individuals representative of physiological and pathological situations, are powerful tools for the integration of information already published. Much information about the molecular mechanisms underlying pathologies can now be generated from bioinformatic strategies. Under previously developed design was built a database, the OralOme. This work aims to create a database, the OvisOme, applying the same methodology developed for human health now for storage and cataloging of proteins identified from the partial proteomes of Ovis aries. The creation of this bioinformatics tool will contribute to the development of diagnostic methods in life, able to detect major diseases that are rife in flocks of sheep Serra da Estrela. The development database is compiled by the proteins identified by several studies published for manual Ovis aries, noting all the information on the individual characteristics of the donor of the sample, type of biological sample, techniques for identifying proteins and whole known information cataloged for each protein. The development of a method of diagnosis in living passes through the design of the harvesting, storage and characterization of the quality of the sample protocols. So within this study was also aimed at developing the whole strategy for collecting samples of saliva in sheep, transport, storage and evaluation of sample quality. The creation of a database of flocks of sheep saliva Serra da Estrela is a key objective for the future, for the establishment of early diagnosis using saliva as a fluid for evaluation of proteins that identify each pathology, determined by in silico analysis using OvisOme bioinformatics tool developed under this work.
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Keane, Colm. "Novel Biomarkers in DLBCL". Thesis, Griffith University, 2015. http://hdl.handle.net/10072/365557.
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Diffuse large B cell lymphoma (DLBCL) is the commonest aggressive lymphoma. Despite the advent of combined chemo-‐immunotherapy, one third of patients still die from their disease. Prognostication of the disease still relies on a clinical scoring system known as the International Prognostic Index (IPI). This divides patients into risk categories. However marked heterogeneity within IPI sub-‐categories persist. The IPI is a clinical score based predominantly on estimates of patient fitness and tumour burden, but does not utilize information regarding the biology of the tumour cell or the immune tumour microenvironment (TME), in which the malignant B cells reside. The latter is the focus of this thesis.
The anti-‐CD20 monoclonal antibody rituximab has improved the outcome for patients with DLBCL, however the impact of host genetics on its effectiveness is still unclear. The mechanisms of action for rituximab include antibody dependent cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC). Recent reports suggest genetic polymorphisms in the FCGR3A receptor (expressed on NK-‐cells and monocytes which mediate ADCC) may be a predictor of event free and overall survival in B-‐cell lymphoma. Data also implicates the same polymorphism in the susceptibility to rituximab induced late-‐onset neutropenia (LON). There remains no data on the impact of genetic polymorphisms on either outcome or LON in genes involved in the CDC pathway such as C1qA. One hundred and fifteen DLBCL patients treated with ‘Ru CHOP’ (rituximab/cyclophosphamide/vincristine/doxorubicin/prednisolone)
chemou immunotherapy were compared with 105 healthy Caucasian controls with regards to FCGR3Aq V158F and C1qAq A276G polymorphisms. Event free and overall survival (EFS and OS) and LON incidence were analysed for linkage to either polymorphism.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Andersson, Martina. "Local, intestinal biomarkers for early detection of colorectal cancer". Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-445701.
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Colorectal cancer (CRC) is one of the deadliest cancers in the world. The early stage of the disease is usually asymptomatic and therefore screening methods for colorectal cancer need to improve. There is a need for early detection of CRC as treatment is less effective in the advanced stage of the disease. The current standard screening methods are endoscopy and fecal immunochemical blood tests. Endoscopy is a commonly used method to diagnose the patient, but it is costly, time consuming, and rather unpopular for the patients. An alternative could be to develop targeted molecular imaging probes that specifically deliver agents for example magnetic resonance imaging to colon adenomas and adenocarcinomas. This alternative would be non-invasive and able to detect the disease before morphological changes become evident. Biomarkers are used as an objective indicator of an altered biological process. Here, a literature study was conducted to identify protein biomarkers that are overexpressed in early stages of CRC. This study has focused on biomarkers that could be used to target imaging agents to cancerous lesions. Thus, the biomarkers need to be membrane-bound and expressed on the luminal side of the gastrointestinal tract. This will help future research to develop orally administered targeted imaging probes. Furthermore, a smaller literature search was conducted to identify cell and mouse models representing early stages of CRC. This was done to facilitate translational research going from in vitro to in vivo. Ideally the same protein is available in cell lines, mouse models and humans to enable translational research. This work has resulted in the selection of 7 different proteins that are upregulated during early stages of CRC. These proteins are potentially apically located and therefore possible targets for monoclonal antibodies. These findings might lead to a novel way for preventive patient screening and hopefully reduce the mortality for colorectal cancer.
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Kant, Prashant. "Changes in biomarkers of colorectal cancer risk and biomarkers of inflammation following weight loss". Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590418.
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Liu, Faye Fang. "Biomarkers for chronic arsenic poisoning /". [St. Lucia, Qld.], 2004. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe18519.pdf.
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Rittman, Timothy. "Connectivity biomarkers in neurodegenerative tauopathies". Thesis, University of Cambridge, 2015. https://www.repository.cam.ac.uk/handle/1810/248866.
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The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks. The primary tauopathies are a group of neurodegenerative diseases affecting movement and cognition. In this thesis I study Progressive Supranuclear Palsy (PSP) and the Corticobasal Syndrome (CBS), two parkinsonian disorders associated with accumulation of hyperphos- phorylated and abnormally folded tau protein. I contrast these two disorders with Parkinson’s disease (PD), which is associated with the accumulation of alpha-synuclein but has a genetic association with the MAPT gene encoding tau. Understanding the tauopathies to develop effective treatments will require a better grasp of the relationships between clinical syndromes and cognitive measures and how the anatomical and neurochemical networks that underlie clinical features might be altered by disease. I investigate simple clinical biomarkers, showing that a two-minute test of verbal fluency is a potential diagnostic biomarker to distinguish between PD and PSP and that the ACE-R and its subscores could play a role in monitoring cognition over time in PD, PSP and CBS. I assess the implementation of network analysis in Functional Mag- netic Resonance Imaging (fMRI) data, introduce Maybrain software for graphical network analysis and visualisation. I go on to show an overlap between graph theory network measures and I identify three main factors underlying graph network measures of: efficiency and distance, hub characteristics, network community measures. I apply these measures in PD, PSP and the CBS. All three diseases caused a loss of functional connectivity in com- parison to the control group that was concentrated in more highly connected brain regions and in longer distance connections. In ad- dition, widely localised cognitive function of verbal fluency co-varied with the connection strength in highly connected regions across PD, PSP and CBS. To take this further, I investigated specific functional covariance networks. All three disease groups showed reduced connectivity between the basal ganglia network and other networks, and between the anterior salience network and other networks. Localised areas of increased co- variance suggest a breakdown of network boundaries which correlated with motor severity in PSP and CBS, and duration of disease in CBS. I explore the link between gene expression of the tau gene MAPT and its effects on functional connectivity showing that the expression of MAPT correlated with connection strength in highly connected hub regions that were more susceptible to a loss of connection strength in PD and PSP. I conclude by discussing how tau protein aggregates and soluble tau oligomers may explain the changes in functional brain networks.
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Mohamed, M. "Epigenetic biomarkers in prostate cancer". Thesis, Queen's University Belfast, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426926.
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Yang, Chen Xi. "Blood-based biomarkers of asthma". Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62626.
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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
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Isenberg, Jordan. "Novel diagnostic ocular toxoplasmosis biomarkers". Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=95115.
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Purpose: Ocular toxoplasmosis is the most common etiology of posterior uveitis. The high incidence of macular scarring associated with ocular toxoplasmosis is a leading cause of visual morbidity. Serum biomarkers of the disease would aid in its diagnosis. This work was designed as a pilot study to detect potential biomarkers. Methods: Blood serum samples were collected from four groups of nine patients each; healthy, uveitic, one single-toxoplasmic event and recurrent events. Protein profiles were generated by SELDI-ToF-MS and 2-DE. Proteins were sequenced using tandem-MS. A tree-based decision classification system was developed. Results: 50 markers of ocular toxoplasmosis and 46 markers of recurrent disease were discovered by MS; 47% were cross-validated; 14 biomarkers were selected for validation and all were visualized by SDS-PAGE. 2-DE yielded 57 differentially expressed bands, 20 of which were excised and identified. Conclusions: This pilot study sough to elucidate blood serum biomarkers for ocular toxoplasmosis, as no biomarker for ocular toxoplasmosis exists currently. This study demonstrates the potential for SELDI-ToF-MS and well as other MS technologies to identify novel biomarkers for this disease.Objectif : La toxoplasmose oculaire est la cause principale de l'uvéite postérieure. Les cicatrices maculaires associées à la toxoplasmose oculaire sont à la base de la morbidité visuelle. Des marqueurs sérum sanguin de la maladie en faciliter le diagnostic. Méthodes : Les échantillons de sérum sanguin ont été recueillis auprès de quatre groupes de neuf participants composées de patients : sains, avec uvéite, ayant subit un seul événement toxoplasmique et ayant subit des événements récurrents. Des profils protéiques ont été générés par SELDI-ToF-MS et le 2-DE. Les protéines ont été séquencées à l'aide de tandem MS. Un système de classification basé sur des arbres décisionnels a été élaboré. Résultats : 50 marqueurs de la toxoplasmose oculaire et 46 marqueurs de récidive de la maladie ont été découverts par MS. 47% de ces marqueurs ont été validés par recoupement et 14 biomarqueurs ont été retenus pour validation. Tous ont été visualisés par SDS-PAGE. 2-DE, ce qui a abouti à 57 différentiellements exprimés en bandes dont 20 ont été excisées et identifiées. Conclusions : Cette étude pilote visait à identifier des biomarqueurs sériques potentiels de la toxoplasmose oculaire. Ici, on a dénoté l'utilité de la technologie SELDI-ToF-MS et des autres technologies pour identifier de nouveaux biomarqueurs pour cette maladie.
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Nogueira, da Costa Andre. "Mechanism-based biomarkers for deoxynivalenol". Thesis, University of Leeds, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531519.
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Svendsen, Claus. "Earthworm biomarkers in terrestrial ecosystems". Thesis, University of Reading, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326956.
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Jadon, Deepak. "Biomarkers of psoriatic arthritis phenotypes". Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.683546.
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Background: Psoriatic arthritis (PsA) is a chronic heterogenous inflammatory arthritis with five phenotypes. The two least studied phenotypes are investigated in this thesis, including: psoriatic spondyloarthropathy (PsSpA) and psoriatic arthritis mutilans (PAM). The aims of this thesis were to determine the prevalence, clinical characteristics and radiographic characteristics of PsSpA and PAM in a cohort of PsA patients, and serum-soluble bone- turnover biomarkers of these phenotypes. Aims: Comparisons were made with PsA patients without axial disease (pPsA), and ankylosing spondylitis (AS) patients. Methods: A prospective single-centre cross-sectional study was conducted of PsA and AS patients. Serum on psoriasis-only patients (PsC) and healthy controls (HC) were also obtained. Multivariate clinical, radiographic, genetic and serum biomarker comparisons were made between these five groups of subjects. Results: The study enrolled 201 PsA and 201 AS patients, who were then reclassified as 118 PsSpA, 127 pPsA and 157 AS cases, alongside 200 PsC and 50 HC subjects. Several clinical biomarkers, imaging biomarkers, serum-soluble biomarkers and genetic biomarkers were identified that differentiate PsSpA from pPsA and AS. PsSpA affected a significant proportion of PsA patients, and was not a milder version of AS. PsSpA involvement was as disabling and clinically impactful as AS. PAM was found to be associated with PsSpA, and clinical biomarkers of PAM occurrence and radiographic progression were identified. Conclusions: In conclusion, this thesis indicates that PsSpA is on a spectrum of musculoskeletal disease, in between pPsA and AS; with PsSpA comprising a continuum itself, and with a phenotype expression related to disease duration. These findings may prompt the inception of an international-consensus classification system for PsSpA, for which there is a great clinical need. Given that PsSpA has its own discrete clinical and biomarker signature, its clinical management and research should be tailored from that of pPsA and AS. Ultimately this may further the effort for stratified and personalised medicine.
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Castrignanò, Erika. "Enantiomeric profiling of chiral biomarkers". Thesis, University of Bath, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715278.
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Wastewater-based epidemiology (WBE) is an innovative tool that, unlike traditional epidemiological approaches, is capable of providing real-time profiling of community health and lifestyle along with emerging trends and changes in pattern usage of drugs in wastewater. By using human urinary excreted indicators, so-called “biomarkers”, WBE provides estimates at population level. Therefore, the choice and the evaluation of suitable biomarkers of exposure to drugs is of fundamental importance for the public health monitoring. Moreover, since many drugs are chiral, the investigation on enantiomeric profiling of chiral biomarkers provides a new dimension to WBE. To aid enantiomeric profiling in WBE, sensitive enantioselective methodologies are required. In this thesis, two novel multiresidue analytical methods based on chiral liquid chromatography coupled to mass spectrometry were developed and validated. The first method investigated the main human biomarkers for the detection of illicit drugs of abuse and potentially abused licit drugs. New biomarkers were investigated, such as mephedrone, PMA and all MDMA’s metabolites. Furthermore, a case study on mephedrone posed the basis for a novel approach towards biomarker selection in estimation of human exposure to chiral drugs with limited metabolism data. As a result, mephedrone was a suitable biomarker due to its stability in wastewater. In addition, some of its metabolites were also proposed as potential candidates for mephedrone use. The second method explored biomarkers of quinolones’ use, as they represent one class of antibiotics with rising concern in antibiotic resistance. The most comprehensive panel of quinolones’ biomarkers was considered for the first time in WBE studies. Both methodologies were applied to wastewaters from eight locations in Europe allowing the first pan-European studies on enantiomeric profiling of chiral biomarkers. Key findings of this research included: the detection of high mephedrone loads only in the UK, thus indicating human consumption; the detection of HMMA, a MDMA metabolite, as a suitable indicator of MDMA consumption and the determination of different synthetic production routes of methamphetamine across Europe. With regards to quinolones’ biomarkers, higher ofloxacin loads were found in Southern European cities along with differences in enantiomeric fraction with respect to Northern ones. Moreover, ofloxacin’s metabolites showed ofloxacin use and ulifloxacin was found as a result of prulifloxacin consumption. Therefore, enantiomeric profiling led to an understanding of: (i) new patterns of emerging drugs of abuse, (ii) changes in patterns of classical illicit drugs and (iii) quinolones with the verification of the origin of drug residue, potency of abused drug and its synthetic route and (iv) quinolones’ metabolic profiles. Moreover, the simultaneous determination of quinolones’ biomarkers in European samples allowed for the verification of spatial and temporal trends of quinolones’ use and the occurrence of their resistance genes. This proof-of-concept research will facilitate further advances in the WBE field.
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Bennett, Stuart James. "Oxidative stress biomarkers in dementia". Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/1449/.
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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which is thought to affect 26.6 million individuals worldwide. There is growing concern over a worldwide dementia epidemic that is predicted to develop over the coming decades. The evidence thus far suggests that increased levels of oxidative stress and vascular risk factors are two major contributors, amongst others, to AD development. The thesis aimed to investigate markers of oxidative stress in AD plasma. Moreover, the oxidative status of specific proteins was investigated using both hypothesis driven and proteomic approaches. Results presented in this thesis suggest that global plasma protein oxidation levels are not different when AD and control subjects are compared, but that individual plasma proteins are specific targets for oxidative modification in AD. The thesis explores different methodologies to assess oxidative changes in AD. In addition it demonstrates that emerging novel and powerful mass spectrometry techniques can be employed successfully to identify several proteins modified by oxidation, providing an initial starting point for further investigation.
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Zubajlo, Rebecca Elizabeth. "Quantitative biomarkers for tissue characterization". Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/111898.
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Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 97-104).
This research proposes and examines noninvasive, quantitative techniques to characterize tissue. The primary metrics investigated include estimation of longitudinal speed of sound and shearwave elastography. Additional metrics investigated include bioimpedance and functional tests specifically for muscle health quantification. Diagnosing and monitoring of health of muscle and liver tissue is the motivating clinical need. These proposed metrics and techniques are noninvasive, quantitative, and do not require calibration. Current standards of care for liver and muscle health include biopsy for liver and muscle or electromyography for muscle. Functional tests, also a gold standard for functional muscle health, are not as quantitative or robust as the metrics proposed here due to changes from patient type and mobility level. The metrics proposed here do not have the limitations as the current gold standards and can be applied robustly to patients for screening, diagnosis, and monitoring of disease - making medicine more precise and personalized.
by Rebecca Elizabeth Zubajlo.
S.M.
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Parekh, Bhavin. "Volatile biomarkers of blood glucose". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609459.
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Dawson, Sarah-Jane. "Molecular biomarkers in breast cancer". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609742.
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Hodgson, Karen. "Biomarkers of antidepressant treatment outcomes". Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/biomarkers-of-antidepressant-treatment-outcomes(dcd101e2-4f7b-423c-8354-29c3d827fd91).html.
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Whilst antidepressants are widely prescribed, there is a large degree of variation between patients in terms of treatment outcomes. Furthermore, the mechanisms by which these drugs exert their effects remain unclear. In this thesis, genetic biomarkers of antidepressant outcomes have been explored, in order to better understand the molecular mechanisms underpinning effective antidepressant treatment. The research presented here use data from the GENDEP project, which is a large pharmacogenetic study of depressed patients receiving antidepressant treatment. Firstly, the pharmacological underpinnings of antidepressant-associated side effects were used to categorise these side effects and conduct a candidate gene analysis. Whilst a significant association between variation within the HTR2C gene and serotonergic side effects was found, the observation was not replicated in a second sample. Secondly, the role of variability in drug metabolism rates in treatment outcomes was investigated. Examining genotypic information on the cytochrome P450 enzymes, no associations with treatment response, side effects or study discontinuation were observed. Furthermore, serum concentrations of antidepressant were unrelated to treatment response or overall burden of side effects, predicting only a minority of specific side effects. Thirdly, transcriptomic changes with drug administration were explored in relation to treatment efficacy. Two genes were identified where changes in expression levels were significantly associated with treatment response amongst patients taking nortriptyline. Furthermore, using a network-based approach, changes in gene expression across one module of coexpressed genes showed significant correlation with symptom improvement; this biological network generalised across different antidepressant medications. Finally, genomic and transcriptomic data were combined, in an examination of the genetic control of gene expression. This analysis then was used to gain an insight into the molecular processes that link genotype to phenotype. The evidence presented within this thesis, when considered in combination with existing literature, highlights that antidepressant efficacy is a complex trait, influenced by many genes of small effect. Nevertheless, by layering together different levels of information, we can begin to dissect the molecular mechanisms involved in antidepressant action.
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Rufo, João Pedro Cavaleiro. "Serum biomarkers in elderly asthma". Master's thesis, Universidade da Beira Interior, 2013. http://hdl.handle.net/10400.6/1338.
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Asthma is a chronic disease of the airways that can affect all ages. It is usually
undertreated in the elderly population, resulting in complications and increased severity for
the patient. Different phenotypes may imply different treatments and therefore it becomes
important to correctly determine which type of asthma the patient is suffering from.
Biomarkers of asthma have been clinically studied in order to help discriminate among the
different phenotypes of the disease, cytokines being among the most promising. Our main
goal was to measure six serum cytokines, including IL-1β, IL-6, IL-8, IL-10, IL-12p70 and TNFα, in an elderly population with asthma.
The population of this study included 16 elderly patients with allergic asthma, 20
elderly patients with non-allergic asthma, 9 elderly control individuals, as well as 11 young
adult control individuals. The serum of the experimental subjects was quantified for the six
aforementioned cytokines by flow cytometry, using the Cytometric Bead Array (CBA) Human
Inflammatory Cytokines Kit (BD Biosciences).
The results showed that the measured levels of TNF-α, IL-10 and IL-8 were increased in
the non-allergic asthmatics group, although with no statistical significance. IL-6 was
significantly increased in the elderly non-allergic asthmatic group, when compared to both
control groups and when compared to the young adult controls alone, but no significant
differences were found when comparing to the elderly control group separately. IL-1β median
levels were shown to be elevated in the young adults control group, but also without a
significant statistical difference. IL-12p70 was not detected in any subject.
In conclusion, we could not define a pattern of changes in the measured cytokine levels
related to phenotype differences or aging, although it is possible to notice a trend for
increased levels of severity cytokines (TNF-α, IL-6 and IL-8) in non-allergic asthmatic elderly
individuals, suggesting that this phenotype of asthma is indeed more severe than its
counterpart. So far, this is the only study that measured the aforementioned serum
inflammatory cytokines in an elderly population with asthma.A asma é uma doença crónica das vias aéreas que afeta todas as idades e é incorretamente tratada ou sub-diagnosticada na população idosa, resultando em complicações para o doente e numa diminuição da qualidade de vida. Diferentes fenótipos podem requerer diferentes tratamentos e, portanto, é necessário diagnosticar corretamente qual o tipo de asma de que o doente sofre. Apesar de grande parte do tratamento e pesquisa se concentrarem na asma alérgica, existem várias outras formas da doença que requerem atenção, tal como a asma neutrofílica ou asma não-alérgica, que afeta normalmente os doentes mais velhos. A doença pulmonar obstrutiva crónica (DPOC), também muito comum em idosos, pode prejudicar ainda mais o diagnóstico da asma, devido às semelhanças entre as duas doenças. Biomarcadores da asma estão a ser estudados clinicamente com vista a aumentar o poder discriminativo entre os diferentes fenótipos da doença, estando as citocinas dentro dos mais promissores. Assim sendo, o nosso principal objetivo foi medir seis citocinas, nomeadamente a IL-1β, IL-6, IL-8, IL-10, IL-12p70 e TNF-α, no sangue periférico de uma população de idosos asmáticos. Pretendíamos também usar a citometria de fluxo para quantificar as citocinas, de modo a podermos comparar facilmente os resultados e estabelecer padrões citocínicos. Também tínhamos como objectivo avaliar alterações nos padrões citocínicos relacionadas com a idade, usando um grupo controlo de adultos jovens. Por fim, pretendíamos investigar possíveis alterações nos padrões citocínicos relacionados com cada fenótipo da asma (alérgica ou não-alérgica). A população deste estudo foi constituída por 16 idosos com asma alérgica, 20 idosos com asma não-alérgica, 9 idosos não asmáticos para controlo, assim como 11 adultos jovens não asmáticos para controlo, recrutados através de uma base de dados. Os indivíduos foram inseridos nos respectivos grupos pelos resultados de testes cutâneos, medição da IgE total e específica, e pelas respostas dadas a um questionário. As citocinas previamente referidas foram quantificadas no soro dos indivíduos por citometria de fluxo, usando o Cytometric Bead Array (CBA) Human Inflammatory Cytokines Kit (BD Biosciences). Os resultados obtidos mostraram que o TNF-α, a IL-10 e a IL-8 se encontravam elevadas no grupo dos asmáticos não alérgicos, apesar da diferença não ser significativa. A IL-6 encontrava-se significativamente elevada no grupo dos idosos com asma não-alérgica, quando comparada com ambos os grupos de controlo e quando comparada com o grupo dos adultos jovens individualmente, embora não tenham sido encontradas diferenças significativas quando comparada com o grupo de controlo dos idosos, separadamente. Os níveis de IL-1β encontravam-se elevados no grupo dos adultos jovens, porém sem significado estatístico. A IL8 encontrava-se geralmente mais elevada nos idosos. A IL12p70 não foi detectada em nenhum indivíduo. Concluindo, medimos as citocinas previamente referidas no sangue periférico de uma população idosa, cumprindo assim o nosso objectivo principal. Porém, não foi possível definir um padrão de altercações a nível das citocinas relacionado com diferenças entre os fenótipos ou relacionadas com o envelhecimento, embora tenha sido possível notar uma tendência para um aumento das citocinas ligadas à severidade (TNF-α, IL-6 e IL-8) no grupo dos idosos com asma não-alérgica, o que nos leva a concluir que este fenótipo da asma é, de facto, mais severo, tal como sugere a bibliografia. O principal ponto forte é o facto deste ser o primeiro estudo a medir estas seis citocinas no soro de idosos com asma. Uma limitação deste estudo centra-se no facto dos voluntários terem sido classificados como asmáticos através das respostas a um questionário, não tendo, portanto, nenhuma confirmação clínica da existência da patologia. Isto pode ter levado à inclusão de voluntários nos grupos errados. Para obtenção de melhores resultados os voluntários deveriam ser recrutados após o diagnóstico efetuado por um especialista e submetidos a testes complementares, como por exemplo a espirometria, de modo a garantir a correta inserção dos indivíduos nos grupos. Outros dos marcadores referenciados neste trabalho, como a proteína catiónica dos eosinófilos (ECP) e a YKL-40, também aparentam ter algum potencial para a monitorização e diagnóstico da asma, devendo ser investigados.
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Clarke-Harris, Rebecca. "Predictive epigenetic biomarkers of adiposity". Thesis, University of Southampton, 2015. https://eprints.soton.ac.uk/382960/.
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Sangster, Jodi Kirsten. "Cardiac Biomarkers in Hyperthyroid Cats". Thesis, Virginia Tech, 2013. http://hdl.handle.net/10919/50542.
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Background: Hyperthyroidism has substantial effects on the circulatory system. The cardiac biomarkers NT-proBNP and troponin I (cTNI) have proven useful in identifying cats with myocardial disease but have not been as extensively investigated in hyperthyroidism.Hypothesis: Plasma NT-proBNP and cTNI concentrations are higher in cats with primary cardiac disease than in cats with hyperthyroidism and higher in cats with hyperthyroidism than in healthy control cats.
Animals: Twenty-three hyperthyroid cats, 19 cats with HCM without congestive heart failure, and 19 euthyroid, normotensive healthy cats eight years of age or older. Fourteen of the hyperthyroid cats were re-evaluated three months after administration of 131I.
Methods: A complete history, physical examination, complete blood count, serum biochemistries, urinalysis, blood pressure measurement, serum T4 concentration, plasma concentrations of NT-proBNP and cTNI, and echocardiogram was prospectively obtained from each cat.
Results: Hyperthyroid and HCM cats had plasma NT-proBNP and cTNI concentrations that were significantly greater than healthy older cats, but there was no significant difference between hyperthyroid and HCM cats with respect to concentration of either biomarker. In hyperthyroid cats that were re-evaluated three months after 131I treatment, plasma NT-proBNP and cTNI concentrations as well as ventricular wall thickness decreased.
Conclusions and Clinical Relevance: Although there may be a role for NT-proBNP in monitoring the cardiac response to treatment of hyperthyroidism, neither NT-proBNP nor cTNI can be used to distinguish hyperthyroid cats from cats with HCM. Therefore, the thyroid status of older cats should be ascertained prior to interpreting results of cardiac biomarker testing.
Master of Science
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Beck, Stephen. "Biomarkers as Predictors of Ankylosis". The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274908825.
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Peng, Hongying. "ROC Curves for Ordinal Biomarkers". University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1543582492604243.
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Fernandes, Mónica Figueiredo. "Biomarkers in Canis lupus familiaris". Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/14127.
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Mestrado em MicrobiologiaIntrodução- Os animais de companhia como o cão desempenham hoje um papel a nível familiar e social importante podendo atuar como agentes em programas terapêuticos e de socorrismo. A qualidade de vida dos animais de companhia e o correspondente impacto na saúde pública pode beneficiar com o diagnóstico precoce e a intervenção terapêutica adequada. Com a evolução das abordagens Ómicas, nomeadamente dos estudos de proteómica foi gerado um grande volume de dados que retratam o perfil de proteínas característico de diversas situações patológicas. No entanto a informação gerada encontra-se dispersa por inúmeros artigos científicos e também por bases de dados diversas. A reunião de toda a informação molecular disponível numa única base de dados permitirá a integração da informação existente, facilitando estudos que visem encontrar os mecanismos moleculares subjacentes a patologias bem como encontrar biomarcadores que permitam o diagnóstico precoce de patologias. Objetivo- Este trabalho tem como objetivo criar uma base de dados que reúna toda a informação existente sobre os proteomas parciais de Canis lupus familiaris, o CanisTecOme. Com a construção da estrutura da base de dados CanisTecOme é demonstrada através de análises diversas in silico, a metodologia a seguir para extrair informação diversa sobre as proteínas implicadas em patologias de cão. Estando interessados em estabelecer a saliva como fluido de diagnóstico não invasivo, foi também objetivo desta tese o estabelecimento da metodologia para a recolha, armazenamento e caracterização de amostras de saliva de cão. Materiais e métodos- A base de dados CanisTecOme foi construída por recurso a revisão e anotação manual sobre a informação relativa à caracterização do individuo dador, tipo de amostra biológica, técnicas utilizadas para a identificação da proteína, e toda a informação conhecida sobre cada uma das proteínas catalogada na base de dados. O CanisTecOme tem também anotado as proteínas que já foram propostas como biomarcadores para patologias diversas. A metodologia para o estabelecimento da recolha, armazenamento e caracterização das amostras de saliva de cão foi baseada na já estabelecida para a saliva humana. Conclusão- A estrutura proposta para a base de dados CanisTecOme permite responder a questões como identificar: - As patologias em cão para as quais existe informação sobre as proteínas implicadas; - Os mecanismos moleculares comprometidos em patologias; - A saliva contém proteínas que permitam identificar patologias sistémicas? No que diz respeito à metodologia estabelecida para a recolha, armazenamento e caracterização de amostras de saliva esta mostrou-se com a qualidade adequada para o estabelecimento de um futuro biobanco de saliva animal.
Introduction – Pets such as the dog are important for families and for society in general acting as therapeutic agents and rescue aids. Pets quality of life and the correspondent effect on public health may benefit from early diagnostics and targeted therapeutic actions. The evolution of the Omics sciences, including proteomics resulted in the accumulation of a large volume of data reflecting the protein profile of different pathological situations. However, the information generated is dispersed throughout several scientific articles and data bases. Collecting all information in a single database allows data integration and management used in studies to find molecular biomarkers for early diagnosis. Goal - To create a database with all information on the partial proteomes of Canis lupus familiaris, the CanisTecOme. The methodology to be used in for data management and information gathering using the CanisTecOme database is demonstrated through different in silico analysis. A second objective of this work was the outlining of the basic methodology for dog saliva collection, storage and characterization. This allows the use of saliva as a minimally invasive diagnostic fluid. Materials and methods – Manual curation and annotation of all the information related to the saliva donor, biological sample, techniques used for protein identification and all the information related to the protein identifies was performed. The CanisTecOme has also indicated whether a protein has already been proposed as a biomarker. The methodology for the establishment of the sampling, storage and sample characterization of dogs saliva was based on what is already established for human saliva. Conclusion – The structure proposed for the database enables the answer to the following questions: -Which proteins have been identified in the dog as being present in a pathology? - Which molecular mechanisms are compromised in a pathological situation? - Are there protein in saliva which allow the identification of systemic pathologies in the dog? Furthermore, the methods used for sampling, transport and storage of saliva were adequate for the establishment of a saliva biobank for animal saliva.
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Barra, Cátia Isabel de Almeida. "Inflammatory biomarkers in Alzheimer’s disease". Master's thesis, Universidade de Aveiro, 2014. http://hdl.handle.net/10773/13277.
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Mestrado em Biomedicina MolecularAlzheimer’s disease (AD) is the most common form of dementia. Histopathologically it is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFT) and the extracellular senile plaques (SP), which are surrounded by activated astrocytes and microglia. Neuroinflammation has been associated with some neurodegenerative diseases. In AD the inflammatory process, prompted by increased Aβ production and aggregation, was reported to have a fundamental role in disease pathogenesis. In early stages the inflammation could have a beneficial role in the pathology, since it has been proposed that the microglia and astrocytes activated could be involved in (amyloid β) Aβ clearance. Nevertheless, the chronic activation of the microglia leads to excessive production of the inflammatory components, including cytokines. It promotes alterations in amyloid precursor protein (APP) expression and processing, stimulating the increase of Aβ accumulation, abnormal Tau phosphorylation and, consequently, neurotoxic effects, irreversible damage and loss of neurons. Since chronic neuroinflammation is a feature of AD, inflammatory proteins may constitute potential biomarkers candidates to assist clinical diagnosis of this dementia. Thus, the main aim of this study was to identify putative inflammatory biomarkers for AD by flow citometry analysis. For plasma samples of individuals examined by clinical dementia rating (CDR) and mini mental (MM) diagnostic tests were used. Subjects were subdivided in 3 distinct groups, a control group (CDR-/MM-) and two patient groups, CDR+/MM- and CRD+/MM+, the former may include mild cognitive impairment (MCI) patients and the latest group included 5 patients clinical diagnosed as AD. Data analysis revealed differences in the inflammatory proteins levels of both patients groups (CDR+/MM- and CDR+/MM+) in comparison to healthy individuals (CDR-/MM-). Interleukin-8 (IL-8) plasma levels were statistically different (P<0,05) from control group. Significant correlation between IL-8 concentrations and the CDR stages was also identified. Additionally, correlations of monocyte chemoattractant protein-1 (MCP-1) with both IL-8 and IL-6 were observed. Taken together these findings suggested that IL-8 could be a potential biomarker not only for AD but also for diagnosis of initial stages of dementia.
A doença de Alzheimer (DA) é o tipo de demência mais comum. Histopatologicamente é caracterizada pela presença de tranças neurofibrilares intracelulares (TNF) e de placas senis extracelulares (PS), as quais estão rodeadas pela microglia e por astrócitos. A neuroinflamação tem sido associada com várias doenças neurodegenerativas. Na DA o processo inflamatório, desencadeado pelo aumento da produção e agregação do péptido Aβ, desempenha um papel fundamental na patogénese da doença. Nas fases inicias, a inflamação possui um papel benéfico na patologia, uma vez que tem sido proposto que a microglia e os astrócitos quando ativados estão envolvidos na remoção de β-amilóide (Aβ). No entanto, a ativação crónica da microglia conduz à produção excessiva de componentes inflamatórios, incluindo citocinas. Isto provoca alterações na expressão e processamento da proteína percursora de amilóide (PPA), estimulando o aumento da produção e acumulação de Aβ, fosforilação anormal da proteína Tau e, consequentemente, efeitos neurotóxicos e perda de neurónios. Uma vez que a neuroinflamação crónica é uma característica da DA, proteínas inflamatórias poderão constituir potenciais candidatos a biomarcadores que auxiliem no diagnóstico clínico desta doença. Desta forma, o principal objectivo deste trabalho foi identificar biomarcadores inflamatórios para a DA através da técnica de citometria de fluxo. Para tal, foram analisadas amostras de plasma de doentes que foram, previamente, examinados por testes de avaliação cognitiva, clinical dementia rating (CDR) e mini mental (MM). Os sujeitos foram divididos em três grupos distintos, o grupo controlo (CDR-/MM-) e dois grupos de pacientes, CDR+/MM- e CDR+/MM+. O primeiro grupo de pacientes pode conter indivíduos com ligeiras alterações cognitivas (MCI) e o segundo inclui 5 pacientes clinicamente diagnosticados para DA. A análise dos dados revelou diferenças nos níveis de proteínas inflamatórias de ambos os grupos de doentes (CDR+/MM- e CDR+/MM+) em comparação com os indivíduos saudáveis (CDR-/MM-). Os níveis plasmáticos de interleucina-8 (IL-8) foram estatisticamente deferentes (p<0,05) do grupo controlo. Correlação significativa entre as concentrações de IL-8 e os estados de CDR foi identificada. Adicionalmente, foram observadas correlações entre MCP-1 e IL-8 e a IL-6. Em conjunto, estes resultados sugerem que a IL-8 poderá ser um potencial biomarcador não só para a DA mas também para o diagnóstico precoce de demência.
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Rodrigues, Alison. "Metabolic biomarkers of aminoglycoside nephrotoxicity". Thesis, University of Liverpool, 2014. http://livrepository.liverpool.ac.uk/2008766/.
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Drug-induced nephrotoxicity is a limiting factor to the efficacy and safety of various therapeutics including the aminoglycoside antibiotics. Aminoglycosides, such as gentamicin, cause proximal tubule injury in a significant proportion of individuals they are given to. The onset of this adverse drug reaction is currently managed by the monitoring of serum peak and trough levels and measurement of the classic renal functional markers serum creatinine and blood urea nitrogen. The limitations of these biomarkers are well established but novel, sensitive proximal tubule-specific biomarkers, such as kidney injury molecule-1, are gradually coming to the fore. Still, management of aminoglycoside nephrotoxicity is lacking a personalised strategy whereby the risk of a patient developing proximal tubule injury can be established at the individual level before exposure. Prior studies of gentamicin nephrotoxicity pin-pointed that HMG-CoA reductase inhibitors, also known as statins, could inhibit the accumulation of gentamicin in vitro and therefore reduce the cytotoxicity of the drug. In order to study HMG-CoA reductase and its relationship to aminoglycoside accumulation further, an LC-MS/MS based assay was developed and validated to measure the product of the enzyme, mevalonic acid, in the urine of rats and humans. Urinary mevalonic acid was converted to mevalonolactone at pH 2, extracted alongside a deuterated internal standard using ethyl acetate and quantified by reversed-phase LC-MS/MS. The assay had a broad dynamic range of 0.0156–10 μg/mL with precision <15% CV and accuracy 85–115% to suit the natural variation within species and between non-clinical and clinical samples. To demonstrate the utility of the assay and to ascertain the natural diurnal oscillations in HMG-CoA reductase activity, mevalonic acid was quantified in the urine of rats, mice and healthy children. In rats the excretion of mevalonic acid was significantly greater in urine collected during 22:00–10:00 h (mean 9.7 ± 2.3 μg/mg UCr) compared with 10:00–22:00 h (mean 3.4 ± 1.3 μg/mg UCr). In a human paired urine study, in 60% of individuals, morning collections had significantly greater concentrations of mevalonic acid than evening collections where the morning excretion was, on average, 105% greater. The diurnal rhythm of HMG-CoA reductase activity was investigated in relation to aminoglycoside nephrotoxicity in a repeat-dose gentamicin rat model. A strong positive relationship between pre-dose mevalonate excretion, gentamicin accumulation and kidney injury in the renal cortex was observed. Animals administered gentamicin at 10:00 h experienced greater gentamicin accumulation and kidney injury, compared to animals on the 22:00 h dosing schedule which corresponded to greater mevalonate excretion in the hours prior to 10:00 h compared to 22:00 h. These data support the idea that there is a contributory relationship between HMG-CoA reductase activity, the uptake of gentamicin and subsequent nephrotoxicity. Investigations with the aminoglycoside tobramycin did not reach the same conclusion as no clear relationship was observed. In contrast to the HMG-CoA reductase focussed research, a non-targeted metabonomic approach to understanding gentamicin nephrotoxicity was undertaken. Multivariate analyses of 1H-NMR spectra from gentamicin-exposed rats revealed multiple major perturbations in the urine and serum metabolome, prior to kidney injury molecule-1 elevation (urine OPLS-DA model 12 h post-dose Q2Y=0.93, p=0.007). Depletion of metabolites related to energy production and elevation of metabolites implicated in oxidative stress suggests gentamicin had a profound effect on the mitochondria of the proximal tubule epithelial cells. Quantification of metabolites such as the TCA cycle intermediates could be a non-invasive alternative to monitoring the toxicity of aminoglycosides prior to overt renal functional changes. Multivariate analyses of 1H-NMR urine spectra were also subjected to a pharmacometabonomic approach whereby the pre-dose or early post-dose metabolomewas integrated with post-dose kidney injury molecule-1 measurements in order to group individuals based on their differential response to gentamicin. Early-intervention metabolite signatures were identified to have an inverse relationship to kim-1 excretion, providing further evidence that the TCA cycle intermediates could be useful prognostic biomarkers of gentamicin nephrotoxicity. Analysis of pre-dose profiles identified gut- microbial metabolite 3-HPPA as correlated to the post-dose toxicity of gentamicin; follow up studies demonstrated that 3-HPPA excretion also had a positive relationship to urinary mevalonic acid. Hence, the pharmacometabonomic analyses implicated gut microbial and host HMG-CoA reductase activity as related to the extent of gentamicin nephrotoxicity, which certainly warrants additional investigations. The adoption of targeted and non-targeted biomarker identification techniques has proven successful in this research. Mevalonic acid and HMG-CoA reductase are promising mechanistic factors which may affect susceptibility to aminoglycoside nephrotoxicity in man and research will be facilitated by the development of the LC-MS/MS assay described herein. Certainly, the use of statins as a prophylactic measure against aminoglycoside nephrotoxicity will be explored. Comprehensive analysis of the metabolome has identified the importance of the perturbation of energy metabolism and oxidative stress in the onset and development of gentamicin nephrotoxicity and in addition, integration of these vast data sets with the novel biomarker kidney injury molecule-1 has revealed that the gut microbiome could also influence an individual’s susceptibility to this adverse drug reaction.
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Alfa-Wali, Maryam. "Metabolic biomarkers of colorectal cancer". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11044.
Texto completoResumen
Colorectal cancer (CRC) remains a major public health problem with advanced and recurrent disease being a management challenge due to the lack of efficacy of currently available monitoring tools. Carcinoembryonic antigen is used as a marker for recurrent disease but has limited sensitivity. Early sensitive markers of disease severity and recurrence are required. The aim of this thesis was to identify potential metabolic biomarkers of CRC patients using ‘Metabonomics’ based on proton nuclear magnetic resonance (1H NMR) spectroscopy. The breadth of 1H NMR metabonomics exploring different aspects of CRC pathogenesis was investigated. A global approach profiling a large number of metabolites was undertaken in cell line and chemoprevention studies with subsequent targeted profiling experiments using human polypoid tissue samples. The studies primarily exhibited changes in choline and lipids to be associated with CRC. Although these metabolites are well reported, this thesis presents contemporary metabolic profiling using systems not previously reported. Tumour extracts of CRC xenografts showed higher levels in the ratio of phosphocholine and glycerophosphocholine between poorly and well-differentiated cell lines. Human tissue and biofluids were used to define metabolic phenotypes. Normal and polypoid colorectal tissues were also metabolically characterised by changes in choline using magic angle spinning (MAS) 1 H NMR. Investigating chemoprevention strategies with bile acids in adenoma patients indicated alterations in short chain fatty acids, related to gut microflora metabolism. In clinical studies, higher levels of lactate and glycoproteins were identified in rectal cancer patients, as potential metabolic predictors of response to chemoradiotherapy. A metabolically translational feature of the thesis in a heterogeneous population confers a significant increase in the risk of CRC incidence with metabolic syndrome (MetS). Thus, inferring identification of MetS components as part of screening measures. In vivo studies provide a functional way of networking metabolic pathways to pathological states, thereby unifying perspectives post hoc.
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Cheng, Robert. "Novel Biomarkers of Hepatocellular Carcinoma". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20294.
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The efficacy of current hepatocellular carcinoma (HCC) surveillance has been questioned, with some guidelines removing alpha-fetoprotein (AFP) from screening recommendations and relying on liver ultrasound alone. A prospectively enrolled Australian HCC surveillance cohort showed a combined surveillance method of ultrasound with AFP is more efficacious than ultrasound alone in HCC detection. Survival analyses showed having Asian ethnicity conferred a protective effect on HCC survival. Antiviral therapy improved HCC survival in hepatitis C. Extracellular vesicles (EV) have been shown to be mediators and effectors of cancer gene pathways. In this thesis EV were phenotyped with transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and flow cytometry. TEM qualified the ultrastructure of EV. NTA and flow cytometry demonstrated EV concentration to be increased in hepatitis and HCC. Flow cytometry demonstrated hepatocyte-specific EV concentration to be increased in HCC. EV can carry short segments of RNA including miRNA. In our studies differential expression of plasma EV miRNA was found in HCC compared to cirrhosis and hepatitis. Gene set enrichment analyses of miRNA expression profiles were performed using nCounter and OpenArray, with the finding of more than 80% concordance in cancer gene pathways including p53, epithelial mesenchymal transition, TNF- signalling via NF-, TGF-, kRAS, PI3K/AKT/mTOR, IL-6 JAK/STAT, and Wnt/-catenin. In conclusion, traditional HCC surveillance methods are efficacious. EV and its miRNA profiling may provide a sensitive surveillance, diagnosis and prognostication tool for HCC. nCounter and OpenArray technologies showed differential miRNA expression profiles in HCC plasma EV with enriched gene pathways corresponding to genomic studies in HCC tissue. These findings support future investigations into the utility of plasma EV as a circulating biomarker of HCC.
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Abuaisha, Karim Belkais Faraj. "Prognostic biomarkers of periodontal disease". Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/prognostic-biomarkers-of-periodontal-disease(77882787-a695-42a3-b7e4-7caa8e9c4bde).html.
Texto completoResumen
Objectives: Previous studies in our laboratory have identified the antimicrobial proteins Human Neutrophil Protein 1 – 3 (HNP1-3), Myeloid Related Protein 8 (S100A8/MRP8) and LL-37 as putative periodontal salivary biomarkers. The aims of the studies reported in this thesis were to investigate the diagnostic and prognostic potential of these markers, together with Matrix Metalloproteinase- 8 (MMP-8), serum markers C - reactive protein (CRP) and Interleukin-6 (IL-6), on the initial outcome of nonsurgical periodontal treatment. Material & Methods: We carried out a cross sectional study which aimed to verify and establish a diagnostic threshold for a group of salivary biomarkers (MMP-8, HNP1-3, S100A8 and LL-37) and to test the validity of the diagnostic utility of these biomarkers. A total of 133 unstimulated saliva samples (46 with chronic periodontitis, 38 with aggressive periodontitis and 49 with gingivitis) were analysed by ELISA. In addition multiple markers were combined to give a single combined cut off point by normalising each biomarker to percentage of cut-off point value, (such that x + y = combined cut off point). These pre-determined cut-off points were applied to salivary AMPs levels in an independent cohort originally collected to investigate the effects of diabetes on periodontitis. To investigate prognostic potential a total of 66 participants were recruited to a longitudinal intervention study of patients with moderate–severe Chronic Periodontitis. 53 subjects completed the protocol and were included in the final analysis. Subjects (28 male, 25 female) age range (23-65 years) with were recruited, with 14 smokers and 3 with type II diabetes, and saliva and serum samples were collected prior to periodontal examination. Patients were then given a course of non-surgical periodontal therapy over 2 visits. 8-10 weeks post-operatively saliva/serum sampling and clinical examination were repeated. Salivary MMP-8, S100A8 and HNP1-3 concentrations were all determined by ELISAs. In addition we measured serum levels of CRP and Interleukin 6. Results: In the cross-sectional study the HNP1-3 and S100A8 could differentiate between gingivitis and chronic periodontitis with high specificity (around 90%) and around 75% sensitivity compared to MMP-8 which was able to discriminate between gingivitis and periodontitis (chronic and aggressive) with both high 3 specificity and sensitivity. LL37 showed no significant diagnostic potential. Within the independent cohort the application of pre-determined thresholds, either individual or combined cut-offs, were able to detect periodontitis with specificity of between 75 – 85 % but with very low sensitivity. In addition diabetic status was found to result in significantly increased MMP-8 and S100A8 concentrations in subjects with periodontal disease. In the intervention study, treatment resulted in reductions in the mean: a) number of deep sites (>4mm) (33.57 ± 20.75 vs 18.51 ± 13.87; mean ± SD, p<0.0001); b) probing pocket depths (5.92 ± 0.47 mm vs 4.74 ± 0.76 mm, p<0.0001); c) bleeding index (0.32 ± 0.20 vs 0.21 ± 0.16, p<0.0001); d) plaque index (0.46 ± 0.20 vs 0.37 ± 0.18, p=0.0003). Only the mean concentrations of MMP-8 and S100A8 showed significant reductions post-treatment (MMP-8: 355.4 ± 319.9 ng/ml vs 216.6 ± 217.2 ng/ml, p<0.0001), (S100A8: 1182 ± 1095 ng/ml vs 693.9 ± 719.6 ng/ml, p=0.0007). Only the change in concentrations of MMP-8 were strongly associated with magnitude of treatment response (MMP-8: r2= 0.1, p=0.02). In addition, the baseline levels of MMP-8 & S100A8 were also associated with treatment response (MMP-8: r2= 0.1, p=0.03; S100A8: r2=0.1, p=0.02). Overall, there were 13 out of 53 participants who did not respond to the treatment (24.5% of cases). MMP-8 baseline concentrations were significantly higher in responders (419.3 ± 343.1 ng/ml) than non-responders (158.8 ± 73.3 ng/ml) (p=0.009). MMP-8 concentrations at baseline that were above the cut-off (<182.8 ng/ml) predicted a good response to periodontal treatment with 77% sensitivity and 70% specificity. There was no effect of the single round of non-surgical periodontal treatment on the levels of systemic markers CRP & IL-6, and also there was no correlation between local and systemic markers. Conclusion: These results of both studies suggest that MMP-8, HNP1-3 and S100A8 may be useful to identify cases of periodontitis with good specificity and moderate sensitivity and may give superior results when combined. In addition the salivary MMP-8 and S100A8 showed promising periodontal prognostic ability to detect the likelihood of a good response to treatment, with MMP-8 showed the best results with moderate sensitivity and specificity. However, further validation studies would be useful in larger, non-diabetic cohorts.
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Solanki, Maitri. "Microbiome Biomarkers - Post Mortem Interval". Thesis, Solanki, Maitri (2019) Microbiome Biomarkers - Post Mortem Interval. Masters by Coursework thesis, Murdoch University, 2019. https://researchrepository.murdoch.edu.au/id/eprint/48022/.
Texto completoResumen
Microbiome is the catalog of microbes and their genes. And a biomarker is a substance that can be objectively measured and which can act as an indicator of pathogenic processes, biological processes or pharmacological responses to a therapeutic intervention. Also, the time between physiological death and the examination of the dead body is known as the Post mortem Interval (PMI). Determination of PMI can be a complex problem due to it being influenced by a number of intrinsic and extrinsic factors. Some of the intrinsic factors include age, sex, and pathological and physiological states of the corpse. While the extrinsic factors include temperature, humidity and insect activity. Recently, molecular changes such as protein, RNA and DNA degradation have been studied quiet widely and are seem to be producing promising results in the field of PMI estimation. More specifically, studying RNA degradation after death is considered quiet useful for precise PMI estimation. Some of the different types of RNA that aid in PMI estimation include miRNAs, circRNAs, 18S-rRNA and so on. This study focuses on the potential for estimating PMI using microbiome biomarkers as a tool rather than the tradition PMI estimation by studying various stages of decomposition.
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Lim, Soojin. "Fluorescent Indicators for Disease Biomarkers". PDXScholar, 2012. https://pdxscholar.library.pdx.edu/open_access_etds/262.
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Xanthene dyes are common fluorophores which have been widely used as molecular probes. The xanthene fluorophores can be used as highly selective optical sensors to detect disease biomarkers. A new fluorogenic dye containing an alpha, beta-unsaturated aldehyde moiety exhibits selective fluorescent signal enhancement in the presence of cysteine or peptides containing N-terminal cysteine residues. The mechanism is based on synergistic covalent and supramolecular interactions. A unique rhodamine boronic acid indicator is used in an optimized data collection protocol for wavelength- and time-dependent selectivity of various saccharides and nucleosides. One indicator is thereby capable of selectively distinguishing structurally related analytes in mixtures. Moreover, the rhodamine-based boronic acid responds linearly to increasing riboside concentrations in urine samples, potentially enabling the screening for inborn purine metabolism disorders.
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UTZERI, STEFANIA. "Biomarkers identification in fibromyalgia syndrome". Doctoral thesis, Università degli Studi di Cagliari, 2013. http://hdl.handle.net/11584/266238.
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Fibromyalgia Syndrome (FMS) is a chronic syndrome characterized by widespread pain. FMS is a collection of other symptoms and overlapping conditions contribute to complicate the diagnosis, the assessment and the treatment. Unknown etiology and none laboratory tests have been appropriately validated for the diagnosis of the disease. The comparison of protein patterns in body fluids of diseased and healthy subjects has the potential to identify new disease-specific biomarkers. Some purine nucleotide metabolism disorders such as myoadenylate deaminase (MAD) deficiency report symptoms similar to those seen in FMS.
In consideration of what described above, we carried out a serum proteomic analysis of FMS patients with respect to control subjects searching potentially useful biomarkers for the disease. In addition, we evaluated serum purine metabolite concentrations in patients affected by FMS and the relationships between their levels and FMS clinical parameters.
Twenty-two females affected by FMS (according to the American College of Rheumatology, 1990) and twenty-two healthy women were recruited as controls for analysis of purine metabolite. Sixteen females FMS and twelve controls were enrolled in the study for the analyses of the proteome. Proteomic analysis was performed by combining two-dimensional gel electrophoresis (2-DE) and mass spectrometry (MS) and serum purine levels were quantified using reverse phase high performance liquid chromatographic (RP-HPLC).
In our study, using the proteomic approach, we have identified differentially expressed proteins, such as Transthyretin (TTR), Alpha-1 Antitrypsin (A1AT) and Retinol Binding Protein 4 (RBP4). The serum 4 concentrations of these proteins were significantly higher in FMS patients compared with healthy controls. TTR and RBP4 are retinoid transporters, moreover retinoid dysfunction is related to oxidative stress as well as A1AT. These results support the hypothesis that oxidative stress could be implicated in the pathophysiology of FMS.
Moreover, considerably higher serum concentration of inosine, hypoxanthine and xanthine levels (p<0.001) and lower serum adenosine (p<0.05) were detected in the FMS patients when compared to healthy controls. Our data show a negative correlation between adenosine and the Fibromyalgia Impact Questionnaire (FIQ).
Our results suggest that purines, in particular adenosine and inosine, may be involved in pain transmission in fibromyalgia.
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Rizzi, F. "GENETIC BIOMARKERS OF RENAL FUNCTION". Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/217438.
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ABSTRACT
The present study is part of HYPERGENES Project, focused on the
definition of a comprehensive genetic-epidemiological model of complex
traits like essential hypertension and of intermediate phenotypes related
to hypertension. We specifically focused on the identification of genetic
biomarkers related to Glomerular Filtration Rate (GFR) as index of renal
function.
Chronic kidney disease (CKD), defined as either kidney damage or
decreased kidney function for 3 or more months (GFR < 60 ml/min per
1.73m2) affects about 6-11% of the general population. A strong
relationship has been reported between renal dysfunction, hypertension
and cardiovascular diseases; hypertension is present in more than 80% of
patients with CKD and contributes to progression to end stage renal
disease and to cardiovascular events as well.
Apart from the risk conferred by traditional cardiovascular risk factors,
eGFR has a strong genetic component. We therefore performed a
genotype-phenotype association analysis in subjects affected by essential
hypertension and in a population based cohort. The analyses have been
carried on using: 1) 1,634 hypertensives from the HYPERGENES Discovery
phase and 1,198 hypertensives from the HYPERGENES Validation phase;
2) 2,697 subjects from Epogh-Flemengho population based sample 3)
1,952 subjects from Epogh-Flemengho population based sample with GFR
follow-up data, using the difference between the last and the first
measurement as phenotype of renal function.
Using a Genome wide association (GWA) approach, in the HYPERGENES
Discovery sample we identified a potential novel variant associated with
hypertension and renal function in STAC gene (rs4678878, p-value of
3.83x10-8). This gene is likely involved in a neuron-specific signal
transduction, although its function is not yet completely clear. This result
was not validated in HYPERGENES Validation and in the population based
studies. The finding needs further investigation performing a fine
mapping of the region.
Through a candidate gene approach, we could identify some variants,
mapping in genes already known as associated to renal function (PPARA,
CST3-CST9 region, PRKAG2, ABCA1, NEDD4L).
The identification of genetic variants affecting renal function could help
to better understand not only the GFR variability in the general
population but also the pathophysiology of CKD and progressive kidney
function decline. Ultimately, this could lead to novel tools for diagnosis,
prevention and therapy of CKD.
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Yu, Hannah J. "Role of biomarkers in monitoring Gaucher disease and potential of biomarkers to illuminate pathophysiologic pathways". [New Haven, Conn. : s.n.], 2008. http://ymtdl.med.yale.edu/theses/available/etd-12092008-172633/.
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Miralbell, Blanch Júlia. "Biomarkers of cognitive decline and dementia". Doctoral thesis, Universitat de Barcelona, 2012. http://hdl.handle.net/10803/91068.
Texto completoResumen
Cognitive impairment in the elderly encompasses many forms, ranging from subtle impairments in otherwise cognitively healthy individuals through mild cognitive impairment and dementia. Brain structural and functional changes underlie the observed cognitive impairment.
Complementary to the clinical observation, biomarkers have been proposed as in vivo indicators of the underlying pathophysiology and neurobiological changes in a sufficiently reliable manner that they could be used to detect, track, and predict the disease course over time.
In this thesis we used a combination of epidemiological and clinic-based approaches to investigate the mechanisms underlying vascular cognitive impairment (VCI) and Alzheimer’s disease (AD) and to identify possible biomarkers that could help early diagnosis of such conditions. To do so, a set of circulating and cerebrospinal fluid (CSF) biomarkers were studied in healthy and cognitively impaired subjects. Then, these measures were related to grey matter (GM) volumes, white matter (WM) integrity and cognition.
The first two studies are part of the population-based Barcelona-ASIA neuropsychology study. Study I aimed to compare the cognitive patterns of risk markers for cerebrovascular disease (CVD) with the cognitive profile in relation to novel and traditional vascular risk factors (VRF) in a community-dwelling sample. Biomarkers of inflammation, endothelial dysfunction and vascular thrombosis were selected. Results showed that VRF and circulating markers of inflammation and endothelial dysfunction predicted performance in several cognitive domains. Cognitive patterns of inflammatory markers overlapped those related to VRF. Markers of endothelial dysfunction predicted lower performance in verbal memory.
Study II was designed to further explore the structural changes mediating the relationships between risk markers of CVD and cognition. For that purpose the same set of markers of risk for CVD were related to GM atrophy and WM integrity and cognition. The main finding was an association of inflammation and vascular thrombosis with WM integrity loss in cortico-subcortical pathways and association fibres of frontal and temporal lobes. As expected, none of the biomarkers was related to GM volume changes. Vascular thrombosis also predicted lower performance in processing speed.
The third study is a memory clinic-based investigation that was conducted aiming to test the potential use of CSF biomarkers cut-offs as components for the diagnostic work-up in AD. We assessed GM and cognitive patterns in cognitively impaired subjects using CSF Aβ1-42, t-tau and p-tau181 cut-offs as grouping criteria. Results indicated that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) showed impairment and signs of regional GM atrophy in brain regions characteristic for AD, compared to those with normal levels. More specifically, GM volume differences were found in temporal, inferior parietal, lateral occipital and widespread prefrontal regions.
Studies I and II show that risk markers of inflammation and vascular thrombosis are related to a VCI profile for both cognitive patterns and structural brain changes. A microvascular damage of WM projections in fronto-subcortical pathways, but not GM atrophy, could mediate the association between these pathogenic processes and cognitive performance. Markers of endothelial dysfunction are related to a different cognitive pattern which is characteristic of both vascular and neurodegenerative mechanisms. Study III provides evidence that patients with abnormal CSF levels of t-tau and p-tau (but not Aβ1-42) show cognitive an AD profile according to GM density patterns and cognitive impairment.
Taken together, these results suggest that, complementary to the clinical observation, plasma and CSF markers and structural imaging are well placed to improve early diagnosis of both VCI and AD.El terme deteriorament cognitiu (DC) es refereix al contínuum de canvis cognitius associats a l’envelliment sa i patològic. El diagnòstic precoç de les persones amb DC és clau, ja que els tractaments són més eficaços quan s’inicien als inicis de la malaltia. Els biomarcadors s’han proposat com a eines pel diagnòstic precoç del DC i la demència. Es consideren indicadors in vivo de la patologia i s’han plantejat com a possibles eines pel diagnòstic, pronòstic i seguiment del DC i la patologia subjacent. L’objectiu general de la present tesi era explorar els mecanismes patofisiològics subjacents al deteriorament cognitiu vascular (DCV) i la (MA). Per aquest motiu, vàrem mesurar diversos biomarcadors sanguinis i de LCR en persones sanes i en persones amb diagnòstic de deteriorament cognitiu i vàrem relacionar-los amb canvis de l’estructura cerebral i de la cognició. L’objectiu final era identificar possibles biomarcadors pel diagnòstic precoç d’aquestes malalties. Els estudis I i II s’emmarquen dins del projecte Barcelona-ASIA Neuropsicologia i tenien com a objectiu estudiar la relació entre biomarcadors en plasma de malaltia vascular cerebral (MVC) i canvis estructurals i cognitius. Els resultats obtinguts mostren que els biomarcadors d’inflamació i trombosi vascular es relacionen amb un perfil de deteriorament cognitiu vascular tant a nivell cognitiu com estructural. La lesió microvascular dels tractes de SB còrtico-subcorticals mediaria l’associació entre aquests mecanismes i la cognició. Els marcadors de disfunció endotelial es relacionen amb un perfil cognitiu diferent, que és característic tant de processos vasculars com neurodegeneratius. L’estudi III té com a objectiu valorar el possible ús dels biomarcadors de líquid cefaloraquidi pel diagnòstic de la MA. En concret, vàrem estudiar els perfils estructurals i cognitius en persones amb deteriorament cognitiu emprant punts de tall de líquid cefaloraquidi com a criteri d’agrupació. Els resultats mostren que pacients amb DC i amb nivells patològics de t-tau i p-tau al LCR (però no d’Aβ1-42) presenten un perfil cognitiu i estructural de MA. En conclusió, els resultats obtinguts en la present tesi suggereixen que, complementaris a l’observació clínica, els biomarcadors de LCR i plasma, així com els indicadors de morfologia cerebral podrien ser d’ús pel diagnòstic precoç del DCL i la demència.
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Segura, Castell Mónica. "Peripheral blood biomarkers in Psychiatric Diseases". Doctoral thesis, Universitat Internacional de Catalunya, 2012. http://hdl.handle.net/10803/83727.
Texto completoResumen
Actually, there is a strong incidence of psychiatric diseases, representing a 13% of total burden diseases and 450 million of people affected. The etiology of psychiatric diseases remains unknown. However, scientific evidences suggest a maldevelopment of nervous system (NS). The diagnosis is inaccurate, and international manuals (ICD-10 and DSM-IV) identify pathologies according to a list of symptoms but no underlying biological cause of disease. The aim of the thesis is to identify potential biomarkers -related to the development of NS- in peripheral blood of psychiatric patients diagnosed as different mental diseases, such as autism spectrum disorders (ASD), schizophrenia and bipolar disorders. It is intended to contribute with the improvement of diagnostic, prognostic and treatment of subjects.
The thesis is divided into 4 chapters: 1) study of neurotrophins in ASD, where the results show the relationship of this family of molecules with the disease, 2) study of Latrophilin-3 (LPHN3) in the TEA, which was obtained in association with lower cognitive level of ASD, 3) study of the Eph-receptor A4 in the pathology of schizophrenia and bipolar disorder, results of which show no association, and finally 4) study of Ankyrin-3 (ANK3) in schizophrenia and bipolar disorder, which shown a relationship with bipolar disorder but not with schizophrenia.Actualment, hi ha una forta incidència de les patologies psiquiàtriques, representant un 13% del total de les malalties i 450 milions de persones afectades. L’etiologia de les patologies psiquiàtriques és desconeguda. Tot i així, evidències científiques suggereixen un mal desenvolupament del sistema nerviós (SN). El diagnòstic és poc precís, i els manuals internacionals (ICD-10 i DSM-IV) identifiquen les patologies d’acord a un llistat de símptomes, però sense cap causa biològica subjacent de la patologia. L’objectiu de la tesi és la identificació de biomarcadors potencials –relacionats en el desenvolupament del SN- en sang perifèrica de pacients diagnosticats amb diferents patologies mentals, com ara els trastorns de l’espectre autista (TEA), esquizofrènia i desordres bipolars. És pretén contribuir amb la millora del diagnòstic, el pronòstic i el tractament de les persones que les pateixen. La tesi s’estructura en 4 capítols: 1) estudi de les neurotrofines en els TEA, on els resultats evidencien la relació d’aquesta família de molècules amb la patologia, 2) estudi de la Latrofilina-3 (LPHN3) en els TEA, on s’ha obtingut associació amb el nivell cognitiu més baix dels TEA, 3) estudi del receptor EPH A4 en les patologies d’esquizofrènia i desordres bipolars, resultats del qual no mostren associació i, per últim 4) estudi de la Ankirina-3 (ANK3) en l’esquizofrènia i els desordres bipolars, en el qual si que es troba una relació amb els desordres bipolars, però no amb l’esquizofrènia.
Actualmente, hay una fuerte incidencia de las patologías psiquiátricas, representando un 13% del total de las enfermedades y 450 millones de personas afectadas. La etiología de las patologías psiquiátricas es desconocida. Aún así, evidencias científicas sugieren un mal desarrollo del sistema nervioso (NS). El diagnóstico es poco preciso, y los manuales internacionales (ICD-10 y DSM-IV) identifican las patologías de acuerdo a un listado de síntomas, pero sin ninguna causa biológica subyacente de la patología. El objetivo de la tesis es la identificación de biomarcadores potenciales –relacionados con el desarrollo del SN- en sangre periférica de pacientes diagnosticados con diferentes patologías mentales, como son los trastornos del espectro autista (TEA), esquizofrenia y desordenes bipolares. Se pretende contribuir en la mejora del diagnóstico, el pronóstico i el tratamiento de las personas que las padecen. La tesis se estructura en 4 capítulos: 1) estudio de las neurotrofinas en los trastornos del espectro autista (TEA), en el cual los resultados evidencian la relación de esta familia de moléculas con la patología, 2) estudio de la Latrofilina-3 (LPHN3) en los TEA, donde se ha obtenido una asociación con el nivel cognitivo más bajo de los TEA, 3) estudio del receptor EPH A4 en las patologías de la esquizofrenia y los desordenes bipolares, resultados del cual no muestran asociación y, por último 4) estudio de la Ankirina-3 (ANK3) en la esquizofrenia y los desordenes bipolares, en el cual si que se ha encontrado una relación con los desordenes bipolares, pero no con la esquizofrenia.
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Mena, Sandra. "Protein biomarkers analysis within muscular dystrophies". Thesis, KTH, Skolan för bioteknologi (BIO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215309.
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Bergman, Lina. "Cerebral biomarkers in women with preeclampsia". Doctoral thesis, Uppsala universitet, Institutionen för kvinnors och barns hälsa, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-322780.
Texto completoResumen
Preeclampsia and eclampsia are among the most common causes of maternal and fetal mortality and morbidity worldwide. There are no reliable means to predict eclampsia or cerebral edema in women with preeclampsia and knowledge of the brain involvement in preeclampsia is still limited. S100B and neuron specific enolase (NSE) are two cerebral biomarkers of glial- and neuronal origin respectively. They are used as predictors for neurological outcome after traumatic brain injuries and cardiac arrest but have not yet been investigated in preeclampsia. This thesis is based on one longitudinal cohort study of pregnant women (n=469, Paper I and III), one cross sectional study of women with preeclampsia and women with normal pregnancies (n=53 and 58 respectively, Paper II and IV) and one experimental animal study of eclampsia (Paper V). In Paper I and III, plasma concentrations of S100B and NSE were investigated throughout pregnancy in women developing preeclampsia (n=16) and in women with normal pregnancies (n=36) in a nested case control study. Plasma concentrations were increased in women developing preeclampsia in gestational week 33 and 37 for S100B and in gestational week 37 for NSE compared to women with normal pregnancies. In Paper II and IV, increased plasma concentrations of S100B and NSE were confirmed among women with preeclampsia compared to women with normal pregnancies. Furthermore, increased plasma concentrations of S100B correlated to visual disturbances among women with preeclampsia (Paper II) and plasma concentrations of S100B and NSE remained increased among women with preeclampsia one year after delivery (Paper IV). In Paper V, an experimental rat model of preeclampsia and eclampsia demonstrated increased serum concentrations of S100B after seizures in normal pregnancy (n=5) and a tendency towards increased plasma concentrations of S100B in preeclampsia (n=5) compared to normal pregnancy (n=5) without seizures. Furthermore, after seizures, animals with magnesium sulphate treatment demonstrated increased serum concentrations of S100B and NSE compared to no treatment. In conclusion; plasma concentrations of S100B and NSE are increased in preeclampsia during late pregnancy and postpartum and S100B correlates to visual disturbances in women with preeclampsia. The findings are partly confirmed in an animal model of eclampsia.
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Tran, Vanessa Hoang Medical Sciences Faculty of Medicine UNSW. "Breath biomarkers associated with lung cancer". Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43717.
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Lung cancer (LC) is often diagnosed at advanced stage and as a result, survival rates are low. Recent studies describe exhaled breath and exhaled breath condensate (EBC) as a potential non-invasive method of sampling the airways for assessing inflammation of the respiratory system, and possibly for the early detection of LC. It was hypothesised that higher concentrations of markers and protein will be present in the EBC of LC patients compared to those of normal controls and healthy smokers, and may aid in assessing lung status. Methods: The gaseous phase of breath was investigated for volatile organic compound (VOC) patterns using an electronic nose (eNose) system, in addition to off-line measurements of carbon monoxide (CO) and nitric oxide (NO) levels. The aqueous phase, EBC, was collected during tidal breathing through a glass collection device cooled to 4??C by ice. Nitrite/nitrate (NOx) and pH levels were determined by a fluorescent modification of the Griess method, and silicon chip sensor pH meter, respectively. Protein levels in EBC were examined with a bicinchoninic acid (BCA) assay, silver staining and PAGE techniques, while the levels of tumour markers, CYFRA 21-1 and CEA, were quantified by enzyme-linked immunosorbent assays (ELISA). Results: The eNose machine was not able to produce characteristic VOC profiles from exhaled breath unique to each study group, while no significant difference was observed for mean NOx concentrations in the LC group when compared to other subjects (p=0.8824). Higher protein levels were found in the EBC of LC patient compared to normal controls (p=0.0204), with subsequent measurements of elevated CEA levels observed in the LC group when compared to non-smokers and smokers (p=0.023). Conclusion: This study showed that protein can be detected in the exhaled breath condensate of patients, with a significantly elevated amount in the samples from newly diagnosed LC patients. The mechanism for these differences remains to be determined but may be related to inflammatory changes within the airway, such as vascular protein leakage and release of mediators. Future work may aim to identify the upregulated proteins, and focus on proteomics and tissue microarrays to explore candidate proteins.
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LaPointe, Lawrence C. y larry lapointe@flinders edu au. "Gene expression biomarkers for colorectal neoplasia". Flinders University. School of Medicine, 2009. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20091011.090028.
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The aim of this research was to assemble sufficient experimental evidence about candidate gene transcript expression changes between non-neoplastic and neo- plastic colorectal tissues to justify future assay development involving promis- ing leads. To achieve this aim, this thesis explores the hypothesis that gene expression-based biomarkers can be used to accurately discriminate colorectal neoplastic tissues from non-neoplastic controls.
This hypothesis was tested by first analysing multiple, large, quality controlled data sets comprising gene expression measurements across colorectal phenotypes to discover potential biomarkers. Candidate biomarkers were then subjected to validation testing using a custom-design oligonucleotide microarray applied to independently derived clinical specimens. A number of novel conclusions are reached based on these data. The most important conclusion is that a defined subset of genes expressed in the colorectal mucosa are reliably differentially ex- pressed in neoplastic tissues. In particular, the apparently high prediction accu- racy achieved for single gene transcripts to discriminate hundreds of neoplastic and non-neoplastic tissues provides compelling evidence that the resulting can- didate genes are worthy of further biomarker research.
In addition to addressing the central hypothesis, additional contributions are made to the field of colorectal neoplasia gene expression profiling. These contributions include:
The first systematic analysis of gene expression in non-diseased tissues along the colorectum To better understand the range of gene expression in non-diseased tissues, RNA extracts taken from along the longitudinal axis of the large intestine were studied.
The development of quality control methodologies for high dimen- sional gene expression data Complex data collection platforms such as oligonucleotide microarrays introduce the potential for unrecognized confound- ing variables. The exploration of quality control parameters across five hundred microarray experiments provided insights about quality control techniques.
The design of a custom microrray comprised of oligonucleotide probe- sets hybridising to RNA transcripts differentially expressed in neo- plastic colorectal specimens A custom design oligonucleotide microarray was designed and tested combining the results of multiple biomarker discovery projects.
Introduction of a method to filter differentially expressed genes dur- ing discovery that may improve validation efficiencies of biomarker discovery based on gene expression measurements Differential expression discovery research is typically focused only on quantitative changes in transcript concentration between phenotype contrasts. This work introduces a method for generating hypotheses related to transcripts which may be quali- tatively switched-on between phenotypes.
Identification of mRNA transcripts which are differentially expressed between colorectal adenomas and colorectal cancer tissues Transcripts differentially expressed between adenomatous and cancerous RNA extracts were discovered and then tested in independent tissues.
In conclusion, these results confirm the hypothesis that gene expression profiling can discriminate colorectal neoplasia (including adenomas) from non-neoplastic controls. These results also establish a foundation for an ongoing biomarker development program.
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Huang, Ying. "Evaluating the predictiveness of continuous biomarkers /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/9558.
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Dong, Jianchun. "Label free electronic detection of biomarkers /". Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/5893.
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Hui, King-cheung y 許景祥. "Biomarkers for esophageal squamous cell carcinoma". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41634020.
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Schneider, Katja Susanne Annika. "Electrophysiological biomarkers in genetic movement disorders". Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/15926/.
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Background: Neurodegenerative diseases are diseases of the nervous system with progressive course leading to death. Treatment remains symptomatic. Development of neuroprotective agents has been hampered for various reasons. This includes the inability of making the diagnosis accurately early in the course and the lack of reliable disease progression markers which could be used in future treatment trials. Transcranial magnetic stimulation (TMS) is a non-invasive and pain-free method for assessment of brain function. Methods: Here we evaluated TMS and its potential of serving as a reliable biomarker for neurodegenerative diseases with genetic cause. After clinical delineation of our patient cohorts with Huntington's chorea and young-onset Parkin-related Parkinsonism, we enrolled both patients as well as asymptomatic/presymptomatic gene-carriers. Patients, carriers and age-matched healthy controls were studied using TMS to establish an electrophysiological footprint of these conditions. Results: We found abnormalities in electrophysiological parameters which were present in manifesting patients and/or non-manifesting gene mutation carriers. In HD, both presymptomatic and early manifest patients had increased resting and active motor cortex thresholds. Short afferent inhibition (SAI), a measure of sensory-motor integration, was reduced in manifesting patients only. SAI changes were inversely correlated with clinical parameters like predicted years to onset and UHDRS motor score. Abnormalities in Parkin patients included prolonged central motor conduction time (CMCT), while thresholds and cortical inhibitory activity were normal. Asymptomatic carriers had increased motor thresholds and abnormal inhibitory measures (SICI recruitment) while CMCT was normal. Conclusion: We conclude that TMS may be a potential biomarker for neurodegenerative genetic diseases: 1) to detect changes early in the disease course and to monitor disease progression; 2) to help differentiating between clinically similar diseases on the basis of certain electrophysiological patterns; and 3) to give insight into underlying mechanisms of the disorders studied. Our findings suggest the potential for future research.
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Wilson, Richard Henry. "Biomarkers of risk in colorectal cancer". Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.337047.
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