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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Molecular profiling of oesophageal squamous cell carcinomas in the South African population

Brown, Jacqueline 08 March 2012 (has links)
Ph.D., Faculty of Health Sciences, University of the Witwatersrand, 2011 / Oesophageal squamous cell carcinoma (OSCC) has a high prevalence in the Asiatic belt and areas of Africa. In South Africa (SA), the incidence of this cancer in the Eastern Cape is one of the highest in the world. The molecular carcinogenesis of this disease remains unresolved. Single nucleotide polymorphism (SNP) array technology provides a high resolution technique to determine DNA copy number imbalances across the whole genome. DNA copy number changes can affect oncogenes and tumour suppressor genes, contributing to carcinogenesis. The aim of this study was to map common chromosomal break points previously identified in five SA OSCC cell lines by multi colour fluorescence in situ hybridisation (FISH) and to characterise copy number changes in these cell lines and OSCC patient’s specimens using SNP array technology. Genome wide copy number analysis was performed on the cell lines and 51 OSCC retrospective samples from the Eastern Cape region using Affymetrix® 500K SNP arrays. A number of genes were significantly affected by copy number changes across specimens. The copy number status of some of these candidate genes identified by arrays, were verified by (FISH) in a subset of the samples. Expression of the EPHA3, FGF3, FGF4, FGF19 and C-MYC candidate genes was assessed in the cell lines and four fresh samples. The common translocation break point previously detected in 5 cell lines involving chromosome 3p11.2 correlated with deletions affecting the EPHA3 gene in 4 of the 5 cell lines and was deleted in 74% of the OSCC cohort. EPHA3 is an ephrin A3 receptor tyrosine kinase that has been shown to have both oncogenic and tumour suppressor functionality. In addition, significant regions of amplification and deletion identified genes (CCND1, C-MYC, FHIT, SFRP1, SFRP2, FGF3, FGF4, FGF19, SMAD4, SMAD6 and FBXW7) involved in the Wnt, TGF-β and FGF. Deletion of the genes, WRN, ATM, RAD18 and XRCC4 involved in DNA repair pathways, may contribute to genetic instability that is characteristic of OSCC. This study has highlighted some molecular pathways that may contribute to better understanding carcinogenesis of OSCC in South Africa.
2

Tracking down gene intefrity within fragile sites: Do they play a role in oesoplageal cancer?

Brown, Jacqueline 16 November 2006 (has links)
Faculty of Science School of Pathology 9900713m Cell #: 083 718 9093 / Oesophageal cancer (OC) is the third most common malignancy in South Africa (SA), affecting 1 in 20 and 1 in 76 black males and females respectively. Squamous cell carcinoma (SSC) is an aggressive disease showing a poor prognosis due to late diagnosis. Identification of genetic changes associated with these tumours may shed light on its pathophysiology and aetiology in SA. The chromosomal status of five OC cell lines, established in SA, was assessed to identify possible common chromosomal alterations by M-FISH (multicolour fluorescence in situ hybridisation) and specifically the fragile site loci, FRA3B and FRA16D by FISH (Fluorescence in situ hybridisation). The genes at these loci, FHIT (Fragile Histidine Triad) and WWOX (WW domain containing oxidoreductase) respectively, were analysed by RT-PCR (Reverse transcriptase polymerase chain reaction). FHIT was aberrantly expressed in four of the five cell lines while WWOX expression was normal. The EGFR (epidermal growth factor receptor) locus is frequently amplified and this gene is also over-expressed in OC. Increased EGFR expression was previously found in three of the cell lines, for this reason, particular attention was paid to markers involving the EGFR locus on 7p. An interesting marker chromosome seven was identified in one of the cell lines and further analysis, using a specific EGFR probe, revealed an amplification unit involving EGFR in this cell line. Common translocations involving chromosomes 3 and 1 as well as 3 and 22 were identified in two cell lines; these may involve a locus involved in OC and warrants further investigation.
3

Short hairpin RNA-directed knockdown of epidermal growth factor receptor in human oesophageal squamous carcinoma cell lines

Killick, Mark Andrew 27 May 2008 (has links)
Epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase which activates, upon EGFR binding, a number of signaling pathways including the mitogenic protein kinase pathway (MAPK) and phosphatidylinositol 3-kinase cascade (PI3K). Over expression of EGFR is a common feature in variety of human cancers including lung, colorectal, breast, pancreatic and oesophageal cancers and results in autonomous cell growth, enhanced metastatic potential, tissue invasion and increased resistance to current cancer therapeutics. Thus EGFR has been identified as a potential target in cancer therapeutics. Using the RNA interference (RNAi) pathway, the aim was to specifically knockdown expression levels of endogeneous EGFR in human oesophageal squamous carcinoma cell (HOSCC) lines. The RNAi pathway was initiated through the transfection of three specifically designed short hairpin RNAs (shRNAs) against human EGFR. The shRNAs were specifically designed using bioinformatics tools and their individual knockdown efficacy determined through the introduction of an exogeneous based target reporter systems, psiCHECK and pcieGFP. Expression levels of EGFR were determined using Western blot analysis followed by densitometry. Knockdown of EGFR was achieved by all three EGFR shRNAs in the three HOSCC cell lines (WHCO1, WHCO5 and WHCO6) despite low transfection levels of ~10%. Greastest knockdown of EGFR (85%) was achieved by EGFR sh2 in WHCO5. EGFR sh2 and sh1 resulted in average knockdown of EGFR of ~ 65% in WHCO1 and WHCO5 respectively. Weakest knockdown of EGFR (~ 20%) was obtained by all three EGFR shRNAs following transfection of WHCO6. RNAi-based approaches therefore show substantial potential for the specific and efficient targeting of EGFR in human cancer cells.
4

Markers of treatment response for gastro-oesophageal cancers

Mirza, Ahmad January 2012 (has links)
Introduction: The incidence of gastro-oesophageal cancers has increased considerably over the last decade. As the disease is associated with a poor prognosis, there is a need to identify markers of treatment response which could be used in the future to improve the management of gastro-oesophageal tumours. Aims: 1) To compare the ability of published histological grading criteria (Becker, Mandard and Ninomiya) to assess response to neo-adjuvant chemotherapy (NCT) in gastro-oesophageal cancers. 2) To evaluate the expression of thymidylate synthase (TS) in pre-treatment diagnostic biopsy samples as a predictive marker of response to NCT. 3) To investigate whether measurements of hypoxia obtained using pimonidazole are prognostic for treatment outcome in patients with gastro oesophageal adenocarcinoma (ACC). 4) To study the prognostic significance and clinicopathological associations of epithelial mesenchymal transition (EMT) related proteins S100A4, Vimentin and Snail1 in gastro-oesophageal junction (GOJ) tumours. 5) To evaluate the ability of dynamic contrast enhanced (DCE) MRI to assess chemoradiotherapy (CRT) induced changes in oesophageal cancer. Methods: 1) Formalin fixed paraffin embedded (FFPE) tumour blocks and haematoxylin and eosin stained slides of samples from resected tumours (n=66) were obtained from patients who received NCT for gastric and GOJ tumours. The slides were scored independently by two observers and kappa scores calculated. 2) Pre-treatment diagnostic tissue biopsy samples were obtained from 45 patients with gastric and GOJ cancer who received NCT. TS expression was assessed using immunohistochemistry (IHC) and scored by two observers. The clinical and pathological data were analysed. 3) 57 patients were prospectively administered intravenous pimonidazole and the tumour specimens were collected both at staging laparoscopy and resection. IHC was performed to assess pimonidazole expression and determine its association with clinico-pathological factors. 4) Tissue microarrays were prepared from resection specimens from GOJ ACC. IHC was performed to investigate EMT related protein expression. 5) DCE-MRI was performed on five patients diagnosed with oesophageal cancer treated with CRT. Multiple pharmacokinetic parameters were evaluated. Findings: 1) Becker's histological grading criteria was the most reproducible and prognostic of outcome. The incidence of complete histological response (5%) was low in patients receiving NCT. 2) No prognostic benefit of TS expression was identified. 3) Results from only 34 patients were available for analysis. 77% pimonidazole positivity was observed. Preoperative anaemia was associated with significant tumour pimonidazole expression (p=0.04). Pimonidazole was not prognostic for outcome. 4) The overall positive expression was S100A4 (85%), Vimentin (14%) and Snail1 (89%). The increased expression of S100A4 at the tumour body (p=0.02) and luminal surface (p=0.01) was associated with a poor outcome. 5) Significant changes were measured in DCE-MRI pharmacokinetic parameters after CRT. Conclusion: 1) Becker's histological response grading criteria should be further studied in routine clinical practice for response assessment to NCT. 2) TS should be explored further as a marker of NCT response in gastro-oesophageal cancer. 3) Hypoxia is a characteristic feature of upper gastrointestinal ACC and is associated with anaemia. 4) S100A4 is the most useful marker of EMT in GOJ adenocarcinoma. 5) DCE-MRI tracer kinetic parameters should be explored in a larger study to assess their ability to monitor the efficacy of and predict response to neo-adjuvant treatment.
5

Cancers of the Oesophagus: Exploring the Roles of Smoking, Alcohol and Gastro-oesophageal Reflux

Nirmala Pandeya Unknown Date (has links)
ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.
6

Cancers of the Oesophagus: Exploring the Roles of Smoking, Alcohol and Gastro-oesophageal Reflux

Nirmala Pandeya Unknown Date (has links)
ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.
7

Cancers of the Oesophagus: Exploring the Roles of Smoking, Alcohol and Gastro-oesophageal Reflux

Nirmala Pandeya Unknown Date (has links)
ABSTRACT Background Oesophageal cancer has a high mortality; it is the 6th most common cause of death due to cancer worldwide. Of the common subtypes of oesophageal cancer, it is the adenocarcinomas that have been rising rapidly in incidence throughout the western world. The incidence of adenocarcinomas now exceeds the previously common squamous cell carcinoma. These recent changes in the incidence patterns of oesophageal cancer suggests that the environmental risk factors associated with these subtypes differ, and that changes in the prevalence of these exposures over time are the most likely explanation for the observed shifts in the incidence. However, due to its low incidence until a few decades ago, the adenocarcinoma subtype has been less studied compared to squamous cell carcinoma, and the environmental factors associated with this cancer have not been so clearly defined. Smoking and alcohol have been the strongest environmental risk factors reported for oesophageal squamous cell carcinoma (OSCC) whereas for oesophageal adenocarcinoma (OAC), the effect of smoking appears to be weaker, and the evidence for an effect of alcohol is scant and inconsistent. However, epidemiologic studies consistently identify people with frequent symptoms of gastro-oesophageal reflux (GOR) as having the highest risk of OAC, but the effect of GOR on OSCC has been negligible. Furthermore, it has been argued that adenocarcinoma occurring at the gastro-oesophageal junction (GOJAC) may have different aetiology again. Together, these reports suggest the three subtypes of oesophageal cancers (OAC, GOJAC and OSCC) may arise through different mechanisms with different strengths in the impact of risk factors. This thesis investigated the independent associations of smoking, alcohol and gastro-oesophageal reflux on cancers of the oesophagus by considering the possibility of variation in the risks due to differences in the dose effect patterns of various measures such as smoking, alcohol and GOR. Method Data from a population-based case-control study of oesophageal and ovarian cancers in Australia were used. Study participants comprised histologically confirmed cases of OSCC (n=308), OAC (n=367) and GOJAC (n=426) who were frequency matched to 1580 controls from the general population. Exposure history for both cases and controls were derived from health and lifestyle questionnaires. Unconditional multivariate logistic regression was used to calculate the odds ratios and 95% confidence intervals for the risk factors analysed. In addition, generalised additive model with a logit link was also used to explore and present the non-linearity in the dose effect pattern for continuous exposures adjusting for other confounding factors. The effects of two exposures combined on these cancers were assessed by obtaining synergy index. Results Smokers were at significantly higher risk of all three subtypes of oesophageal cancer with the risk greatest for OSCC. The effect of smoking was greater for adenocarcinoma occurring at the gastro-oesophageal junction compared to that of the oesophagus. Of the various measures of smoking, duration was significantly associated with all three subtypes of cancer whereas intensity was associated with only OSCC and GOJAC and the dose effect was non-linear. Time since quitting was associated with a steady decline in risk of all three cancers emphasising the health benefits of quitting among smokers. Alcohol was not associated with OAC or GOJAC but was significantly associated with OSCC among those drinking in excess of 170g/week. The association between alcohol and OSCC was modified by smoking; the association with alcohol was significantly greater among current smokers with effect. Low to moderate wine consumption was associated with significant risk reduction for all three cancers compared to non-drinkers. Increased frequency of GOR symptoms was associated with increased risks of OAC and GOJAC, although the risk of OSCC was constrained to frequent GOR symptoms only. The effect of GOR symptoms were exacerbated by smoking whereas it was weakened by regular NSAID use. Lastly, the sensitivity analysis that assessed the effect of non-participation among controls in the estimated effect of smoking and BMI (the two risk factors most likely to be affected by non-participation) showed a slight overestimation of effect of smoking assuming higher exposure rate among non-participants but not BMI while the effect remained strong and statistically significant. Conclusion Smoking, alcohol and GOR symptoms were the environmental factors strongly associated with all subtypes of oesophageal cancers. However, the dose effect patterns of these exposures varied by cancer subtypes. Smoking and alcohol were the larger contributing factors for OSCC whereas smoking and GOR symptoms had greater impact on OAC and GOJAC. Low to moderate wine consumption and regular NSAID use reduced the risk of all three subtypes significantly. While selection bias may have led to mildly inflated risks for smoking, the effects persisted even when modelled under extreme scenarios of biased participation amongst controls, and there was no evidence that selection bias materially affected the other associations.
8

Molecular genetic analysis of ceruloplasmin in oesophageal cancer

Strickland, Natalie 03 1900 (has links)
Thesis (MSc (Genetics))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: Oesophageal cancer (OC) is characterised by the development of malignant tumours in the epithelial cells lining the oesophagus. It demonstrates marked ethnic variation, with squamous cell carcinoma (SCC) being more prevalent in the Black population and adenocarcinoma (ADC) occurring more often in Caucasians. The aetiology of this complex disease has been attributed to a variety of factors, including an excess of iron (resulting in increased tumourigenesis), oesophageal injury and inflammation. The present study attempted to determine the mutation spectrum of the regulatory and coding regions of the ceruloplasmin (CP) gene, involved in iron metabolism, in the Black South African OC population. The patient cohort was comprised of 96 (48 male and 48 female) unrelated individuals presenting with SCC of the oesophagus. The control group consisted of 88 unrelated, healthy population-matched control individuals. The techniques employed for mutation detection in this study included polymerase chain reaction (PCR) amplification, heteroduplex single-strand conformation polymorphism (HEX-SSCP) analysis, restriction fragment length polymorphism (RFLP) analysis followed by bidirectional semi-automated DNA sequencing analysis to verify the variants identified. Mutation detection of CP resulted in the identification of fourteen previously described (5’UTR-567C→G, 5’UTR-563T→C, 5’UTR-439C→T, 5’UTR-364delT, 5’UTR-354T→C, 5’UTR-350C→T, 5’UTR-282A→G, V223, Y425, R367C, D544E, IVS4-14C→T, IVS7+9T→C and IVS15-12T→C) and four novel (5’UTR-308G→A, T83, V246A and G633) variants. Statistical analysis revealed that two of the novel variants were significantly associated with OC in this study; the promoter variant 5’UTR-308G→A (P=0.012) and the exonic variant G633 (P=0.0003). It is possible that these variants may contribute to OC susceptibility in the Black South African population. OC symptoms generally present late in the development of the disease, and as a result treatment after diagnosis is highly ineffective. Early detection of symptoms and subsequent treatment is therefore the most effective manner of disease intervention. In high incidence areas, such as the Transkei region of South Africa, the implementation of a screening programme would be the ideal way to achieve this goal. The information that can be gathered from the identification of potential modifier genes for OC can lead to improvements in early detection, which in turn may lead to advancements in the treatment and counselling to individuals with OC. To our knowledge, this is the first study concerning CP and its effects on iron dysregulation in the Black South African population with oesophageal cancer. / AFRIKAANSE OPSOMMING: Oesofageale kanker word gekenmerk deur die ontwikkeling van kwaardaardige gewasse in die epiteelweefsel van die oesofageale voering. Hierdie siekte demonstreer opvallende etniese variasie, met plaveisel selkarsinoom meer algemeen in die Swart populasie en adenokarsinoom meer algemeen in die Kaukasiese populasie. Die ontwikkeling van hierdie komplekse siekte word aan ‘n aantal faktore toegeskryf, insluitend ‘n oormaat yster (wat lei tot ‘n vermeerdering van gewasse) en oesofageale besering en -ontsteking. Die doel van die hierdie studie was om die mutasie spektrum van die regulatoriese- en koderingsarea van die ceruloplasmin (CP) geen, betrokke in yster metabolisme, in die Swart Suid Afrikaanse oesofageale kanker populasie te bepaal. Die pasiënt groep het bestaan uit 96 (48 manlik en 48 vroulik) onverwante individue met plaveisel selkarsinoom van die oesofagus. Die kontrole groep het uit 88 nie-geaffekteerde onverwante, populasie spesifieke individue bestaan. Die tegnieke aangewend vir mutasie deteksie in hierdie studie sluit in polimerase kettingsreaksie amplifikasie, heterodupleks enkelstring konformasie polimorfisme analise en restriksie fragment lengte polimorfisme analise, gevolg deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise om die geïdentifiseerde variante te bevestig. Mutasie deteksie van CP het tot die identifikasie van veertien reeds beskryfde (5’UTR-567C→G, 5’UTR-563T→C, 5’UTR-439C→T, 5’UTR-364delT, 5’UTR-354T→C, 5’UTR-350C→T, 5’UTR-282A→G, V223, Y425, R367C, D544E, IVS4-14C→T, IVS7+9T→C en IVS15-12T→C) en vier nuwe (5’UTR-308G→A, T83, V246A en G633) variante gelei. Statistiese analise het getoon dat twee van die nuwe variante betekenisvol geassosieerd was met oesofageale kanker in hierdie studie; die promotor variant 5’UTR-308G→A (P=0.012) en die eksoniese variant G633 (P=0.0003). Dit is moontlik dat hierdie variante mag bydra tot oesofageale kanker vatbaarheid in die Swart Suid Afrikaanse populasie. Oesofageale kanker simptome vertoon gewoonlik op ‘n latere stadium in die ontwikkelingsproses van die siekte, en as ‘n gevolg is behandeling na diagnose hoogs oneffektief. Vroegtydige identifikasie van die simptome en daaropvolgende behandeling is die mees effektiewe manier vir ingryping. In hoë voorkoms streke, soos die Transkei gebied van Suid Afrika, sal die implementasie van ‘n siftingsprogram die ideale manier wees om hierdie doel te bereik. Die inligting wat dan versamel word, insluitend identifisering van modifiserende gene vir oesofageale kanker, kan lei tot ‘n verbetering in vroegtydige deteksie van die siekte. In effek kan dit dan lei tot beter behandeling en berading vir individue met oesofageale kanker. So ver ons kennis strek, is hierdie die eerste studie wat CP en sy effek op yster disregulasie in die Swart Suid-Afrikaanse populasie met oesofageale kanker behels.
9

Characterisation of the promoter region of the SLC40A1 gene implicated in iron metabolism

Vervalle, Jessica 12 1900 (has links)
Thesis (MSc)--Stellenbosch University, 2010. / ENGLISH ABSTRACT: Oesophageal cancer (OC) is a disease characterised by development of malignant tumours in the cell lining of the oesophagus. The disease is divided into two subtypes, which shows marked ethinic variation, with adenocarcinoma (ADC) being more prevalent in Caucasians and squamous cell carcinoma (SCC) more prevalent in the Black population. There are several factors that have been associated with OC development, including oesophageal injury and inflammation, as well as excess iron, which contributes to increased tumour growth. Investigation into OC development is essential due to the rapidly increasing incidence rates and the poor survival rate of this complex disease. The present study aimed to investigate nucleotide variation in the promoter region of SLC40A1, a gene implicated in iron metabolism, in a Black South African OC population. The patient group encompassed 80 (41 males and 39 females) unrelated patients presenting with SCC of the oesophagus. The control group consisted of 71 unrelated, healthy population-matched control individuals. The techniques applied for mutation detection in this study included polymerase chain reaction (PCR) amplification, heteroduplex single stranded conformation polymorphism (HEXSSCP) analysis, restriction fragment length polymorphism (RFLP) analysis and hybridisation probe analysis. Identified variants were confirmed by bi-directional semi-automated DNA sequencing analysis. Statistical analysis was performed to determine associations between identified variants and disease incidence, as well as between identified variants and various iron parameters. Mutation analysis of the promoter region of SLC40A1 resulted in the identification of nine previously described (-1470C/T, -1461T/C, -1399G/A, -1355G/C, -1098G/A, -750G/A, -501T/C, - 23A/G and -8C/G) and three novel, (-1087G/C, -663C/T and -637G/A) variants as well as a previously described trinucleotide repeat. Statistical analyses revealed statistically significant association between -501T/C and OC in this population (P = 0.004). Statistical investigation of the effect of the variants on iron parameters revealed various statistically significant associations. The survival rate of OC remains poor due to absence of early symptoms and therefore late diagnosis of the disease, after which treatment is highly ineffective. Treatment of OC would significantly improve with earlier detection and treatment. This can be achieved by establishing a screening programme in the populations of high risk areas, such as the Transkei area in Southern Africa. Therefore investigation into nucleotide variation of potential modifier genes is of great importance to improved diagnosis, treatment and counselling to individuals presenting with OC. To our knowledge, this is the first study investigating the promoter region of SLC40A1 and possible associations with iron dysregulation in the Black South African population with OC. / AFRIKAANSE OPSOMMING: Oesofageale kanker is ‘n siekte wat gekenmerk word deur die ontwikkeling van kwaadaardige gewasse in the selvoering van die oesofagus. Die siekte word verdeel in twee subtipes wat opvallende etniese variasie toon, met adenokarsinoom wat meer algemeen in die Kaukasiese populasie voorkom en plaveisel selkarsinoom wat meer algemeen in die Swart populasie is. Daar is verskeie faktore wat verbind word met die ontwikkeling van oesofageale kanker, insluitend oesofageale besering en ontsteking, asook ‘n oormaat yster wat bydra tot verhoogde gewasgroei. Ondersoek met betrekking tot die ontwikkeling van oesofageale kanker is noodsaaklik as gevolg van die verhoogde voorkoms-tempo en die swak oorlewingsyfers van hierdie komplekse siekte. Die huidige studie het beoog om die nukleotied variasie in die promoter area van SLC40A1, ‘n geen betrokke in yster metabolisme, in ‘n Swart Suid-Afrikaanse oesofageale kanker populasie te ondersoek. Die pasiënt-groep het bestaan uit 80 (41 mans en 39 vrouens) onverwante pasiënte by wie plaveisel selkarsinoom van die oesofagus voorgekom het. Die kontrole groep het bestaan uit 71 onverwante, gesonde bevolkings-soortgelyke individue. Die tegnieke wat gebruik is vir mutasie opsporing in hierdie studie sluit in: polimerase kettingreaksie amplifikasie, heterodupleks enkelstring konformasie polimorfisme (HEX-SSCP) analise, restriksie fragment lengte polimorfisme (RFLP) analise en hibridisasie peiler analise. Geïdentifiseerde variante is bevestig deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise. Statistiese analise is uitgevoer om moontlike assosiasies tussen geïdentifiseerde variante en siekte voorkoms, sowel as tussen geïdentifiseerde variante en verskeie yster parameters te bepaal. Mutasie analise van die promoter area van SLC40A1 het gelei tot die identifikasie van nege voorheen bekende (-1470C/T, -1461T/C, -1399G/A, -1355G/C, -1098G/A, -750G/A, -501T/C, - 23A/G and -8C/G) en drie nuwe (-1087G/C, -663C/T and -637G/A) variante, sowel as ‘n bekende trinukleotied herhaling. Statistiese analise het getoon dat daar ‘n statistiese betekenisvolle assosiasie tussen -501T/C en oesofageale kanker in hierdie populasie voorkom (P = 0.004). Statistiese ondersoek van die effek van die geïdentifiseerde variante op yster parameters het verskeie statisties betekenisvolle assosiasies getoon. Die oorlewingsyfers van oesofageale kanker bly laag as gevolg van die afwesigheid van vroeë simptome en dus word die siekte eers op ‘n laat stadium gediagnoseer, waarna behandeling hoogs oneffektief is. Behandeling van oesofageale kanker sou betekenisvol verbeter met vroegtydige identifikasie en behandeling. Dit is bereikbaar deur die vestiging van ‘n siftingsprogram vir die populasies van hoë risiko areas, soos die Transkei area in Suidelike Afrika. Ondersoeke na die nukleotied variasie van potensiële modifiserende gene kan daarom van groot belang wees vir verbeterde diagnose, behandeling en berading van individue met oesofageale kanker. Sover as wat ons kennis strek, is hierdie die eerste studie wat die promoter area van die SLC40A1 geen en die moontlike effek op yster disregulasie in ‘n Swart Suid-Afrikaanse populasie met oesofageale kanker ondersoek.
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The performance of circulating biomarkers in the prediction of response to neoadjuvant therapy in patients with oesophago-gastric cancer

Bunting, David Mark January 2016 (has links)
Introduction The prognosis in oesophago-gastric cancer is poor with less than 15% patients surviving beyond 5 years after diagnosis. The addition of neoadjuvant therapy has been shown to increase survival in patients suitable for curative surgery. However, the additional gains are modest and the majority of patients do not respond sufficiently from therapy to gain any benefit. There is an urgent need to identify markers that can predict response to neoadjuvant therapy in order provide safer, more effective, individualised treatment regimes. Methods A prospective, multi-centre, collaborative study was undertaken in patients with oesophago-gastric cancer undergoing neoadjuvant therapy and potentially curative surgery. Levels of circulating biomarkers M2-Pyruvate kinase, alkaline phosphatase, CA19-9, CEA and CA 72-4 were measured in patients before and after administering the first cycle of chemotherapy. Binary logistic regression analysis was performed to assess the ability of biomarkers to predict histological response to therapy. Results 165 patients were recruited to the main study. 105 patients had complete histopathological data for analysis. There were 27 responders and 78 non-responders to neoadjuvant therapy. There were no differences in pre-therapy demographic, pathological or treatment factors between the two groups. Responders had less post-operative lymphovascular invasion (P= 0.004) and higher R0 resection rates (P=0.03). Pre-therapy M2-Pyruvate kinase levels were lower in responders compared to non-responders (P=0.037) and levels were able to predict response with each unit increase in the biomarker level being associated with a 4.1% decrease in the likelihood of response (P=0.027). M2-PK levels were not associated with any pre-operative demographic, clinical or pathological factors. Conclusions Pre-therapy dimeric M2-PK levels can predict response to neoadjuvant therapy in patients with oesophago-gastric cancer. The test could be of clinical value for 1 in every 8 patients undergoing the test.

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