Browsing by Author "Hall, Pauline"

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    The fumonisin B₁-fed rat as a model for liver injury, oval ('progenitor') cell proliferation, and carcinogenesis
    (1999) Lemmer, Eric Richard; Hall, Pauline; Shephard, Enid; Cruse, Peter
    Fumonisin B₁ (FB₁‚ ) is a carcinogenic mycotoxin produced by the fimgus Fusarium moniliforme in maize, and is hepatotoxic and hepatocarcinogenic in rats. The goal of this dissertation was to characterise the FB₁-fed rat as a model for liver injury and carcinogenesis, and to examine the role of oval ('progenitor') cells during these processes. Male Fischer 344 rats were fed FB₁ 250 mg/kg diet for five weeks, and this basic feeding regimen was modified in individual experiments. Short-term feeding of FB₁ caused a severe 'toxic' hepatitis, apoptosis and regeneration of hepatocytes, fibrosis, proliferation of OV-6 positive oval cells, and formation of GST pi positive hepatic foci and nodules. Oval cells were noted inside some of the hepatic nodules. There were marked increases in the expression of mRNA transcripts for mature TGF-β1 and c-myc in livers of FB₁-fed animals. The overexpression of TGF-β1 by hepatocytes may be responsible for the prominent apoptosis and fibrosis seen with liver injury due to FB₁. Increased expression of c-myc and TGF-β1 may cooperate during FB₁-induced promotion of liver tumours, possibly by providing an environment that selects for the growth of TGFβ1-resistant transformed liver cells. In rats given FB₁ in the presence of dietary iron overload, FB₁ augmented iron-induced lipid peroxidation in the liver. However, dietary iron loading appeared to protect against the cancer-promoting properties of FB₁, possibly due to a stimulatory effect on hepatocyte regeneration. Long-term feeding of FB₁ caused fibrosis and regenerative nodules, dysplastic hepatic nodules, cholangiofibrotic lesions, intraductal cholangiocarcinomas, and a hepatocellular carcinoma. 2-Acetylaminofluorene enhanced the effects of FB₁ in the liver, presumably by blocking hepatocyte regeneration in response to FB₁ toxicity. Proliferating oval cells were found inside/adjacent to GST pi positive lesions, dysplastic nodules, and cholangiofibrotic lesions, suggesting that oval cells may be involved in FBI-induced hepato- and cholangiocarcinogenesis in the liver. Furthermore, the OV-6 antigen was expressed by proliferating oval cells and bile ductules, hepatic nodules, cholangiofibrotic lesions, and cystic lesions, indicating that all of these cells may have a common ('stem') cell of origin. In conclusion, the FB₁-fed rat is a promising model for the study of liver injury, oval ('progenitor') cell proliferation, and carcinogenesis.
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    Oesophageal squamous cell carcinogenesis : a study of cell cycle regulatory proteins by immunohistochemistry
    (2004) Soldin, Ryan Peter; Hall, Pauline
    Oesophageal squamous cell carcinoma (OSCC) is a highly malignant tumour that has a poor prognosis and shows marked regional variation in its incidence, implicating environmental factors. South Africa is one of several countries that has areas of high incidence. The exact aetiopathogenesis of OSCC is not well understood. Current environmental risk factors include alcohol, tobacco, human papillomavirus (HPV) infection and nutritional factors including; low intake of Vitamins A, C and riboflavin, lack of fruit and vegetables, ingestion of fungal contaminated foods and consumption of extremely hot beverages. This study was a retrospective immunohistochemical study done on paraffin embedded tissues. The histopathology, grading and staging of all resected squamous cell carcinomas over a twenty one year period from 1982 to 2002, were reviewed. Sixty eight patients were identified; all had an oesophagectomy for OSCC at Groote Schuur Hospital, a tertiary referral centre. Clinical details regarding gender, race, age, smoking or alcohol usage and survival data were collected. Survival data was updated to 23 June 2003. Two paraffin blocks representing OSCC and normal mucosa for each patient were retrieved from the archives in the Division of Anatomical Pathology. In addition, 16 cases of reflux oesophagitis were included for comparison. Initial immunohistochemical staining for HPV (Dako- clone KlH8) was undertaken but the negative results necessitated a shift in the focus of this study to that of cell cycle regulatory proteins. The tissues were evaluated for p53 (Dako - clone D0-7), p2l (Novocastro - clone 4Dl0), cyclin DI (Dako - clone DCS-6) and cyclin E (Novocastro - clone 13A3). Expression was interpreted as positive if 10% or more of the tumour cell population stained. Expression was also stratified into three levels (1, 2 and 3) depending on the percentage positive staining. Normal mucosa did not stain for any of the cell cycle regulators. OSCC stained as follows: 61.8% for p53, 27.9% for p21, 22.1 % for cyclin E and 44.1% for cyclin Dl. Reflux oesophagitis stained as follows: 31.2% for cyclin DI, 12.5% for p21 and 0% for both p53 and cyclin E. Subsequent statistical analysis failed to reveal any prognostic significance to the expression of cell cycle regulators, nor could expression or level of expression be associated with stage, grade, age, gender or alcohol use. There was however a significant relationship between cyclin DI and smoking. In addition, expression of p53 discriminated between malignant and reactive oesophageal lesions. Advancing age proved to be associated with an increased risk of mortality. Lastly, histopathological staging proved to be the most significant prognostic factor in this study.
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    A Study to investigate the role of p27 and Cyclin E immunoexpression as a prognostic factor in early breast carcinoma
    (BioMed Central Ltd, 2011) Pillay, Komala; McCleod, Heather; Chetty, Runjan; Hall, Pauline
    BACKGROUND: Cyclin E and p27 expression is easy to assess in human tissues by standard immunohistochemical techniques. Immunohistochemistry is cost effective, relatively easy to perform and will play more of a role in the future management of cancer. The aim of this study was to investigate the role of p27 and cyclin E immunoexpression as a prognostic factor in early breast carcinoma. METHODS: Cyclin E and p27 immunohistochemistry was performed on sixty six cases of breast carcinoma submitted over a five year period to the Division of Anatomical Pathology, Groote Schuur hospital; Whittaker and Associates; and PathCare. All tumours included in this study were less than 5 cm in diameter (pT1 and pT2 stage) and all the patients had wide local excisions performed. Follow up information was obtained from patient folders in the Department of Radiation Oncology. RESULTS: There was no significant association of cyclin E and p27 expression with distant metastasis free survival (MFS) for all invasive carcinomas in contrast to grade, lymph node spread and vascular invasion. However, there was a statistically significant direct association of cyclin E with distant metastases in all invasive carcinomas, in the subgroup of infiltrating duct carcinomas (IDC) and in the node negative group when cyclin E was stratified as negative and positive (low/high). In this study of early breast carcinoma, only 9/66 cases showed cyclin E expression. Of these, four patients had distant metastases, one patient had a local recurrence and four patients were alive at last follow-up. Furthermore, cyclin E expression was significantly associated with grade, lymph node spread, oestrogen receptor status and histological type. None of the lobular carcinomas showed cyclin E positivity and only one case of lobular carcinoma presented with distant metastases.59/66 cases were positive (low/high) for p27 while seven cases were negative, 22 cases showed low expression and 37 cases demonstrated high p27 expression.p27 was significantly associated with oestrogen receptor status only for all invasive carcinomas and in the IDC group. There was no statistical relationship between p27 and cyclin E, but 50 (76%) tumours with positive p27 expression were negative for cyclin E. There were similar results for the invasive ductal carcinoma subgroup. CONCLUSION: This study shows that p27 and cyclin E are not good independent prognostic markers for early breast carcinoma in contrast to grade, lymph node spread and vascular invasion for all invasive carcinomas. However, cyclin E provides some prognostic value as there is a direct statistical association with the development of distant metastases. Many previous studies have correlated overexpression of cyclin E with an aggressive course. The inverse relationship between p27 and cyclin E expression which has been reported in the literature has been highlighted, but this was not statistically significant. Most cases showed positive p27 expression and negative Cyclin E expression. This may be due to the early stage of the disease.