No description available.

No description available.

No description available.

No description available.

This work is focussed on the analysis of breast tumour physiology by pharmacokinetic modelling of dynamic contrast enhanced MRI (DCE-MRI) data. DCEMRI consists of the intravenous bolus injection of a small molecular weight contrast agent into the patient followed by the rapid acquisition of MR images across both breasts. Due to the leaky nature of the lesion microvasculature there is a greater uptake of contrast agent within the tumour than in the surrounding tissues. The dynamic contrast enhanced MR signal curve can be fitted by compartmental analysis providing information linked to the tumour’s permeability and flow. The effect of the DCE-MRI acquisition parameters on the accuracy of the estimated pharmacokinetic quantities was investigated together with the assumptions lying behind the pharmacokinetic model used for the fitting. Contrast enhanced MRI data were also examined using a fractal measure of tumour heterogeneity with the aim of assessing whether this could be a potential predictor of the tumour response to chemotherapy. Among the factors believed to play an important role in terms of tumour treatment is an increased interstitial fluid pressure (IFP) in the central areas of some large tumours. Here DCE-MRI data were analyzed in a way to see whether it could provide any information related to IFP distribution across tumour volumes. Finally, when performing quantitative DCE-MRI, particular care needs to be taken in the choice of an arterial input function (AIF) which accurately describes the passage of the contrast agent bolus at the lesion location. Here a new approach was proposed and demonstrated for the estimation of a tumour capillary input function together with lesion pharmacokinetic parameters. This was achieved by optimizing the capillary input function with a measure of the patient’s cardiac output, a parameter which is expected to vary depending on the patient’s pathology/physiology.

Submitted in partial fulfillment of the requirements for the degree of Doctor of Technology: Clinical Technology, Durban Institute of Technology, 2005. / Fumonisin B1 (FB1) and ochratoxin A (OTA) represent examples of mycotoxins of greatest public health and agro-economic significance. They exert adverse effects on humans, animals and crops that result in illnesses and economic losses. Fumonisin B1 are cancerpromoting metabolites of Fusarium proliferatum and F verticillioides, (formerly moniliforme), and are implicated in oesophageal cancer. Ochratoxins are metabolites of both Aspergillus and Penicillium species. These compounds are known for their nephrotoxic effects in all animal species and may promote tumours in humans. In man OTA exhibits unusual toxicokinetics, with a half-life in blood of 840 h (35 days) after oral ingestion. Although much is known regarding the toxicology of these toxins, little is known of the effects of these toxins on the immune system. The aim of this study was to determine and compare the immunornodulating effects of FB1 and OTA in human carcinoma. Initial experiments involved isolating lymphocytes and neutrophils from healthy volunteers. The isolated cells were exposed to either FB1 or OTA on a dose and time dependent level and LD50 of the toxins was determined. Thereafter, challenge tests were performed, whereby lymphocytes and neutrophils isolated from volunteers, oesophageal cancer patients and breast cancer patients were exposed to the LD50 dose of either FB1 or OTA for the appropriate time. The effect of the toxins was demonstrated by viability studies, light microscopy and electron microscopy. Cytokine receptors (CK, TNF and CSF) were evaluated by immuno-cytochemical methods and the levels of circulating cytokines (IL -1, IL-6, IL-8, IL-10 and TNF-a) were determined using ELISA kits. / D

University of Macau / Institute of Chinese Medical Sciences

University of Macau / Institute of Chinese Medical Sciences

Genomic instability and aneuploidy, which are ubiquitous hallmarks of cancer cells, encompass both structural and numerical chromosome aberrations. Strikingly, cancer cells often display recurrent patterns of aneuploidy which are thought to be contingent on selection pressures within the tumour microenvironment maintaining advantageous karyotypes. However, it is currently unknown if individual chromosomes are intrinsically vulnerable to missegregation, and therefore whether chromosome bias may also contribute to pathological aneuploidy patterns. Moreover, the earliest responses to chromosome missegregation in non-transformed cells, and how these are overcome in cancer, has remained elusive due to the difficult nature of isolating nascent aneuploid cells. Results. Individual chromosomes displayed recurrent patterns of biased missegregation in response to a variety of cellular stresses across cell lines. Likewise, a small subset of chromosomes accounted for a large fraction of segregation errors following one specific mechanism driving aneuploidy. This was supported by the discovery that chromosomes 1 and 2 are strikingly susceptible to the premature loss of sister chromatid cohesion during prolonged prometaphase arrest. Additionally, I have elucidated the arrangement of individual metaphase human chromosomes, highlighting missegregation vulnerabilities occurring at the metaphase plate periphery following nocodazole wash-out. Finally, I have developed a novel system for isolating nascent aneuploid cells, suggesting the earliest transcriptome responses to chromosome missegregation in non-transformed human cells involve ATM and BCL2-mediated apoptosis.

Tam Wai-Kwan Karen. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 109-128). / Abstracts in English and Chinese. / Thesis committee --- p.i / Statement --- p.ii / Abstract --- p.iii / Acknowledgements --- p.vi / Abbreviations --- p.vii / Table of Contents --- p.ix / List of Tables --- p.xii / List of Figures --- p.xiv / Chapter 1. --- Introduction --- p.1 / Chapter 2. --- Literature Review --- p.2 / Chapter 2.1 --- Introduction of Cordyceps --- p.2 / Chapter 2.2 --- Pharmacological functions of Cordyceps --- p.3 / Chapter 2.2.1 --- Functions in respiratory system --- p.3 / Chapter 2.2.2 --- Functions in renal system --- p.7 / Chapter 2.2.3 --- Functions in hepatic system --- p.8 / Chapter 2.2.4 --- Functions in cardiovascular system --- p.9 / Chapter 2.2.5 --- Functions in endocrine and steroid system --- p.10 / Chapter 2.2.6 --- Functions in the immune system --- p.11 / Chapter 2.2.7 --- Functions in nervous system --- p.15 / Chapter 2.2.8 --- Controls in glucose metabolism --- p.15 / Chapter 2.2.9 --- Anti-oxidation activity --- p.16 / Chapter 2.2.10 --- Anti-tumor activity --- p.18 / Chapter 2.3 --- Active ingredients of Cordyceps and their related biological activities --- p.20 / Chapter 2.3.1 --- Polysaccharides --- p.20 / Chapter 2.3.2 --- Nucleosides --- p.21 / Chapter 2.3.2.1 --- Adenosine --- p.21 / Chapter 2.3.2.2 --- Cordycepin --- p.24 / Chapter 2.4 --- Proteomic tools in studies of the change in protein expression --- p.25 / Chapter 2.4.1 --- Two-dimensional electrophoresis --- p.27 / Chapter 2.4.2 --- Mass Spectrometry --- p.28 / Chapter 3. --- Methods and Materials --- p.30 / Chapter 3.1 --- Cell lines and culture conditions --- p.30 / Chapter 3.2 --- Trypan blue exclusion method --- p.30 / Chapter 3.3 --- Cell counting --- p.31 / Chapter 3.4 --- Anti-proliferation assay --- p.31 / Chapter 3.5 --- Anti-proliferation assay of normal cell line --- p.32 / Chapter 3.6 --- Determination of ic50 --- p.33 / Chapter 3.7 --- Sample preparation for proteins studies --- p.33 / Chapter 3.8 --- Protein quantitation --- p.34 / Chapter 3.9 --- Gel electrophoresis --- p.36 / Chapter 3.10 --- Image analysis --- p.37 / Chapter 3.11 --- In-gel digestion and MALDI-ToF MS --- p.37 / Chapter 3.12 --- Statistical Analysis --- p.39 / Chapter 3.13 --- Chemicals --- p.39 / Chapter 4. --- Results --- p.41 / Chapter 4.1 --- MTT assay --- p.41 / Chapter 4.1.1 --- The anti-proliferating activity of adenosine against cancer cell lines (HepG2 and SV7tert) and normal cell line (Hs68) --- p.41 / Chapter 4.1.2 --- The anti-proliferating activity of cordycepin against cancer cell lines (HepG2 and SV7tert) and normal cell line (Hs68) --- p.42 / Chapter 4.1.3 --- The anti-proliferation effects of adenosine and cordycepin --- p.42 / Chapter 4.2 --- Changes in protein expression --- p.50 / Chapter 4.2.1 --- "Corresponding drug treatment of cell lines (HepG2, SV7tert and Hs68)" --- p.50 / Chapter 4.2.2 --- "Comparison of protein profiles from cells (HepG2, SV7tert or Hs68) under the normal and drug treated (with either adenosine or cordycepin) conditions" --- p.51 / Chapter 4.2.2.1 --- HepG2 study --- p.51 / Chapter 4.2.2.2 --- SV7tert study --- p.52 / Chapter 4.2.2.3 --- Hs68 study --- p.52 / Chapter 4.2.3 --- Protein identification --- p.53 / Chapter 4.2.3.1 --- HepG2 cell line --- p.53 / Chapter 4.2.3.2 --- HepG2-changes in protein expressions after adenosine treatment --- p.54 / Chapter 4.2.3.3 --- HepG2-changes in protein expressions after cordycepin treatment --- p.54 / Chapter 4.2.3.4 --- SV7tert cell line --- p.54 / Chapter 4.2.3.5 --- SV7tert-changes in protein expressions after cordycepin treatment --- p.55 / Chapter 4.2.3.6 --- Hs68 cell line --- p.55 / Chapter 4.2.3.7 --- Hs68-changes in protein expressions after cordycepin treatment --- p.56 / Chapter 5. --- Discussion --- p.89 / Chapter 5.1 --- anti-proliferation assays --- p.89 / Chapter 5.2 --- changes in protein expression: --- p.90 / Chapter 5.2.1 --- Protein alterations in HepG2 --- p.91 / Chapter 5.2.1.1 --- Changes in protein expression (membrane protein and transport: Trimethyllysine hydroxylase) --- p.91 / Chapter 5.2.1.2 --- Changes in protein expression (protein synthesis and folding: carboxypeptidase E) --- p.92 / Chapter 5.2.1.3 --- Changes in protein expression (membrane proteins and transport: calumenin and electron transfer flavoproteins) --- p.93 / Chapter 5.2.2 --- Protein alterations in SV7tert --- p.94 / Chapter 5.2.2.1 --- Changes in protein expression (protein synthesis and folding: BiP(GRP78)) --- p.94 / Chapter 5.2.2.2 --- Changes in protein expression (cell defense and tolerance: Hsp60 (chaperonin); TANK binding kinase-1) --- p.96 / Chapter 5.2.2.3 --- Changes in protein expression (metabolism: prolyl 4-hydroxylase; aldolase A; glyceraldehyde-3-phosphate dehydrogenase) --- p.97 / Chapter 5.2.2.4 --- Changes in protein expression (cell growth and division: βII tubulin; HnRNP Al) --- p.100 / Chapter 5.2.3 --- Protein alterations in Hs68 --- p.101 / Chapter 5.2.3.1 --- Changes in protein expression (metabolism: triosephosphate isomerse 1) --- p.101 / Chapter 6. --- Discussion --- p.103 / Chapter 6.1 --- The antiproliferating activities of adenosine and cordycepin --- p.103 / Chapter 6.2 --- "Effects of adenosine and cordycepin on the changes in protein expressions in HepG2, SV7tert and Hs68" --- p.104 / Chapter 6.3 --- Problems and improvements in two-dimensional gel electrophoresis --- p.105 / Chapter 7. --- Conclusion and future prospectives --- p.107 / References --- p.109