Rozprawy doktorskie na temat „Cancer – Microbiology”
Kliknij ten link, aby zobaczyć inne rodzaje publikacji na ten temat: Cancer – Microbiology.
Utwórz poprawne odniesienie w stylach APA, MLA, Chicago, Harvard i wielu innych
Sprawdź 50 najlepszych rozpraw doktorskich naukowych na temat „Cancer – Microbiology”.
Przycisk „Dodaj do bibliografii” jest dostępny obok każdej pracy w bibliografii. Użyj go – a my automatycznie utworzymy odniesienie bibliograficzne do wybranej pracy w stylu cytowania, którego potrzebujesz: APA, MLA, Harvard, Chicago, Vancouver itp.
Możesz również pobrać pełny tekst publikacji naukowej w formacie „.pdf” i przeczytać adnotację do pracy online, jeśli odpowiednie parametry są dostępne w metadanych.
Przeglądaj rozprawy doktorskie z różnych dziedzin i twórz odpowiednie bibliografie.
1
Arat, Seda. "A Systems Biology Approach to Microbiology and Cancer". Diss., Virginia Tech, 2015. http://hdl.handle.net/10919/75149.
Pełny tekst źródłaStreszczenie:
Systems biology is an interdisciplinary field that focuses on elucidating complex biological processes (systems) by investigating the interactions among its components through an iterative cycle composed of data generation, data analysis and mathematical modeling. Our contributions to systems biology revolve around the following two axes:
- Data analysis: Two data analysis projects, which were initiated when I was a co-op at GlaxoSmithKline, are discussed in this thesis. First, next generation sequencing data generated
for a phase I clinical trial is analyzed to determine the altered microbial community in human
gut before and after antibiotic usage (Chapter 2). To our knowledge, there have not been
similar comparative studies in humans on the impacts on the gut microbiome of an antibiotic
when administered by different modes. Second, publicly available gene expression data is
analyzed to investigate human immune response to tuberculosis (TB) infection (Chapter 3).
The novel feature of this study is systematic drug repositioning for the prevention, control
and treatment of TB using the Connectivity map.
- Mathematical modeling: Polynomial dynamical systems, a state- and time- discrete logical
modeling framework, is used to model two biological processes. First, a denitrification pathway
in Pseudomonas aeruginosa is modeled to shed light on the reason of greenhouse gas
nitrous oxide accumulation (Chapter 4). It is the first mathematical model of denitrification
that can predict the effect of phosphate on the denitrification performance of this bacterium.
Second, an iron homeostasis pathway linked to iron utilization, oxidative stress response and
oncogenic pathways is constructed to investigate how normal breast cells become cancerous
(Chapter 5). To date, our intracellular model is the only expanded core iron model that can
capture a breast cancer phenotype by overexpression and knockout simulations.Ph. D.
2
Al, Kamal Nasrah Ali. "Immunotherapy for human breast cancer". Wright State University / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=wright1452814566.
Pełny tekst źródła
3
Ciesielski, Francisco Isaak Nícolas [UNESP]. "Microrganismos oportunistas e exógenos na microbiota bucal de pacientes oncológicos submetidos à radioterapia de cabeça e pescoço". Universidade Estadual Paulista (UNESP), 2010. http://hdl.handle.net/11449/91426.
Pełny tekst źródłaStreszczenie:
Made available in DSpace on 2014-06-11T19:25:20Z (GMT). No. of bitstreams: 0
Previous issue date: 2010-02-08Bitstream added on 2014-06-13T18:53:14Z : No. of bitstreams: 1
ciesielski_fin_me_araca.pdf: 340364 bytes, checksum: 27a652e37436beb5112aa9fdd7fb42ce (MD5)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
O objetivo deste estudo foi avaliar a ocorrência de microrganismos exógenos e oportunistas (bactérias entéricas, pseudomonados, leveduras e Helicobacter pylori) na cavidade bucal de pacientes submetidos à radioterapia para tratamento de câncer de cabeça e pescoço. Cincoenta pacientes que iria receber radioterapia foram examinados antes, durante e 30 dias após radioterapia. Amostras de saliva, mucosa e biofilme foram coletadas e os microrganismos foram detectados por cultura e Reação em Cadeia da Polimerase (PCR). Candida albicans, C. tropicalis, C. krusei, C. glabrata e C. parapsilosis foram as leveduras mais prevalentes nos pacientes submetidos a radioterapia. Gêneros Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus, e Pseudomonas forma as bactérias mais frequentemente cultivadas. As bactérias alvo foram cultivadas de 77.8% dos pacientes edêntulos e 46.9% dos pacientes dentados 30 dias após a radioterapia. Por PCR, estes microrganismos foram detectados em todos os pacientes edêntulos e 78.1% dos pacientes dentados. Bactérias não orais e espécies de Cândida foram mais prevalentes nestes pacientes. Modificações no meio ambiente oral devido a radioterapia parecem facilitar a colonização por estes microrganismos.
The aim of this study was to evaluate the occurrence of opportunistic and exogenous microrganisms (enteric bacteria, pseudomonads, yeasts and Helicobacter pylori) in the oral cavity of patients undergoing radiotherapy (RT) for treatment of head and neck cancer. Fifty patients receiving RT were examined before, during and 30 days after RT. Saliva, mucosa, and biofilm samples were collected and microorganisms were detected by culture and Polymerase Chain Reaction (PCR). Candida albicans, C. tropicalis, C. krusei, C. glabrata and C. parapsilosis were the most prevalent yeasts in patients submitted to RT. Genera Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus, and Pseudomonas were the most frequently cultivated bacteria. Targeted bacteria were cultivated from 77.8% edentulous and 46.9% dentate patients 30 days after RT. By PCR, these microorganisms were detected from all edentulous patients and from 78.1% of dentate patients. Non-oral bacteria and Candida species were prevalent in these patients. Modifications of the oral environment due to RT seem to facilitate the colonization of these microorganisms.
4
Mas, de Xaxars Rivero Teresa. "Descripció i quantificació de la microbiota intestinal associada al càncer colorectal". Doctoral thesis, Universitat de Girona, 2012. http://hdl.handle.net/10803/94513.
Pełny tekst źródłaStreszczenie:
Colorectal Cancer is the main type of cancer in Spain. Up to 90% of the cases are sporadic in nature and its aetiology is still unclear. It is supposed to be a multi-factorial disease, where factors play an important role in the tumor onset and development, like microbiota. The main goal of this study was to describe and quantify the bacterial community of the intestinal mucosa associated to colorectal cancer patients. This work has revealed the existence of a bacterial dysbiosis in colorectal cancer patients, which is in agreement with previous research. Specific phylotypes previously descrived using stool samples and also new phylotypes were associated with this disease.Furthermore, streptococcal populations have been studied and also a case report from a patient who present an infection caused by E. faecalis at the same time of CRC diagnosed. Future research should focus on specific aspects of intestinal microbiota such as its interaction with the host, together with the mechanisms by which bacteria can affect on the onset of tumor in the colon.El càncer colorectal és el tipus de càncer més abundant a Espanya. Fins el 90% dels casos són d'origen espontani i la seva etiologia és desconeguda malgrat existeixen diversos factors que poden afectar en el desenvolupament tumoral, com la microbiota. L'objectiu d'aquesta tesi ha estat analitzar la composició de la comunitat microbiana en mostres de mucosa intestinal quantitativa i qualitativament. Els resultats mostren una disbiosi en els malalts de càncer colorectal i una associació amb l'augment o disminució d'espècies bacterianes, així com l'augment de determinats filotips/gèneres. També s'ha analitzat les poblacions d'estreptococs i l'exposició d'un cas clínic d'un pacient amb càncer colorectal amb una infecció causada per E. faecalis. Estudis focalitzats en aspectes més específics de la relació hoste-microbiota, així com explorar nous mecanismes induïts per bacteris són necessaris per comprendre alguns aspectes de la carcinogènesis colorectal.
5
Ciesielski, Francisco Isaak Nícolas. "Microrganismos oportunistas e exógenos na microbiota bucal de pacientes oncológicos submetidos à radioterapia de cabeça e pescoço /". Araçatuba : [s.n.], 2010. http://hdl.handle.net/11449/91426.
Pełny tekst źródłaStreszczenie:
Orientador: Elerson Gaetti Jardim JúniorBanca: Alvimar Lima de Castro
Banca: Luis Fernando Landucci
Resumo: O objetivo deste estudo foi avaliar a ocorrência de microrganismos exógenos e oportunistas (bactérias entéricas, pseudomonados, leveduras e Helicobacter pylori) na cavidade bucal de pacientes submetidos à radioterapia para tratamento de câncer de cabeça e pescoço. Cincoenta pacientes que iria receber radioterapia foram examinados antes, durante e 30 dias após radioterapia. Amostras de saliva, mucosa e biofilme foram coletadas e os microrganismos foram detectados por cultura e Reação em Cadeia da Polimerase (PCR). Candida albicans, C. tropicalis, C. krusei, C. glabrata e C. parapsilosis foram as leveduras mais prevalentes nos pacientes submetidos a radioterapia. Gêneros Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus, e Pseudomonas forma as bactérias mais frequentemente cultivadas. As bactérias alvo foram cultivadas de 77.8% dos pacientes edêntulos e 46.9% dos pacientes dentados 30 dias após a radioterapia. Por PCR, estes microrganismos foram detectados em todos os pacientes edêntulos e 78.1% dos pacientes dentados. Bactérias não orais e espécies de Cândida foram mais prevalentes nestes pacientes. Modificações no meio ambiente oral devido a radioterapia parecem facilitar a colonização por estes microrganismos.
Abstract: The aim of this study was to evaluate the occurrence of opportunistic and exogenous microrganisms (enteric bacteria, pseudomonads, yeasts and Helicobacter pylori) in the oral cavity of patients undergoing radiotherapy (RT) for treatment of head and neck cancer. Fifty patients receiving RT were examined before, during and 30 days after RT. Saliva, mucosa, and biofilm samples were collected and microorganisms were detected by culture and Polymerase Chain Reaction (PCR). Candida albicans, C. tropicalis, C. krusei, C. glabrata and C. parapsilosis were the most prevalent yeasts in patients submitted to RT. Genera Citrobacter, Enterobacter, Enterococcus, Klebsiella, Proteus, and Pseudomonas were the most frequently cultivated bacteria. Targeted bacteria were cultivated from 77.8% edentulous and 46.9% dentate patients 30 days after RT. By PCR, these microorganisms were detected from all edentulous patients and from 78.1% of dentate patients. Non-oral bacteria and Candida species were prevalent in these patients. Modifications of the oral environment due to RT seem to facilitate the colonization of these microorganisms.
Mestre
6
Leveille, Simon. "Combination strategies in the development of oncolytic cancer therapy". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106483.
Pełny tekst źródłaStreszczenie:
The ability of certain viruses to exploit cancer cell abnormalities for their own replication represents a remarkable opportunity in the development of cancer therapy. Although oncolytic viruses such as Vesicular Stomatitis virus (VSV) possess a variety of intrinsic properties that can be exploited to this end, important aspects of their nature are not optimized for this purpose and may benefit from refinement. Therefore, strategies to enhance VSV's direct or immune-mediated tumor cell killing have been designed and tested in the course of the studies presented in this thesis. First, VSV was engineered to express the CD::UPRT suicide enzyme that allowed the conversion of a non-toxic, systemically delivered drug into a cytotoxic chemotherapeutic compound only at the tumor site. This strategy demonstrated a synergistic enhancement of tumor cell killing, with lysis of non-infected cancer cells contributing to increased efficacy in tumor cells partially resistant to VSV. In addition, combination treatment was optimized in vivo by taking into consideration the kinetics of virus replication at the tumor and the bioavailability of the non-toxic pro-drug. Results not only demonstrated enhanced therapeutic effects on tumor-bearing mice but also highlighted important characteristics of in vivo VSV replication kinetics. A second strategy combined VSV with an immunomodulatory approach in an attempt to boost VSV-induced anti-tumor adaptive immune response. Using Flt3L growth factor to promote dendritic cell population augmentation, antigen presentation capacity was highly enhanced concomitantly with VSV oncolysis. Although improving therapeutic outcome, the strategy did not improve anti-tumor adaptive immune response. The approach uncovered an unexpected aspect of the immune response: VSV treatment was found to profoundly affect the viability of immune cells and dendritic cells at the tumor and to block their migration to the draining lymphoid organs. Consequently, tumor antigen presentation was abolished. The absence of tumor antigen presentation following VSV treatment is a mechanistic explanation for the limited ability of VSV to induce a tumor-specific adaptive immune response. Altogether, the strategies developed in the course of this work enhanced VSV's oncolytic properties and greatly advanced our general understanding of VSV anticancer therapy.Certains virus possèdent la capacité d'exploiter les défauts métaboliques des cellules cancéreuses pour leur propre réplication. Ces virus, nommés virus oncolytiques, représentent une remarquable opportunité pour le développement de thérapies contre le cancer. Malgré cette prédisposition, certaines caractéristiques des virus oncolytiques ne sont pas optimales pour cette fonction et pourraient être améliorées. Dans cette optique, des stratégies visant à augmenter l'oncolyse induite par le virus Vesicular Stomatitis (VSV) ont été développées et testées chez la souris au cours de ce doctorat. Dans un premier temps, VSV a été modifié génétiquement afin qu'il exprime l'enzyme suicide CD ::UPRT lui permettant de réaliser la conversion d'un composé non-toxique administré de façon systémique en composé cytotoxique uniquement au site de la tumeur. La stratégie a permis de démontrer une augmentation synergique de la lyse des cellules cancéreuses ainsi que l'induction de la mort de cellules cancéreuses non infectées et partiellement résistantes au VSV. De plus, la combinaison in vivo a été optimisée afin de tenir compte de la cinétique de réplication du virus à la tumeur ainsi que de la biodisponibilité de la drogue. Les résultats ont permis non seulement d'obtenir une amélioration de l'effet thérapeutique mais également de souligner d'importantes caractéristiques de la réplication virale in vivo. Dans une seconde stratégie, VSV a été combiné avec une approche d'immunomodulation ayant pour but d'engendrer une réponse immunitaire acquise spécifique à la tumeur. En employant le facteur de croissance Flt3L qui favorise la prolifération et la différentiation des cellules dendritiques, la capacité de présentation d'antigènes a été grandement renforcée simultanément à l'oncolyse induite par VSV. En dépit du fait que la combinaison n'a que partiellement amélioré l'effet thérapeutique, elle a révélé un aspect inattendu de la réponse immunitaire engendrée par VSV. Les résultats ont démontré que VSV affecte grandement la viabilité des cellules immunitaires et des cellules dendritiques à la tumeur, qu'il bloque leur migration aux organes lymphatiques et que, par conséquent, la présentation d'antigènes tumoraux est abolie. La démonstration de l'absence de présentation d'antigènes tumoraux suivant le traitement oncolytique de VSV représente un important concept expliquant la piètre capacité de VSV en ce qui a trait à l'induction d'une réponse immunitaire aquise spécifique à la tumeur. En conclusion, les stratégies développées aux cours de ces travaux ont permis d'améliorer les propriétés oncolytiques de VSV ainsi que de grandement contribuer à la compréhension de la thérapie anti-cancer de VSV.
7
Lampraki, Eirini-Maria. "Role of the histone demethylase KDM6A in pancreatic cancer". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/38933/.
Pełny tekst źródła
8
Plummer, Kathleen Hope. "Cancer and Infection". Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5293.
Pełny tekst źródłaStreszczenie:
E. coli is the most frequently isolated Gram negative pathogen from bacteremia in cancer patients and is repeatedly recovered from many other extraintestinal illnesses. These infections are commonly endogenous in nature and interfere with the treatment of cancer resulting in increased healthcare costs, morbidity, and mortality rates. Cancer and the treatments related to cancer cause alterations in the microbiome of the gut and other organs. Despite this point, there is a serious lack of knowledge about the genetic types of E. coli infecting cancer patients. This gap results in vague prevention strategies and limited treatment options for cancer patients. Multi Locus Sequence Typing (MLST) was used to successfully genotype 105 sequentially collected E. coli isolates from patients admitted to H. Lee Moffitt Cancer Center (HLMCC, Tampa, FL) with confirmed extraintestinal infections between 2010 and 2012. In total, 24 distinct genotypes (STs) have been identified in this dataset using EcMLST (STEC Reference Center). Of these, ST34 constituted 39% of the isolates and may represent a disseminating clone at HLMCC. Furthermore, 17 isolates not found in the EcMLST database have been identified. Importantly, phylogenetic analysis of DNA sequence data for MLMCC E. coli revealed only 22% of HLMCC E. coli clustered with ECOR reference strains commonly attributed to the B2 phylogroup of extraintestinal pathogenic E. coli (ExPEC). Four HLMCC E. coli belonging to ST171 and attributed to life-threatening blood infections clustered with Shiga toxin (Stx) producing E. coli (STEC) strain TW06296. HLMCC E. coli belonging to ST34 clustered with enteroaggregative E. coli (EAEC) strain TW10263. Importantly, these non-B2 phylogroup strains demonstrated more pathogenic potential than HLMCC E. coli clustered with B2 ExPEC,which included a higher incidence of bacteremia and sepsis, as well as resistance to first-line antibiotics. Upon further investigation, ST34 may equate to ST131 by another MLST database. These findings suggest that isolates previously characterized as commensal and intestinal pathogenic E. coli have an increased ability to cause infection outside of the gastrointestinal tract in cancer patients and that selective pressures are contributing to increased antibiotic resistance. These findings may change the approach to clinical management of E. coli infections at cancer centers.
9
Hand, Nicholas. "Development of a Recombinant Attenuated Salmonella Cancer Vaccine". Thesis, The George Washington University, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10635177.
Pełny tekst źródłaStreszczenie:
New treatments for neuroblastoma are desperately needed; high-risk neuroblastoma patients have a less than 50% five-year survival rate despite intensive treatment. The greatest impact on improving survival rates for cancer patients in recent years is the result of a number of immunotherapeutic approaches. A proportion of high-risk neuroblastoma patients undergo spontaneous regression, possibly mediated by the immune system, indicating the potential of immunotherapies targeting neuroblastoma-associated antigens. Recombinant attenuated Salmonella vaccines (RASV) are cost-effective and have shown efficacy against a number of pathogen-associated antigens and are easily adapted for use as cancer immunotherapies. Here we cloned survivin, a neuroblastoma tumor-associated antigen into RASV expression plasmids to develop 24 RASV candidate vaccines with an array of select phenotypes. While conventional recombinant attenuated Salmonella vaccines are permanently attenuated, the RASV used here are engineered with inducible in vivo attenuation and other delayed phenotypes shown to improve immune responses. Survivin expression did not impact the growth or stability of any of the RASV constructs. Six of the constructs were tested in vivo, the RASV survived in the gut lumen, and all RASV-immunized mice produced anti-Salmonella responses. Protein/adjuvant immunized mice produced humoral and cellular survivin specific immune responses; however two independent in vivo experiments showed that no survivin specific immune responses were induced in survivin-expressing RASV immunized mice. Based on the results, a number of improvements to the future development of the vaccine are suggested.
10
Riggio, Alessandra I. "The role of Runx1 in genetic models of breast cancer". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/9103/.
Pełny tekst źródłaStreszczenie:
Given the recent discovery of RUNX1 somatic mutations in biopsies of breast cancer patients, the overall purpose of the present thesis consists of using different in vivo and ex vivo experimental systems in the attempt to answer two main questions: firstly, if the Runx1 gene plays any causative role in the context of breast cancer; and secondly, if its putative function is symptomatic of a tumour suppressor gene and/or of a pro-oncogene. By characterizing the effects of Runx1 deletion in two different breast cancer mouse models (i.e. the MMTV-PyMT and the Wnt/β-catenin-driven models of mammary tumourigenesis), this thesis provides the first in vivo evidence of a dualistic role played by the gene in the context of breast cancer. Runx1 would in fact appear to act as a tumour suppressor at early stages of the disease, whilst as a pro-oncogene at later stages of mammary tumourigenesis. To fully comprehend the significance of these major findings, the introduction will first provide a brief description on the RUNX family of genes, as well as on the state-of-the-art knowledge of RUNX1’s role in both mammary gland and breast cancer biology. As such, particular attention will then be given not only to the ontogeny, endocrine regulation and composition of the murine mammary gland, yet also to the high degree of heterogeneity, the putative “cell-of-origin(s)” and the different experimental models commonly used to study breast cancer. Through the aforementioned rationale, it is hoped that the introduction will serve as a platform which may hold the key for unveiling the controversial role played by RUNX1 in the context of breast cancer.
11
MacDonald, Patricia. "Defining functional domains within GPNMB important for breast cancer cell invasion". Thesis, McGill University, 2011. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=96829.
Pełny tekst źródłaStreszczenie:
Glycoprotein non-metastatic melanoma protein B (GPNMB)/Osteoactivin (OA) is a transmembrane protein that is commonly expressed in basal/triple-negative breast cancer. Our group discovered that GPNMB/OA is sufficient to enhance the migration and invasion of weakly metastatic murine breast cancer cells in vitro, and promotes the formation of bone and lung metastases in vivo. In this study, we sought to fully characterize the pro-invasive role of GPNMB/OA in human breast cancer cells by defining those motifs/domains within GPNMB/OA that are required to promote breast cancer cell invasion. In addition, we have sought the identity of putative GPNMB/OA interacting proteins that may be involved in promoting GPNMB/OA-mediated effects on breast cancer cell invasion and metastasis. To accomplish this, a panel of GPNMB/OA mutants were generated and expressed in the GPNMB/OA null BT-549 and MDA-MB-453 human breast cancer cells and subjected to in vitro invasion assays characterization. A candidate approach based on previous literature reports was used to facilitate the identification of GPNMB/OA protein binding partners in addition to attempting mass spectrometry analysis. Finally, a transgenic mouse model was created that expresses human GPNMB/OA under the control of the Mouse Mammary Tumor Virus (MMTV) promoter to further explore the role of GPNMB/OA on mammary gland development and tumorigenesis in vivo. Our results indicate that human GPNMB/OA is sufficient to induce enhanced invasion of BT549 breast cancer cells in vitro, which requires both the cytoplasmic tail and RGD recognition motif. Characterization of the MMTV-GPNMB/OA transgenic mice revealed that GPNMB/OA does not negatively affect normal mammary duct development in virgin females and no mammary tumors have developed to date. We conclude that GPNMB/OA is indeed capable of inducing invasion of breast cancer cells in vitro, which may require the participation of integrins and/or the residues/motifs within the cytoplasmic tail responsible for recruiting signalling molecules to this region of GPNMB/OA.Glycoprotein non-metastatic melanoma protein B (GPNMB), aussi connu sous le nom de Ostéoactivine (OA), est une protéine transmembranaire fréquemment exprimée dans les tumeurs mammaires appartement au sous-type triple négatif. Notre groupe a mis en évidence que l'expression de GPNMB/OA est suffisante pour accroître, in vitro, les capacités migratoires et invasives associées aux cellules murines de cancer du sein faiblement métastatiques. In vivo, l'expression de GPNMB/OA est caractérisée par une augmentation de la formation des métastases osseuses et pulmonaires. Dans cette étude, nous avons cherché à caractériser le rôle pro-invasif associé à l'expression de GPNMB/OA dans les cellules humaines de cancer du sein en identifiant les domaines ou motifs de GPNMB/OA impliqués dans le phénotype invasif des cellules de cancer du sein. D'une part, nous avons entrepris l'identification de protéines interagissant avec GPNMB/OA et qui pourraient participer aux phénotypes associés à l'expression de GPNMB/OA. Pour ce faire, nous avons généré une série de mutants pour la protéine GPNMB et nous les avons exprimées dans les lignées cellulaires BT-549 et MDA-MB-453, qui n'exprime normalement pas GPNMB/OA, que nous avons par la suite soumis à des essais d'invasion in vitro. D'autre part, une étude de la littérature scientifique, associée à une analyse par spectrométrie de masse, ont été utilisées pour identifier les protéines partenaires potentielles de GPNMB/OA. Finalement, nous avons généré une lignée de souris transgénique qui exprime la forme humaine de GPNMB/OA sous le contrôle du promoteur Mouse Mammary Tumor Virus (MMTV). Ce modèle murin a été utilisé pour étudier le rôle de GPNMB/OA sur le développement de la glande mammaire et sur la tumorigenèse in vivo. Ainsi, ces travaux ont démontré que la forme humaine de GPNMB/OA est suffisante pour induire une augmentation des propriétés invasives des cellules BT549 et que ce phénotype requiert à la fois la région cytoplasmique et le motif RGD de la protéine GPNMB/OA. La caractérisation, des souris transgéniques MMTV-GPNMB/OA a révélé, pour sa part, que GPNMB/OA n'interfère pas avec le développement normal des glandes mammaires chez les femelles vierges et aucune tumeur n'a été détectée à ce jour. L'ensemble de nos données démontre que GPNMB/OA est capable d'induire les propriétés invasives associées aux cellules de cancer du sein, et que ce phénotype requiert l'interaction du motif RGD de la protéine GPNMB avec les intégrines et/ou des résidus ou motifs présents dans la partie cytoplasmique de GPNMB/OA et qui pourraient induire le recrutement de molécule de signalisation dans cette région de GPNMB/OA.
12
Port, Jennifer Lynne Forbes. "Investigating the therapeutic potential of NUAK1 for the treatment of colorectal cancer". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/9125/.
Pełny tekst źródła
13
Rodgers, Lisa. "The phosphagen system in prostate cancer". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8520/.
Pełny tekst źródła
14
Giampazolias, Evangelos. "Investigating non-apoptotic cell death in cancer". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8056/.
Pełny tekst źródła
15
Dewar, Emma Louise. "Alpha-1-acid glycoprotein as a potential biomarker of breast cancer in 'at risk' individuals". Thesis, Edinburgh Napier University, 2015. http://researchrepository.napier.ac.uk/Output/9835.
Pełny tekst źródłaStreszczenie:
The identification of a blood-based diagnostic biomarker for breast cancer (BC) would be particularly beneficial to those at increased risk of developing BC and could result in earlier detection which may increase survival rates due to earlier treatment. Alterations in α-1-acid glycoprotein (AGP) glycosylation levels occur during disease and this study sought to determine the diagnostic potential of AGP glycan variation in triple negative breast cancer (TNBC) compared to BC of unknown type and healthy controls as well as women at increased risk of developing BC compared to age-matched healthy controls. AGP was isolated from blood of two different sample populations using low pressure chromatography. AGP purity was confirmed using SDS-PAGE and concentration determined using spectrophotometry. Structural analysis of AGP glycan monosaccharide and oligosaccharide content was undertaken using high pH anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Increased AGP concentrations were observed, in comparison to their controls, in BC of unknown type, TNBC and “at-risk” samples. Quantitative alterations in monosaccharide composition were also present. N-acetylgalactosamine (GalNAc) was present in over 88% of TNBC samples and was inversely correlated with age. For the TNBC groups, GalNAc was also present at higher levels in samples of individuals with family history of BC. There was an overall increase in GlcNAc levels compared to age-matched healthy controls and GalNAc presence in 81% of “at risk” samples. Oligosaccharide analysis revealed increased branching in BC of unknown type and TNBC < 35 years of age, whereas the “normal” healthy population and TNBC >35 possessed less branching. A similar trend was observed between the “at risk” samples and the age-matched controls. These branching patterns aligned well with the corresponding monosaccharide data. Overall, this study indicated that alterations in AGP levels and glycosylation exist between TNBC compared to BC of unknown type and “normal” healthy controls as well as an “at risk” population and age-matched healthy controls. The data could underpin the development of a new diagnostic BC biomarker.
16
Gupta, Elera Gaytri Devi. "Effect of Antioxidants and Oxidative Stress on Different Cancer Cell Types". BYU ScholarsArchive, 2012. https://scholarsarchive.byu.edu/etd/3227.
Pełny tekst źródłaStreszczenie:
Vaccinium cyanococcus, most commonly known as blueberry, is a fruit native to North America that is known for its unique taste and high antioxidant content. The skin, seed and juice of both organically and conventionally grown blueberry extract were analyzed for antioxidant content using both the Hydrophilic and Lipophilic Oxygen Radical Absorbance Capacity (ORAC) assays. Results from the Hydrophilic ORAC test showed that conventionally grown blue berries had a higher antioxidant capacity across all samples, while the Lipophilic ORAC assay showed that the antioxidant concentration of organically cultivated blueberry juice was highest, but conventionally grown blueberry seed and skin extract showed higher antioxidant content. The vitamin C content of both conventional and organic blueberries were analyzed using High Performance Liquid Chromatography (HPLC), where the organic blueberries showed a higher vitamin C concentration. In general, both organic and conventional blueberries are rich in antioxidants, and therefore, possess potential health benefits that require further study.
17
Braidwood, Lynne. "Oncolytic HSV1716 in combination with targeted anti cancer agents : identification of synergistic interactions and their mechanisms of synergy". Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7999/.
Pełny tekst źródłaStreszczenie:
Oncolytic viruses are multifunctional cancer agents with huge clinical potential, and recently the first Herpes Simplex Virus (HSV) oncolytic virus has been approved as a licensed cancer treatment. Increasingly, it is becoming apparent that no one cancer treatment is likely to be a ‘golden bullet’ – a treatment that, on its own is enough to cure all cancers. The answer seems to lie in combination therapies; by combining more than one type of treatment the chances of success, in terms of patient survival, increase. The aim of the project was to investigate the potential of HSV1716 in combination with other anti-cancer agents. As there is a vast array of current and potential cancer therapies, a high throughput screen using a range of cancer cell lines spanning a number of indications currently of clinical interest to Virttu Biologics was set up. This exploratory screen revealed a number of interesting results – synergies between HSV1716 and other drugs were seen across a number of different classes of drugs. This thesis first describes this ‘fishing’ exercise, then investigates the mechanism of action by which a subset of those drugs, highlighted as acting either synergistically or enhancing the amount of cell death in combination with HSV1716, are acting. mTOR inhibitors (targeted agent), doxorubicin (a chemotherapeutic) and two receptor tyrosine kinases, Sorafenib and Sunitinib, were identified in the screen. Subsequent analysis of these combination revealed that, despite the differences between the classes of drugs, all worked to greatly reduce viral replication, indicating that mechanisms other than viral oncolysis are killing cancer cells. The mechanism by which these cells were dying was investigated, HSV1716 in combination with mTOR inhibitors increased levels of intrinsic, mitochondrial driven apoptosis. Much of the observed enhanced cell killing was seen at low level of HSV1716 infection – where only 1 in 10 cells was infected with virus. It was postulated that there is also some form of secreted signal that sensitises non infected cells to apoptosis. If this is the case these cells may be sensitised to the effect of drugs – and hence the levels of cell killing would be increased relative to the non viral sensitised cells. The experiments detailed in this thesis indicate that this is indeed the case: HSV1716 infected cells secrete a ‘death signal’ that can be exported to non-infected cells. This signal itself increases cell death in non-infected cells but may also sensitise cells to the effect of drugs. Within the clinic, oncolytic viruses are effective agents at reducing tumour bulk by viral oncolysis and promote an anti-tumour immune response. The work presented in this thesis suggests that the virus may also induce infected cells to secret a factor that sensitises the surrounding cancer cells, generally resistant to apoptosis, to become more sensitive to apoptosis. These sensitised cells are then more susceptible to the effects of other anti-cancer agents.
18
Murray, Abner A. "Plant Virus Nanoparticle In Situ Cancer Immunotherapies". Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1532370850718292.
Pełny tekst źródła
19
Lungu, Gina Florentina. "Role of hypoxia and hypoxia induced factors in the development of breast cancer brain metastasis". [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3082.
Pełny tekst źródła
20
Derkits, Sahra. "Investigating the role of Pten and Lkb1 in traditional and serrated mouse models of colorectal cancer". Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/4909/.
Pełny tekst źródłaStreszczenie:
Colorectal cancer (CRC) is the fourth most common cancer in the UK. Despite intensive research that identified the key driver mutations, the precise consequences of each mutation and how they modify therapeutic response is unclear. More recently, it has been shown that the serrated subgroup of CRC, which is driven by oncogenic KRAS or BRAF mutations, is associated with the poorest survival. Germline mutations in either Phosphatase and tensin homologue (PTEN) and Liver kinase B1 (LKB1) cause intestinal hamartomas that can progress to CRC. However, there is an ongoing debate whether tumourigenesis arises from the epithelial or the mesenchymal compartment of the gut and the contribution of these mutations to sporadic CRC. The aim of this thesis was to: • Address the role of Pten and Lkb1 in the murine intestinal epithelium • Determine if these mutations cooperate with other driver mutations such as Apc and KRas. • Understand the mechanistic basis that drives changes in homeostasis and tumourigenesis. • Use recently developed small molecule inhibitors that target these aforementioned candidate pathways. Neither Pten nor Lkb1 deficiency was sufficient to drive neoplasia in the murine intestinal epithelium. Loss of Pten in the murine epithelium does not alter intestinal homeostasis and appears to be redundant. Lkb1 deficiency causes an expansion of the goblet cells linage and activation of the Hippo pathway but only when either KRas or Apc mutations are present does this result in accelerated tumourigenesis. Pten and KRas cause MAPK and PI3K pathway hyperactivation that results in hyperproliferation and serration of the murine gut. These precursor lesions are sensitive to MEK, PI3K/mTOR and surface Wnt inhibition. KRas driven tumours from either Lkb1 or Pten deficient mice acquire a Wnt pathway hyperactivation that drives invasion and metastasis in mice and leads to resistance of PI3K/mTOR and surface WNT inhibition. Taken together my data has shown that KRAS mutation can initiate tumours via a serrated route which on the further deregulation of Wnt signalling convert to tumours resembling classical CRC. Importantly these tumours are now Wnt ligand independent and appear treatment resistant, analogous to the human tumours that are adenocarcinoma that bear a serrated signature. Importantly loss of either LKB1 or PTEN accelerated tumourigenesis down either the serrated or the classical route and suggests key roles for these proteins in sporadic colorectal carcinogenesis. Given the drug resistance of our models, they could be utilized as excellent therapeutic testing models that may more closely recapitulate the human disease.
21
Sowerby, Zoe. "Bacterial n-nitrosation and nitrite reduction in the model organism Neisseria subflava". Thesis, Nottingham Trent University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241830.
Pełny tekst źródła
22
Steer, Toni. "Bacteriology of dietary anti-carcinogens in relation to colon cancer and the potential use of dietary intervention : effects of prebiotics and probiotics". Thesis, University of Reading, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272262.
Pełny tekst źródła
23
FOY, KEVIN CHU. "COMBINATION IMMUNOTHERAPY WITH HER-2/NEU AND VEGF PEPTIDE MIMICS IN BOTH TRANSGENIC AND TRANSPLANTABLE MOUSE MODELS OF HUMAN BREAST CANCER". The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299532419.
Pełny tekst źródła
24
Guffey, Catherine R. "Linking obesity to colorectal cancer| Recent insights into plausible biological mechanisms". Thesis, University of South Carolina, 2013. http://pqdtopen.proquest.com/#viewpdf?dispub=1537648.
Pełny tekst źródłaStreszczenie:
Obesity has emerged as a leading environmental risk factor for the development of CRC. However, the mechanisms underlying this relationship have not yet been fully explained. Recent literature has focused on 1) inflammatory processes, 2) adipokines, and 3) estrogen. Obesity-enhanced inflammation is largely orchestrated by increases in adipose tissue macrophages leading to the secretion of TNF-alpha, MCP-1, and IL-6, all of which are linked to CRC. Adiponectin is decreased with obesity and has been reported to be negatively associated with CRC, while leptin, which is increased, is positively associated with the disease. Estrogen has been shown to influence CRC, although its role remains controversial; some studies have implicated estrogen as being protective, while others have suggested it to be a risk factor. We highlight the most important recent advances that have been made on the aforementioned mechanisms that are thought to link obesity to CRC.
25
Miller, Megan Jo. "Novel HER3 and IGF-1R Peptide Mimics and Synthetic Cancer Vaccines". The Ohio State University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=osu1408981670.
Pełny tekst źródła
26
Phillips, Elisabeth. "Tamoxifen resistance in breast cancer : a proteomic approach". Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3270/.
Pełny tekst źródłaStreszczenie:
Tamoxifen is an effective and well-tolerated treatment for early disease and/or pre-menopausal patients with breast cancer (BC); although many women go on to develop resistance. Currently the five-year survival rate following Tamoxifen resistance (TR) is < 20%; hence the mechanisms need to be better understood. Recent research has focussed on specific pathways, however additional mechanisms are involved and we investigated these using cell line models of BC (MCF7) and TR using a variety of proteomic approaches. Differential expression and phosphorylation of proteins between the MCF7 and TR cell lines were detected by antibody arrays; which detected changes in Mitogen Activated Protein Kinases and Receptor Tyrosine Kinases family members, and in apoptosis related proteins. There were 21 novel proteins found to be altered in TR. 262 quantifiable proteins were found using SILAC; 29% over expressed in resistance and 25% down regulated. 5 were subsequently picked for validation by Western blot and 2 of these (IQGAP1 and cortactin) were chosen for further investigation with siRNA and functional assays. IQGAP1 was found to play a role in TR; as decreasing expression of IQGAP1 using SiRNA decreased the proliferation of TR cells and significantly modulated the TR cells ability to invade matrigel.
27
Weagel, Evita Giraldez. "Biomarker Analysis and Clinical Relevance of Thymidine Kinase 1 in Solid and Hematological Malignancies". BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/6881.
Pełny tekst źródłaStreszczenie:
Despite the global effort to discover and improve ways to detect, treat, and monitor cancer, it still remains the second leading cause of death in the United States and poses a major health and economic burden worldwide. While traditional treatments like surgery, chemotherapy, radiation therapy, and hormone therapy have been successful and have decreased cancer mortality, cancer incidence in all sites continues to rise. Consequently, there is an immediate need to find new therapeutics for the treatment of cancer. In recent years, and with the continuing push towards personalized medicine, cancer biomarkers have become crucial to detect, treat, and monitor cancer. Thymidine kinase 1 (TK1) has been identified as a cancer biomarker with diagnostic, prognostic, and therapeutic potential. TK1 is a nucleotide salvage pathway enzyme responsible for maintaining a balance in the cell nucleotide pool and providing the cell with thymidine monophosphate, which upon further phosphorylation is incorporated into DNA during cell replication. TK1 has been found to be upregulated in the serum of cancer patients. Serum TK1 (sTK1) has been used as an early diagnostic and prognostic biomarker in many types of cancer and has been shown to be a better proliferation biomarker than Ki67. In this dissertation, we described the characterization of TK1 as a cancer biomarker that associates with the plasma membrane of hematological malignancies such as Burkitt's lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, acute T cell lymphoma, and solid malignancies such as lung, breast, and colon cancer. We also describe the different oligomeric TK1 forms that are found on the cell membrane and show that membrane TK1 has activity. We assess the clinical relevance of TK1 in all these malignancies, looking at tissue expression as well as gene expression from patients from The Cancer Genome Atlas database. We find that TK1 is not expressed on the surface of normal cells, whether they are proliferating or not, making TK1 a unique cancer biomarker, with the potential to be used in targeted therapy. We also find that TK1 expressed on the surface may be involved in the invasion potential of cancer cells. The knowledge gained from this study will help researchers working in clinical research and cancer immunotherapeutics to potentially use TK1 as a biomarker and cancer target, and thus providing another weapon against cancer. In this dissertation, we described the characterization of TK1 as a cancer biomarker that associates with the plasma membrane of hematological malignancies such as Burkitt's lymphoma, acute lymphoblastic leukemia, acute promyelocytic leukemia, acute T cell lymphoma, and solid malignancies such as lung, breast, and colon cancer. We also describe the different oligomeric TK1 forms that are found on the cell membrane and show that membrane TK1 has activity. We assess the clinical relevance of TK1 in all these malignancies, looking at tissue expression as well as gene expression from patients from The Cancer Genome Atlas database. We find that TK1 is not expressed on the surface of normal cells, whether they are proliferating or not, making TK1 a unique cancer biomarker, with the potential to be used in targeted therapy. We also find that TK1 expressed on the surface may be involved in the invasion potential of cancer cells. The knowledge gained from this study will help researchers working in clinical research and cancer immunotherapeutics to potentially use TK1 as a biomarker and cancer target, and thus providing another weapon against cancer.
28
Webster, Rebecca. "Complementary investigations of the molecular biology of cancer : assessment of the role of Grb7 in the proliferation and migration of breast cancer cells; and prediction and validation of microRNA targets involved in cancer". University of Western Australia. School of Medicine and Pharmacology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0179.
Pełny tekst źródłaStreszczenie:
[Truncated abstract] For this thesis, the molecular biology of cancer was approached from two directions. Firstly, an investigation was conducted on the role of growth factor receptor-bound protein 7 (Grb7) in breast cancer. Grb7 is an adapter molecule that binds to a variety of proteins, including the growth factor receptor and proto-oncogene, ErbB2, and mediates signalling to downstream pathways. It has been linked to cell migration and an invasive phenotype, and is of interest as a therapeutic target. To investigate the role of Grb7 in breast cancer, preliminary experiments were performed that, firstly, determined the expression of wild-type Grb7 and a splice variant, Grb7V, in a range of cell lines, and secondly, aided the development of a protocol for treating cells with short interfering RNA (siRNA) against Grb7 and the ErbB ligand, heregulin (HRG), in a cell system appropriate for measuring the functional outcomes. Using this protocol in conjunction with CellTitre (CT) proliferation assays, it was demonstrated that Grb7 does not play a role in the proliferation of either unstimulated or HRG-stimulated SK-BR-3 breast cancer cells. Furthermore, using the protocol in conjunction with Boyden chamber migration assays, it was shown that inhibition of Grb7 expression has a slight stimulatory effect on HRG-stimulated SK-BR-3 cell migration. Thus, Grb7 was found to play only a minor role in the migration of SK-BR-3 cells, suggesting that it is not an ideal anti-cancer target for breast cancers modelled by this cell system. Concurrently, a second investigation was conducted, which similarly sought insight into the molecular biology of cancer, but adopted a more strategic approach. ... These results provide evidence for a biologically significant role for the miR-7-mediated regulation of EGFR expression. A microarray experiment was also performed to identify genes that were down-regulated following treatment with miR-7 compared to NS precursor. Of 248 down-regulated genes, including EGFR, 37 promising new miR-7 target candidates were identified. Functional clustering of down-regulated genes and promising target candidates suggested that miR-7 may have functionally-related targets involved in processes including cell motility and brain-associated functions. This investigation thus yielded a program capable of accurately predicting a miRNA target not predicted by any other target prediction program, verified a previously unknown miRNA:target interaction with functional consequences in cancer cells and provided the first steps towards investigating miR-7-mediated regulation in greater depth. Furthermore, EGFR was, to our knowledge, the first example of a verified miRNA target with target sites that are not conserved across mammals, an observation with important implications for computational target prediction and the evolution of miRNA regulatory systems. In addition, the demonstrated growth inhibitory and cytotoxic effects of miR-7 on lung cancer cells raise the possibility of a miR-7-based therapeutic for the treatment of EGFR-overexpressing tumours.
29
Monteverde, Tiziana. "Investigating the function and regulation of NUAK1 and its role in non-small cell lung cancer". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8701/.
Pełny tekst źródła
30
Smith, Richard LeRoy. "Cis-regulatory Sequence and Co-regulatory Transcription Factor Functions in ERα-Mediated Transcriptional Repression". BYU ScholarsArchive, 2009. https://scholarsarchive.byu.edu/etd/2261.
Pełny tekst źródłaStreszczenie:
Estrogens exert numerous actions throughout the human body, targeting healthy tissue while also enhancing the proliferative capacity of breast cancers. Estrogen signaling is mediated by the estrogen receptor (ER), which binds DNA and ultimately affects the expression of adjacent genes. Current understanding of ER-mediated transcriptional regulation is mostly limited to genes whose transcript levels increase following estrogen exposure, though recent studies demonstrate that direct down-regulation of estrogen-responsive genes is also a significant feature of ER action. We hypothesized that differences in cis-regulatory DNA was a factor in determining target gene expression and performed computational and experimental studies to test this hypothesis. From our in silico analyses, we show that the binding motifs for certain transcription factors are enriched in cis-regulatory sequences adjacent to repressed target genes compared to induced target genes, including the motif for RUNX1. In silico analyses were tested experimentally using dual luciferase reporter assays, which indicate that several ER binding sites are estrogen responsive. Mutagenesis of transcription factor motifs (for ER and RUNX1) reduced the response of reporter gene. Further experiments demonstrated that co-recruitment of ER and RUNX1 is necessary for repression of gene expression at some target genes. These findings highlight a novel interaction between ER and RUNX1 and their role in transcriptional repression in breast cancer.
31
Foster, Jessica. "Investigating the relationship between UbcH10 and the anaphase promoting complex/cyclosome". Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8024/.
Pełny tekst źródłaStreszczenie:
UbcH10 functions as an E2-conjugating enzyme for the Anaphase-Promoting Complex/Cyclosome (APC/C) E3-ubiquitin ligase, and helps to facilitate the APC/C-dependent ubiquitylation of substrates during mitosis and G1. UbcH10 is also a proto-oncogene product that is overexpressed in a number of human cancers. Despite its ability to promote APC/C ubiquitin ligase activity, and initiate tumourigenesis, very little is known about the UbcH10 interactome. Here we used immunoprecipitations-coupled to mass spectrometry to identify the UbcH10 interactome in HeLa and RPE-1 cells. Of those proteins identified, Geminin and Cdt1 have been determined previously to be APC/C substrates. Further studies confirmed that PDZ-RhoGEF was a novel UbcH10-interacting protein, and identified PDZ-RhoGEF as a novel APC/C substrate. PDZ-RhoGEF was shown to be degraded in early mitosis in a SAC-insensitive manner, whilst overexpression of wild-type (WT) UbcH10 was shown to induce the premature degradation of PDZ-RhoGEF. ASPP1 and ASPP2 were also shown to interact with UbcH10 and be targeted for degradation by the APC/C in a SAC-sensitive manner; over expression of WT UbcH10 induced the premature degradation of both ASPP1 and ASPP2. ASPP2 was shown to be a substrate for APC/C-targeted ubiquitylation, whilst an ASPP2 species lackinf APC/C degrons stimulated p53 transcriptional activity better than WT ASPP2.
32
Tsim, Selina. "Diagnostic and prognostic biomarkers of malignant pleural mesothelioma". Thesis, University of Glasgow, 2018. http://theses.gla.ac.uk/30687/.
Pełny tekst źródłaStreszczenie:
Malignant Pleural Mesothelioma (MPM) is an aggressive intrathoracic malignancy with an overall poor prognosis. MPM is associated with asbestos exposure but has a long latency period between exposure and disease development. Incidence of MPM in the UK is therefore still rising, predicted to reach a peak in 2020. The majority of patients with MPM present with breathlessness, frequently due to a pleural effusion and/or chest pain. Diagnosis of MPM can be difficult. Radiological detection of early stage MPM in particular can be challenging, as pleural tumour, nodularity or significant pleural thickening may not be evident. Diagnosis is further complicated by the low yield of pleural fluid cytology examination in MPM and pleural biopsy is therefore usually required to allow definitive diagnosis. This can be achieved under image guidance, at surgical thoracoscopy or at local anaesthetic thoracoscopy (LAT). A significant number of patients are either elderly or have co-morbidity precluding general anaesthesia and surgical thoracoscopy. Image-guided pleural biopsy is not always feasible, particularly in the absence of significant pleural thickening. LAT remains a limited resource in the UK. A non-invasive biomarker of MPM, which could be performed early in the patient’s presentation, and that could be available to most hospitals, would therefore be a major clinical advance, allowing clinicians to direct appropriate patients to specialist centres with access to LAT and specialist MDT input where MPM appears likely. There have been several potential blood biomarkers identified in the mesothelioma literature, including the most widely studied, Mesothelin, and more recently Fibulin-3 and SOMAscanTM. Unfortunately study results have been variably limited by retrospective study design, inconsistent sampling time points, inconsistent results and lack of external validation, therefore despite initial promising results, none of these biomarkers have entered routine clinical practice for diagnosis. Similarly, utility of imaging biomarkers such as perfusion Computed Tomography (CT), Positron Emission Tomography (PET) and Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) has been limited by high radiation dose, limited availability, and requirement for bulky (and therefore late stage) disease for assessment respectively. In chapter 2, study design, recruitment and preliminary results of the DIAPHRAGM (Diagnostic and Prognostic Biomarkers in the Rational Assessment of Mesothelioma) study are reported. A prospective, multi-centre study was designed, recruiting patients with suspected pleural malignancy (SPM) at initial presentation to secondary care services, from a mixture of academic and more clinical units in the UK and Ireland, in addition to asbestos-exposed control subjects. In one of the largest biomarker studies in mesothelioma to date, 639 patients with SPM and 113 asbestos-exposed control subjects were recruited over three years. Data cleaning is being finalised by the Cancer Research UK Clinical Trials Unit Glasgow at the time of writing. Preliminary results reveal that 26% (n=154) patients recruited to the SPM cohort were diagnosed with MPM, 33% (n=209) had secondary pleural malignancy and 34% (n=218) were diagnosed with benign pleural disease. A final diagnosis is awaited in 7% (n=47) at the time of writing. SOMAscanTM and Fibulin-3 biomarker analyses are ongoing and DIAPHRAGM will definitively answer the question of diagnostic utility of these blood biomarkers in routine clinical practice, in a ‘real-life’ MPM population, relative to that of Mesothelin. In chapter 3, contrast-enhanced MRI was performed in patients with suspected MPM and a novel MRI biomarker of pleural malignancy defined (Early Contrast Enhancement – ECE). ECE was defined as a peak in pleural signal intensity at or before 4.5 minutes after intravenous Gadobutrol administration. ECE assessment was successfully performed in all patients who underwent contrast-enhanced MRI. This included patients with pleural thickening < 10mm (49/58 (84%)), the mean pleural thickness of all patients was 5mm. ECE demonstrated good overall diagnostic performance for the detection of pleural malignancy (sensitivity 83% (95% CI 61 – 94), specificity 83% (95% CI 68 - 91%), positive predictive value 68% (95% CI 47 – 84%), negative predictive value 92% (95% CI 78 – 97%)), comparable to morphology assessment at CT morphology and MRI morphology by experienced thoracic radiologists. In addition, ECE demonstrated good reproducibility (inter-observer κ = 0.864), superior to subjective morphology assessment at CT and MRI. Mean signal intensity gradient (MSIG), a marker of patient’s contrast enhancement pattern, correlated with tumour Microvessel Density (MVD) using Factor VII immunostain (Spearman’s rho = 0.43, p=0.02). Additionally, a high MSIG (>0.533AU/s), indicative of high tumour vascularity, was associated with poor median overall survival (12 months vs. 20 months, p=0.047). Staging of MPM represents an additional challenge to clinicians. This is due to the complex morphology and often rind-like growth pattern of MPM. In addition, delineation of pleural disease from adjacent structures such as intercostal muscle and diaphragm can be difficult to assess, particularly at CT, which is the most commonly used imaging modality for diagnostic and staging assessment in MPM. Current clinical staging frequently underestimates extent of disease, with a significant proportion of patients being upstaged at time of surgery, and is limited by high inter-observer variability. Recent studies have reported the prognostic significance of CT-derived tumour volume; however, many of these studies have been limited by the laborious or complex nature of tumour segmentation, significant inter-observer variability or challenges encountered in separating pleural tumour from adjacent structures, which are often of similar density. MRI is superior to CT in the detection of invasion of the chest wall and diaphragm in MPM. In Chapter 4, MRI was used to quantitatively assess pleural tumour volume in 31 patients with MPM using novel semi-automated segmentation methodology. Four different segmentation methodologies, using Myrian® segmentation software were developed and examined. Optimum methodology was defined, based on the accuracy of volume estimates of an MRI phantom, visual-based analysis, intra-observer agreement and analysis time. Using the optimum methodology, there was acceptable error around the MRI phantom volume (3.6%), a reasonable analysis time (approximately 14 minutes), good intra-observer agreement (intra-class correlation coefficient (ICC) 0.875) and excellent inter-observer agreement (ICC 0.962). Patients with a high MRI-estimated tumour volume (≥300cm3) had a significantly poorer median overall survival (8.5 months vs. 20 months) and was a statistically significant prognostic variable on univariate (HR 2.273 (95% CI 1.162 – 4.446), p=0.016) and multi-variate Cox proportional hazards model (HR 2.114 (95% CI 1.046 – 4.270), p=0.037).
33
Muthalagu, Nathiya. "Understanding the mechanism of MYC induced vulnerabilities". Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/7464/.
Pełny tekst źródła
34
Woodham, Emma. "Investigating the role of the Rho GTPase Cdc42 in the migration and invasion of the melanocyte lineage". Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8195/.
Pełny tekst źródła
35
Li, Xiaona. "Mass spectrometry-based metabolomics study on KRAS-mutant colorectal cancer and rheumatoid arthritis". HKBU Institutional Repository, 2018. https://repository.hkbu.edu.hk/etd_oa/540.
Pełny tekst źródłaStreszczenie:
Ample studies have shown that perturbation of metabolic phenotype is correlated with gene mutation and pathogenesis of colorectal cancer (CRC) and rheumatoid arthritis (RA). Mass spectrometry (MS)-based metabolomics as a powerful and stable approach is widely applied to bridge the gap from genotype/metabolites to phenotype. In CRC suffers, KRAS mutation accounts for 35%-45%. In previous study, SLC25A22 that encodes the mitochondrial glutamate transporter was found to be overexpressed in CRC tumor and thus to be essential for the proliferation of CRC cells harboring KRAS mutations. However, the role of SLC25A22 on metabolic regulation in KRAS-mutant CRC cells has not been comprehensively characterized. We performed non-targeted metabolomics, targeted metabolomics and isotope kinetic analysis of KRAS-mutant DLD1 cells with or without SLC25A22 knockdown using ultra-high performance liquid chromatography (UHPLC) coupled to Orbitrap MS and tandem MS (MS/MS). In global metabolomics analysis, 35 differentially regulated metabolites were identified, which were primarily involved in alanine, aspartate and glutamate metabolism, urea cycle and polyamine metabolism. Then targeted metabolomics analysis on intracellular metabolites, including tricarboxylic acid (TCA) cycle intermediates, amino acids and polyamines, was established by using LC-MS/MS coupled with an Amide BEH column. Targeted metabolomics analysis revealed that most TCA cycle intermediates, aspartate (Asp)-derived asparagine, alanine and ornithine (Orn)-derived polyamines were strongly down-regulated in SLC25A22 knockdown cells. Moreover, the targeted kinetic isotope analysis using [U-13C5]-glutamine as isotope tracer showed that most of the 13C-labeled TCA cycle intermediates were down-regulated in SLC25A22-silencing cells. Orn-derived polyamines were significantly decreased in SLC25A22 knockdown cells and culture medium. Meanwhile, accumulation of Asp in knockdown of GOT1 cells indicated that oxaloacetate (OAA) was majorly converted from Asp through GOT1. Exogenous addition of polyamines could significantly promote cell proliferation in DLD1 cells, highlighting their potential role as oncogenic metabolites that function downstream of SLC25A22-mediated glutamine metabolism. SLC25A22 acts as an essential metabolic regulator during CRC progression as promotes the synthesis of TCA cycle intermediates, Asp-derived amino acids and polyamines in KRAS-mutant CRC cells. Moreover, OAA and polyamine could promote KRAS-mutant CRC cell growth and survival. Rheumatoid arthritis (RA) is a chronic, inflammatory and symmetric autoimmune disease and a major cause of disability. However, there is insufficient pathological evidence in term of metabolic signatures of rheumatoid arthritis, especially the metabolic perturbation associated with gut microbiota (GM). Based on consistent criteria without special diet and therapeutic intervention to GM, we enrolled 50 RA patients and 50 healthy controls. On basis of the platform of UHPLC-MS and GC-MS, were performed for the non-targeted metabolomics to investigate alterations of endogenous metabolites in response to RA inflammation and interaction with GM. 32 and 34 significantly changed metabolites were identified in urine and serum of patients with RA, respectively. The altered metabolites were identified by HMDB, METLIN database or authentic standards, and mostly metabolites were attributed into tryptophan and phenylalanine metabolism, valine, leucine and isoleucine biosynthesis, aminoacyl-tRNA biosynthesis and citrate cycle. To obtain alterations of more components in tryptophan and phenylalanine metabolism, we developed and validated a targeted metabolomics method of 19 metabolites by using LC-QqQ MS. Combining the results of targeted metabolomics with global metabolomics, significantly up-regulated kynurenine (KYN), anthranilic acid (AA) and 5-hydroxylindoleacetic acid (HIAA) simultaneously in urine and serum was found to implicate the activation of tryptophan metabolism under the condition of RA, which acted pro-inflammatory roles in inflammation and was closely correlated with GM. IDO/TDO functioned as a pro-inflammation mediator was overexpressed in RA patients. Urinary kynurenic acid and serum serotonin that have impacts on anti-inflammation in immune system were down-regulated in RA patients. The levels of phenylacetic acid and phenyllactic acid serving as a pro-inflammatory and an anti-inflammatory agent, respectively, increased in serum of patients with RA. Moreover, certain essential amino acids (EAAs), and mostly conditional EAAs were decreased in RA patients, which have been reported to inhibit cell proliferation of immune cells. In particular, deficiency of branched chain amino acids (BCAAs, valine and isoleucine) was observed in serum of patients with RA, which may lead to muscle loss and cartilage damage. The specificity of all altered metabolites resulted from RA was considerably contributed through the GM-derived metabolites. The findings revealed that GM-modulated RA inflammation was mainly resulted from tryptophan and phenylalanine metabolism, and amino acid biosynthesis, which may provide more information for better understanding the RA mechanism.
36
Natarajan, Gayathri. "THE USE OF A TEC KINASE INHIBITOR, IBRUTINIB, FOR THE DEVELOPMENT OF IMMUNOTHERAPIES AGAINST CANCER AND LEISHMANIASIS". The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1461200133.
Pełny tekst źródła
37
Miranda, Alexandra de Sousa Montenegro. "Characterisation of LVI-1 (WDR76) as a candidate tumour suppressor gene". Thesis, University of Glasgow, 2006. http://theses.gla.ac.uk/4967/.
Pełny tekst źródłaStreszczenie:
The central aim of this study was to characterise the expression of the candidate tumour suppressor gene, LV/-J (lentivirus integration-I) and its products. The LVI-J gene (WDR76) was discovered as a target for disruption by proviral insertional mutagenesis in a case of pre-B cell lymphoma in a FIV infected cat {Beatty, 1998 5 lid; Beatty, 2002 7 lid}. As LV/-J is highly conserved, my work focused on the human and murine orthologues to take advantage of the superior resources available for these species. My work showed potentially important differences in expression of the human and mouse genes with respect to promoter use and length of 3' untranslated sequences. The murine gene is transcribed mainly from the distal PI promoter, which appears to be a bi-directional element shared with the adjacent MJapJ gene, while the human gene transcripts are derived exclusively from the proximal P2 promoter. Direct analysis by RT-PCR showed that the murine gene could also be expressed from the P2 promoter. These findings have significant implications for Lvi-l protein expression as the P2 transcripts are predicted to express larger proteins with a distinct N-terminal sequence. To characterise the LV/-J gene products, rabbit polyclonal antisera were raised to GST fusion proteins expressed in bacteria. Use of the murine anti-ml.vi-I antiserum in Western blotting identified a protein of the expected size (58 kDa) based on translation of the major mRNA species from the PI promoter. Immunofluorescence and confocal microscopy suggested that this protein is localised mainly in the cytoplasm. Although the function of LVI-I is unknown, its closest relative in the human genome is DDB2, a protein involved in repair of UV-induced DNA damage. Regulation of LVI-I expression was examined after UV irradiation, providing preliminary evidence of responses at transcriptional and post-transcriptional levels. Further leads were followed by analogy with the yeast orthologue of LVI-I, YDLI56W, but no evidence of a complex between LVI-I and MSH6 was found. In conclusion, while function of the LVI-I gene remains to be establishes, it provides the basis for future characterisation of this highly conserved and potentially important eukaryotic gene.
38
Alegre, Melissa Marie. "Thymidine Kinase 1: Diagnostic and Prognostic Significance in Malignancy". BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4049.
Pełny tekst źródłaStreszczenie:
Thymidine kinase 1 (TK1) is a cancer biomarker which has diagnostic and prognostic potential in a variety of malignancies. TK1 is significantly elevated in the serum and tumor tissue of most malignancies. This increase in TK1 can be detected in the very early stages of malignancy, including in pre-malignant disease with an increased risk for progression. Several studies have demonstrated that elevated TK1 is found in serum months before any clinical symptoms of malignancy. It has also been demonstrated that TK1 is elevated months before clinical recurrence of malignancy. This work first sought to demonstrate the early nature of TK1 expression in breast tumor tissue and pre-malignant tissue. We found that TK1 is elevated in breast hyperplasia tissue and breast carcinoma tissue. In this study we also identified some cases of ‘normal’ tumor margins (considered normal by current pathological standards) which also had elevated TK1 expression. Conversely, true normal breast tissue from noncancerous individuals had no reported elevation in TK1 expression. This study illustrated that TK1 is elevated in pre-malignant breast hyperplasia tissue, as well as some 'normal' tumor margins. TK1 expression was significantly elevated in lung, prostate, colon, esophagus, stomach, liver, and kidney tissues. This work further investigated TK1 expression in a variety of malignant tissue including the two leading causes of cancer mortality in men: lung and prostate cancer. In our study, TK1 was significantly elevated in lung and prostate cancer but not significantly elevated in prostate hyperplasia tissue. TK1 expression also increased with increasing grade in prostate carcinoma tissue. Overall, this work demonstrated that TK1 is a good universal marker of malignancy and is elevated in early cancer development. Despite the potential for TK1 as both a screening and monitoring treatment tool, there have been significant challenges associated with developing a clinically relevant method of TK1 detection. This work proposes one clinically relevant method of detection, namely a TK1 ELISA. Using preoperable lung cancer patients and normal controls, we developed a sensitive and specific ELISA which shows highly statistically significant differences in serum TK1 levels between stage 1 and stage 2 lung cancer compared with normal controls. In fact, this TK1 ELISA is more sensitive and accurate than the traditional TK radioassay, which was unable to detect differences in TK1 between early stage lung cancer and normal patients. Although elevated TK1 is not lung cancer specific, we reported significantly elevated TK1 levels in lung cancer sputum. Screening of sputum and serum for TK1 may be one method for the early detection of lung cancer. Overall, we report TK1 has promising diagnostic potential in a variety of malignancies. We also propose one sensitive and specific method to detect TK1 levels which may easily be adapted to meet current clinical applications. We hope this work will help propel TK1 forward into clinical view in the coming years.
39
Kershaw, Rachael Maria. "Delayed response of the CYS326 variant of the DNA repair protein OGG1 to cellular oxidative stress". Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/3035/.
Pełny tekst źródłaStreszczenie:
Reactive oxygen species (ROS) are generated via endogenous and exogenous sources. ROS are involved in essential cellular processes but when present in excess, can overwhelm antioxidant defences and induce a range of damaging DNA lesions. The most commonly oxidised DNA base is guanine. This generates products including 7,8-dihydro-8-oxodeoxyguanine (8-oxo dG) which can result in G:C->T:A transversion mutations, frequently found in human cancers. Oxidative damage is also implicated in normal cellular ageing and degenerative diseases. 8-oxo dG repair is initiated by the base excision repair enzyme 8-oxoguanine DNA glycosylase 1 (OGG1). Modulation of OGG1 activity in oxidising conditions has implications for mutation prevention. This thesis investigates regulation of OGG1 under oxidising conditions using BSO, which increases intracellular ROS. Chapter 3 shows that following BSO treatment, mouse OGG1 activity in mouse embryonic fibroblast (MEF) cells increases with no change in mRNA levels, whereas identical treatment has no effect on rat OGG1 activity in MH1C1 cells but modulates protein levels. A human OGG1 (hOGG1) variant with serine exchanged for cysteine at codon 326 (Cys326-hOGG1) is associated with reduced repair ability under oxidising conditions. Chapter 4 describes the development of mOGG1-/- MEF cells stably expressing Ser326- or Cys326-hOGG1 and in chapter 5 these cells are used to investigate Ser326- and Cys326-hOGG1 activity, gene expression, protein localisation, homo-dimer formation and retention within an insoluble nuclear fraction following BSO treatment. Data presented shows that the activity of both Ser326- and Cys326-hOGG1 increase following BSO treatment but Ser326-hOGG1 peak activity occurs 12 hours prior to that of Cys326-hOGG1. This increased activity is not associated with increased gene expression or protein, or any protein localisation change; however, Cys326-hOGG1 is retained to a lesser extent in an insoluble nuclear fraction following BSO treatment. The findings presented in this thesis show that OGG1 activity is modulated post-transcriptionally in response to increased ROS and provide a possible mechanism behind impaired Cys326-hOGG1 repair in oxidising conditions, further supporting the role of Cys326-hOGG1 in the process of carcinogenesis.
40
Machado, Lee Richard. "Molecular mechanisms of T cell homing in Hodgkin's lymphoma : implications for T-cell-based therapies". Thesis, University of Birmingham, 2004. http://etheses.bham.ac.uk//id/eprint/579/.
Pełny tekst źródłaStreszczenie:
Recent years have seen important advances in the area of T cell-based therapy for human malignancies. Epstein Barr virus-associated tumours like Hodgkin’s Lymphoma provide important models in this field. If a T cell-based therapy is to be effective however, T cells must be capable of trafficking to the tumour. To address this, the molecular mechanisms of T cell homing to Hodgkin’s Lymphoma were explored. Chemokine and adhesion receptors were examined on infiltrating T cells. CXCR3, CXCR4 and CCR7 were expressed on major T cell populations with CXCR5, CXCR6, CCR4 and CCR5 on minor populations. Tumour cells expressed CXCL10, CXCL12 and CCL21. Vessels expressed ICAM-1, CXCL12, CCL17 and CCL21. Tumour cell lines secreted factors that mediated chemotaxis of lymphoblasts in vitro and TIL demonstrated chemotaxis to CXCL12 but not CCL17. VAP-1 was expressed on vessels and a tissue-binding assay was evaluated to examine VAP-1 function. T cell clones generated as part of an existing clinical trial of adoptive T cell therapy were found to express a polarised Tc1 phenotype (CXCR3, CXCR6 and ccr5), which was typically independent of target antigen specificity, CD4/CD8 and donor status. However, lack of CCR7 expression and an inability to capture to VCAM-1 in a chemokine dependent manner suggested that clones expanded in vitro using existing protocols may be inefficient at trafficking to tumour tissue and thus may require modification of their homing phenotype.
41
Zhao, Hongyan. "Development and application of high-field asymmetric waveform ion mobility spectrometry and mass spectrometry for the investigation of fibroblast growth factor signalling". Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/7022/.
Pełny tekst źródłaStreszczenie:
The deregulation of FGF signalling is closely linked to many human diseases, including cancer. Through phosphorylation and dephosphorylation processes, FGF signalling is finely controlled. The thesis presented focuses on applying mass spectrometry tools to investigate FGF signalling using the breast carcinoma SUM52 cell line. High-Field Asymmetric Waveform Ion Mobility Spectrometry (FAlMS) is a technique that separates and focuses ions at atmospheric pressure. It has been demonstrated the application of LC-FAIMS-MS/MS results in increased signal-to-noise ratios and improved dynamic range in analysis of complex proteomics samples. The LC-FAIMS-MS /MS method for large-scale quantitative analysis was optimized and the performance of LC-MS/MS and LC-FAIMS-MS/MS was compared. Results showed the two techniques shared good complementarity. The incorporation of FAIMS resulted in an increase of novel phosphosites and multiply-phosphorylated peptides. Next, a modified FAlMS interface was evaluated for proteomic analyses. This novel FA IMS device exhibited potential in enhancing proteomic analysis showing an increase in peak capacity and proteome coverage and a lower level of redundancy. Next, SRM was applied for accurate quantitation of75 phosphopeptides in a time-resolved way. The data revealed that these phosphorylation sites showed different associations with FGFJ stimulation. Expression patterns were clustered into early, mid- and late stage response.
42
Irvine, David Arthur. "Defining novel therapeutic targets in chronic myeloid leukaemia stem cells : targeting self-renewal through hedgehog pathway inhibition". Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4584/.
Pełny tekst źródła
43
AQBI, HUSSEIN F. "Preconditioning of the tumor microenvironment by means of low dose chemotherapies for an effective immunotherapy of breast cancer". VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/6025.
Pełny tekst źródłaStreszczenie:
Breast cancer mortality is mainly due to distant recurrence of the disease arising from dormant tumor cells established by cancer therapies. Patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.
Although immunotherapy of breast cancer by means of anti-HER2 antibodies prolongs survival of breast cancer patients, disease recurrence remains a major challenge. On the other hand administration of human vaccines against infectious disease in a preventive setting or during latency/dormancy has been successful in offering a cure. Here, we sought to use adoptive immunotherapy (AIT) at the time of tumor dormancy in order to prevent progression of breast cancer. We used a low dose immunogenic chemotherapy by means of 5-FU, Adriamycin, and Cyclophosphamide (FAC) in order to stabilize tumor progression prior to AIT using autologous tumor-reactive lymphocytes. Low dose FAC established local tumor dormancy, inhibited distant tumor dormancy occurring long before distant metastasis, and induced predominate a Ki67- quiescent type of tumor dormancy, which is less susceptible to tumor immunoediting. Dormant tumor cells expressed the cell survival pathways, including the endothelin receptor/ligand (ETRA, ETRB and ET-1) and PD-L1, thereby protecting them from elimination by AIT. In addition, tumor-reactive CD8+ T cells also produced ET-1 as a survival ligand for ETRA positive tumor cells. A combination of AIT with the blockade of tumor cell survival pathways resulted in a significant improvement of AIT against tumor dormancy. We also showed that the inhibition Bcl-xL downstream of the tumor cell survival pathways is specifically effective against dormant tumor cells, suggesting a combination of AIT with small molecules inhibitors of Bcl-xL. Altogether, we showed that distant tumor dormancy is established long before distant recurrence of breast cancer, and that the expression of several tumor cell survival pathways in dormant cells protects them from immunotherapy. Our results suggest that immunotherapeutic targeting of tumor dormancy combined with the blockade of a common downstream cell survival pathway could prevent tumor progression and recurrence of the disease.
44
Garrett, Andrew Robert. "Antioxidants in Cancer Research and Prevention: Assay Comparison, Structure-Function Analysis, and Food Product Analysis". BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/2735.
Pełny tekst źródłaStreszczenie:
Recent epidemiological studies have suggested that the development and progression of several chronic diseases may be initiated or augmented by oxidative stress. Reactive oxygen species and reactive nitrogen species react readily with and can damage nucleic acids, proteins, and lipids. While biological systems are equipped antioxidant defenses to cope with oxidative stress, oxidative damage may still occur when oxidative stress overwhelms antioxidant defenses. This damage, if left unchecked, may lead to a variety of degenerative diseases, including heart disease, Alzheimer's Disease, Parkinson's Disease and cancer. Several assays have been designed to describe the antioxidant activity of various phytochemicals, vitamins, and other compounds. The ORAC and TOSC assays have emerged as industry standards for measuring antioxidant activity due to their high reliability and sensitivity. Until recently, however, little has been done to assess the relative correlation between these two assays. Furthermore, no assay has been developed to measure changes in antioxidant activities of cells in response to oxidative stress. The current work investigates the correlation between measured antioxidant activities of samples in the both the ORAC and TOSC assays. Recent antioxidant research also focuses on relating chemical structure to antioxidant activity. Previous research in this area has included a broad range of chemical groups, but no study has attempted to formulate a structure-function framework that has applicability to compounds of any group. The current work uses amino acids as a simplest-case model for studying the relationships between chemical structure and antioxidant activity. One particular area of emerging research has centered around comparing organic and conventionally grown food products. The impetus of these investigations lies in claims made by organic supporting groups that these food products are generally more beneficial than their conventional counterparts. Despite the rapid rise in popularity of organic foods, there remains a dearth of research investigating these claims. The current work compares the antioxidant activities of organic and conventionally grown blueberries and apples.
45
Lu, Daniel Kee. "The Rad51 family of proteins: Interactions, vitamin D, and implications in head and neck cancer". Scholarly Commons, 2013. https://scholarlycommons.pacific.edu/uop_etds/191.
Pełny tekst źródłaStreszczenie:
Protection of the genome from carcinogenic consequences of DNA double-strand breaks (DSBs) is accomplished through the pathways of non-homologous end-joining (NHEJ) or homologous recombinational repair. Five human proteins with homology to Rad51 known as the Rad51 paralogs, Rad51B, Rad51C, Rad51D, XRCC2, and XRCC3, whose loss of function in cell lines leads to high chromosomal instability. Previous studies have shown Rad51C participate in two paralog protein complexes, one containing Rad51B, Rad51C, Rad51D and XRCC2 (BCDX2) and the other containing only Rad51C and XRCC3 (CX3). However, the only structural data available is the crystal structure of RecA, the bacterial homolog, the determination of the N-terminus of human Rad51 by NMR, and the crystal structure of Pyroccocus furious Rad51. Currently the Alvinlla pompejana Rad51C has been cloned, expressed and is currently being crystallized in the Tainer laboratory (UC Berkeley) since the human Rad51C protein has proven too difficult to be utilized. To test functional association of Hs Rad51B and Hs XRCC3 to Ap Rad51C. The human proteins were heterologously expressed in Pichia pastoris and the other expressed in E. coli. The proteins were extracted and interaction was tested through co-immunoprecipitation. Initial results depict weak binding or an unstable interaction between Hs Rad51B and Ap Rad51C. Hs XRCC3 and Ap Rad51C interaction remains unclear and requires further testing. Additionally, we have utilized a cellular model of HNSCC to identify whether the down-regulation of Rad51 after application of VD 3 is concomitant with the down-regulation of NBS1. NBS1 is a DNA repair protein involved in both pathways of DNA double-strand break repair, non-homologous end-joining and homologous recombinational repair. It has recently been demonstrated that NBS1 binds to Rad51 aiding in its localization to sites of DNA damage. VD 3 is a potential chemopreventive agent in the treatment of head and neck cancer. For the in vitro model Rad51 and NBS1 protein were both extracted from SCC25 and MCF-7 cancer cell lines were treated with 100 nM of VD 3 . For the in vivo model hamsters cheek pouch tissue sections with VD 3 treated and DMBA over the course of 14 weeks were used. Rad51 and NBS1 staining is restricted to the nuclei of the basal cell layer of the epithelium in VD 3 treated animals as compared to untreated controls where staining is evident throughout the dysplastic epithelium and is not restricted to nuclei. Unlike the western blot data of Rad51 that shows similar downregulation as the immunocytochemistry, the western blot analysis of NBS1 is unclear. However, the immunocytochemistry suggests that NBS1 is also downregulated by VD 3 in vivo, and therefore, it may be implied that both the HRR and NHEJ pathways are involved in the cellular effects of VD 3 in HNSCC.
46
Macpherson, Iain Roderick James. "A study of p120-catenin and its tyrosine phosphorylation in cancer cell adhesion and invasion". Thesis, Connect to e-thesis, 2007. http://theses.gla.ac.uk/1008/.
Pełny tekst źródła
47
Kodigepalli, Madhav Karthik. "Role and Regulation of SnoN/SkiL and PLSCR1 Located at 3q26.2 and 3q23, Respectively, in Ovarian Cancer Pathophysiology". Scholar Commons, 2014. https://scholarcommons.usf.edu/etd/5426.
Pełny tekst źródłaStreszczenie:
Ovarian cancer is one of the most common causes of gynecological cancer related deaths in women. In 2014, the estimated number of deaths due to ovarian cancer is 14,270 with occurrence of over 22, 240 new cases (National Cancer Institute, http://seer.cancer.gov/statfacts/html/ovary.html). Despite improvement in treatment strategies, the 5-year survival rate is still below 50% mainly due to chemoresistance and relapse. Amplification of chromosomal region 3q26 is a common characteristic in various epithelial cancers including ovarian cancer. This region harbors various oncogenes including the TGFβ signaling mediators EVI1 and SnoN/SkiL, PKCι and PIK3CA amplified at 3q26.2 and 3q26.3, respectively, in ovarian cancers. Previous studies indicate that these genes can exhibit cooperative oncogenicity by cross-regulating one another and facilitating cancer development. Our earlier studies demonstrated that treatment of ovarian cancer cells with arsenic trioxide (As2O3) promotes cytoprotective autophagy regulated by induction of SnoN to antagonize the cytotoxic effects of As2O3. Since exact mechanisms underlying As2O3-induced SnoN expression and cytoprotective responses were unclear, we hypothesized that SnoN may be regulated by signaling pathways involving genes amplified at the 3q26 locus.
Phospholipid scramblase 1 (PLSCR1) is located at 3q23 proximal to the amplified 3q26 region. It had been implicated in disruption of plasma membrane asymmetry by mediating phospholipid scrambling, a process critical for cellular events such as blood coagulation and apoptosis. However, recent findings have led to more investigations on the role and regulation of PLSCR1 in cancer development and immune responses. PLSCR1 expression is regulated by various stimuli including growth factors (EGF, G-CSF, and SCF), cytokines (IFN), and differentiation-inducing agents (ATRA). Despite these studies, transcriptional regulation of PLSCR1 remains incompletely understood. Numerous studies have suggested a critical role for PLSCR1 in the pathophysiology of various cancers including leukemia, ovarian cancer, colorectal cancer, and metastatic liver cancer. However, the precise contribution of PLSCR1 and its regulation in ovarian cancer development is unclear. Since PLSCR1 (at 3q23) is located in close proximity to SnoN/SkiL (at 3q26.2), we hypothesized that PLSCR1 expression in ovarian cancer cells could be regulated by SnoN. Herein, we present studies that primarily focus on understanding the role and regulation of SnoN/SkiL (a TGFβ pathway regulator) and PLSCR1 (an interferon-regulated gene), which are located at 3q26.2 and 3q23, respectively, in epithelial ovarian cancer.
In Chapter 3, we determined that activation of the PI3K signaling pathway mediates SnoN expression and cytoprotective responses upon stimulation of ovarian cancer cells with As2O3. We first identified that As2O3 stimulation leads to activation of EGFR and its downstream signaling mediators as well as modulates its interaction with the adaptor proteins, ShcA and Grb2. Interestingly, while treatment with a general SFK inhibitor (PP2), reduced the As2O3-induced EGFR activation and SnoN induction, a more specific inhibitor SU6656 did not alter SnoN expression. Further, via studies utilizing specific inhibitors and siRNA targeting PI3K, we determined that inhibition of PI3K signaling pathway decreases SnoN induction and increases apoptosis in ovarian cancer cells in response to As2O3. This suggests that PI3K (PIK3CA) activity is required for the As2O3-mediated SnoN induction and the cell survival responses in ovarian cancer cells. Finally, we determined by siRNA-mediated knockdown that EGFR and MAPK1 alter As2O3-induced cell death response independently of SnoN induction.
In Chapter 4, via bioinformatic analyses, we identified that PLSCR1 DNA copy number and mRNA expression is elevated in ovarian cancer patients and cell lines relative to immortalized (Tag/hTERT) normal ovarian surface epithelial (OSE) cells. Interestingly, altered PLSCR1 DNA and mRNA levels were correlated with SnoN in ovarian cancers. We next identified that SnoN knockdown leads to a significant (~35%, P2O3 transcriptionally downregulates PLSCR1 in a ROS-independent mechanism. Furthermore, PLSCR1 knockdown, similar to SnoN knockdown increases ovarian cancer cell sensitivity to As2O3. PLSCR1 knockdown increases cleaved PARP (marker of apoptosis) with a consequent reduction in LC3-II levels (marker of autophagosomes). Collectively, these studies implicate PLSCR1 in the pathophysiology of ovarian cancers and in altering the chemotherapeutic responses in ovarian cancer cells.
PLSCR1 is an IFN-regulated gene and mediates antiviral/immune responses. More recent studies in plasmacytoid dendritic cells have implicated PLSCR1 in regulating TLR9 signaling upon stimulation with CpG ODN. However, whether PLSCR1 could mediate the innate immune responses upon stimulation with dsDNA remained unclear. In Chapter 5, we identified that stimulation of normal ovarian and mammary epithelial cells with dsDNA (empty plasmid) markedly induces PLSCR1 consequent with activation of IRF3, a downstream mediator of TLR signaling that transcriptionally regulates the expression of type 1 IFNs. Interestingly, IRF3 knockdown ablates the dsDNA-induced PLSCR1 expression suggesting that PLSCR1 induction in response to dsDNA could be mediated by IRF3. Additionally, we have determined that dsDNA stimulation induces nucleic acid sensing TLRs, TLR9 and TLR4 as well as IFN-α and IFN-β mRNAs. Interestingly, dsDNA stimulation did not induce PLSCR1 or IRF3 activation in ovarian cancer cells suggesting that the mechanisms of IRF3 activation and PLSCR1 induction in response to dsDNA might be dysregulated in ovarian cancers.
Collectively, our studies demonstrate a possible synergistic role of SnoN and PLSCR1 in ovarian cancer pathophysiology and suggest a potentially dysregulated role of PLSCR1 in the dsDNA-induced immune responses of malignant epithelial cells relative to normal epithelial cells. These studies could potentially lead to development of a novel combinatorial therapeutic strategy that targets both these molecules for improving treatment of patients with ovarian carcinoma.
48
Kennedy, Helen F. "Viridans streptococcal bacteraemia in paediatric immunocompromised patients with malignant disease". Thesis, University of Glasgow, 2001. http://theses.gla.ac.uk/2214/.
Pełny tekst źródłaStreszczenie:
Amongst the paediatric haematology/oncology patients attending the Royal Hospital for Sick Children, Glasgow, episodes of viridans streptococcal bacteraemia increased from 12% of al microbiologically documented bacteraemias (i.e. 10/81) in 1993 to 22% (18/83) in 1994. During the first year of this project (which started in December 1994), ITU support was required following the development of viridans streptococcal bacteraemia on 6 occasions, and of these, there were two fatalities. The overall aim of this study was to improve the management of this infection and to explore preventative strategies. Three different approaches were adopted: (1) an extensive epidemiological analysis was undertaken - to include all episodes of viridans streptococcal bacteraemia from December 1994 to December 2000. (2) Phenotypic, followed by genotypic analyses of isolates of viridans streptococci from mouth swabs and blood cultures were carried out to determine whether the mouth was in fact the source of organisms responsible for this infection. (3) Extensive antibiotic susceptibility studies were performed on all isolates of viridans streptococci from blood culture. In total, 69 episodes of viridans streptococcal bacteraemia occurred in 54 children. The infection was more often associated with patients with haematological malignancy (particularly AML), than those with solid tumours, and in the majority (84%) of episodes, the patients suffered from chemotherapy-induced mucositis or other forms of oral compromise. Forty-eight episodes of infection (70% of total) responded well to antimicrobial therapy with no evidence of additional clinical complications. However, in 21 cases (30% of total), pulmonary complications developed, with 8 of these requiring mechanical ventilation and supplemental oxygen. Five of these 8 cases also developed septic shock. S. oralis was the species most commonly isolated from blood culture (63% of total isolates of viridans streptococci) and S. mitis represented 25% of total isolates. Polymicrobial bloodstream infection occurred in 23% of episodes.
49
Nichols, Brandt Alan. "The Role of Nuclear BMP2 in the Cell Cycle and Tumorigenesis". BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/4167.
Pełny tekst źródłaStreszczenie:
Bone morphogenetic protein 2 (BMP2) is a secreted growth factor that is essential for proper embryonic development and proliferation. Our laboratory discovered a nuclear variant of BMP2 (nBMP2) which is produced when translation is initiated at an alternative start codon within the BMP2 gene. When translation occurs at the downstream start codon, the resulting protein lacks the ER signal peptide, thereby allowing cytoplasmic translation and nuclear localization. Our aim is to distinguish the role of this nuclear localized variant from secreted BMP2. Overexpression of nBMP2 in HEK293 and HT29 cell lines resulted in a higher percentage of cells in proliferative phases of the cell cycle. We determined that nBMP2 does not regulate cell cycle progression by inducing hyperphosphorylation of retinoblastoma protein (Rb), but it may regulate the cell cycle by interacting with ROC1. In order to examine the role of nBMP2 in vivo, we have generated a mouse model in which a mutation of the nuclear localization signal (NLS) disrupts nuclear localization of nBMP2. Aberrant crypts were more abundant in nBmp2NLStm azoxymethane (AOM) treated mice than in wild type mice. Furthermore, H&E staining of colonic tissue showed that mutant mice have increased levels of dysplasia and aberrant crypt foci. This work suggests that nBMP2 is involved in regulating cell cycle progression and proliferation, and therefore may play a role in tumorigenesis.
50
Fullwood, Rebecca A. "The Role of Viral Interleukin-6 in Tumor Development of Kaposi's Sarcoma-Associated Herpesvirus Lymphomas". BYU ScholarsArchive, 2016. https://scholarsarchive.byu.edu/etd/6194.
Pełny tekst źródłaStreszczenie:
Kaposi's sarcoma herpesvirus (KSHV) is a cancer-causing virus, primarily affecting AIDS patients. KSHV is found in 3-10% of the U.S. population and can cause a range of cancers in the highly immunosuppressed; these cancers include Kaposi's sarcoma, pleural effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). The current techniques for treating these cancers are relatively ineffective, largely due to their inefficiency at targeting tumors formed by the infection. One protein produced by KSHV, the viral homolog of interleukin-6 (vIL-6), is thought to play a major role in tumor development post-infection. Here a novel animal model is implemented to study the ways vIL-6 affects tumor development through growth factors and other cytokines within infected highly immune-deficient Rag2-/-γc-/- mice. Mice were subcutaneously injected with one of three types of cells: B cells infected with a wild-type (WT) KSHV, B cells infected with mutant KSHV without the gene for viral interleukin 6, and a negative control of uninfected B cells. After allowing time for tumors to develop the mice were sacrificed and the tumors assessed. Analysis of the physical properties of the tumors, as well as markers expressed by the tumors, were used to help determine whether vIL-6 could be an appropriate target when treating these cancers. In this study vIL-6 was seen to influence certain B cell markers (CD30), as well as onset of tumors (with no significant increase in overall tumor mass, but with marginally statistically significant increase in tumor number). This indicates that although vIL-6 could play a small role as a target for cancer, further investigation into the relationship of CD30 in these types of cancers needs to be explored. It was also found that the KSHV viral-infection decreases the development of tumors compared with uninfected immortalized B cells (BJAB). Not only would results from this experiment help develop new treatments, and change the lives of those suffering with cancers induced by KSHV, but they would provide a foundation for future studies with these types of cancers.