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Koh, Yun Sing, and n/a. "Generating sporadic association rules." University of Otago. Department of Computer Science, 2007. http://adt.otago.ac.nz./public/adt-NZDU20070711.115758.
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Association rule mining is an essential part of data mining, which tries to discover associations, relationships, or correlations among sets of items. As it was initially proposed for market basket analysis, most of the previous research focuses on generating frequent patterns. This thesis focuses on finding infrequent patterns, which we call sporadic rules. They represent rare itemsets that are scattered sporadically throughout the database but with high confidence of occurring together. As sporadic rules have low support the minabssup (minimum absolute support) measure was proposed to filter out any rules with low support whose occurrence is indistinguishable from that of coincidence. There are two classes of sporadic rules: perfectly sporadic and imperfectly sporadic rules. Apriori-Inverse was then proposed for perfectly sporadic rule generation. It uses a maximum support threshold and user-defined minimum confidence threshold. This method is designed to find itemsets which consist only of items falling below a maximum support threshold. However imperfectly sporadic rules may contain items with a frequency of occurrence over the maximum support threshold. To look for these rules, variations of Apriori-Inverse, namely Fixed Threshold, Adaptive Threshold, and Hill Climbing, were proposed. However these extensions are heuristic. Thus the MIISR algorithm was proposed to find imperfectly sporadic rules using item constraints, which capture rules with a single-item consequent below the maximum support threshold. A comprehensive evaluation of sporadic rules and current interestingness measures was carried out. Our investigation suggests that current interestingness measures are not suitable for detecting sporadic rules.
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Robertson, Brent 1962. "The epidemiology of sporadic cryptosporidiosis." Monash University, Dept. of Epidemiology and Preventive Medicine, 2001. http://arrow.monash.edu.au/hdl/1959.1/8968.
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Gottschalk, Harald. "Amalgams for the O'Nan Sporadic Group." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=964667029.
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Arnardơttir, Snjơlaug. "Studies in sporadic inclusion body myositis /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-572-7/.
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Bradley, John David. "Symmetric presentations of two sporadic groups." Thesis, University of Birmingham, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422333.
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Khudhur, Peshawa Mohammed. "Sporadic simple groups of low genus." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6592/.
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Let X be a compact connected Riemann surface of genus g and let f∶ X →P1 be a meromorphic function of degree n. Classes of such covers are in one to one correspondence with the primitive systems, which are tuples of elements (x1,x2,⋯,xr) in the symmetric group Sn taken up to conjugation and the action of the braid group, such that x1.x2.⋯.xr=1 and G=〈x1,x2,⋯,xr〉 is a primitive subgroup G of Sn. This thesis is a contribution to the classification of primitive genus g ≤ 2 systems of sporadic almost simple groups.
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Brown, Iain. "Gene therapy for sporadic ovarian cancer." Thesis, University of Aberdeen, 2000. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU602008.
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Ovarian cancer accounts for more deaths than all other gynaecological cancers taken together. The 5 year survival rate can be as high as 80% for cases diagnosed early, but the asymptomatic nature of the disease means that it is most frequently detected in the later stages. By this time, disease has invariably spread beyond the ovaries and the survival rate drops to around 30%. Treatment of ovarian cancer often fails due to a high rate of chemoresistance and novel methods of treatment and detection are required to increase the survival chances of patients. This study sought to determine whether gene therapy for sporadic ovarian cancer could offer a novel and more successful treatment option for the disease. Mutation or abnormal expression of the p53 gene has already been shown to be the most common genetic even in ovarian cancer, being involved in up to 70% of cases. Wild-type p53 was delivered, using liposomes, into p53 mutant ovarian cancer cell lines and this resulted in a restoration of the wild-type functions of the gene, namely cell cycle arrest and apoptosis. The results from the cell line studies suggested that restoration of the wild-type p53 function limit or reduce tumour progression and increase the sensitivity of the tumour to chemotherapy. A mouse model of human peritoneal ovarian cancer was then constructed and the wild-type p53 gene was administered in liposomes into the peritoneum. The results suggested that p53 gene therapy prevents tumours from growing in the mice, when compared to a control gene. It is now known that p53 gene therapy for humans is being clinically assessed. There are a proportion of tumours that do not harbour an abnormal p53 gene, raising the possibility that other tumour suppressor gene mutations may play a role in the molecular genetic control of growth arrest and apoptosis. P53-dependent, apoptosis-regulating family members bcl-2 and bax were analysed immunohistochemically to determine their involvement in ovarian cancer. Both proteins were significantly associated with malignancy and also with overall length of survival, but not associated with the various prognostic factors such as stage and differentiation of tumour. It is unlikely that these genes will become targets for gene therapy in ovarian cancer. Mutation, deletion and hypermethylation of the p53-independent pi6 gene, alter its function, resulting in loss of G1 cell cycle arrest control. The status of methylation of the pi 6 promoter in ovarian tumours was determined and combined with mutation data, resulting in the conclusion that abnormal pi 6 was not a common event in ovarian cancer and is therefore not a likely candidate for gene therapy. This study has contributed to the evergrowing wealth of knowledge on the molecular genetic events of ovarian cancer, and has shown that gene therapy for sporadic ovarian cancer as a clinical application is feasible.
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Curtis, Lucy Jane. "Genomic instability in sporadic colorectal cancer." Thesis, University of Edinburgh, 1998. http://hdl.handle.net/1842/21178.
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This thesis has examined aspects of two forms of instability prominent in sporadic colorectal cancer, microsatellite instability (MSI) and chromosomal instability. Microsatellite instability describes a phenotype in which mutation of microsatellite sequences is widespread, probably due to defects of components of the mismatch repair pathway. Clonal chromosomal abnormalities, frequently observed in sporadic colorectal cancer, probably arise because of instability at the chromosomal level, and there is substantial, though not conclusive, evidence that they may result from defects of the p53 protein. Several lines of evidence suggest that chromosomal instability and defects of p53 may represent a mechanism, or mechanisms, of tumourigenesis distinct from that driven by defects of mismatch repair system. In this project, a series of experiments were undertaken to investigate the microsatellite instability phenotype, its possible cause, and the extent to which it coexists and interacts with chromosomal instability and p53 abnormalities. MSI was examined in a large population of sporadic human colorectal cancers and related to clinical and pathological tumour features in order to define traits which may suggest a distinct biological basis. Such instability was found to confer significant survival advantage, and to be inversely related to abnormality of the p53 protein, supporting the notion that these defects represent distinct tumorigenic pathways. In an attempt to discover the cause of microsatellite instability, mutation analysis of a likely candidate gene, hMSH2, was undertaken in selected case. This analysis yielded few exonic gene mutations supporting data from other studies which suggest that hMSH2 is not an important cause of the MSI phenotype in sporadic colorectal cancer. To further investigate the MSI phenotype, the behaviour of stable and unstable microsatellites over a period of time was examined through use of a series of xenografted human cancers. This demonstrated maintenance of the primary tumour phenotype in all xenografts over several months' passage in vivo, adding weight to the argument that microsatellite instability is persistent and is driven by an underlying retained defect.
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Eversley, Chevonne D. Threadgill David W. "Integrative genomic analysis of sporadic colorectal cancer." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2874.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Jun. 4, 2010). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum in Genetics and Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
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Richardson, Philip Jonathan. "Sporadic geometries and their universal representation groups." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313684.
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Thorpe, Alison Jane. "Autoantibodies in hereditary and sporadic breast cancer." Thesis, University of Nottingham, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.546524.
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Collins, N. "BRCA2 in familial and sporadic breast cancer." Thesis, Institute of Cancer Research (University Of London), 2000. http://publications.icr.ac.uk/10070/.
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The breast cancer susceptibility gene BRCA2 is located on chromosome 13q 12-13. Using breast and ovarian cancers from a BRCA2-linked family, loss of the wild type BRCA2 allele was demonstrated in seven out of eight informative cases (87.5%) indicating that BRCA2 was a recessive oncogene. Analysis of 73 sporadic breast tumours and 12 breast cancer cell lines revealed loss of heterozygosity (LOH) in 22 (30%) of the primary tumours and seven (58%) of the breast cancer cell lines. However, it was not clear from these studies that the target for the observed LOH was the gene BRCA2 or RBl at chromosome 13q14 as the region ofLOH included both genes in all but a single case. Despite the presence of elevated levels of LOH, several separate mutation screening studies of sporadic breast and ovarian tumours have shown that somatic mutations of BRCA2 in sporadic breast and ovarian cancer are very rare. To investigate the possibility that other mechanisms of BRCA2 allelic inactivation might be operative, the methylation status of a CpG island within the promoter region of BRCA2 was examined in 64 sporadic breast tumours and 18 breast and ovarian cancer cell lines. Three CpG dinucleotides within this island were unmethylated in all the normal tissue samples (lymphocytes) examined. These three CpG dinucleotides remained unmethylated in all the breast tumours examined. Moreover, expression of BRCA2 in breast and ovarian cancer cell lines was not obviously correlated with evidence of loss of heterozygosity. These analyses indicate that methylation of the promoter region of BRCA2 and possibly other mechanisms of transcriptional silencing are unlikely to be a common mechanism of gene inactivation in these tumours. To investigate the prevalence of BRCA2 mutations, lymphocyte DNAs from a British, population-based series of 617 breast cancers diagnosed before age 45 were screened for mutations. Mutations were detected in 14 women ( 2.3%, 6/14 43% under age 35 and 8/14 57% age 36-45). This study and a parallel study of BRCA1 demonstrate that BRCA2 and BRCA1 make approximately equal contributions to early onset breast cancer in the UK. Moreover, although BRCA1 and BRCA2 account for breast cancer susceptibility in a substantial proportion of multiple case families, they only account for a small proportion of the overall familial risk conferred by an early onset case. This indicates the existence of other susceptibility genes that are more common but confer lower risks than BRCA1 and BRCA2.
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Tilley, Louise. "Genetic risk factors in sporadic Alzheimer's disease." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311748.
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Ryba, A. J. E. "Algebras related to some sporadic simple groups." Thesis, University of Cambridge, 1985. https://www.repository.cam.ac.uk/handle/1810/272929.
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Harris, Elena Yavorska. "Symmetric representation of elements of sporadic groups." CSUSB ScholarWorks, 2005. https://scholarworks.lib.csusb.edu/etd-project/2844.
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Uses the techniques of symmetric presentations to manipulate elements of large sporadic groups and to represent elements of these groups in much shorter forms than their corresponding permutation or matrix representation. Undertakes to develop a nested algorithm and a computer program to manipulate elements of large sporadic groups.
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Shabrokh, Elika. "Mitochondrial Biology in Sporadic Inclusion Body Myositis." Diss., Virginia Tech, 2014. http://hdl.handle.net/10919/47782.
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Sporadic Inclusion Body Myositis (sIBM) is an inflammatory muscle disease that strikes individuals at random and accounts for approximately 1/3 of all idiopathic inflammatory myopathies. It is characterized by progressive weakness of distal and proximal muscles and is the most common muscle disorder in individuals over 50 years of age. Currently, there is no known cause, cure, or enduring treatment for sIBM, although a number of theories as to its cause have been proposed. One theory proposes that activation of the inflammatory/ immune response is the primary trigger resulting in muscle degeneration and protein abnormalities, while an alternative theory suggests that sIBM is a degenerative muscle disease with abnormal pathogenic protein accumulation, in particular Abeta, being a primary cause that triggers an inflammatory/ immune response. Mitochondrial abnormalities have been observed in skeletal muscle from patients diagnosed with the disease, however the role of the mitochondria in disease pathology is still unclear. The aim of this dissertation was to evaluate: 1) the role of the mitochondria in the development of sIBM and 2) the role of amyloid beta on mitochondrial function in skeletal muscle. A better understanding of the role of the mitochondria in the development of sIBM may help to identify novel prevention and/ or treatment strategies.Ph. D.
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Boggild, Michael Derek. "Molecular genetic studies of sporadic pituitary adenomas." Thesis, University of Leicester, 1995. http://hdl.handle.net/2381/34167.
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Tumour formation may result from the activation of dominant oncogenes or by inactivation of recessive, tumour suppressor genes. The role of such mutations in the development of pituitary tumours has been studied. Tumours from 88 patients, representing the 4 major classes of pituitary adenoma, were investigated. In DNA extracted from matched leucocyte and tumour samples allelic deletions were sought with 15 probes identifying restriction fragment length polymorphisms on chromosomes 1, 5, 10, 11, 13, 17, 20 and 22. Evidence of amplification or re-arrangement of 10 recognised cellular oncogenes (NRAS, MYCL1, MYCN, MYC, HRAS, BCL1, HSTF1, SEA, KRAS2 and FOS) was sought in tumour DNA. Activating dominant mutations of the oncogene Gsalpha were detected using the polymerase chain reaction to amplify exons 7-10 and hybridising the product to normal and mutant allele specific oligonucleotides. Allelic deletions on chromosome 11 were identified in 16 tumours (18%) representing all 4 major sub-types. Deletions on other autosomes were observed in less than 6% of tumours. Three adenomas had deletions on multiple autosomes, two of these were aggressive and recurrent. Mutations of Gsalpha were confirmed to be specific to somatotrophinomas, being identified in 36% of such tumours in this series. No evidence of amplification or rearrangement of other recognised cellular oncogenes was found. Inactivation of a recessive oncogene on chromosome 11 is an important and possibly early event in the development of the 4 major types of pituitary adenoma whilst activating mutations of Gsalpha are confirmed to be specific to somatotrophinomas. Two aggressive tumours were found to have multiple autosomal losses, suggesting a multi-step progression in the development of tumours of this phenotype.
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Gros-Louis, François. "Genetics of familial and sporadic amyotrophic lateral sclerosis." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111859.
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Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) form a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of all cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. The research projects presented here aim to investigate the role of different cell types and tissues in the pathology of SOD1-linked ALS, and to identify new genetic factors involved in sporadic ALS cases. LoxP transgenic mice expressing mutated G85R SOD1, allowing transgene expression in cell and tissue specific manner, have been successfully generated. However, mice, up to 2.5 years of age, did not develop any motor neuron deficits or any developmental abnormalities. We concluded that this might be due to insufficient level of the transgene expression in our transgenic animals. Also, a number of candidate genes for ALS have been identified, such as ALS2, VEGF, PRPH, CHGA and CHGB, based on their pattern of expression and biological function. These genes have been screened for mutations in a cohort of ALS patients and, we have identified one basepair deletion in the ALS2 and in the PRPH genes, and we have also found a strong genetic association between the CHGA and CHGB genes with ALS. An in-vitro cell transfection approach has been used to investigate the biological effects of mutations within the PRPH genes and, of particular interest, this technique has revealed the first functional variants in a neurofilament associated gene ever describe in ALS.
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Sengupta, Neel. "Somatic copy number alterations in sporadic colorectal cancers." Thesis, Queen Mary, University of London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538378.
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Wortham, Noel Christopher. "Functional genetics of hereditary and sporadic uterine leiomyomas." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445159/.
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Uterine leiomyomas (fibroids) are common benign neoplasms arising from the smooth muscle layer of the uterus, the myometrium. Despite their prevalence in reproductive age women, little is understood of their pathobiology. The work in this thesis examined genetic and functional factors involved in the aetiology of sporadic leiomyomas, those in the hereditary leiomyomatosis and renal cell cancer syndrome, and leiomyomas from patients of African/Afro-Caribbean ethnicity, who develop more severe tumours at an earlier age. Work was carried out studying: the role of apoptosis in the tumours mutations in the FH gene and mtDNA and copy number change by microarray CGH. The findings of this work demonstrated further differences between the pathobiology of HLRCC leiomyomas, compared to sporadic lesions, particularly with regard to the mechanisms of resistance to apoptosis of each tumour type. Furthermore, germline FH mutations, which cause HLRCC, were excluded as a major cause of overall uterine leiomyoma prevalence in both sporadic cases, and in African/Afro-Caribbean women. A 1Mb resolution microarray CGH screen demonstrated a number of novel regions of copy number change, not previously reported, that may harbour novel genes involved in leiomyoma development. Furthermore, this study identified a minimal region of 7q deletion of 3.82Mb. Progressing from this, a tiling-path resolution CGH microarray specific for chromosome 7q was constructed and a number of tumours from different ethnicities were tested. This array narrowed the minimal region of deletion to 273kb on 7q22.2, a region containing 2 genes, SRPK2 and MLL5, either of which could potentially be involved in uterine leiomyoma aetiology. The results from this array also demonstrated a common overlap in the pathobiology of uterine leiomyomas from Caucasian and African/Afro-Caribbean women, who demonstrated equal frequencies of 7q deletion.
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West, Nicholas J. "Studies in sporadic and familial colorectal adenomatous polyps." Thesis, St George's, University of London, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.675935.
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Evidence exists to suggest that diets high in omega-3 fatty acids may be protective against the development of colorectal cancer with in vitro and pre-clinical models. Additionally, patients with a sporadic or genetic (eg familial adenomatous polyposis (FAP)) predisposition to developing colorectal adenomatous polyps exhibit altered cell kinetics in their colorectal mucosa as compared to normal subjects. The mam body of this thesis encompasses two clinical, randomised, placebo controlled trials. The first, EPA/POL/02 assessed whether subjects with a history of sporadic colorectal adenomata had any beneficial modulation of their colorectal mucosal cytokinetics following six months treatment of eicosapentaenoic acid (EPA) in free-fatty acid form (EPA-FFA), at doses of 19/day or 2g/day, when compared to placebo. One hundred and fifty two subjects were randomised in a 1: 1: 1 ratio. At 6 months, cell proliferation was significantly reduced in the 2g/d group. There were no significant changes in apoptosis scores across the groups. There were also marked increases in the omega-3 fatty acid profiles in this group. The second study, EPA/POL/03 assessed whether 6 months treatment with 2g/day of EPA-FFA exhibited chemopreventative activity in subjects with familial adenomatous polyposis (FAP) compared to placebo. Fifty five patients with F AP and an intact rectal remnant were randomised to treatment (n=28) or placebo (n=27). Treatment was assessed by changes in number and size of polyps within an assessable area of the rectum, together with global rectal burden, as measured by video endoscopy records. Treatment with 2g/day for 6 months was associated with a significant reduction in number, size and overall rectal polyp burden. Mucosal levels of EPA were increased in the treatment arm which was safe and well tolerated. EPA-FF A therefore holds promise as a chemopreventative agent against colorectal cancer.
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Cox, Rachel Mary. "On the origin of sporadic neutral sodium layers." Thesis, University of East Anglia, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365136.
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Fraser, Judith Anne. "The BRCA1 gene product and sporadic breast cancers." Thesis, University of Aberdeen, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247765.
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Isolated in 1994, the BRCA1 gene encodes a 1863 amino acid protein, the role of which remains undetermined. BRCA1 germ-line mutations, which result in loss of functional full-length protein, are associated with familial breast and ovarian cancer. This would suggest an important tumour suppressor role for the BRCA1 protein. No somatic mutations have been described in BRCA1 in sporadic breast cancer cases. Defective transcription or post transcriptional modification of the BRCA1 protein may however precipitate the same outcome of a loss-of-function protein product facilitating the development of sporadic breast cancer as indeed has already been suggested. Progress in the study of BRCA1 has been impeded by the lack of availability of specific, sensitive antibodies. These problems have led to confusion regarding the sub-cellular localisation and postulated functions of BRCA1. This study has endeavoured to answer three questions. Firstly, are the monoclonal antibodies used specific for the BRCA1 protein? Secondly, by immunohistochemical techniques, what is the sub-cellular localisation of the BRCA1 protein within a cohort of primary sporadic breast cancers? And finally, what is the relationship between BRCA1 expression and pathological, biological and survival parameters within a group of 200 primary sporadic breast cancer cases? Results demonstrate Ab2 to detect a 110 kDa protein consistent with the D11b BRCA1 splice variant. This localised to the cytoplasm in both immunohistochemical and western blot settings. Initial pilot study data suggested Ab2 labelling of sporadic breast cancer cases to be of prognostic significance. This was not supported in an expanded study of 200 cases which confirmed that intensity of immunohistochemical labelling was not an independent prognostic indicator in sporadic breast cancer. Ab1 was confirmed to be non-specific.
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Macarthur, Mairi. "Sporadic colorectal cancer : the role of chronic inflammation." Thesis, University of Aberdeen, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.440593.
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In this thesis, an in silico investigation of available online microarray data found that normal colon, polyps and CRC have distinct gene expression patterns and that several key inflammation-related genes are up-regulated in polyps. This was also the findings of a pilot microarray study using Affymetrix human GeneChip® technology on normal colon and polyps biopsied from one individual. Validation of the microarray data for IL-1B and il-8 was performed by RT-PCR and also revealed an overall up-regulation of these genes in polyp compared to normal colon. A CRC case-control study was then used to assess the role of pro-inflammatory single nucleotide polymorphisms (SNPs) in IL-1B (-31 T/C), TNF-A (-308 G/A), TGF-B (-509 C/T) and IL-10 (-592 C/A, -1082 G/A) in sporadic CRC in the North East of Scotland. Their interaction with aspirin use was also investigated. Whilst statistically significant associations were not found between any of the SNPs and CRC alone, a statistically significant halving in risk of CRC (OR, 0.50; 95% CI, 0.27-.097) was found in carriers of the variant IL-10-592 A allele who were regular aspirin users. Finally, the frequencies of 2 promoter, one exonic and one 3’-UTR COX-2SNPs were assessed in a Scottish population. The -899 and -197 COX-2 promoter SNPs were not identified but the allele frequencies of the exon-3 and 3’UTR COX-2 SNPs were similar to those reported in previous Caucasian studies. Further analysis including the COX-2 -765 G>SNP showed that -765 GG homozygotes infected with H. pylori had a significantly increased risk of developing pre-malignant changes of gastric cancer (OR 5.7, 95% CI, 2.3-14.1). This result is in keeping with previous studies which have suggested that the variant C allele is associated with reduced COX-2 suppression and inflammatory response.
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Rannikmäe, Kristiina. "Genetic associations with sporadic cerebral small vessel disease." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/23585.
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Background: Cerebral small vessel disease (SVD) causes substantial cognitive, psychiatric and physical disabilities. Despite its common nature, SVD pathogenesis and molecular mechanisms remain poorly understood, and prevention and treatment are probably suboptimal. Identifying the genetic determinants of SVD will improve understanding and may help identify novel treatment targets. The aim of this thesis is to better understand genetic associations with SVD through investigating its pathological, radiological and clinical phenotypes. Methods: To unravel the genetic associations with SVD, I used three complementary approaches. First, I performed a systematic review looking at existing intracerebral haemorrhage (ICH) classification systems and their reliability, to help inform future studies of ICH genetics. Second, I performed a series of systematic reviews and meta-analyses, investigating associations between genetic polymorphisms and histopathologically confirmed cerebral amyloid angiopathy (CAA). Third, I performed meta-analyses of existing genome-wide datasets to determine associations of >1000 common single nucleotide polymorphisms (SNP) in the COL4A1/COL4A2 genomic region with clinico-radiological SVD phenotypes: ICH and its subtypes, ischaemic stroke and its subtypes, and white matter hyperintensities. Results: The reliability of existing ICH classification systems appeared excellent in eight studies conducted in specialist centres with experienced raters, although these existing systems have several limitations. In my systematic evaluation of CAA genetics, meta-analyses of 24 studies including 3520 participants showed robust evidence for a dose-dependent association between APOE ɛ4 and histopathological CAA. There was, however, no convincing association between APOE ɛ2 and presence of CAA in a meta-analysis of 11 studies including 1640 participants. Meta-analyses of five studies including 497 participants showed, contrary to an existing popular hypothesis, that while APOE 4 may increase the risk of developing severe CAA vasculopathy, there is no clear evidence to support a role of ɛ2. There were few data about the role of APOE in hereditary CAA, but in the three studies that had looked at this, there was no evidence for an association between APOE ɛ4 and CAA severity. There were too few studies and participants to draw firm conclusions about the effect of non-APOE ε2/ε3/ε4 genetic polymorphisms on CAA, but there were positive associations with TGF-β1, TOMM40 and CR1 genes in four studies. Finally, in my meta-analyses of the COL4A1/COL4A2 genomic region, three intronic SNPs in COL4A2 were associated with SVD phenotypes: significantly with deep ICH, and suggestively with lacunar ischaemic stroke and WMH. Conclusions: I have shown that while existing ICH classification systems appear to have very good reliability, further research is needed to determine their performance in different settings. For large population-based prospective studies of ICH genetics, anatomical systems are likely to be more feasible, scalable and appropriate, although they have limitations and will need to be further developed. Using systematic reviews and meta-analyses, I have confirmed a dose-related association between APOE ɛ4 and histopathological CAA, but also demonstrated that, despite popular acceptance, there is insufficient data to draw firm conclusions about the association with APOE ɛ2. I found some positive associations with CAA in other genes, which merit replication in further larger studies, and showed that there is currently insufficient data about the role of APOE in hereditary CAA. Finally, I identified a novel association between a locus in a known hereditary SVD gene – COL4A2 – and sporadic SVD. This highlights a new and successful approach for selecting candidate genes and can be expanded in future studies to include other known hereditary SVD genes.
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Jacobi, Ch, and C. Arras. "6 hr tide seen in sporadic E layers." Universität Leipzig, 2018. https://ul.qucosa.de/id/qucosa%3A31768.
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The GPS radio occultation technique is used to study sporadic E (Es) layer plasma irregularities of the Earth’s ionosphere on a global scale using COSMIC/FORMOSAT-3 satellite constellation GPS signal-to-noise ratio (SNR) profiles. The maximum deviation from the mean SNR is attributed to the height of the Es layer. Es are produced by ion convergence due to vertical wind shear in the presence of a horizontal component of the Earth magnetic field, while the wind shear is provided mainly by solar tides. Indeed, close correlation between Es and wind shear phases have already been found for the semidiurnal and terdiurnal tidal components. Here, we present the global distribution of quarterdiurnal (QDT) signatures in Es occurrence rates. We find that, in accordance with upward energy flux, negative vertical phase
gradients of QDT Es signatures are observed. The maximum signal of QDT Es is found at altitudes above 100 km. In the southern hemisphere, maximum QDT Es occurrence rates are found in winter and during equinoxes. In the northern hemisphere, however, at altitudes above 100 km strong QDT activity is also visible.Die GPS-Radiookkultationstechnik wird verwendet, um ionosphärische Plasmairregularitäten in Verbindung mit sporadischen E- (Es) Schichten auf globaler Skala zu untersuchen. Verwendet werden Signal-Rauschverhältnis- (SNR-) Profile. Die maximale Abweichung vom mittleren SNR wird der Höhe der Es-Schicht zugeordnet. Es werden durch Ionenkonvergenz aufgrund von vertikaler Windscherung in Anwesenheit einer horizontalen Komponente des Erdmagnetfeldes hervorgerufen, wobei die Scherung hauptsächlich durch solare Gezeiten verursacht wird. Tatsächlich wurden schon früher deutliche Übereinstimmungen zwischen dem Auftreten von Es und den Phasen der halb- und dritteltägigen Gezeiten gefunden. Hier stellen wir die globale Verteilung der vierteltägigen (QDT) Signaturen in Es- Auftretensraten vor. Es zeigt sich dass, in Übereinstimmung mit einem aufwärts gerichteten Energietransport, negative vertikale Phasengradienten der QDT in Es auftreten. Die maximale Auftretenswahrscheinlichkeit liegt bei Höhen oberhalb von 100 km. Auf der Südhemisphäre fällt das Maximum der QDT in Es-Auftretensraten in den Winter, während auf der Nordhemisphäre oberhalb von 100 km auch im Sommer starke QDT-Aktivität zu verzeichnen ist.
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Hope, Mairi E. "Sporadic colorectal cancer : role of the commensal microbiota." Thesis, University of Aberdeen, 2005. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU200894.
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There are vast numbers of bacteria present within the human colon and many studies have implicated these in CRC development. Despite this evidence, microbial diversity present at the mucosal surface has not been well characterised, with many investigations using culturing methods or extrapolating from analysis on faecal material. In this thesis, molecular analysis of colonic mucosal microbial diversity (caecum to rectum) in 10 healthy individuals revealed that each individual harboured their own microbial cohort that remained constant throughout the colon. Detailed 16S rDNA cloning and sequence analysis of caecal and rectal tissue from 1 individual reflected DGGE findings and showed the majority of sequences affiliated with the low G + C bacterial phylum, namely Clostridium cluster IV, XIVa and also the Bacteroides subphylum. DGGE and sequence analysis of a faecal sample from the same individual showed major differences in microbial diversity compared to tissue samples. DGGE analysis of paired neoplastic and adjacent normal mucosa samples revealed differences in microbial populations between the 2 tissues in a significant number of paired polyp samples. A number of cancer/normal tissue paired samples also displayed altered microbial diversity. Lectin immunohistochemistry was performed on selected healthy individuals and a number of paired neoplastic/normal colonic samples in order to determine host carbohydrate expression. Analysis of healthy tissue revealed individual glycosylation patterns, whilst neoplastic samples often showed altered glycosylation. Changes in host glycosylation did not appear to correlate with microbial diversity. RT-PCR was used to investigate gene expression of several fucosyltranferases in healthy individuals and selected neoplastic tissues. Downregulation in FUT3 expression was found in cancer tissue, correlating with loss of fucose-specific lectin staining in cancer tissue samples.
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Liperovsky, V. A., O. A. Pochotelov, E. V. Liperovskaya, M. Parrot, C. V. Meister, and O. A. Alimov. "Modifications of sporadic E-layers caused by seismic activity." Universität Potsdam, 1998. http://opus.kobv.de/ubp/volltexte/2007/1479/.
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Contents:
1 Introduction
2 Formation and destruction of sporadic E-layers
3 Temporal variations of parameters of sporadic E-layers
during earthquake preparation
3.1 Temporal variations of fbEs with time-scales of a few hours
3.2 Study of fbEs variations with characteristic time-scales of 0.5-3 hours
3.3 Variations of the parameters of sporadic E-layers
with characteristic time-scales of 15-45 minutes
3.4 Sporadic E-layer variations with characteristic time-scales
of 2-15 minutes
4 On the spatial scales of sporadic E-layer disturbances
related to seismic activity
5 Complex experimental researches of the ionosphere,
electromagnetic noise and the geomagnetic field
5.1 Ionospheric and electromagnetic phenomena
of the Kayraccum earthquake in 1985
5.2 Comparison of anomalies with characteristic time-scales of
2-3 hours for ionospheric E- and F-layers, and temporal behaviour
of electromagnetic noise emission intensity
5.3 Night airglow emissions in the E-region before earthquakes
and sporadic E-layer variations
6 Physical models of lithosphere-ionosphere links
6.1 Lithosphere-ionosphere links due to AGW
6.2 Electromagnetic models for the lithosphere-ionosphere coupling
6.3 Sporadic E-layers as current generators
7 Discussion and conclusion
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Young, Alison Claire. "Significance of VHL changes in sporadic renal cell carcinoma." Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581867.
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The von Hippel-Lindau (VHL) tumour suppressor gene is central to the development of sporadic conventional clear cell renal cell carcinoma (ccRCC). The role VHL plays as part of a ubiquitin ligase targeting HIF-a for proteasomal degradation underpins many changes seen in ccRCC but the importance of other VHL functions and the clinical significance of specific genetic/epigenetic changes are not clear. Genetic and epigenetic analysis of VHL gene in 86 tumours from patients with ccRCC was carried out, adding to the 96 tumours already analysed in an ongoing study within the group. Overall, loss of heterozygosity (LOH) was found in 89.2%, mutation in 74.6% and methylation in 30.9%. Evidence of biallelic inactivation (LOH and mutation or methylation alone) was "found in 84.9% whilst no involvement of VHL was found in only 4% of samples, consistent with VHL involvement in the majority of conventional ccRCCs. Associations between mutation and gender (p=0.0189), LOH and grade (p=0.0097) and methylation and grade (p=0.0159) were found with a possible association between methylation and gender (p=0.0835). There was a suggestion of LOH and mutation correlating with a better overall survival compared to patients with no VHL involvement and a similar relationship was seen with methylation; however sample numbers were small in the no VHL group and neither reached statistical significance.
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Mistry, Sushilaben Harkisandas. "The role of p14ARF in familial and sporadic melanoma." Thesis, University of Leeds, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413193.
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Fytterer, Tilo, Christina Arras, and Christoph Jacobi. "Terdiurnal signatures in midlatitude sporadic E layers occurrence rates." Universität Leipzig, 2013. https://ul.qucosa.de/id/qucosa%3A16409.
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Global Positioning System radio occultation measurements by the FORMOsa SATellite mission-3/Constellation Observing System for Meteorology, Ionosphere and Climate satellites were used to analyse the behaviour of the signature of the terdiurnal tide in sporadic E (ES) layers at midlatitudes (43°N – 63°N). According to theory, the occurrence of ES is expected when the vertical zonal wind shear, which is mainly owing to solar tides, is negative. 4-year means, based on 3-monthly running mean zonal means from December 2006 - November 2010, were constructed for the terdiurnal oscillation in the occurrence frequency of ES. Comparison of the results with VHF meteor radar observations of the terdiurnal tide and the 8-hr oscillation in the vertical zonal wind shear at Collm, Germany (51.3°N, 13°E) shows a clear correspondence between the 8-hr Es and wind shear signature.Radiookultationsmessungen auf der Basis von GPS-Messungen der FORMOsa SATellite mission-3/Constellation Observing System for Meteorology, Ionosphere and Climate-Satelliten wurden verwendet, um die Signatur der 8-stündigen Gezeiten in den Auftrittsraten von sporadischen E (Es)-Schichten zu analysieren. Nach der allgemein anerkannten Windscherungstheorie treten Es-Schichten im Bereich negativer vertikaler Windscherung auf, welche in der unteren Thermosphäre hauptsächlich durch solare Gezeiten hervorgerufen werden. Speziell werden hier 4-jährige Mittelwerte saisonal gemittelter Auftrittsraten untersucht um die 8-stündige Signatur zu finden. Ein Vergleich mit Radarmessungen des Windes über Collm zeigt, dass die saisonale und tägliche Variabilität der 8-stündigen Komponente der Es-Raten sehr gut mit derjenigen der gemessenen Windscherung übereinstimmt.
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McLaughlin, Heather Ward. "Modeling sporadic Alzheimer's disease using induced pluripotent stem cells." Thesis, Harvard University, 2014. http://nrs.harvard.edu/urn-3:HUL.InstRepos:13094355.
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Despite being the leading cause of neurodegeneration and dementia in the aging brain, the cause of Alzheimer's disease (AD) remains unknown in most patients. The terminal pathological hallmarks of abnormal protein aggregation and neuronal cell death are well-known from the post-mortem brain tissue of Alzheimer's disease patients, but research into the earliest stages of disease development is hindered by limited model systems. In this thesis, an in vitro human neuronal system was derived from induced pluripotent stem (iPS) cell lines reprogrammed from dermal fibroblasts of AD patients and age-matched controls. This allows us to investigate the cellular mechanisms of AD neurodegeneration in the human neurons of sporadic AD (SAD) patients, whose development of the disease cannot be explained by our current understanding of AD. We show that neural progenitors and neurons derived from SAD patients show an unexpected expression profile of enhanced neuronal gene expression resulting in premature differentiation in the SAD neuronal cells. This difference is accompanied by the decreased binding of the repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF) transcriptional inhibitor of neuronal differentiation in the SAD neuronal cells. The SAD neuronal cells also have increased production of \(amyloid-\beta\) and higher levels of tau protein, the main components of the plaques and tangles in the AD brain.
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Nishijo, Koichi. "Mutation analysis of the RECQL4 gene in sporadic osteosarcomas." Kyoto University, 2005. http://hdl.handle.net/2433/144775.
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Johnson, Suzanne Michelle. "Molecular analysis of sporadic breast cancer in younger women." Thesis, University of Leicester, 2001. http://hdl.handle.net/2381/29385.
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This thesis presents molecular genetic evidence to support the hypothesis that sporadic breast carcinomas occurring in this younger age group are biologically different. 31 cases of infiltrating ductal carcinoma occurring in women aged 35 years were analysed for loss of heterozygosity and microsatellite instability at 10 polymorphic microsatellite markers in three key chromosomal intervals: 17p 13 (p53), 17q 11-21 (BRACA1 ) and 13q 12-13 (BRCA2). An elevated incidence of LOH was detected at BRCA1(65%) and BRCA2 (74%) when compared to a control group of matched postmenopausal cases (aged 55-72 years) of 35% and 40% LOH respectively (x2 = 5.22, 1 d.f. P < 0.025, x2 = 12.6, 1d.f. P<0.01). MSI was rare. 17/28 cases aged 35 years showed reduced expression of BRCA1 at the mRNA level by RT-PCR, and LOH at BRCA1 was detected in 13 of these (x2 = 5.22 (1d.f.) 0.025. 0.01). In addition, BRCA1 protein expression was reduced or absent in the tumours in comparison to a control group of 31 normal breast samples taken from reduction mammoplasties. 10/31 cases aged 35 years were positive for p53 expression using immunohistochemistry and SSCP analysis of exons 5-8 revealed altered migration in 9/10 cases. Sequencing confirmed the presence of missense mutations in the DNA binding domain in two of the tumours. In summary, these data demonstrate a high frequency of genetic alterations supporting a role for BRCA1, BRCA2 and p53 in the development of this particular group of sporadic breast carcinomas in young women.
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Macleod, Margaret-Ann. "The clinico-pathological phenotype of sporadic Creutzfeldt-Jakob disease." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/28507.
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Creutzfeldt-Jakob Disease (CJD) is a rare neurodegenerative disorder of the human central nervous system. It occurs in four main forms, defined essentially according to aetiology: sporadic, variant, iatrogenic and familial. All forms of the disease are characterised by the deposition of an abnormal cellular protein, the prion protein (PrP^sc), within the brain. Definitive diagnosis depends on identifying this along with other neuropathological changes such as spongiform degeneration and astrocytic gliosis. To date variant CJD has followed a relatively stereotyped clinical course with fairly consistent pathological findings. However, various clinico-pathological phenotypes of sporadic CJD have been described. It is believed the disease phenotype is influenced by a number of factors including agent strain (PrP^res isotype being used as a surrogate marker), and genotype (particularly a polymorphism at codon 129 of the prion protein gene). Data on 99 cases of sporadic CJD and 43 cases of variant CJD were analysed. The sporadic CJD cases were divided into 6 sub-groups, according to genotype at codon 129 (either methionine homozygous, valine homozygous or heterozygous) and PrP^res isotype (either type 1 or 2A). Some trends in clinico-pathological phenotype were found. Notably, the methionine homozygous cases with type 1 PrP^res isotype formed the majority of cases and followed a reasonably uniform disease course. The other groups tended to include atypical cases. These differences did not achieve statistical significance and there was considerable overlap amongst cases. 14-3-3 protein and the use of MR imaging were analysed. The results suggest that these investigations may improve the diagnostic classification of sporadic CJD. The variant CJD cases followed a relatively consistent clinico-pathological course, consistent with a distinct aetiology and probably a distinct strain. The data do not support the hypothesis that different strains of the sporadic CJD agent cause distinct clinico-pathological phenotypes.
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Mitchell, Anna Louise. "Genomic analyses of familial and sporadic autoimmune Addison's disease." Thesis, University of Newcastle upon Tyne, 2013. http://hdl.handle.net/10443/2477.
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Autoimmune Addison’s disease (AAD) is a rare and highly heritable endocrinopathy. It is a complex genetic disease, meaning that it is due to a combination of interacting environmental and genetic factors. To date, the majority of the substantial genetic component to AAD aetiology remains undefined. In this study, a combination of hypothesis-driven (candidate gene) and discovery-driven (genome-wide) approaches have been used to search for novel genetic determinants of AAD. PCR-based approaches were undertaken to study the potential role of the CYP21A1P pseudogene in AAD. CYP21A1P is highly homologous to the CYP21A2 gene which encodes 21-hydroxylase, the primary autoantigen in AAD. In individuals with AAD, CYP21A1P is more likely to be absent from the genomic DNA sequence than in controls. qPCR and in situ hybridisation have been successfully combined to identify CYP21A1P transcripts in thymic, and fetal adrenal, tissue. These data perhaps indicate a role for CYP21A1P in induction of immune tolerance, with its loss being associated with autoimmunity against the steroidogenic apparatus. Taking a broader candidate gene approach, the largest association analysis in AAD to date, of twenty candidate genes in six European AAD cohorts, suggests a role for NF-κB1, IL23A and GATA3 variants in susceptibility to AAD in individual European cohorts, and a role for STAT4 more universally in AAD. SNP array technology has been used to conduct the first genome-wide linkage and association analysis in AAD. The linkage study, including 23 families, has linked regions on chromosomes 6, 7, 9 and 18 to disease. A genome-wide association analysis, comparing the 50 familial AAD cases to the Wellcome Trust 1958 UK Birth Cohort control group, revealed clusters of associated SNPs on chromosomes 2 and 6. iii This body of work has illustrated some of the challenges in investigating a rare, complex genetic disorder, and how international collaboration can help to resolve some of these issues. In the course of this work, in addition to identifying a number of novel genetic determinants to AAD, exciting preliminary results have been generated which will need to be followed up. It is hoped that once these preliminary findings are replicated and further investigated, they will contribute significantly to an increase in our understanding of the pathogenesis of AAD, with the long-term aim of identifying novel means of treating the disease, altering its natural history or even preventing it.
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Whyman, Gavin John. "Sporadic breast cancer in young women : a microarray investigation." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29849.
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The aim of this thesis was to test the hypothesis that sporadic breast cancers in young women arise because of a profile of genetic alterations specific to that age group. Previous studies by our research group had identified a higher frequency of Loss of Heterozygosity (LOH) in the BRCA1, BRCA2 and p53 intervals in younger breast cancer cases (55 years); BRCA1 and P53 data had been related to protein expression. Investigations of BRCA2 protein and mRNA expression were inconclusive. A higher frequency of skewed X chromosome inactivation was identified in young women (55 years) with sporadic breast cancer in this study (P = 0.017), which might suggest the involvement of an X linked gene in the genesis of these tumours. Although it was not possible to relate cDNA expression levels to genomic copy number changes for individual tumours, the analysis of gene expression changes using Affymetrix Gene Chips identified a number of novel gene targets showing elevated expression in young breast cancers when compared to normal breast organoids. Several statistically significant candidate genes were investigated, and gene expression changes confirmed by qRT-PCR and for RBBP4 by immunohistochemistry. Of the significant gene targets that were ranked by SAM analysis DDB2 and RARRES3 are the most noteworthy. Statistically significant differences in the level of expression of these two genes might suggest that they are novel markers of young breast cancers, meriting investigation in a larger series of cases.
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Catalán, García Marc. "Mitochondrial profile and amyloidogenic molecules in sporadic inclusion body myositis." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/586382.
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Sporadic inclusion body myositis (sIBM) is the most common myopathy in elderly. This disease causes muscle wasting with both distal and proximal affectation. Quadriceps and finger flexors are muscle typically affected. At pathological level, three different features are present in muscle biopsies: inflammation, mitochondrial abnormalities and degeneration. The presence of T-cell infiltrate, ragged-red fibers and rimmed vacuoles are some features linked to these pathological processes. Protein misfolding and aggregation lead to the formation of the mentioned rimmed vacuoles, composed by many different misfolded proteins: β-amyloid, caveolin, phosphor-Tau among others. The accumulation of β-amyloid is also a hallmark of Alzheimer’s disease (AD), which presents some parallelisms with sIBM.
In this work, we aimed to evaluate the mitochondrial state in muscle from sIBM patients but also in peripheral blood mononuclear cells (PBMC) to describe the molecular abnormalities that mitochondria could present in this disease. In addition, we aimed to measure plasmatic molecules related to inflammation, mitochondria and degeneration, in search for plasmatic biomarkers in sIBM patients but also in dermatomyositis and polymyositis, both diseases from the inflammatory myopathy group, like sIBM.
Regarding mitochondrial analysis, muscle biopsies from 23 sIBM patients were analyzed, as well as 18 controls free of muscle disease. In addition, PBMC from 14 sIBM patients and from 20 controls were assessed as well. MtDNA levels and also mitochondrial respiratory chain complex IV (COX) activity were significantly decreased in muscle from sIBM patients compared to controls. Interestingly, when analyzing PBMC, dysfunction in COX activity was also found. In this tissue, a deregulation in mitochondrial protein synthesis was also found. As 57% of the sIBM patients presented mtDNA deletions, we aimed to evaluate if the presence of mtDNA deletions correlate with impaired mitochondrial parameters. sIBM patients with mtDNA deletions presented the lowest amount of mtDNA, and those patients without deletions showed values more similar to controls. A similar pattern was found when correlating the presence of MFN-2, a protein involved in mitochondrial dynamics. Again, patients with mtDNA deletions presented the lowest amount of this protein, and patients without deletions showed an intermediate values between patients with deletions and controls.
Regarding the analysis of plasmatic molecules related to sIBM pathological features, inflammatory, mitochondrial and amyloidogenic molecules were analyzed in plasma samples from 21 sIBM, 20 controls and also in 14 plasma samples from dermatomyositis (DM) and polymyositis (PM) patients, which constitute an inflammatory myopathy different from sIBM group. Inflammatory (IL-6 and TNF-α) and mitochondrial-related (circulating mtDNA, FGF-21 and CoQ) molecules did not show significant differences between groups. However, amyloidogenic molecules (BACE-1, PS-1 and sAPPβ) were increased in sIBM patients respect to controls but also respect to the DM and PM group confirming its implication in sIBM pathogenesis. Sensitivity and specificity test showed that BACE-1 would be the most suitable biomarker for sIBM diagnosis.
This thesis describes at molecular level the mitochondrial implication in the disease, and also reinforces the amyloidogenic component in sIBM. In addition, it proposes a plasmatic and non-invasive biomarker that could help in the sIBM diagnosis, especially in discriminating between other inflammatory myopathies, like polymyositis.La miositis per cossos d’inclusió en la seva forma esporàdica (MCI) és la miopatia més comú en individus de més de 50 anys tot i ser una malaltia rara. Cursa amb atròfia muscular progressiva distal i proximal i actualment no es coneix cura. A nivell histopatològic presenta un component inflamatori, un component mitocondrial i un component degeneratiu. Degut al seu component degeneratiu i a la similitud de les proteïnes que formen aquests cossos d’inclusió, s’ha establert un possible paral·lelisme amb la malaltia d’Alzheimer. Els objectius d’aquesta tesi doctoral són explorar a nivell molecular les alteracions mitocondriales en la MCI en múscul, però també en cèl·lules mononuclears de sang perifèrica (CMSP), ja que és un teixit menys invasiu. A més, com a segon objectiu principal pretén d’estudiar mol·lècules relacionades amb la inflamació, amb el mitocondri i amb la degeneració en plasma d’aquests pacients per tal de demostrar la seva implicación amb la etiopatogènia i a més per establir nous marcadors menys invasius que permetin diagnosticar la malaltia i diferenciarla d’altres malalties similars com la dermatomiositis i la polimiositis. Fent referència a l’estudi mitocondrial, tant la quantitat de DNA mitocondrial com l’activitat del complex IV de la cadena mitocondrial (COX) es van trobar disminuïts en músculs dels pacients amb MCI. D’altra banda, amb l’estudi de les CMSP, també vam trobar disminuïda l’activitat de la COX, i a més una desregulación de la síntesis de proteïnes mitocondrials. Donat que un 57% dels pacients va presentar delecions múltiples al DNA mitocondrial, la presència d’aquestes delecions correlacionava amb una menor quantitat de DNA mitocondrial i a més amb un decrement de proteïna MFN-2, implicada en la dinàmica mitocondrial. Amb l’estudi de les molècul·les plasmàtiques, es van analitzar en plasma de pacients amb MCI, en controls però també en pacients amb dermatomiositis i polimiositis mol·lècules relacionades amb la inflamació (IL-6 i TNF-α), amb el mitocondri (DNA mitocondrial circulant, FGF-21 i enzim CoQ) i amb la amiloidogènesi (BACE-1, PS-1 i sAPPβ). Les mol.lècules amiloidogèniques es trobaven incrementades en els pacients amb MCI respecte controls i altres miopatíes inflamatòries, demostrant la seva impliació en la etiopatogènia i obtenint un cert valor diagnòstic. Amb aquesta tesi, s’ha demostrat la implicació mitocondrial en la etiopatogènia de la MCI, i s’han trobat alteracions en plasma de mol·lècules amiloidogèniques que, a més, tenen potencial diagnòstic per diferenciar aquesta malaltia d’altres miopatíes inflamatòries com la polimiositis.
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Rice, Judd Christopher. "Epigenetic silencing of BRCA1 and maspin in sporadic breast cancer." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/289142.
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The RNA expression of the tumor suppressor genes BRCA1 and maspin are frequently decreased or lost in sporadic breast cancer. We hypothesized that inactivation of these genes was due to aberrant epigenetic silencing at the level of gene transcription. In this study we show that aberrant cytosine methylation of the BRCA1 and maspin CpG island promoters is a common event in the inactivation of these genes in sporadic breast cancer cell lines. Furthermore, we show that the methylation-associated inactivation of BRCA1 occurs in 15-30% of sporadic breast cancer patient specimens and our data suggests that the methylation-associated inactivation of maspin occurs in ∼70% of advanced sporadic breast cancers. Additional studies indicate that the methylation associated inactivation of these genes is coincident with the repressive epigenetic events of histone hypoacetylation and chromatin condensation. These data suggest that aberrant cytosine methylation, histone hypoacetylation and chromatin condensation act together in the BRCA1 and maspin promoters to inactivate their transcription, thereby, contributing to the progression of sporadic breast cancer.
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de, Foy K. "Analysis of candidate tumour suppressor genes in sporadic ovarian tumours." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598448.
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The aim of this thesis was to identify genes which are important in the initiation and/or progression of sporadic ovarian cancer. A series of ovarian teratomas and carcinomas was collected and three candidate tumour suppressor genes were analysed. The c-mos gene is an ovarian teratoma susceptibility gene in mice; its absence causes the growth of these tumours. Twenty human ovarian teratomas were collected and the coding region of the c-mos gene was analysed for somatic and germline mutations. No disease-causing alterations were found. Germline mutations of the BRCA2 gene predispose individuals to breast and ovarian cancer. To determine whether mutations in BRCA2 are important in sporadic ovarian cancer, loss of heterozygosity studies and mutation analysis were carried out on BRCA2 in a series of sporadic epithelial ovarian tumours. Loss of heterozygosity was identified in 46% of tumours. Four truncating mutations were identified in 50 tumours, two of which were germline and two somatic. All four mutations were accompanied by loss of the second allele. These results suggest that BRCA2 behaves as a tumour suppressor gene but that somatic mutations are not a common even in sporadic ovarian cancer. The insulin-like growth factor II receptor gene (IGF2R) on chromosome 6q is in a region which is frequently lost in ovarian tumours. A loss of heterozygosity analysis of the IGF2R locus in 38 informative epithelial ovarian tumours demonstrated 55% with loss of one allele. To perform mutation analysis of IGF2R, the technique of fluorescent chemical cleavage of mismatch was established in the laboratory and used to analyse IGF2R cDNA from 18 tumours. No disease-causing alterations were identified. Antibodies were used to examine the expression of the IGF2R protein through immunohistochemical studies of 53 ovarian tumour tissue sections. Seven tumours were identified in which epithelial tumour cells stained negatively for IGF2R. No correlation could be found between immunohistochemical results and LOH and mutation analysis results, suggesting that IGF2R is probably down-regulated at the level of transcription or translation in those samples which showed negative staining.
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Ahmed, M. "Investigating novel therapeutic approaches for sporadic inclusion body myositis (sIBM)." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1343623/.
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Sporadic inclusion body myositis (sIBM) is the most common acquired muscle disease affecting adults over the age of 50. Although the aetiology of this disease remains unclear, there is evidence for both inflammatory and myodegenerative processes in sIBM muscle pathology. In particular, abnormal protein aggregation is characteristic of affected muscle, with inclusion bodies incorporating amyloid-beta precursor protein (β-APP) among many others. Therapeutic interventions tested to date for sIBM have targeted the immune system; but none have been beneficial and sIBM currently remains untreatable. In this study, an in vitro model of the degenerative pathology seen in sIBM was established by over-expressing β-APP in primary muscle cultures. This resulted in the formation of inclusion bodies immuno-reactive for β-APP and other sIBM-relevant proteins, as well as increased cytotoxicity, proteasome dysfunction, mitochondrial abnormalities and TDP-43 mis-localisation; all observed in sIBM patient muscle. The heat shock response (HSR) is an acute endogenous cytoprotective mechanism that responds to misfolded proteins. Up-regulation of the HSR was examined by treatment with Arimoclomol, a co-inducer of the HSR, which showed beneficial effects in this in vitro model of IBM by significantly improving cell survival and attenuating cellular pathology. Since proteasome dysfunction has been implicated in sIBM pathology, I also examined the effects of pharmacological inhibition of the proteasome on muscle cells in culture. Proteasome inhibition did not result in the appearance of several key features of sIBM, suggesting that this is not a suitable approach to modeling sIBM. However, treatment with Arimoclomol was seen to significantly improve proteasome function and cell survival in these experiments. Using the β-APP model, eight novel pharmacological agents, with known anti-aggregation properties, were subsequently screened and one agent was found to significantly ameliorate the disease outcomes established in this model. The results of this Thesis show that β-APP over-expression in vitro recapitulates many of the characteristic features of sIBM and can be used successfully to screen potential therapies. In particular, Arimoclomol and one novel agent have been identified as potential therapeutic agents for IBM.
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Messori, Gabriele. "The sporadic nature of meridional heat transport in the atmosphere." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/22158.
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The present study analyses meridional atmospheric heat transport, due to transient eddies, in the European Centre for Medium-Range Weather Forecasts ERA-Interim reanalysis data. Probability density functions of the transport highlight the dominant role played by extreme events. In both hemispheres, events in the top 5 percentiles typically account for over half of the net poleward transport. As a result of this sensitivity to extremes, a large fraction of the heat transport by transient eddies, at a given location and season, is realised through randomly spaced bursts (a few per season), rather than through a continuum of events. Abstract Fast growing atmospheric modes are associated with a large heat transport, suggesting a link between these bursts and growing baroclinic systems (defined here as motions in the 2.5-6 day band). However, wavelet power spectra of the transport extremes suggest that they are driven by very precise phase and coherence relationships, between meridional velocity and moist static energy anomalies, acting over a broad range of frequencies (2-32 days). Motions with periods beyond 6 days play a key role in this framework. Moreover, these longer periods are found to be mainly driven by planetary-scale motions. Notwithstanding this, the heat transport bursts can be matched to specific synoptic-scale patterns. The bursts are therefore interpreted as the signatures of travelling synoptic systems superimposed on larger scale motions. The dominant role of extreme events can be reproduced in highly idealised simulations. Both a statistical model, where atmospheric motions are assumed to be linear superpositions of sinusoidal curves, and a two-layer model, representing heat transport as a quantised process effected by point vorticity anomalies, are successful in simulating the transport bursts. The fact that two very different idealised models both reproduce the transport's sporadic nature suggests that this must be an intrinsic property of waves in the atmosphere.
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Distler, Marius, Daniela E. Aust, Jürgen Weitz, Christian Pilarsky, and Robert Grützmann. "Precursor Lesions for Sporadic Pancreatic Cancer: PanIN, IPMN, and MCN." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-147337.
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Pancreatic cancer is still a dismal disease. The high mortality rate is mainly caused by the lack of highly sensitive and specific diagnostic tools, and most of the patients are diagnosed in an advanced and incurable stage. Knowledge about precursor lesions for pancreatic cancer has grown significantly over the last decade, and nowadays we know that mainly three lesions (PanIN, and IPMN, MCN) are responsible for the development of pancreatic cancer. The early detection of these lesions is still challenging but provides the chance to cure patients before they might get an invasive pancreatic carcinoma. This paper focuses on PanIN, IPMN, and MCN lesions and reviews the current level of knowledge and clinical measures.
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Eusebi, Leonardo Henry Umberto <1979>. "Clinicopathological and molecular features of sporadic early onset colorectal cancers." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7300/.
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The increasing occurrence of CRC developing in young patients with no identified genetic predisposition, defined as sporadic early onset colorectal cancers (EOCRCs), demands maintaining a high index of suspicion when people below 50 years of age present with symptoms.
To define the clinicopathological features and the stage at presentation of EOCRCs, as well as to understand whether the histological, immunohistochemical and molecular analyses were associated with particular clinicopathological parameters and oncologic outcome, a total of 94 cases of EOCRCs diagnoses between 2006 and 2014 at the Sant’Orsola University Hospital were studied.
Indeed, EOCRCs appear frequently as an aggressive disease located in the sigmoid colon and rectum, and most patients are symptomatic at the time of presentation, mainly presenting with rectal bleeding, haematochezia or abdominal pain.
The genetic basis in the majority of early onset colorectal carcinomas remains unknown, however, most EOCRCs, not related hereditary syndromes, appear to arise through the same pathways as sporadic CRCs, such as the classical adenoma-carcinoma sequence, but with only rare involvement of the methylator pathway.
Taken together, the analyses described in this study suggest that, in the absence of screening programs for patients under 50 years of age, the risk factor of a family history and the presence of symptoms may be considered as an indication for prompt endoscopic investigation in these patients, since this may reduce the stage of disease at diagnosis and likely have an impact on improving survival.
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Wright, Benjamin. "Graphs associated with the sporadic simple groups Fi₂₄ and BM." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/graphs-associated-with-the-sporadic-simple-groups-fi24-and-bm(dcdd493b-929d-4f91-a6bc-48c6b5fda3ba).html.
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Our aim is to calculate some graphs associated with two of the larger sporadicsimple groups, Fi₂₄ and the Baby Monster. Firstly we calculate the point line collinearity graph for a maximal 2-local geometry of Fi₂₄. If T is such a geometry, then the point line collinearity graph G will be the graph whose vertices are the points in T, with any two vertices joined by an edge if and only if they are incident with a common line. We found that the graph has diameter 5 and we give its collapsed adjacency matrix. We also calculate part of the commuting involution graph, C, for the class 2C of the Baby Monster, whose vertex set is the conjugacy class 2C, with any two elements joined by an edge if and only if they commute. We have managed to place all vertices inside C whose product with a fixed vertex t does not have 2 power order, with all evidence pointing towards C having diameter 3.
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Rylah, Paul J. "Observations of Sporadic-E utilising high frequency oblique sounding techniques." Thesis, University of Leicester, 1999. http://hdl.handle.net/2381/30615.
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Sporadic-E is an 'abnormal', altitude-confined intensification of the E-region plasma density. Its presence may both enable and disable an oblique propagation circuit, depending on the prevalent propagation path geometry, the ambient ionospheric conditions, and the plasma structure of the layer itself. This thesis studies the plasma characteristics of sub-auroral sporadic-E layers, utilising oblique HF 'Chirp' sounders, deployed during times of both quiet and disturbed geomagnetic activity. During largely quiet geomagnetic conditions, a relationship is established between the sporadic-E top frequency, ftEs, and the layer's signal strength (SS), at a fixed sounder 'Probing Frequency' (PF) such that SS (ftEs/PF)n, with values of 'n' varying between ~ zero and ~ 20. The resulting 'curve' is derived primarily for 'overdense' sporadic-E reflections and is interpreted in terms of the sporadic-E plasma 'cloud' model. A gaussian distribution of differing cloud plasma densities is demonstrated to best model the observed sporadic-E signal strength characteristics. However, this signal strength relationship is increasingly inapplicable to the minority of sporadic-E layers arising from equivalent vertical top frequency (vftEs) growth rates, greater than ~ 0.6 MHz per five minute time interval. Indeed, for vftEs growth rates greater than ~ 1.2 MHz per five minutes, the signal strength is independent of the top frequency. These observations are again consistent with the plasma cloud model, though field-aligned irregularities and off great circle path propagation may account for some of the more temporary vftEs growths. The thesis concludes with a study of correlated observations of sporadic-E layers and ~ 1 m scale plasma irregularities, as detected by the Wick receiver of the SABRE (Sweden And Britain Radar-aurora Experiment) VHF backscatter radar. The correlated occurrence of the two plasma features, coincided, primarily, with substorm activity. On occasions it was also noted that the backscatter S/N ratio correlated closely with the sporadic-E top frequency, the observation being interpreted in terms of the enhanced auroral electric fields.
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Miller, A. D. "Development of new therapeutic strategies for sporadic Inclusion Body Myositis." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1469260/.
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Sporadic inclusion body myositis (IBM) is the commonest myopathy acquired after 50 years of age and causes significant disability. No effective treatment exists despite several clinical trials of immunotherapies. This reflects a lack of pre-clinical disease models. The work described in this thesis began with development of such a system, in which disease relevant pathological outcome measures were characterised in vitro using primary satellite cell cultures. Through over-expression of β-Amyloid Precursor Protein or exposure to inflammatory mediators IL1β and TNFα, IBM-like pathology was induced. Myotubes demonstrated ubiquinated intracellular aggregates, increased expression of MHC Class I, cytoplasmic translocation of TDP-43, ER stress, calcium dyshomeostasis and activation of NFκB. As some of these are proposed to be central pathogenic mechanisms in IBM, they provide a panel of tools on which to assess new IBM treatment strategies. The effects of heat shock response augmentation were examined using Arimoclomol, a co-inducer of the transcription factor HSF-1 that drives expression of key endogenous Heat Shock Proteins. Arimoclomol treatment ameliorated several IBM-relevant features, represented by improved cell viability, reduced ER stress, inhibition of NFκB and reduced cytoplasmic translocation of TDP-43. These data supported further evaluation of HSR manipulation as a potential therapy for IBM. Therefore, Arimoclomol was advanced into a randomised, placebo-controlled clinical trial involving 24 patients with IBM over one year. The primary outcome measure was safety and tolerability. Muscle biopsy was performed before and after the treatment phase to evaluate HSP expression and histopathological changes. Together, this in vitro model and clinical trial represent a novel translational research pathway in IBM, the lack of which has hampered the development of effective treatments for this disease.
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Forsberg, Karin. "Misfolded superoxide dismutase-1 in sporadic and familial Amyotrophic Lateral Sclerosis." Doctoral thesis, Umeå universitet, Patologi, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-47550.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome of unknown etiology that most commonly affects people in middle and high age. The hallmark of ALS is a progressive and simultaneous loss of upper and lower motor neurons in the central nervous system that leads to a progressive muscle atrophy, paralysis and death usually by respiratory failure. ALS is not a pure motor neuronal syndrome; it extends beyond the motor system and affects extramotor areas of the brain as well. The majority of the patients suffer from a sporadic ALS disease (SALS) while in at least ten percent the disease appears in a familial form (FALS). Mutations in the gene encoding the antioxidant enzyme superoxide dismutase-1 (SOD1) are the most common cause of FALS. More than 165 SOD1 mutations have been described, and these confer the enzyme a cytotoxic gain of function. Evidence suggests that the toxicity results from structural instability which makes the mutated enzyme prone to misfold and form aggregates in the spinal cord and brain motor neurons. Recent studies indicate that the wild-type human SOD1 protein (wt-hSOD1) has the propensity to develop neurotoxic features. The aim of the present study was to investigate if wt-hSOD1 is involved in the pathogenesis of SALS and FALS patients lacking SOD1 mutations and to evaluate the neurotoxic effect of misfolded wt-hSOD1 protein in vivo by generating a transgenic wt-hSOD1 mice model. We produced specific SOD1-peptide-generated antibodies that could discriminate between the misfolded and native form of the enzyme and optimized a staining protocol for detection of misfolded wt-hSOD1 by immunohistochemistry and confocal microscopy of brain and spinal cord tissue. We discovered that aggregates of misfolded wt-hSOD1 were constitutively present in the cytoplasm of motor neurons in all investigated SALS patients and in FALS patients lacking SOD1 gene mutations. Interestingly, the misfolded wt-hSOD1 aggregates were also found in some motor neuron nuclei and in the nuclei of the surrounding glial cells, mainly astrocytes but also microglia and oligodendrocytes, indicating that misfolded wt-hSOD1 protein aggregates may exert intranuclear toxicity. We compared our findings to FALS with SOD1 mutations by investigating brain and spinal cord tissue from patients homozygous for the D90A SOD1 mutation, a common SOD1 mutation that encodes a stable SOD1 protein with a wild-type-like enzyme activity. We observed a similar morphology with a profound loss of motor neurons and aggregates of misfolded SOD1 in the remaining motor neuron. Interestingly, we found gliosis and microvacuolar degeneration in the superficial lamina of the frontal and temporal lobe, indicating a possible frontotemporal lobar dementia in addition to the ALS disorder. Our morphological and biochemical findings were tested in vivo by generating homozygous transgenic mice that over expressed wt-hSOD1. These mice developed a fatal ALS-like disease, mimicking the one seen in mice expressing mutated hSOD1. The wt-hSOD1 mice showed a slower weight gain compared to non-transgenic mice and developed a progressive ALS-like hind-leg paresis. Aggregates of misfolded wt-hSOD1 were found in the brain and spinal cord neurons similar to those in humans accompanied by a loss of 41 % of motor neurons compared to non-transgenic litter mates. In conclusion, we found misfolded wt-hSOD1 aggregates in the cytoplasm and nuclei of motor neurons and glial cells in all patients suffering from ALS syndrome. Notable is the fact that misfolded wt-hSOD1 aggregates were also detected in FALS patients lacking SOD1 mutations indicating a role for SOD1 even when other genetic mutations are present. The neurotoxicity of misfolded wt-hSOD1 protein was confirmed in vivo by wt-hSOD1 transgenic mice that developed a fatal ALS-like disease. Taken together, our results support the notion that misfolded wt-hSOD1 could be generally involved and play a decisive role in the pathogenesis of all forms of ALS.
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Berlin, Daniel. "The role of HFE (hemochromatosis) gene mutations in sporadic Alzheimer disease /." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78245.
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Although a central etiology for Alzheimer disease (AD) has not yet been determined, support has amassed for the notion that oxidative stress may be involved in the pathogenesis of AD. The disruption of iron homeostasis and iron's excessive deposition in AD brain tissues has received increased attention due to the metal's capacity to promote the production of harmful free radicals. Several studies have recently examined whether DNA mutations involved in the iron overload disorder, hemochromatosis, pose an increased risk of acquiring AD. However, the small sample size and low generalizability of previous studies have warranted further investigation. We genotyped 213 AD patients, 106 Mild Cognitively Impaired (MCI) individuals, and 63 Normal Elderly Control (NEC) subjects for the H63D and C282Y HFE mutations to examine whether a relationship exists between HFE gene status and AD presentation in our patient population. DNA analysis was conducted by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). We did not find any statistically significant associations between HFE gene status and the clinical, demographic, or neuropsychological aspects of AD in our patient population. Interesting trends that fell short of statistical significance included: (a) a deleterious effect of HFE mutations on motor performance, (b) an influence of H63D homozygosity on an earlier onset of cognitive decline, and (c) an influence of H63D homozygosity on an accelerated progression from MCI to AD.
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Lindberg, Daniel. "Molecular Genetic Studies of Sporadic and MEN1-Associated Endocrine Pancreatic Tumors." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7595.
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