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1
Kon, Samantha Swee Chin. "Habitual gait speed : a novel prognostic marker in COPD?" Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/56925.
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Forced expiatory volume in one second (FEV1) is the most widely accepted marker in COPD. However, COPD is now well recognised as a multisystem and heterogeneous disease, and it is unlikely that a single marker could reflect the complex range of observed pathophysiologic changes. Exercise intolerance is a common symptom in COPD, and reflects both lung and skeletal muscle dysfunction. Logistical issues often mean physical performance is not routinely measured objectively in all clinical settings. Gait speed is an easy, quick to perform established measure of physical performance in the elderly, and has been recommended as a “vital sign” or “global marker of well-being” that reflects biological rather than chronological age. Functional decline is common to both ageing and COPD but gait speed has not been validated in COPD. In 586 patients with stable COPD, usual gait speed over 4 metres (4MGS) had excellent reliability and showed concurrent validity with well-established measures in COPD. Stratification according to slow 4MGS identified significant impairments in exercise capacity and poor health-related quality of life. Subsequent studies showed that 4MGS was responsive to intervention with pulmonary rehabilitation (n=301) and longitudinal decline at one year (n=162). Using both distribution- and anchor-based approaches the minimum clinically important difference was estimated to be 0.11ms-1. In a cohort of patients with stable COPD (n=402), slower 4MGS was associated with significantly increased risk of all-cause mortality at three years, and provided prognostic information independent of FEV1. In a prospective cohort of 213 patients admitted to hospital with an acute exacerbation of COPD, slower 4MGS was associated with significantly increased odds of all-cause readmission at 90 days. The 4MGS is a reliable measure of physical performance that has potential utility as a simple assessment tool to provide a more comprehensive assessment of patients with COPD.
2
Holtkötter, Hannah [Verfasser]. "Novel marker systems for forensic body fluid identification / Hannah Holtkötter." Ulm : Universität Ulm, 2018. http://d-nb.info/1166756602/34.
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Gahunia, Harpal Kaur. "A novel cartilage biochemical marker (CM-1), isolation, purification and characterization." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape9/PQDD_0020/NQ45732.pdf.
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Juhász, Margit Lai Wun. "Murine CD248 and its cytoplasmic domain : characterising a novel tumour and inflammation marker." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/42573.
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CD248 is a member of a family of transmembrane glycoproteins containing an N-terminal C-type lectin-like domain. This family includes thrombomodulin and CD93, proteins known to modulate immunity, cell proliferation and homeostasis. CD248 is expressed in perivascular and stromal cells, during embryonic development and post-natally during inflammation and cancer. In the mesenchymal compartment of most normal adult tissues, CD248 expression is not detectable. It is believed that CD248 is involved in cross-talk between endothelial cells and pericytes, thereby playing a role in growth, metastasis and angiogenesis associated with the development of tumours and inflammatory lesions.
Intracellular signaling, mediated via the cytoplasmic domain of CD248, promotes tumour growth and inflammation. CD248 knock-out mice and mice expressing CD248 lacking the cytoplasmic domain were resistant to tumour growth and inflammatory arthritis. Although signaling pathways have not been delineated, examination of the cytoplasmic domain of CD248 reveals three highly conserved putative phosphorylation sites and a PDZ-binding motif. We hypothesised that these structural features are important for CD248 function.
We generated a variety of murine CD248 pcDNA constructs that encode CD248 with mutations in the cytoplasmic domain. We confirmed that all the mutants were transcribed and translated. Mutant proteins were expressed on the cell surface, in a similar manner to wildtype CD248. Introduction of some mutant forms CD248 into cells caused CD248 to exhibit different intracellular localisation and induced changes in cellular morphology compared to wildtype. Limited functional studies demonstrated CD248-dependent alterations in cellular MMP-9 production. The findings underline an important role of CD248’s cytoplasmic domain in regulating cellular morphology and function that may impact its role in health and disease.
Extracellular interacting partners for CD248 have been previously described. Searches for intracellular partners interacting with the cytoplasmic domain have been less successful. Our results strongly suggest that these exist. Co-immunoprecipitation studies have revealed several putative interacting proteins that set the stage for future confirmatory and functional analyses.
The cytoplasmic domain of CD248 is important to study as it holds much promise as a therapeutic target for proliferative disorders. The information gathered in this project may be used to delineate clinically relevant CD248 signaling pathways.
5
Лобода, Андрій Миколайович, Андрей Николаевич Лобода, Andrii Mykolaiovych Loboda, and M. Tutuola. "Cystatin C - A novel marker of kinder injury in the newborns with asphyxia." Thesis, Сумський державний університет, 2013. http://essuir.sumdu.edu.ua/handle/123456789/32303.
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In clinical practice, kidney injury is detected when serum creatinine concentrations increase over a short period of time, with or without oliguria. To assess renal function in neonates is used determination of glomerular filtration rate (GFR) after creatinine. But creatinine concentration is not a decisive marker. Changes in serum creatinine may be influenced by other factors, which are not directly related to kidney damage, such as age, sex, body mass and nutritional status.
When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/32303
6
Akarca, Ayse. "Immunohistochemical studies for identification of biomarkers in haematological malignancies: An approach for potential novel therapeutic targets." Doctoral thesis, Università di Siena, 2021. http://hdl.handle.net/11365/1127626.
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Lymphoid neoplasms are a subgroup of haematological malignancies that affect circulating lymphocytes. The clinical and biological heterogeneity of lymphoid neoplasms can lead to difficulty in accurate diagnosis in this group of diseases. The advancement in effective and feasible detection platforms has enabled novel biomarkers to improve diagnosis and prognosis, in addition to assist in patient stratification and personalised treatments for these diseases. Although there have been improvements in high-throughput diagnostic techniques, the conventional immunohistochemistry (IHC) remains the most widely used platform for biomarker assessment in the field of tissue pathology. As this conventional technique has certain limitations, multiplex IHC (MIHC) approaches have found ways to overcome these challenges, therefore becoming the main focus of immunotherapy for lymphoid neoplasms. This particular effective and proficient technology can simultaneously target multiple molecule/protein of interest within the tumor microenvironment to determine the status of immune cell activation and the presence of protein expression. MIHC is advantageous in providing information about the underlying immune evasion mechanisms, which play a vital role in the development of prognostic and diagnostic biomarkers. This thesis focuses on the novel use of IHC/MIHC approaches and their current role in biomarker development to be used in diagnosis, prognosis, and the potential treatment strategies within haematological malignancies in specific lymphoid neoplasms.
7
Traore, Karim. "Characterization of novel rice germplasm from West Africa and genetic marker associations with rice cooking quality." Texas A&M University, 2005. http://hdl.handle.net/1969.1/4146.
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Genetic resource enhancement is the foundation of any good breeding program.
Landraces from West Africa, interspecifics between Oryza sativa and Oryza glaberrima
and improved lines from the West African Rice Development Association and other
research centers were introduced to the Beaumont Rice Research center for in situ
evaluation and characterization. Beside the introduction of seeds, milled samples were
also introduced for grain chemistry analysis. Field evaluation combined with physicochemical
and molecular characterization revealed unique characteristics among African
germplasm. New rice for Africa (NERICA) lines performed well in the USA
environment. Varieties like Nerica 2, Nerica 3, Nerica 4, and Nerica 5 need more
attention because of their superior performance in yield and grain quality. Landraces did
not perform well due to their height and late maturity and their resulting problems with
lodging. The rapid visco analyzer RVA profiles showed that the cultivar Jaya has
unusually strong paste viscosity features. Comparing West Africa samples grown in
Cote dâÂÂIvoire with those grown in Texas, parameters like AA, ASV, Hot, Cool, and CT
were not stongly affected by the environment. According to the Stbk value, cultivars grown in Cote dâÂÂIvoire will cook softer than when they were grown in Texas. The lack
of the environmental effect is somewhat surprising considering the difference in latitude,
soil types, weather patterns, and management practices between the two locations.
Apparent amylose is a key element to characterize a rice cultivar; however certain
varieties like Cocodrie and Dixiebelle have similar apparent amylose content but
dramatically different functional qualities. A population derived from Cocodrie and
Dixiebelle was developed for genotypic and phenotypic analysis of grain chemistry traits
that affect functionality. It was concluded that the amount of soluble amylose in the
grain had a significant effect on flour pasting properties, even when total apparent
amylose content did not vary. Marker association studies revealed that the Waxy
microsatellite and the Waxy exon 10 SNP markers were associated with soluble amylose
content and RVA characteristics. These markers will speed up the development of new
rice cultivars with desirable quality characteristics in West Africa and in the USA.
8
Gasca, Stéphan Emmanuel. "Cordon-bleu, a novel murine developmental marker gene isolated by a gene trap approach." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0020/NQ27650.pdf.
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Limb, Marie. "MUC1 mucin as a tumour marker : investigations into a novel immunoassay and reagent development." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.395584.
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Rolan, Paul Edward. "The exploratory clinical development of tucaresol, an antisickling agent, using a novel surrogate marker /." Title page, contents and abstract only, 1995. http://web4.library.adelaide.edu.au/theses/09M.D/09m.dr744.pdf.
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Thesis (M.D.)--University of Adelaide, Dept of Clinical and Experimental Pharmacology, 1995.<br>Copies of author's previously published articles inserted. Describes the exploratory clinical development of tucaresol, consisting of three studies performed on humans and subsequent in vitro and animal studies investigating the possible effects on the immune system. Demostrates that rational drug design may be an efficient way of selecting potential therapeutic candidates.
11
Aladowicz, E. "RALP, A NOVEL PROGNOSTIC MOLECULAR MARKER IN MELANOMA, IS INVOLVED IN THE NOTCH PATHWAY." Doctoral thesis, Università degli Studi di Milano, 2011. http://hdl.handle.net/2434/155518.
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Melanoma is an aggressive disease with high metastatic potential and resistance to cytotoxic agents. Early-stage melanomas can be successfully cured by surgery and, as in all solid tumours, morbidity and mortality of melanoma are a consequence of local invasion and metastatic spread. The molecular mechanisms involved in the progression of the malignancy, the genetic markers associated to metastatic melanoma dissemination and the acquisition of chemoresistance are only beginning to be defined. An understanding of the molecular biology of melanoma provides a necessary basis to enable the generation of more effective therapeutic modalities.
RaLP, a new member of the SHC family of adaptor proteins was previously characterized in our laboratory as a determinant in the regulation of migration of melanoma cells in short-term assays in vitro. In this study we further characterized the role of RaLP in the progression of melanoma. We have verified that the expression of RaLP significantly correlates with the most important prognostic markers of melanoma (Breslow thickness, Clark’s level of invasion, ulceration, mitotic index and presence of metastasis in lymph nodes) and that patients with RaLP expressing tumours had reduced disease-free survival and overall survival, suggesting that RaLP can be identified as a novel prognostic molecular marker and an independent prediction factor of melanoma progression. We have shown that permanent RaLP silencing does not interfere with the proliferation of three different metastatic melanoma cell lines, while it significantly decreases their migration and this phenomenon was observed even after extended time in culture. The phenotype could be rescued by the overexpression of RaLP in the silenced cells, suggesting that RaLP is a central molecule that positively regulates migration of melanoma cells. Besides regulating migratory abilities of the melanoma cells, RaLP positively influences their invasive potential, by regulating collagen matrix digestion. We also tested cell – cell and cell – ECM adhesion abilities of melanoma cells after RaLP ablation. We observed that RaLP decreases adhesion of the cells to each other in cell – cell adhesion assays and negatively regulates adhesion of melanoma cells to different matrices in cell – ECM adhesion assay. Analyzing gene expression profiles of RaLP – proficient and – deficient cells we have shown that RaLP is involved in the regulation of the NOTCH molecular pathway.
Our in vitro studies suggest that RaLP expression in melanoma might facilitate dissociation of metastatic cells from a tumour mass by loosening cell – cell adhesion, and favour invasion of the surrounding tissues. We still do not know the exact signalling cascade by which RaLP regulates cell motility and adhesion processes and additional studies are necessary to fully understand its role in melanoma progression.
12
Konieczny, Marek [Verfasser], and Marco [Akademischer Betreuer] Düring. "Clinical application of novel marker for cerebral small vessel disease / Marek Konieczny ; Betreuer: Marco Düring." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1229835636/34.
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Dräger, Carolin [Verfasser]. "Safety and efficacy of a novel live marker vaccine against Classical swine fever virus / Carolin Dräger." Greifswald : Universitätsbibliothek Greifswald, 2017. http://d-nb.info/1124411291/34.
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Losito, O. F. "Doing without antibiotics : the pMB1 origin of replication as a novel selectable marker in enteric bacteria." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1384826/.
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Plasmids are used in the biopharmaceutical industry for the production of recombinant proteins, recombinant DNA for DNA vaccines and as non-viral vectors for gene therapy. Antibiotic- resistance genes are used for plasmid selection and to ensure plasmid maintenance. Regulatory bodies like the European Medicines Agency have introduced guidelines to limit the use of antibiotics and their resistance genes in the manufacture of therapeutics. Therefore, it is important to develop novel, effective methods for antibiotic-free plasmid selection. Cobra Biologics has designed a novel mechanism for antibiotic-free plasmid selection called oriSELECT. oriSELECT uses RNAI and RNAII, the antisense RNAs of the pMB1 plasmid origin of replication (ori) as the selectable marker. These two RNAs are involved in replication and its control of almost all plasmid vectors used commercially and academically. By placing the RNAII sequence in the E. coli chromosome upstream of either a toxic gene or a repressor for an essential gene, cell growth should be inhibited. In cells containing a plasmid with the pMB1 replicon producing RNAI, transcription of the growth inhibitor is blocked allowing cell growth and survival. This work describes the testing of various cassettes useful for oriSELECT and the construction of oriSELECT strains.
15
Smit, Corneli. "Pyramiding of novel rust resistance genes in wheat, utilizing marker assisted selection and doubled haploid technology." Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85613.
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Thesis (MSc)--Stellenbosch University, 2013.<br>ENGLISH ABSTRACT: Wheat rust, caused by the Puccinia spp., is a global biotic cause of wheat yield losses. This disease can effectively be combatted by implementing rust resistant wheat cultivars. The release of new resistant wheat cultivars is however prolonged due to the time needed to fix resistance genes in a good quality background and develop pure breeding wheat lines. The aim of this study was the pyramiding of novel species derived leaf and stripe rust resistance genes in bread wheat lines through the utilization of high throughput marker assisted selection and microspore derived doubled haploid technology.<br>AFRIKAANSE OPSOMMING: Koringroes het wêreldwyd verliese in koringopbrengste tot gevolg. Dit word veroorsaak deur die Puccinia fungi. Hierdie siekte kan effektief beveg word deur die verbouing van roesbestande kultivars. Die vrystel van nuwe weerstandbiedende kultivars is egter ‘n langdurige proses weens die tyd verbonde daaraan om weerstandsgene te fikseer in ‘n genetiese agtergrond met ‘n goeie kwaliteit en om dan suiwertelende lyne te ontwikkel. Die doelwit van hierdie studie was om nuwe spesie-verhaalde blaar- en streeproes weestandsgene in koringlyne te stapel met behulp van merker bemiddelde seleksie en mikrospoor geassosieerde verdubbelde haploïede tegnologie.
16
Shyshynova, Inna. "A Novel Approach to Identification of Diagnositc Markers in Prostate Cancer." Case Western Reserve University School of Graduate Studies / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1152729787.
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Konishi, Sayuri. "A transmembrane glycoprotein,gp38,is a novel marker for immature hepatic progenitor cells in fetal mouse livers." Kyoto University, 2011. http://hdl.handle.net/2433/147338.
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Scivoletto, Salvatore. "A novel marker for heart failure: Cross sectional area assessment in a large vein by conductance catheter." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2015. http://amslaurea.unibo.it/8513/.
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The present study investigates the feasibility of a new application able to check the heart failure status in a patient through the estimation of the venous distension. In this way it would be possible to follow up patients, avoiding invasive or expensive exams such as cardiac catheterization and echocardiography. Moreover, the devices would also be able to diagnose the decline of the disease, in order to allow a new adaptation to therapy, and vice versa to check the improvement in the patient’s conditions after the CRT device implant.
This thesis is essentially divided into three parts: an analytical model was used to obtain an estimation of the error committed for the calculation of the CSA and to understand how the accuracy and sensitivity depend on the different configurations of the electrodes and the catheter position inside the vein; secondly, an in-vitro experiment was carried out in order to verify the practical feasibility for these kinds of measurements, in a very simplified model; in the end, several animal experiments were done to test the in-vivo practicability of the proposed method.
The obtained results showed the feasibility of this approach. In fact, the error committed in the estimation of CSA, during the animal experiments, can be considered acceptable (CSAerror_max ≈ -14%). Moreover, it has been demonstrated that the conductance catheter allows assessing, not only the vein CSA, but also the breathing of the animal.
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Hochschartner, Gerald. "Revealing the past : the potential of a novel small nucleolar RNA (snoRNA) marker system for studying plant evolution." Thesis, University of St Andrews, 2011. http://hdl.handle.net/10023/1695.
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Despite the existence of various molecular marker systems there are still limitations in distinguishing between closely related species based on molecular divergence, especially when hybridization events have occurred in the past. The characterisation of plant small nucleolar RNA (snoRNA) genes and their organisation into multigene clusters provides a potential nuclear marker system which could help in resolving the phylogenetic history of plants and might be applicable in DNA barcoding. Using closely and distantly related Senecio species, I investigated a combination of fragment length and sequence variation of snoRNA genes/snoRNA gene clusters to assess the utility of this marker system for barcoding and resolving species relationships. SnoRNA gene and gene cluster sequences identified in Arabidopsis thaliana were used to find homologues in other species and subsequently used for the design of universal primers. Most of the universal primer pairs designed were successful in amplifying snoRNA fragments in most Senecio species and fragment length variation between and within species could be detected. Furthermore, the combination of some fragment length datasets produced by different primer pairs enabled the separation of species and the detection of reticulate evolution indicating a high potential of snoRNA gene/gene cluster fragment length polymorphisms (SRFLPs) for phylogenetic reconstructions in Senecio and other plant genera. Most of the examined gene clusters showed a similar gene order in Senecio and Arabidopsis. However, the majority of these clusters appeared to exhibit more copies in Senecio, some of which were distinguishable by a combined sequencing/fragment profiling approach, and shown to be putative single copy regions with the potential to be used as co-dominant markers. However, a high number of paralogues and possible differences in copy number between species excludes these regions from being used in DNA barcoding. This is because specific primers would have to be developed for specific copies which would preclude development of a universal application for barcoding. None of the regions showed enough sequence variation to delimit distinctly closely related Senecio species and were therefore also considered to be unsuitable for DNA barcoding. Although most snoRNA genes and gene clusters might be inapplicable for DNA barcoding, they are likely to be valuable for phylogenetic studies of species groups, genera and families. On this scale, specific primers might act universally and the number of paralogous copies is likely to be equal across the species group of interest.
20
Lambert, Carol-Ann. "A novel marker technique : using miniature inverted-repeat transposable elements (MITEs) in combination with resistant gene analogues (RGAs)." Thesis, Stellenbosch : Stellenbosch University, 2001. http://hdl.handle.net/10019.1/52117.
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Thesis (PhD)--Stellenbosch University, 2001.<br>ENGLISH ABSTRACT: Given the organisation of the maize genome as well as demands placed on the
saturation of molecular linkage maps it would be desirable to identify informative
molecular markers that is located or linked to genic rich areas.
Sequences of gene products from different gene classes were investigated. Proteins
containing a nucleotide binding site (NBS) and leucine-rich repeat (LRR) region
comprise the largest class of disease resistance proteins. Resistant gene analogue
(RGA) primers belonging to this specific class were derived from previous published
literature studies. By means of similarity studies of short stretches of conserved
amino acid and DNA sequences, primers were developed that belonged to the
peroxidase and reductase gene classes. A novel class of transposable element was
identified, that occurred in the gene rich areas of a diverse range of grass genomes.
Of all the MITE families described so far, the Heartbreaker (Hbr) and Hb2 family
elements were of particular interest.
The unique properties of MITEs, especially their high copy number, polymorphism,
stability and preference for genic areas together with the RGA primers, were
exploited to develop a new marker technique for the isolation of a class of molecular
marker with a strong preference for genic areas.
Using the publicly available recombinant inbred population, Tx303 x C0159, 196
MITE/RGA markers were added to the existing recombinant inbred linkage map
consisting of ±1033 already established markers. It became apparent that just like
loci for disease resistance, the 196 MITE/RGA fragments were not randomly
distributed across the maize genome but occurred in clusters spread across the ten
maize chromosomes. Ninety-two (92) of the MITE/RGA fragments showed
significant correlation to previously mapped maize resistance genes. To establish
the conservation and specificity of both the Hbr and Hb2 elements, sequences of 19
MITE/RGA fragments were ascertained. When comparing the partial MITE element
sequences from these fragments, a high degree of element conservation was observed. One fragment showed good sequence correlation to a NADPH He Toxin
reductase protein product and mapped to the same chromosomal location as the
hm1 gene locus in maize. This fragment can be considered a candidate gene for
resistance against the pathogen, Helminthosporium carbonum. The Hbr primer used
proved to be very specific for the Heartbreaker MITE element, this was in contrast to
the non-specificity of the Hb2 primer.
The applicability of this technique was tested on two maize diseases that cause
immense damage in the maize production industries in South Africa. Fourteen
MITE/RGA markers were used to fine map the putative chromosomal locations for
the HtN1, Ht1, Ht2 and Ht3 genes that confer resistance. against Setosphaeria
turcica, the northern corn leaf blight (NelS) pathogen in maize. Three MITE/RGA
fragments were identified that aided in the saturation of the linkage map for
quantitative trait resistance (QTl) against gray leaf spot (GlS) in maize.
This novel MITE/RGA technique presented a unique opportunity to search for
additional candidate genes by using polymerase chain reaction (peR) analysis.
When compared to the conventional amplified fragment length polymorphism (AFLP)
technique, the MITE/RGA technique proved to be just as efficient but was more cost
effective and less time consuming.<br>AFRIKAANSE OPSOMMING: Die organisasie van die mielie genoom as ook die vereistes wat daar geplaas word
op die versadiging van koppelingskaarte, vereis dat daar meer klem geplaas word op
die ontwikkeling van molekulêre tegnieke wat merkers in geenryke areas identifiseer.
Die volgordes van geenprodukte, wat behoort tot verskillende geenklasse, is deeglik
bestudeer. Proteïenprodukte wat bestaan uit 'n nukleotiedbindingsarea (NBA) en 'n
leusienryke herhalende (LRH) area is een van die grootste klasse waaronder
siekteweerstandsproteïene sorteer. Polimerase kettingreaksie (PKR) inleiers wat
behoort tot hierdie spesifieke klas, is verkry vanuit vorige publikasies. Deur kort
gekonserveerde aminosuur en DNS volgordes te vergelyk is inleiers ontwikkel wat
behoort tot die peroksidase en reduktase gene klasse. 'n Nuwe klas
transponeerbare elemente wat voorkom in die geenryke areas van diverse gras
genome, is geïdentifiseer. Van al die miniatuur inversie herhalende transponeerbare
elemente (MITE) wat al geïdentifiseer is, is die twee elemente, Heartbreaker (Hbr) en
Hb2, van groot belang.
Unieke eienskappe van die MITEs, veral hul hoë kopie aantal, polimorfiese-indeks,
stabiliteit asook voorkeur vir geenryke areas, tesame met die weerstandsgeen
analoë (WGA) inleiers, is gebruik om 'n nuwe merker tegniek te ontwikkel. Hierdie
nuwe tegniek identifiseer 'n klas merker wat 'n sterk voorkeur het vir geenryke areas.
Deur gebruik te maak van die openbare beskikbare rekombinante ingeteelde (RI)
populasie, Tx303 x C0159, is 196 MITE/WGA-merkers gekarteer op die bestaande
RIL koppelingskaart, wat alreeds bestaan uit ±1033 gevestigde merkers. Net soos
die lokusse vir siekteweerstand het dit geblyk dat hierdie 196 merkers in groepe
voorkom wat verspreid is oor die tien mielie chromosome. Twee-en-negentig (92)
van die 196 gekarteerde MITE/WGA-merkers het betekenisvolle korrelasie gewys
met reeds gekarteerde mielie weerstandsgene. Die volgordes van 19 MITE/WGAfragmente
is bepaal om sodoende die spesifisiteit en mate van konservering van die
Hbr and Hb2 elemente te bereken. 'n Hoë mate van element konservering is waargeneem. Een fragment het In baie goeie volgorde korrelasie gewys met In
NADPH HG toksien reduktase proteïen produk en karteer op dieselfde
chromosomale posisie as die hm1 geen lokus. Hierdie fragment kan gesien word as
In kandidaatgeen vir weerstand teen die mielie patogeen, Helminthosporium
carbonum.
Die toepasbaarheid van hierdie tegniek is getoets op twee siekte toestande, wat lei
tot groot verliese in die mielie industrie, in Suid-Afrika. Veertien van die MITE/WGAmerkers
is gebruik om die waarskynlike chromosomale posisies van die HtN1, Ht1,
Ht2 en Ht3 gene, wat weerstand bied teen Setosphaeria turcica, die noordelike mielie
blaarvlek (NMBV) patogeen, fyner te karteer. Drie MITE/WGA fragmente is
geïdentifiseer wat gehelp het in die versadiging van die koppelingskaart vir die
kwantitatiewe kenmerk weerstandbiedenheid (KKW) teen grys blaarvlek (GBV) in
mielies.
Deur gebruik te maak van polimerase kettingreaksie (PKR) analise, verskaf hierdie
tegniek die moontlikheid om te soek vir addisionele kandidaatgene. Hierdie tegniek
is ook vergelyk met die konvensionele geamplifiseerde fragment lengte polimorfisme
(AFLP) tegniek. Daar is gevind dat die nuwe tegniek net so informatief is, maar wel
meer koste effektief en tyd besparend.
21
Noudomi, Seishiro. "CD146 is a novel marker for highly tumorigenic cells and a potential therapeutic target in malignant rhabdoid tumor." Kyoto University, 2016. http://hdl.handle.net/2433/217140.
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Fu, Peng [Verfasser], and Jörg-Christian [Akademischer Betreuer] Tonn. "Membrane Hsp70 expression in gliomas : a novel, hypoxia-related marker for primary glioblastoma / Peng Fu. Betreuer: Jörg-Christian Tonn." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1027949266/34.
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Schäkel, Knut, Claudia Poppe, Elfriede Mayer, Christine Federle, Gert Riethmüller, and Ernst Peter Rieber. "M-DC8+ Leukocytes – A Novel Human Dendritic Cell Population." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-135252.
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Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123dim and CD11c– CD123high) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2–1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class II molecules, CD33 and low levels of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc=γRIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Miller, Aaron Christopher. "Clostridium difficile infection as a novel marker for hospital quality, efficiency and other factors associated with prolonged inpatient length of stay." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1884.
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Excess inpatient length of stay (LOS) varies between hospitals and is burdensome to patients and the overall healthcare system. Variation in LOS has often been associated with hospital-level factors, such as hospital efficiency and quality. Clostridium difficile infection (CDI) is an increasingly common hospital-acquired (HA) infection. This thesis explores the connection between hospital incidence of CDI and excess LOS in patients without a CDI. It is hypothesized that HA-CDI incidence may act as a "proxy variable" to capture unobserved hospital characteristics, such as hospital quality or efficiency, associated with prolonged LOS. In addition, hospitals with longer LOS may tend to observe more HA-CDI cases prior to discharge. This thesis analyzes the ability of CDI incidence to capture excess LOS variation across hospitals, while controlling for CDI cases that occur after discharge.
We use data on hospital inpatient visits, spanning the years 2005-2011, from three data sources distributed by the Healthcare Cost and Utilization Project: the Nationwide Inpatient Sample (NIS), and the State Inpatient Databases (SID) for California and New York. The NIS provides discharge records from a nationwide sampling of hospitals in a given year. The SIDs are longitudinal populations of inpatient records in each state, and patient records can be linked across stays. We compute a variety of different measures of hospital CDI incidence and identify HA-CDI cases that occur after a patient is discharged.
Various multivariable regression models are analyzed to predict LOS at an individual patient level. A generalized linear modeling approach is used, and different distributions and link functions are compared using the Akaike information criterion. A multilevel modeling approach is also used to estimate the amount of between-hospital variation in LOS that can be explained by HA-CDI incidence.
We find CDI incidence to be a strong predictive factor for explaining a patient's LOS and is one of the strongest predictive variables we identified. Moreover, CDI incidence appears to primarily capture between-hospital variation in excess LOS. Although we find evidence that present-on-admission indicators may underreport cases of HA CDI, our findings suggest the connection between CDI incidence and excess LOS is driven primarily by CDI cases that are HA. In addition, when we account for HA-CDI cases that occur post-discharge, the relationship between CDI incidence and LOS appears even stronger. Our results suggest that CDI incidence may be a powerful tool for making comparisons of excess LOS across hospitals.
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Wang, Chao. "Microfluidics for particle manipulation : new simulation techniques for novel devices and applications." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:8125980e-0603-4425-b0fa-89a4fdfdf464.
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This thesis focuses on fundamental aspects of microfluidic systems and applies relevant findings to innovative designs for advanced particle manipulation applications. Computational Fluid Dynamics (CFD) is adopted for fluid modeling, based on the Finite Volume method. The accuracy of the solutions obtained is confirmed by grid sensitivity analysis and by comparisons with experimental work. Curved microchannel features and the induced Dean flow are studied through a parametric space exploration and simulations. The Lagrange-Euler coupling method – Surface Marker Point methodology – is applied to simulate large-size particles (of comparable size to the channel). Through this simulation approach, all the forces on such particles are directly derived through solving the governing equations and the influence of these particles on the flow is considered in a fully coupled manner. A new approach – the Frozen Flow & Flow Correction Coefficient method – is developed, making trans-relaxation-time simulations possible and improving computational efficiency significantly, for 3D simulations of arbitrary shape and size microparticles in complicated microfluidic channels. Detailed comparisons between simulation results and experiments involving particle sedimentation and particle equilibrium position have been conducted for methodology validation. Mechanisms of hydrodynamic particle manipulation are then studied, including hydrodynamic focusing and separation. It is found that the Tubular Pinch effect, Dean flow and the Radial Pressure Gradient effect interact to yield two distinct particle separation mechanisms. For advanced applications, particle focusing, non-magnetic and magnetic separation for neutrally buoyant particles are proposed, based on newly gained insight on the above-mentioned mechanisms. Appropriate channel designs have been proposed both for particle focusing and size-based particle separation, while the vertical-magnetic-Dean separation scheme is highlighted for magnetic separation. Finally, a new integrated system is proposed, that combines the above novel designs into a device-like ensemble. It promises to offer functionality for biomaterial separation and detection, including different types of cells, antigens and biomarkers.
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Liu, Wen [Verfasser]. "Stem cell marker expression of canine neoplasia generated cell subpopulations and effect of novel arylindolylmaleimides on canine lymphoma cell lines / Wen Liu." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2015. http://d-nb.info/1080825509/34.
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Mousavinasab, F. (Firoozeh). "Effects of lifestyle and genetic factors on the levels of serum adiponectin, a novel marker of the metabolic syndrome, in Finnish servicemen." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514285042.
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Abstract
Metabolic syndrome (MetS) is a combination of disorders that increase one's risk for type 2 diabetes (DM2) and cardiovascular disease (CVD). Both lifestyle and genetic factors have been established to be involved in the aetiology of MetS. Improving our knowledge about the pathophysiology of MetS could provide more effective therapeutic approaches and reduce the risk of developing DM2 and CVD. Lower levels of adiponectin, an adipose-derived protein, has been shown to be associated with the components of MetS. Common variants in a number of candidate genes related to MetS have been shown to be associated with changes in the serum adiponectin level.
This study was designed to evaluate the putative effects of military lifestyle, as well as common polymorphisms of the peroxisome proliferator activated receptor gamma 2 (PPARγ2), insulin receptor substrate-1 (IRS-1) and adiponectin (APM1) genes on serum adiponectin level in a cohort of Finnish servicemen.
Results of this study have showed that serum adiponectin significantly decreased during the six-month follow up in military service compared to baseline levels. This decrease was even shown in subjects that experienced a 5-10 % weight loss after six-months. Subjects with the Ala12Ala genotype of PPARγ2 had significantly higher levels of serum adiponectin compared with subjects with the Pro12Ala and Pro12Pro genotypes. Subjects having the X12Ala genotype of PPARγ2 with > 10% weight reduction showed a significant increase in serum adiponectin compared to other groups during the follow up. Those having the Ala12Ala genotype of PPARγ2 + Gly972Gly genotype of IRS-1 combination had significantly higher adiponectin compared with subjects with the Pro12Pro + Gly972Gly and Pro12Ala + Gly972Gly genotype combinations. Adiponectin levels were significantly higher in men with the T276T genotype compared with subjects with the G276T or G276G genotypes of SNP+276 of the APM1 gene.
In conclusion, this study shows a possible impact of a military lifestyle as well as, candidate gene variations, and their interactions upon the regulation of serum adiponectin levels as a marker of MetS. This study could serve as a pilot for the further extensive studies with longer follow up periods as well as more accurate information on specific lifestyle factors.
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Cui, Tiantian [Verfasser], Iver [Akademischer Betreuer] Petersen, Peter F. [Akademischer Betreuer] Zipfel, and Sven [Akademischer Betreuer] Perner. "Human complement factor H is a novel diagnostic marker for lung adenocarcinoma / Tiantian Cui. Gutachter: Iver Petersen ; Peter F. Zipfel ; Sven Perner." Jena : Thüringer Universitäts- und Landesbibliothek Jena, 2012. http://d-nb.info/1019125055/34.
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Nyström, Hanna. "Stromal collagens in colorectal cancer and in colorectal liver metastases : tumour biological implications and a source for novel tumour markers." Doctoral thesis, Umeå universitet, Kirurgi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-67860.
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Background: Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality. About 50 % of patients with CRC will develop subsequent liver metastases (CLM). The survival for untreated CLM is only a few months and liver resection provides the only chance for a lasting cure. It is therefore essential to detect CLM early, enabling successful surgical resection and achieving a long-term cure. There are no optimal tumour markers for CRC or CLM. The best marker available is Carcinoembryonic Antigen (CEA), a marker found elevated in about 50-60% of patients with CLM, but also in many other conditions. The main focus of cancer research has been on the malignant cancer cell. However, a tumour consists of more than cancer cells. A major part of all solid tumours is made up by the stroma. The tumour stroma is defined as the non-malignant cells of a tumour such as fibroblasts, the cells of the vascular and immune systems as well as the extracellular matrix (ECM). The basement membrane (BM) is a specialized form of the ECM in which type IV collagen is the major protein component. All epithelial cells need a contact to the BM and the definition of an invasive cancer is the degradation of the BM and the spread of cancer cells beyond this structure. Different metastatic growth patterns of CLM have previously been described, namely the desmoplastic, pushing and replacement type of CLM. These differ in their stromal reaction in the border, which separates the tumour from the normal liver. In this thesis the tumour stroma of CRC and CLM is studied with a special emphasis on stromal collagens. The aim is to investigate whether stromal collagens/ circulating type IV collagen can be used as tumour markers for CRC and CLM, and to compare this to the conventional marker CEA. The circulating type IV collagen level is also measured in liver metastases from other primary tumours than CRC. Furthermore, the differences between the stroma of a primary CRC that metastasizes to the liver when compared to a CRC that never spreads are analysed. Additionally, the metastatic growth pattern of CLM is studied in relation to the primary tumour, stromal components and survival. We also sought out to find whether CRC cell lines possess the trait to produce ECM proteins endogenously, and in response to a normal liver stroma in a novel organotypic model for CLM. Methods: Expression patterns of type I, III and IV collagen were studied by immunofluorescence (IF), chemical staining and immunohistochemistry (IHC) in normal colorectal tissue, normal liver, CRC, CLM, benign liver lesions and in liver metastases of other origin than CRC. Circulating plasma levels of type IV collagen were analysed in healthy controls, patients with CRC (T stage I-III) and in patients with CLM. Samples were analysed at the time of diagnosis, during and after oncological and surgical treatment and at the time of relapsing or progressive disease. Additionally, circulating levels were analysed in patients with benign liver lesions and in liver metastases of other origin than CRC. The metastatic growth pattern of CLM was classified according to earlier descriptions. CRC cell lines were studied regarding their production of type IV collagen. The growth, invasiveness and stromal production in CRC cell lines were also investigated in a new organotypic model for CLM using human liver specimens. Results: Circulating type IV collagen levels are increased in patients with CLM and other epithelial-derived liver metastases, and is found normal in patients with primary CRC (stage I-III), with liver metastases from tumours of non-epithelial origin, benign liver lesions and in healthy controls. The type IV collagen levels in patients with CLM reflect the tumour burden in the liver, decreases in response to therapy and is found increased in progressive or relapsing disease. The combination of circulating type IV collagen and CEA increased the sensitivity and specificity for detecting CLM. Livermetastatic CRC displayed an increased stromal production when compared to non-metastatic CRC, with an increased type IV collagen expression in the direct vicinity of the CRC cells. The earlier described growth patterns of CLM were verified, with the pushing type of CLM associated with a short survival and poor outcome. Furthermore, CRC cell lines possess the trait of endogenously producing type IV collagen. The novel organotypic liver model revealed that CRC cell lines grown in the context of normal liver stroma, devoid of other cells, does not elicit a desmoplastic reaction. Conclusion: Circulating type IV collagen is a promising tumour marker for CLM, where the levels reflect the hepatic tumour burden and can detect disease relapse after liver surgery. The combination of the tumour markers CEA and type IV collagen is superior to CEA alone. The stromal composition of primary CRC predicts the risk of subsequent CLM and the metastatic growth pattern of CLM is related to survival.
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Schäkel, Knut, Claudia Poppe, Elfriede Mayer, Christine Federle, Gert Riethmüller, and Ernst Peter Rieber. "M-DC8+ Leukocytes – A Novel Human Dendritic Cell Population." Karger, 1999. https://tud.qucosa.de/id/qucosa%3A27632.
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Dendritic cells (DC) constitute a heterogeneous leukocyte population having in common a unique capacity to induce primary T cell responses and are therefore most attractive candidates for immunomodulatory strategies. Two populations of blood DC (CD11c+ CD123dim and CD11c– CD123high) have been defined so far. However, their direct isolation for experimental purposes is hampered by their low frequency and by the lack of selective markers allowing large scale purification from blood. Here we describe the monoclonal antibody (mAb) M-DC8, which was generated by immunizing mice with highly enriched blood DC. This mAb specifically reacts with 0.2–1% of blood leukocytes and enables their direct isolation by a one-step immunomagnetic procedure from fresh mononuclear cells. These cells can be differentiated from T cells, B cells, NK cells and monocytes using lineage-specific antibodies. M-DC8+ cells express HLA class II molecules, CD33 and low levels of the costimulatory molecules CD86 and CD40. Upon in vitro culture M-DC8+ cells spontaneously mature into cells with the phenotype of highly stimulatory cells as documented by the upregulation of HLA-DR, CD86 and CD40; in parallel CD80 expression is induced. M-DC8+ cells display an outstanding capacity to present antigen. In particular, they proved to be excellent stimulators of autologous mixed leukocyte reaction and to activate T cells against primary antigens such as keyhole limpet hemocyanin. Furthermore, they induce differentiation of purified allogeneic cytotoxic T cells into alloantigen-specific cytotoxic effector cells. While the phenotypical analysis reveals similarities with the two known blood DC populations, the characteristic expression of Fc=γRIII (CD16) and the M-DC8 antigen clearly defines them as a novel population of blood DC. The mAb M-DC8 might thus be a valuable tool to determine circulating DC for diagnostic purposes and to isolate these cells for studies of antigen-specific T cell priming.<br>Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Öhlund, Daniel. "Basement membrane collagens in pancreatic cancer : novel stroma-derived tumor markers and regulators of cancer cell growth." Doctoral thesis, Umeå universitet, Kirurgi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-37555.
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Background: Among the common malignancies, pancreatic cancer has the shortest long-term survival. The aggressive, rapid, and infiltrative growth pattern of pancreatic cancer, together with the lack of specific symptoms, often leads to late diagnosis. Metastases are frequently found at the time of diagnosis, which prevents curative surgical treatment. Good tumor markers would enable early detection, thus improving the prognosis. Unfortunately, no such markers are available in the clinic. The tumor stroma is defined as the non-malignant cells and the extracellular matrix (ECM) of a cancer. Pancreatic cancer is characterized by an abundant tumor stroma, rich in ECM proteins such as collagens, which have been shown to play important roles in tumor progression. Furthermore, pancreatic cancer cells produce large quantities of ECM proteins, especially the basement membrane (BM) protein type IV collagen. All epithelial cells are anchored to a BM, which must be degraded in order for an in situ cancer to become invasive. Matrix metalloproteinases (MMPs) are enzymes involved in BM degradation. In this thesis, the tumor stroma of pancreatic cancer is studied, focusing on the BM proteins type IV and type XVIII collagen, with the aim to clarify if the stroma could be a source of novel tumor markers for this form of cancer. Additionally, the role of type IV collagen produced by the cancer cells is studied. Methods: Expression patterns of type IV and type XVIII collagen, MMPs involved in collagen degradation, and collagen receptors (integrins) were studied by immunoflourescence in both normal and pancreatic cancer tissue, and in pancreatic cancer cell lines. Circulating plasma levels of type IV and type XVIII collagen and conventional tumor markers (TPS, Ca 19-9, CEA and Ca 125) were measured in controls and pancreatic cancer patients at the time of diagnosis and after treatment. The role of cancer cell produced type IV collagen was studied in human pancreatic cancer cell lines by functional blocking of integrin receptors (integrin a1, a2 and b1) and integrin-binding sites on type IV collagen, and by siRNA-induced down-regulation of type IV collagen synthesis. Proliferation was analyzed by a luminescence based cell viability assay, migration by time-lapse microscopy, and apoptosis by M30-neoepitope detection. Results: MMPs involved in BM degradation were upregulated in pancreatic cancer tissue. The expression of type XVIII collagen shifted from a general BM expression pattern in normal tissue, to mainly being found in the tumor vasculature in pancreatic cancer. Type IV collagen, on the other hand, remained highly expressed in the vicinity of the cancer cells. The a1, a2, and b1 integrin receptors were highly expressed at the cancer cell surface. Both down-regulation of type IV collagen synthesis and blocking the integrin/type IV collagen interaction decreased cell proliferation and migration. The proliferative capacity was rescued by the addition of exogenous type IV collagen. Furthermore, the circulating levels of both type IV and type XVIII collagen were increased in pancreatic cancer patients at the time of diagnosis compared to controls. After treatment, the levels were normalized for type XVIII collagen, whereas the levels of type IV collagen remained high after surgery. High postoperative levels of type IV collagen were associated with short overall survival. A similar association to short survival was found for preoperative type XVIII collagen levels. No such associations to survival could be detected for the conventional markers. Conclusion: The results of this thesis show that type IV and type XVIII collagens can serve as tumor markers for pancreatic cancer with advantages compared to conventionally used markers. Additionally, evidence is provided of an autocrine loop, involving type IV collagen and its integrin receptors, with importance for retaining a proliferative and migratory phenotype in pancreatic cancer cells.
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Knappe, Nathalie [Verfasser], and Viktor [Akademischer Betreuer] Umansky. "Partial reprogramming of melanoma cells mimics the phenotype switch and reveals SNAI3 as a novel invasion-associated marker / Nathalie Knappe ; Betreuer: Viktor Umansky." Heidelberg : Universitätsbibliothek Heidelberg, 2015. http://d-nb.info/1180396308/34.
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Liu, Chia-Hao [Verfasser], and Michael [Akademischer Betreuer] Lanzer. "Linkage analysis identifies an ubiquitin transferase gene as a novel marker for reduced quinine and quinidine responsiveness in Plasmodium falciparum / Chia-Hao Liu ; Akademischer Betreuer: Michael Lanzer." Heidelberg : Universitätsbibliothek Heidelberg, 2012. http://d-nb.info/1180068084/34.
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Liu, Yueyang [Verfasser], Viktor [Akademischer Betreuer] Magdolen, Birgit [Gutachter] Luber, and Viktor [Gutachter] Magdolen. "Kallikrein-related peptidase 10: a novel independent prognostic marker in advanced high-grade serous ovarian cancer and triple-negative breast cancer / Yueyang Liu ; Gutachter: Birgit Luber, Viktor Magdolen ; Betreuer: Viktor Magdolen." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1183910061/34.
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Jeffery, Penelope Lorrelle. "An Investigation into the role of the ghrelin axis in hormone-dependent cancer and characterisation of a novel Exon 3-deleted preproghrelin isoform and its murine homologue." Thesis, Queensland University of Technology, 2005. https://eprints.qut.edu.au/16260/1/Penelope_Jeffrey_Thesis.pdf.
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Ghrelin is a 28 amino acid peptide hormone with a unique octanoic acid modification that has an extensive range of physiological effects, including stimulation of growth hormone (GH) release, appetite regulation, and modulation of reproductive functions. The cognate receptor for ghrelin is the growth hormone secretagogue receptor (GHS-R), a G protein-coupled receptor with two documented isoforms, the functional GHS-R type 1a and the C-terminally truncated GHS-R type 1b. Several ghrelin variants have also been identified in addition to the n-octanoylated form of ghrelin. In our laboratory, we have identified a novel exon 3-deleted preproghrelin variant that retains sequence for the mature ghrelin hormone and also encodes a novel C-terminal peptide (designated as C-terminal 3 peptide). There is emerging evidence to suggest that the ghrelin axis, encompassing ghrelin, several ghrelin variants and both forms of the GHS-R, is implicated in tumour growth. The objective of this project is to investigate the role of the ghrelin axis in hormone-dependent cancer and to further characterise the expression and function of the novel exon 3-deleted preproghrelin isoform.
Hormone-dependent cancers, including prostate and breast cancers, are significant causes of morbidity and mortality in the Western world. Improved diagnoses and treatments earlier in the progression of the disease are urgently required to improve patient outcomes. Growth factors play an integral role in prostate and breast cancer, particularly in the emergence of aggressive, hormone-refractory disease that is resistant to standard therapies. We have previously identified ghrelin as being a novel growth factor for prostate cancer cells in vitro and have hypothesised that this may be extended to other hormone-dependent cancer types including breast cancer.
In the current study, techniques including real-time quantitative RT-PCR, Western blot analysis and immunohistochemistry have been used to determine and quantitate ghrelin, exon 3-deleted preproghrelin and GHS-R expression in prostate and breast cancer. Ghrelin and exon 3-deleted preproghrelin are highly expressed in prostate cancer tissues compared to expression levels in normal prostate glands. Similarly, breast carcinoma specimens display greater immunoreactivity for ghrelin and exon 3-deleted preproghrelin than normal breast tissues. Expression of the exon 3-deleted preproghrelin mRNA isoform is upregulated in the oestrogen-independent, highly malignant MDA-MB-435 breast cancer cell line compared to the non-tumourigenic MCF-10A breast epithelial cell line, suggesting that augmented transcription of the isoform is associated with an increased malignant potential in breast cancer. The functional GHS-R type 1a is expressed in normal breast tissue and breast cancer specimens and cell lines. In contrast, the truncated GHS-R type 1b isoform is exclusively expressed in breast carcinoma. These data suggest that GHS-R type 1b, ghrelin and exon 3-deleted preproghrelin display potential as novel diagnostic markers for prostate and breast cancer.
These studies have been the first to demonstrate that ghrelin may have an important role in cell proliferation in breast and prostate cancer. Functional assays demonstrated that (10nM) ghrelin stimulated proliferation in the LNCaP prostate cancer cell lines (45.0 ± 1.7% above control, P <0.01) and rapidly activated the ERK 1/2 mitogen-activated kinase (MAPK) pathway in both PC3 and LNCaP cell lines. It does not, however, protect these cells from chemically-induced apoptosis. The MAPK inhibitors PD98059 and U0126 blocked ghrelin-induced MAPK activation, as well as cell proliferation, in both cell lines. Prostate cancer cells secrete mature ghrelin in vitro, and may therefore stimulate MAPK pathways in an autocrine manner. Ghrelin also appears to act as a growth factor in breast cancer cell proliferation, as the growth of MDA-MB-435 and MDA-MB-231 breast cancer cell lines is significantly increased by ghrelin treatment. Our findings suggest that the ghrelin axis could provide an important new target for adjunctive therapies for both breast and prostate cancer.
The C-terminal 3 peptide derived from exon 3-deleted preproghrelin may be an important new component of the ghrelin axis and studies into its function are currently in progress. Although it did not induce MAPK cascades or stimulate proliferation in prostate or breast cancer cell lines, the discovery of a murine counterpart, exon 4-deleted preproghrelin, indicates that it is highly conserved. Exon 4-deleted preproghrelin is expressed in all mouse tissues examined, with stomach being the predominant site of synthesis. Other components of the ghrelin axis were also found to be present in a wide-range of mouse tissues including brain, ovary and prostate. This comprehensive report has paved the way for future work with in vivo mouse models of cancer.
This study has provided a substantial basis for the further evaluation of ghrelin, exon 3-deleted preproghrelin and the GHS-R type 1b as novel diagnostic/prognostic markers for prostate and breast cancer and supports the rationale for targeting the ghrelin axis for treatment of these tumours.
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Corbett, Christopher. "Novel markers of liver fibrosis." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/5603/.
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With chronic liver disease rising, the need to stage of liver disease and fibrosis accurately is paramount as it helps guide therapy and informs prognosis. Liver biopsy is a flawed gold standard, associated with morbidity and mortality. Application of simple non-invasive tests to assess fibrosis could provide a safe way of identifying patients in greatest need of intervention and of monitoring response to therapy. I have shown in this thesis that transient elastography is an excellent tool for ruling out significant fibrosis in patients with chronic liver disease. It is easy to learn and successful scanning correlates well with histological liver fibrosis. I have also shown that Use of APRI with a cut off of >1.5-2 and Fib-4 >3.25 can provide prognostic value for overall and liver-related mortality in patients with viral hepatitis. Finally I have assessed a range of potential new biomarkers showing that combining measuring serum levels of the chemokine CXCL10 and the endothelial adhesion receptor VAP-1 can increase the correlation strength with fibrosis stage. Using morphometric analysis of liver fibrosis I show that the same markers can be linked to quantitatively measured fibrosis, removing subjective bias and reducing inter and intra-operator variance in histological assessment.
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Smyth, Rosemary. "Investigation of novel urinary markers of hepatotoxicity." Thesis, University College London (University of London), 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417145.
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Welsh, Paul. "Inflammatory markers as novel predictors of cardiovascular disease." Connect to e-thesis, 2008. http://theses.gla.ac.uk/86/.
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Thesis (Ph.D.) - University of Glasgow, 2008.<br>Ph.D. thesis submitted to the Division of Cardiovascular and Medical Sciences, Faculty of Medicine, University of Glasgow, 2008. Includes bibliographical references. Print version also available.
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Welsh, Paul I. "Inflammatory markers as novel predictors of cardiovascular disease." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/86/.
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Inflammation is widely considered to be an important contributing factor in atherogenesis and the risk of atherothrombotic complications. Baseline measurements of some inflammatory markers are known to be predictive risk factors for future cardiovascular disease (CVD) events in prospective epidemiological studies. Inflammatory markers dominant in the literature are acute phase response (APR)-associated and include fibrinogen, C-reactive protein (CRP) and, more recently, interleukin- (IL-) 6. This thesis reviews the literature and suggests the need for further research into novel inflammatory markers of CVD risk. The broad aim was to expand on limited existing data and ascertain if circulating levels of four novel inflammatory markers (tumour necrosis factor alpha [TNF alpha], IL-18, soluble CD40 ligand [sCD40L], and matrix metalloproteinase-9 [MMP-9]) are associated with classical cardiovascular risk factors, and with future CVD events in several epidemiological studies. In studies of pre-analytical variables, all four markers had commercially available assays acceptable for epidemiological use, but only IL-18 and TNF alpha displayed assay stability and the ability to be measured in plasma or serum. Due to limited serum samples, MMP-9 and sCD40L were less extensively measured. Results suggest a moderate positive association of MMP-9 with coronary heart disease (CHD) risk (although confounded by smoking and markers of general inflammation), while serum sCD40L may be moderately inversely related to CHD risk. More data is required for these markers. IL-18 and TNF alpha displayed similar degrees of short-term biological variability and regression dilution as CRP. Population distributions of both cytokines were consistent with limited previous reports. Both displayed associations with conventional vascular risk factors (such as age, gender, HDL cholesterol, and smoking), although interestingly, associations with epidemiological measures of obesity were poor. Both cytokines demonstrated moderate associations with vascular disease in a retrospective CHD study. In 3 prospective CHD or CVD studies, IL-18 demonstrated consistent but moderate associations with risk of vascular events in age- and sex-adjusted models (Odds ratio [OR]~1.6 in the top versus bottom third of the population). The association became borderline significant after adjustment for conventional risk markers. Associations of TNF alpha with risk of CHD in these studies were inconsistent, and more data are needed. In 3 prospective stroke studies, TNF alpha demonstrated some moderate associations with acute stroke outcome and recurrent stroke risk, but not with incident stroke in the elderly with vascular disease. IL-18 demonstrated no association with risk or outcome in any stroke study. Meta-analysis in 4 suitable prospective studies showed (in full adjustment models) that IL-18 (OR 1.18 [95% CI 0.95-1.48] comparing extreme thirds) and TNF alpha OR 1.05 [0.67-1.64]) have at best weak independent associations with CVD risk. Therefore these markers are unlikely to add significantly to clinical vascular risk prediction models, although these cytokines may still be of biological significance and potential therapeutic targets. More data is required for these markers. In conclusion IL-18, TNF alpha, MMP-9 and sCD40L may show weak associations with CVD. However, despite animal and tissue models indicating that they may play pivotal roles in atherogenesis, circulating concentrations of these inflammatory markers have limited independent vascular risk associations. Elevated circulating levels of APR-associated markers may sensitively reflect exposure to a wide range of adverse pro-inflammatory stimuli including lifestyle exposures, whereas some other inflammatory markers may not.
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Isohookana, J. (Joel). "Emerging novel prognostic markers in pancreatic ductal adenocarcinoma." Doctoral thesis, Oulun yliopisto, 2018. http://urn.fi/urn:isbn:9789526220352.
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Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, the 5-year survival rate being less than 5%. At the time of diagnosis, 90% of PDACs extend beyond the pancreas and distant metastases are often present. Due to aggressive growth, local expansion and early appearance of metastasis, primary PDAC tumours are local enough for curative surgical resection in only 10–20% of the cases. Adjuvant chemotherapy is indicated in these curative-treated cases, with slight improvement in survival. PDAC is considered to represent a heterogeneous group of biologically and prognostically different malignancies. Characterization of these subgroups is essential and there is an urgent need for more accurate biomarkers and targeted treatments in PDAC. In the current work, we immunohistochemically investigated the expression levels and prognostic values of oxidative stress markers (8-OHdG, Keap1, Prx I, II, III, V and VI), epigenetic histone modifiers (KDM4A, KDM4B, KDM4D and SIRT1–4), and cell-cycle regulators (p16, Rb, CDK4) and DNA-repair enzymes (FEN1 and MGMT) in the cohort of surgically treated PDAC patients. We found that Keap1 expression was associated with better pancreatic cancer-specific survival. Expression of antioxidative peroxiredoxins I, III, V and VI was also connected with a more favourable tumour characteristics and Prx I and VI showed prognostic value. When considering the biology of PDAC, we noticed that pivotal epigenetic regulation also occurred in exocrine pancreatic tissue adjacent to resection margins. Overexpression of the cell-cycle regulator CDK4 and the DNA-repair enzyme FEN1 in the whole population, and elevated expression level of MGMT in the most high-risk patients were connected with worse prognosis. The results of the study can be utilized in the future when individualized therapies are being designed for PDAC patients. Due to occurrence of the epigenetic regulation also in exocrine pancreatic tissue adjacent to resection margins, it could be evaluated in future for routine diagnostics and treatment optimization. The potential role of MGMT in the development of PDAC chemoresistance should be studied in the future<br>Tiivistelmä Haiman duktaalinen adenokarsinooma (PDAC) on yksi aggressiivisimmista syöpäsairauksista. Viiden vuoden elossaoloennuste on vain lähellä 5 prosenttia. Diagnoosihetkellä 90% haiman adenokarsinoomista yltää haiman ulkopuolelle ja usein kasvain on jo lähettänyt etäpesäkkeitä. Kasvutaipumuksen sekä metastasoinnin takia kuratiivinen kirurginen hoito on mahdollista vain 10–20% tapauksista. Liitännäissolunsalpaajahoito on aiheellista näissä kuratiivistavoitteisesti hoidetuissa tapauksissa. Kuitenkin vaikutus kokonaiselossaoloaikaan on melko vähäinen. Uusimman tutkimustiedon valossa PDAC:aa pidetäänkin heterogeenisenä ryhmänä biologisesti ja ennusteellisesti erilaisia tautiryhmiä. Näiden tautiryhmien tunteminen ja tunnistaminen riittävän tarkkojen merkkiaineiden avulla olisi ensiarvoisen tärkeää, jotta hoitoja voitaisiin kohdentaa niistä hyötyville potilaille. Väitöskirjatutkimuksessa selvitimme immunohistokemiallisin menetelmin oksidatiivisen stressin merkkiaineiden (8-OHdG, Keap1, Prx I, II, III, V ja VI), epigeneettisten histonimodifikaattorien (KDM4A, KDM4B, KDM4D ja SIRT1–4) sekä solusyklin säätelijöiden (p16, Rb, CDK4) ja DNA-korjausentsyymien (FEN1 ja MGMT) ilmentymistä ja ennusteellista arvoa kirurgisesti hoidetuilla PDAC-potilailla. Tutkimuksessamme totesimme, että kasvainkudoksen Keap1-ilmentymä yhdistyi parempiennusteiseen taudinkuvaan. Antioksidatiivisten peroksiredoksiinien I, III, V ja VI ilmentyminen yhdistyi niin ikään suotuisampaan kasvaimen fenotyyppiin ja Prx I ja VI osoittivat ennusteellista arvoa. Havaitsimme lisäksi, että PDAC:n biologiaan keskeistesti vaikuttavaa epigeneettistä säätelyä tapahtuu myös malignin haimakudoksen viereisessä eksokriinisessä haimakudoksessa. Solusyklin säätelijä CDK4:n ja DNA-korjausentsyymi FEN1:n voimakas ilmentyminen koko tutkimuspopulaatiossa sekä kohonnut MGMT:n ilmentyminen korkeimman riskin potilailla yhdistyivät huonompaan taudin ennusteeseen. Väitöskirjatyön tutkimustuloksia voidaan tulevaisuudessa hyödyntää, kun tutkitaan yksilöllisiä hoitomuotoja PDAC-potilailla. Koska epigeneettistä säätelyä tapahtuu myös syövän viereisessä eksokriinisessa haimakudoksessa, voidaan tulevaisuudessa tämän kudoksen arviointia mahdollisesti käyttää rutiinisti diagnostiikassa sekä hoidon optimoinnissa. MGMT:n mahdollinen rooli PDAC:n kemoresistenssin kehittymisessä tulisi tulevaisuudessa selvittää
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Varghese, Robin. "Novel Prognostic Markers and Therapeutic Targets for Glioblastoma." Diss., Virginia Tech, 2016. http://hdl.handle.net/10919/71420.
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Glioblastoma is the most common and lethal malignant brain tumor with a survival rate of 14.6 months and a tumor recurrence rate of ninety percent. Two key causes for glioblastomas grim outcome derive from the lack of applicable prognostic markers and effective therapeutic targets. By employing a loss of function RNAi screen in glioblastoma cells we found a list of 20 kinases that can be considered glioblastoma survival kinases. These survival kinases which we term as survival kinase genes, (SKGs) were investigated to find prognostic markers as well as therapeutic targets for glioblastoma. Analyzing these survival kinases in The Cancer Genome Atlas patient database, we found that CDCP1, CDKL5, CSNK1𝜀, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 genes could be used as prognostic markers for glioblastoma with or without temozolomide chemotherapeutic treatment as a covariate. For the first time, we found that patients with increased levels of NEK9 and PIK3CB mRNA expression had a higher probability of recurrent tumors. We also discovered that expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary glioblastoma tumors was associated with tumor recurrence prognosis. To note, of these recurrent prognostic candidates, PIK3CB expression in recurrent tumor tissue had much higher expression compared to primary tissue. Further investigation in the PI3K pathway showed a strong correlation with recurrence rate, days to recurrence and survival emphasizing the role of PIK3CB in tumor recurrence in glioblastoma. In efforts to find effective therapeutic targets for glioblastoma we used SKGs as potential candidates. We chose the serine/threonine kinase, Casein Kinase 1 Epsilon (CSNK1𝜀) as a target for glioblastoma because multiple shRNAs targeted this gene in our loss of function screen and multiple commercially available inhibitors of this gene are available. Casein kinase 1 epsilon protein and mRNA expression were investigated using computational tools. It was revealed that CSNK1𝜀 expression has higher expression in glioblastoma than normal tissue. To further examine this gene we knocked down (KD) or inhibited CSNK1𝜀 in glioblastoma cells lines and noticed a significant increase in cell death without any significant effect on normal cell lines. KD and inhibition of CSNK1𝜀 in cancer stem cells, a culprit of tumor recurrence, also revealed limited self-renewal and proliferation in cancer stem cells and a significant decrease in cell survival without affecting normal stem cells. Further analysis of downstream effects of CSNK1𝜀 knockdown and inhibition indicate a significant increase in the protein expression of β-catenin (CTNNB1). We found that CSNK1𝜀 KD activated β-catenin, which increased GBM cell death, but can be rescued using CTNNB1 shRNA. Our survival kinase screen, computational analyses, patient database analyses and experimental methods contributed to the discovery of novel prognostic markers and therapeutic targets for glioblastoma.<br>Ph. D.
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James, Samantha. "Herpèsvirus de primates et de chauves-souris du nouveau monde : modèles d'étude des relations évolutives hôtes-virus DNA polymerase sequences of New World Monkey Cytomegaloviruses : another molecular marker with which to infer Platyrrhini systematics Novel herpesviruses of neotropical bats and their relationships with other members of the Herpesviridae family." Thesis, Guyane, 2019. http://www.theses.fr/2019YANE0004.
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Les virus appartenant à la famille Herpesviridae (ordre Herpesvirales) sont répartis au sein de trois sous-familles : Alpha-, Beta- et Gamma-herpesvirinae. Ils ont été identifiés à partir d’un large spectre d’espèces hôtes, allant des mammifères aux reptiles en passant par les oiseaux et ont la capacité de persister toute au long de la vie de l’hôte. La plupart de ces virus sont par ailleurs spécifiques d’une espèce hôte. La large distribution des herpèsvirus, associée à une infection généralement asymptomatique chez l’hôte naturel suggèrent que ces virus auraient co-évolué avec leurs hôtes.Mon premier axe de travail a porté sur l’identification de cytomégalovirus (CMV) chez les primates non-humains du Nouveau Monde (PNHNM) afin de voir si la diversification de ces virus suivait celle de leurs hôtes. De fait, une étude préalable conduite sur les primates de l’Ancien Monde avait démontré que les CMV les infectant présentaient un fort signal de co-divergence avec leurs hôtes. Or, parmi les différentes espèces de primates testées, seules quelques-unes provenaient du Nouveau Monde. Afin de répondre à cette question, nous avons effectué un criblage moléculaire de 244 échantillons d'ADN sanguin provenant de 20 espèces d'Amérique centrale et du sud. Par une approche de PCR utilisant des amorces consensus dégénérées ciblant des motifs hautement conservés du gène de l'ADN polymérase des herpèsvirus, nous avons caractérisé de nouvelles séquences virales de sept genres représentatifs des trois familles de PNHNM. Ces résultats démontrent ainsi que la plupart des espèces de PNHNM peuvent être infectées par un virus appartenant au genre Cytomegalovirus. Par ailleurs, les analyses phylogénétiques effectuées, couplées à la datation moléculaire des séquences obtenues, soutiennent cette hypothèse co-évolutive.Mon second axe visait à identifier des herpèsvirus de chauves-souris du Nouveau Monde afin d’en étudier la distribution et la diversité. La recherche d’herpèsvirus chez les chauves-souris est plus récente. Elle a bénéficié de l’intérêt porté à ces mammifères au début des années 2000 du fait de leur rôle de réservoirs de virus potentiellement zoonotiques. C’est à partir de 2007 que les premières séquences d’herpèsvirus de chauves-souris ont été décrites. Il s’en est suivi la description de dizaines de nouvelles séquences identifiées de différentes espèces d’Afrique, d’Asie, d’Océanie, d’Europe et d’Amérique. Néanmoins, la distribution des espèces testées était géographiquement inégale et seules quelques-unes provenaient du Nouveau Monde. Nous avons effectué un criblage moléculaire de 195 échantillons d’ADN sanguin provenant de 11 espèces appartenant à trois familles (Phyllostomidae, Mormoopidae et Molossidae). En utilisant la même approche que celle appliquée au PNHNM, nous avons obtenu des séquences virales (ADN polymérase et/ou Glycoprotéine B) de toutes les espèces testées. Celles-ci se répartissent au sein des sous familles Beta- et Gamma-herpesvirinae. Quatorze séquences partielles du gène de l'ADN polymérase, correspondant à trois beta- et onze gamma-herpèsvirus, ont été identifiées. Douze séquences partielles du gène de la glycoprotéine B, toutes de gamma-herpèsvirus, ont été caractérisées. Chaque séquence était spécifique à une espèce de chauve-souris et, chez certaines espèces, de multiples virus ont été identifiés. Les analyses phylogénétiques de ces séquences ont permis d'identifier des clades spécifiques aux virus de chauve-souris. Ceux composés de séquences obtenues à partir de différentes espèces appartenant à des sous-familles distinctes suivent la taxonomie des chauves-souris. Cette étude confirme l'étonnante diversité des herpèsvirus de chauve-souris et élargit nos connaissances sur leur spectre d'hôtes<br>Viruses belonging to the Herpesviridae family (order Herpesvirales) are enveloped double-stranded DNA viruses distributed into three subfamilies: Alpha-, Beta- and Gamma-herpesvirinae. These viruses have been identified from a wide range of host species, ranging from mammals to reptiles to birds. They have the ability to persist throughout the life of the host in a latent form and to reactivate. Most of these viruses are specific to a host. The wide distribution of herpesviruses, generally associated with an asymptomatic infection in their natural host, suggests that these viruses have co-evolved with their hosts.The first part of this work was dedicated to the identification of cytomegaloviruses (CMV, genus Cytomegalovirus) in New World non-human primates (NWNHP) to see if the diversification of these viruses followed that of their hosts. A previous study on Old World primates had demonstrated that CMVs infecting them showed a strong signal of co-divergence with their hosts. Nevertheless, among the different species of primates tested, only a few were from the New World. To test this hypothesis, we performed a molecular screening of 244 blood DNA samples from 20 Central and South American species. Through a PCR approach using degenerate consensus primers targeting highly conserved motifs of the DNA polymerase gene of herpesviruses, we characterized new viral sequences from 12 species belonging to seven representative genera of the three families of NWNHP. These results demonstrate that most species of NWNHP can be infected with a virus belonging to the Cytomegalovirus genus. In addition, phylogenetic analyzes of the obtained sequences combined with their molecular dating support a co-evolutionary scenario. This study led us to propose that CMVs sequences of NWNHP could serve as a molecular marker with which to infer the not yet fully resolved systematics of these primates.The second part of this work was on identifying herpesviruses from New World bats to study their distribution and diversity. The search for herpesviruses in bats is more recent. In the early 2000s it benefited from studies dedicated to other viral families given their role as reservoirs of potentially zoonotic viruses. The first description of bat herpesvirus sequences dated back from 2007. Over the past decade, dozens of herpesvirus sequences have been described from different bat species on every continent. Nevertheless, the distribution of the tested species was geographically uneven and only a few were from the New World. Molecular screening of 195 blood DNA samples from 11 species belonging to three families (Phyllostomidae, Mormoopidae and Molossidae) was performed. Using the same approach as applied to NWNHP, we obtained viral sequences (DNA polymerase and/or glycoprotein B) from all tested species. These are distributed within the Beta- and Gamma-herpesvirinae subfamilies. Fourteen partial sequences of the DNA polymerase gene, corresponding to three beta- and eleven gamma-herpesviruses, have been identified. Twelve partial sequences of the glycoprotein B gene, all gamma-herpesviruses, have been characterized. Each sequence was specific to a bat species and in some species multiple viruses were identified. Phylogenetic analyzes of these sequences have identified clades specific to bat viruses. Those composed of sequences obtained from different species belonging to distinct subfamilies follow the taxonomy of bats. This study confirms the astonishing diversity of bat herpesviruses and broadens our knowledge on their host spectrum.This work is the largest conducted to date in terms of species diversity of non-human primates and bats from the Neotropical realm. Nevertheless, the samples tested represent only a tiny part of this diversity. Further analyzes, on a broader panel of representative species from other geographic areas will increase our understanding of the evolutionary history of these viruses
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Dhiman, Paula. "Incorporating novel risk markers into established risk prediction models." Thesis, University of Nottingham, 2015. http://eprints.nottingham.ac.uk/30666/.
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Introduction: Risk prediction models are used as part of formal risk assessment for disease and health events in UK primary care. To improve the accuracy of risk prediction, new risk factors are being added to established risk prediction models. However, current methods used to evaluate the added value of these new risk factors have shown to be limited. These limitations can be addressed using health economic methodology, but is yet to be used to evaluate and compare risk prediction models by means of their effectiveness and cost. Methods: A cost effectiveness analysis was performed using a decision tree framework. The decision tree was populated risk model effects and cost measures. The cost-effectiveness analysis derived the incremental cost effectiveness ratio (ICER) using the Youden Index and Harrell’s C-Index performance measures, and the net monetary benefit (INB). A probabilistic sensitivity analysis was performed, based on 10,000 iterations. A range of £0-£100,000 was used for the willingness to pay (WTP), which when combined with the INB, provided the probability the new risk factor was cost effective. This method was applied in two exemplar prospective cohort studies; adding family history (FH) to cardiovascular disease (CVD) risk prediction; and bone mineral density (BMD) to fracture risk prediction. Results: A cost-effectiveness analysis using a decision tree framework was shown to be an effective way of evaluating the added value of the new risk factor. Adding FH to standard CVD risk factors produced an ICER of £799.91 (-£5,962.15 to £5,968.22) and £7,788.76 (-£42,760.16 to £48,962.39) per percentage unit increase in the Youden Index and Harrell’s C-Index, respectively. The maximum probability of FH being cost effective is 0.7, with a minimum WTP of £15,000 (Youden Index). Further, treating low risk patients with statin therapy incorrectly was less costly (£788.40) than not treating them (£916.16). Adding continuous BMD measurement to standard fracture risk factors produced an ICER of £367.25 (-£4,241.88 to £4,828.50) and £4,480.54 (-£22,816.84 to £22,970.55) per percentage unit increase in the Youden Index and Harrell’s C-Index, respectively. The maximum probability BMD being cost-effective is 0.8, with a minimum WTP of £32,500 (Youden Index). Further, using BMD in a binary format to indicate osteoporotic patients, did not improve Harrell’s C-Index of standard fracture risk prediction (∆C-Index=-0.62%). Conclusion: A cost-effectiveness analysis was a novel method to compare two risk prediction models; and to evaluate the added value of a new risk factor. It identifies the added value of a new risk factor; encompassing the statistical and clinical improvement, and cost consequences when using the new risk factor in an established risk prediction model. Based on the added value of FH and BMD, there is a good evidence base to add these risk factors into routine risk assessment of the respective conditions. Increased use of this method could help standardise risk prediction and increase comparability of risk prediction models within diseases; producing a league table approach to evaluate, appraise and identify beneficial new risk factors and better risk prediction models.
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O'Malley, James. "Novel cell surface markers identify routes to iPS cells." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/8883.
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The generation of induced pluripotent stem cells (iPSCs) presents a challenge to normal developmental processes. The low efficiency and heterogeneity of most methods have hindered understanding of the precise molecular mechanisms promoting, and roadblocks preventing, efficient reprogramming. While several intermediate populations have been described, it has proved difficult to characterize the rare, asynchronous transition from these intermediate stages to iPSCs. The rapid expansion of a minor population of reprogrammed cells can also obscure investigation of relevant processes. Understanding of the biological mechanisms essential for successful iPSC generation requires both accurate capture of cells undergoing the reprogramming process and identification of the associated global gene expression changes. Here we demonstrate that reprogramming follows an orderly sequence of stage transitions marked by changes in cell surface markers CD44 and ICAM1, and a Nanog-GFP reporter. RNA-sequencing (RNA-seq) analysis of these populations demonstrates two waves of pluripotency gene up-regulation, and unexpectedly, transient up-regulation of multiple epidermis-related genes, demonstrating that reprogramming is not simply the reversal of normal developmental processes. This novel high-resolution analysis enables the construction of a detailed reprogramming route map, and this improved understanding of the reprogramming process will lead to novel reprogramming strategies.
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Poli, Maurizio. "Novel molecular markers for assessment of human embryo competence." Thesis, University of Oxford, 2016. http://ora.ox.ac.uk/objects/uuid:4c5bffff-d12c-4df1-b5f0-1459298fc45c.
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In vitro fertilization treatments are responsible for 1-5% births in industrialized countries. The safest way to generate a pregnancy is to transfer a single embryo to the mother, reducing the likelihood of multiple gestations. Hence, in order to maximize the chance of success, it is extremely important that the embryo prioritised for transfer is the most capable within the cohort of embryos generated by the patient. Along with cytogenetic components, it has been suggested that embryo protein expression patterns may correlate with its ability to implant. However, embryo proteomics strategies have not been easy to harness mainly due to the complexity of the media the embryos are cultured in, and the low concentration of the proteins that are secreted. In this study, the use of the blastocentesis procedure, which allows the safe retrieval of embryo inner fluid (blastosol), was described. The use of the blasocoel fluid as a source of embryonic DNA for preimplantation genetic assessment was also investigated. From this highly purified embryonic sample, a comprehensive catalogue of proteins present in the human blastosol was generated using standard and custom- made mass spectrometry strategies. The embryonic origin of these proteins was validated by gene expression microarray and RNASeq analysis. These experiments also allowed the identification of differentially expressed genes in the first two cell lineages, the Inner Cell Mass and the Trophectoderm. Finally, a targeted proteomics strategy able to measure part of the previously described protein targets in single blastosol samples was employed. The correlation between the presence and abundance of proteins of interest in single blastosols and several biological characteristics of the embryo, including its chromosomal status, was assessed. These data are of major interest for the understanding of human embryo development. The validated embryo-derived protein catalogue and blastocyst gene expression profiles generated in this study, provides access to a thorough document for consultation in human embryology proteomics-based experiment design, paving the way to next-generation proteomic-based embryo assessment.
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Lee, Wai Suet. "Discovery of Novel Markers of Virus Transmission by Mosquitoes." Thesis, Griffith University, 2019. http://hdl.handle.net/10072/390018.
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Mosquito-borne diseases are responsible for significant human morbidity and mortality throughout the world. Current vector control strategies have been impeded by mosquitoes acquiring resistance to insecticide. Therefore, development of new vector control strategies is urgently needed to complement current strategies. In this thesis, efforts have focused on characterizing the glycan-lectin interactions of Ross River virus (RRV; Togaviridae: Alphavirus) with their mosquito vectors. RRV is the most common arbovirus in Australia that causes clinical manifestations including arthralgia and myalgia. Many studies have shown the importance of viral surface glycans in mediating viral entry into host cells. Moreover, the viral surface glycans varies depending on the cells that they replicate in and this variation can affect the infectivity of virus. However, gaps remain in the role of viral glycans in virus host cell recognition. In Chapter 2, the surface glycans of RRV derived from two different cell lines, C6/36 (Ae. albopictus) and Vero (African green monkey kidney) were characterized using lectin array. Lectin array data revealed that RRV derived from two different cell lines exhibited similar glycan profiles. The glycan structures present on the surface of RRV are mannose, galactose, N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc). To investigate the importance of these viral surface glycans in mediating viral entry into host cells, six lectins targeting these glycan structures were assessed for their ability to bind and block RRV entry into host cells. Of these lectins, two mannose-binding lectins, GNA and ConA, showed inhibition of RRV entry into C6/36 and Vero cells. These results suggest the potential use of mannose-binding lectins to block RRV transmission by mosquitoes. It is well known that cell surface glycans or lectins play important role in viral entry. Therefore, comprehensive surface glycan profiles and carbohydrate-binding characteristics of lectins from five mosquito cell lines were established in Chapter 3. Using lectin and glycan arrays, our results showed differences between the glycan structures and carbohydrate-binding characteristics of mosquito cell lines. In particular, complex-type glycans were detected on the cell surface of Ae. albopictus and An. gambiae. The presence of complex-type glycans as authentic constituents of insect glycans is still controversial and this is an important finding as complex-type glycans play diverse roles in regulation of biological functions.
Zika virus (ZIKV) is primarily transmitted by the Aedes (Ae) mosquito, with Ae. aegypti and Ae. albopictus being the primary vectors. However, controversial findings on the potential of other mosquito species belonging to the genera of Anopheles (An) and Culex (Cx) have been reported. To date, the rationale underlying the specificity of ZIKV in infecting Aedes mosquitoes remain to be an unaddressed issue. In Chapter 4, we seek to characterize the susceptibility of seven cell lines derived from Ae, An and Cx mosquitoes towards ZIKV infection. Indeed, Ae cell lines were permissive to ZIKV infection and supported viral replication up to seven days post infection, while cells lines from An and Cx mosquitoes were unable to support replication. To specifically address if non-susceptible cell lines were due to the incompetence of ZIKV in establishing viral entry, a pseudoZIKV replicon system was utilized. Interestingly, while all Ae cell lines were highly susceptible to pseudoZIKV infection, the non-susceptible An. gambiae cell line (4a-3B) was also highly permissive to pseudoZIKV entry, in contrast to other An and Cx cell lines tested. Therefore, to identify the host factors involved in ZIKV replication in mosquito cells, RNA sequencing (RNAseq) analysis was performed on ZIKV-susceptible Ae and non-susceptible An cells after infection. Through comparative transcriptomics approach, we observed a differential regulation of attacin, an antimicrobial peptide (AMP) that may potentially play a critical role in modulating ZIKV replication in mosquito cells. Further investigations on the expression profile of different classes of AMPs including attacin, cecropin, defensin, diptericin and gambicin in Aedes; and attacin, cecropin, defensin and gambicin in Anopheles cells by qRT-PCR demonstrated that these AMPs were differentially regulated in ZIKV-susceptible and -resistant mosquito cells. These results suggest that the innate immunity may have a role to influence mosquito vector competence.
Species specificity often relies on a specific interaction between a virus ligand and its host cell receptor. Therefore, expression levels of the receptor largely determine the tropisms of viruses. In Chapter 5, we constructed a representative cDNA library from the ZIKV-susceptible Ae. aegypti Aag-2 cell line using the SMART (Switching Mechanism At 5’ end of RNA Template) cDNA synthesis technology. This library will be a useful tool to provide genetic resources for many applications using the proposed strategy including identification of the cellular surface receptors for ZIKV viral entry and host factors required for sustained ZIKV replication in Aedes cells.
Overall, this thesis provides in depth investigations into the glycan-lectin interactions between RRV and their mosquito vectors that may affect vector competence. Our study also identified the potential antiviral lectins that can block virus transmission. Finally, our study shed insights into the host factors involved in modulating ZIKV replication, providing a molecular platform for the future development of effective vector control and to evaluate the risk of emergence of a new vector for mosquito-transmitted viruses.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>Institute for Glycomics<br>Griffith Health<br>Full Text
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NAKO, ALBANA. "A novel sentiment measure and the stock market return." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2014. http://hdl.handle.net/2108/202697.
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The main issue in finance nowadays is to understand the financial market dynamics. This paper attempts to shed light on the relationship between media sentiment and stock market returns. An enormous amount of data are analyzed to define media sentiment. The data are downloaded from Twitter accounts of the main relevant economic financial journals and blogs at present in Italy. After classifying each message in positive, negative and neutral through natural linguistic processing, the investor sentiment index is defined and the VAR model is adopted. The paper demonstrates sentiment index derived from social media content affects the irrational investor’s behavior, therefore the stock market return.
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Lee, Tsz-hang Jimmy, and 李子恆. "Characterization of novel lipocalin LCN14 expressed in mouse." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193542.
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Obesity is one of the leading causes of world-wide life-threatening diseases, such as type 2 diabetes mellitus, atherosclerosis and cardiovascular diseases. So far, there is no effective, promising and safe remedy. Development of cost-effective anti-obesity therapies and promising biomarkers for obesity-related diseases have become a demanding task. Lipocalins, such as LCN13, were recently identified as potential drug target because of its beneficial effects on glucose and fat metabolism in mouse. LCN14 is a putative lipocalin that share high degree of homology with LCN13. In this study, it is experimentally proved that LCN14 is a secretory protein that is mainly expressed in white adipose tissues. It is also demonstrated that serum LCN14 level was significantly increased in mice with HFD treatment, and it was significantly reduced in diet-induced obese and diabetic (db/db) mice. In addition, the degree of suppression of circulating LCN14 was greater than that of LCN13 in diet-induced obese and db/db mice. Therefore, serum LCN14 level could be a promising marker for risk prediction of obesity and its complications. Further investigation is urgently needed to unveil the important roles of LCN14 in metabolism.<br>published_or_final_version<br>Medicine<br>Master<br>Master of Medical Sciences
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Garcia, Michael R. "Identification of novel nuclear markers for use in phylogenetic analysis." Tallahassee, Fla. : Florida State University, 2010. http://purl.fcla.edu/fsu/lib/digcoll/undergraduate/honors-theses/2181925.
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Thesis (Honors paper)--Florida State University, 2010.<br>Advisor: Dr. Gavin J.P. Naylor, Florida State University, College of Arts and Sciences, Dept. of Biology. Includes bibliographical references.
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Bin, Kaderi Mohamed Arifin. "Assessment of Novel Molecular Prognostic Markers in Chronic Lymphocytic Leukemia." Doctoral thesis, Uppsala universitet, Hematologi och immunologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-110371.
Full textAbstract:
The clinical course of chronic lymphocytic leukemia (CLL) is highly heterogeneous, which has prompted the search for biomarkers that can predict prognosis in this disease. The IGHV gene mutation status and certain genomic aberrations have been identified as reliable prognostic markers of clinical outcome for this disorder. However, the search for more feasible prognostic markers in CLL is still being pursued. Recently, certain single nucleotide polymorphisms (SNPs) in the GNAS1, BCL2 and MDM2 genes and the RNA expression levels of the LPL, ZAP70, TCL1, CLLU1 and MCL1 genes were suggested as novel prognostic markers in CLL. In papers I-III, we performed genotyping analyses of the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms in 268-418 CLL patients and related the genotypes with clinical data. Association studies between the polymorphisms and established prognostic markers (i.e. IGHV mutation status, genomic aberrations, CD38 expression) were also performed. Our studies did not find any significant relationship between these SNPs with either clinical outcome or other known prognostic markers in CLL. In paper IV, we measured the RNA expression levels of LPL, ZAP70, TCL1, CLLU1 and MCL1 in 252 CLL cases and correlated these levels with clinical outcome. Here, we verified that high expression of all these RNA-based markers, except MCL1, were associated with an unfavourable prognosis. We also confirmed a close relationship between IGHV mutation status and the RNA-based markers, especially for LPL and CLLU1 expression. Among the RNA-based markers, multivariate analysis revealed LPL expression as the strongest independent prognostic marker for overall survival and time to treatment. Furthermore, the RNA-based markers could add further prognostic information to established markers in subgroups of patients, with LPL expression status giving the most significant results. In summary, data from papers I-III could not verify the GNAS1 T393C, BCL2 -938C>A and MDM2 SNP309 polymorphisms as prognostic markers in CLL. Future SNP markers must hence be confirmed in large, independent cohorts before being proposed as prognostic marker in CLL. In paper IV, we conclude that LPL expression appears to be the strongest among the RNA-based markers for CLL prognostication. Further efforts to standardize LPL quantification are required before it can be applied in the clinical laboratory to predict clinical outcome in this disease.