Evaluation of blood-based microRNAs toward clinical use as biomarkers in common and rare diseases

According to the GLOBOCAN project of the International Agency for Research on Cancer, the top three common cancer diseases worldwide in the year 2020 were breast, lung and colorectal cancer. These are usually diagnosed via imaging methods (e.g. computer tomography) or invasive methods (e.g. biopsy). However, these techniques are potentially risky and expensive and thus not accessible to all patients, resulting in most cancers being detected in an advanced stage. Since the discovery of small non-coding RNAs and specifically microRNAs and their role as gene regulators, many researchers investigate their association with disease development. In particular, researchers examine body fluid based microRNAs which could present potential cost-effective and minimally- or non-invasive alternatives to the previously described established diagnosis methods. This dissertation focuses on microRNAs and investigates their suitability as minimally-invasive blood-borne biomarkers for potential diagnostic purposes. More specifically, the goals of this work are (1) to implement a new method to predict novel microRNAs, (2) to understand stability and characteristics of these small non-coding RNAs, possibly relevant for the last goal, (3) to discover potential diagnostic biomarkers in common and rare diseases. The first goal was addressed by developing miRMaster, a web service to predict new microRNAs. The tool uses machine learning and high-throughput sequencing data to find microRNA candidates that follow the known biogenesis pathways. The second goal was pursued in four publications. First, we performed a large scale evaluation of miRMaster by generating a high-resolution map of the human small non-coding RNA transcriptome for which we analyzed and validated potential microRNA candidates. Next, we examined the influence of seasonal effects on microRNA expression profiles and observed the largest difference between spring and the other seasons. Additionally, we evaluated the evolutionary conservation of small non-coding RNAs in zoo animals and showed that the distribution of sncRNA classes varies across species, while common microRNA families are present in more diverse organisms than assumed so far. Furthermore, we analyzed if microRNAs are technically stable, and whether biological variation is preserved when using capillary dried blood spots as an alternative sample collection device to venous blood specimens. Finally, we investigated the suitability of microRNAs as biomarkers for two diseases: lung cancer and Marfan disease. We identified blood-borne biomarker candidates for lung cancer detection in a large-scale multi-center study via machine learning. For the rare Marfan disease we analyzed the paired messenger RNA and microRNA expression levels in whole-blood samples. This highlighted several significantly deregulated microRNAs and messenger RNAs, which we subsequently validated in an independent cohort. In summary, this thesis provides valuable results toward potential clinical use of microRNAs, and the herein described projects represent comprehensive analyses of them from different perspectives: starting with microRNA discovery, addressing various technical and biological questions and ending with the potential use as biomarkers.Nach Angaben des GLOBOCAN-Projekts der International Agency for Research on Cancer sind die drei häufigsten Krebserkrankungen weltweit im Jahr 2020 Brust-, Lungen- und Darmkrebs. Diese werden in der Regel durch bildgebende Verfahren (z.B. Computertomographie) oder invasive Methoden (z.B. Biopsie) diagnostiziert. Diese Verfahren sind jedoch potenziell risikoreich und teuer und daher nicht für alle Patienten zugänglich. Dies führt dazu, dass die meisten Krebsarten erst in einem fortgeschrittenen Stadium entdeckt werden. Seit der Entdeckung der kurzen nichtkodierenden RNAs und insbesondere der microRNAs und ihrer Rolle als Genregulatoren untersuchen viele Forscher ihren Zusammenhang mit der Krankheitsentwicklung. Insbesondere untersuchen die Forscher die in Körperflüssigkeiten vorkommenden microRNAs, die potenziell kosteneffiziente und minimal- oder nicht-invasive Alternativen zu den bisher beschriebenen etablierten Diagnosemethoden darstellen könnten. Diese Dissertation konzentriert sich auf microRNAs und untersucht deren Eignung als minimal-invasive blutbasierte Biomarker für potenzielle diagnostische Zwecke. Genauer gesagt sind die Ziele dieser Arbeit (1) die Implementierung einer neuen Methode zur Vorhersage neuartiger microRNAs, (2) das Verständnis über die Stabilität und Charakteristika dieser kurzen nicht-kodierenden RNAs, die möglicherweise für das nächste Ziel relevant sind, (3) die Entdeckung potenzieller diagnostischer Biomarker für verschiedene Anwendungen. Das erste Ziel wurde durch die Entwicklung von miRMaster verfolgt, einem Webdienst zur Vorhersage neuer microRNAs. Das Tool nutzt maschinelles Lernen und Hochdurchsatz-Sequenzierungsdaten, um microRNA-Kandidaten zu finden, die den bekannten Wege der Biogenese folgen. Das zweite Ziel wurde in vier Veröffentlichungen verfolgt. Zunächst führten wir eine groß angelegte Evaluierung von miRMaster durch, indem wir eine High-Resolution Map des menschlichen Transkriptoms kurzer nichtkodierender RNAs erstellten, für die wir potenzielle microRNA-Kandidaten analysierten und validierten. Anschließend untersuchten wir den Einfluss saisonaler Effekte auf die microRNA-Expressionsprofile und beobachteten den größten Unterschied zwischen dem Frühling und den anderen Jahreszeiten. Darüber hinaus untersuchten wir die evolutionäre Erhaltung kurzer nichtkodierender RNAs in Zoo-Tieren und zeigten, dass die Verteilung der kurzer nichtkodierenden RNA-Klassen zwischen den Arten variiert, während gemeinsame microRNA-Familien in verschiedeneren Organismen vorkommen als bisher angenommen. Darüber hinaus analysierten wir, ob microRNAs technisch stabil sind und ob die biologische Variation erhalten bleibt, wenn kapillares Trockenblut als alternatives Probenentnahmeverfahren zu venösen Blutproben verwendet werden. Schließlich untersuchten wir die Eignung von microRNAs als Biomarker für zwei Krankheiten: Lungenkrebs und Marfan-Krankheit. In einer groß angelegten multizentrischen Studie identifizierten wir mit Hilfe von maschinellem Lernen Biomarker-Kandidaten aus dem Blut für die Erkennung von Lungenkrebs. Für die seltene Marfan-Krankheit analysierten wir die gepaarten Expressionsniveaus von messengerRNA und microRNA in Vollblutproben. Dabei wurden mehrere signifikant deregulierte microRNAs und messengerRNAs festgestellt, die wir anschließend in einer unabhängigen Kohorte validierten. Zusammenfassend lässt sich sagen, dass diese Arbeit wertvolle Ergebnisse im Hinblick auf die potenzielle klinische Verwendung von microRNAs liefert. Die hier beschriebenen Projekte stellen umfassende Analysen aus verschiedenen Blickwinkeln dar: angefangen bei der Entdeckung von microRNAs, über verschiedene technische und biologische Fragen bis hin zur potenziellen Verwendung als Biomarker

Kavisli Ahşap Lamine Elemanlarda Biçim (Form) Kararlılığı Performansının Belirlenmesi

The following determines performance stability of curved laminated wood elements made with a vacuum membrane press. For this purpose, 13 layers of 1.5 mm thick beech (Fagus orientalis Lipsky), sessile oak (Quercus petrean Liebl) and pine (Pinus sylvestris) veneer layers were glued with D4 adhesive using a vacuum membrane press and curved laminated wood samples were prepared. Diagonal compression test was applied on the prepared samples. The highest diagonal compression strength difference found between beech laminate and oak laminate was statistically insignificant. Most low strength samples consisted of laminated pine.Bu çalışmada, vakumlu membran preste üretilmiş kavisli ahşap lamine elemanların biçim (form) kararlılığı performanslarının belirlenmesi amaçlanmıştır. Bu amaca uygun olarak 1,5 mm kalınlığında Doğu kayını (Fagus orientalis Lipsky), sapsız meşe (Quercus petrean Lieble) ve sarıçam (Pinus sylvestris) papel kaplamalar, PVAc dispersiyonu D4 tutkalı ile vakumlu membran preste yapıştırılarak 13 katmandan oluşan kavisli lamine ahşap örnekler hazırlanmıştır. Hazırlanan numunelere diyagonal basma direnci deneyi uygulanmıştır. Sonuç olarak, diyagonal basınç direnci en yüksek kayın laminasyonda çıkarken meşe laminasyon ile arasındaki fark istatistiksel olarak önemsiz çıkmıştır. En düşük direnç değerini sarıçam laminasyon örnekler vermiştir

Examination of prospective science teachers’ achievement on basic geography topics and effectiveness of poster-based teaching for learning these topics

The purposes of this study were to examine prospective teachers’ achievement levels in basic geography topics and the effectiveness of a poster–based teaching for learning these topics. For the first goal, the study used an ex post facto quantitative research design, and the achievement level was quite low. The reason for this might be defective teaching methods, and it was needed to study an effective teaching method. For the second goal, the study used a one–group pre–posttest quasi–experimental research design, and the treatment was quite effective

Total serum protein predicted mortality in patients with st-elevation myocardial ınfarction who underwent primary percutaneous coronary ıntervention: Results of 8-year follow-up

Objectives: ST-elevation myocardial infarction (STEMI) is globally one of the leading causes of mortality. Determining modifiable mortality predictors to improve outcomes is critical. Total serum protein (TSP) is a composite indicator of immunity, nutrition, and inflammation and it plays a vital role in biological pathways contributing to cardiovascular diseases. TSP level has not been evaluated in patients with STEMI in the prediction of mortality previously. Materials and Methods: The patients diagnosed with STEMI between March 2007 and May 2009 were included in the study. TSP was obtained at admission to the hospital. Follow-up period of the study was 8 years and primary endpoint was all-cause mortality. Participants were separated according to the presence of mortality and clinical parameters compared between these two groups. Results: The mean age of the total 99 patients was 61±12.4 years and 82 (82.8%) of them were male. While left ventricular ejection fraction (LVEF) (p=0.001), serum albumin (p=0.014), and TSP (p<0.001) were lower, serum creatinine was higher (p=0.003) in the mortality group. Diabetes mellitus (p=0.007), increased age (p=0.027), LVEF (p=0.006), serum creatinine level (p=0.023), and TSP (hazard ratio: 0.159, 95% confidence interval: 0.062-0.408, p<0.001) predicted mortality independently. Conclusion: TSP level predicted all-cause mortality independently in STEMI patients who underwent primary percutaneous coronary intervention during 8-year follow-u

Antioxidant Defense System in Behcet’S Disease

DergiPark: 379004tmsjBehcet’s disease (BD), first described by the Turkish dermatologist Hulusi Behcet in 1937, is characterized by triad of symptoms that include oral aphthous lesions, genital ulcerations and iritis with hypopyon. The etiopathogenesis is not yet fully explained, although reactive oxygen species produced (ROS) by the hyperfunction of neutrophils which are significant for the immune response are thought to play a role. Antioxidant defense system protects the body against the harmful effects of reactive oxygen species. Normally, there is a balance between reactive oxygen species and antioxidant defense system but as levels of reactive oxygen species are above the body’s neutralization and elimination ability disrupts the balance. With the imbalance, increased levels of reactive oxygen species disrupt biomolecules such as lipids, proteins, nucleic acids and cause cell, tissue and organ damage. Studies with parameters associated with antioxidant defense system are included in our study. When viewed as whole, most of the studies support that imbalance between oxidants/antioxidants plays a role in etiopathogenesis of Behcet’s disease but it should not be forgotten that there are studies show otherwise. Reactive oxygen species affect patients with active disease more than patients with inactive disease. In conclusion, studies classified in detail with larger group of patients on Behcet’s disease are needed. If patients’ clinical findings and levels of oxidants and antioxidants are interpreted together in the studies, they can be used to monitor the disease and success of the therap

A Radiographic Study of Location of Mental Foramen in a Selected Turkish Population On Panoramic Radiograph

Purpose of this study was to investigate the most common position of the mental foramen in a selected Turkish population. The study sample included three hundred and sixty one panoramic radiographs of selected Turkish population taken in Faculty of Dentistry, University of Gazi. The most common position of the mental foramen was between the first premolar and the second premolar (71.5%). The mental foramen was symmetrical in 90.4% of patients. In this study, the difference of the location of the mental foramen in different ethnics groups was discussed. Clinicians and anthropologists should expect to find the position of the mental foramen to be symmetrical and between the first premolar and the second premolar teeth