Biplots of compositional data

The singular value decomposition and its interpretation as a linear biplot has proved to be a powerful tool for analysing many forms of multivariate data. Here we adapt biplot methodology to the speciffic case of compositional data consisting of positive vectors each of which is constrained to have unit sum. These relative variation biplots have properties relating to special features of compositional data: the study of ratios, subcompositions and models of compositional relationships. The methodology is demonstrated on a data set consisting of six-part colour compositions in 22 abstract paintings, showing how the singular value decomposition can achieve an accurate biplot of the colour ratios and how possible models interrelating the colours can be diagnosed.Logratio transformation, principal component analysis, relative variation biplot, singular value decomposition, subcomposition

Intestinal Metaplasia and Gastric Carcinoma

Previous studies have suggested that gastric carcinogenesis is a multistage process involving first gastritis, then intestinal metaplasia, dysplasia of increasing severity and finally carcinoma. The exact role of intestinal metaplasia in the histogenesis of gastric carcinoma has been the subject of much debate. Recent work has identified an intestinal metaplasia variant (Type IIb) which appears to be significantly associated with a particular histological type of gastric carcinoma. The aim of the studies carried out in the preparation of this thesis was to investigate the histogenesis of gastric carcinoma with particular reference to the role of intestinal metaplasia in this process. The material studied was a series of gastrectomy specimens resected for both benign and malignant disease. In addition fetal stomachs, endoscopic biopsy material from a group of patients who had undergone gastric surgery for peptic ulcer disease, and an animal experimental model of gastric carcinogensis were studied to examine specific aspects of the carcinogenetic sequence. The methods utilised in the studies involved histological assessment, mucin and immunocytochemical techniques and cell kinetic analysis. The results of the histological investigation indicate that the presence and amount of intestinal metaplasia in the gastrectomy material is related to variables such as age and inflammatory change rather than the presence of a tumour. The results also demonstrate that the presence of the type lIb variant is related to age, inflammation and ulceration within the gastrectomy rather than the presence of any particular tumour sub-type. The results of the mucin and immunocytochemical studies identified a series of phenotypic changes in the stages of gastric carcinogenesis which did not lend support to the role of intestinal metaplasia in the histogenesis of gastric carcinoma. The cell kinetic study documented the changes in cellular proliferation that occur in the stages of gastric carcinogenesis. A series of cell kinetic abnormalities in the gastric mucosa of patients who had undergone gastric surgery for benign disease were identified. These abnormalities were shown to be related to alkaline reflux gastritis. It is suggested that intestinal metaplasia and its variants do not represent a premalignant stage in the histogenesis of gastric carcinoma

Metallochaperones regulate intracellular copper levels.

Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Negative Autoregulation by FAS Mediates Robust Fetal Erythropoiesis

Tissue development is regulated by signaling networks that control developmental rate and determine ultimate tissue mass. Here we present a novel computational algorithm used to identify regulatory feedback and feedforward interactions between progenitors in developing erythroid tissue. The algorithm makes use of dynamic measurements of red cell progenitors between embryonic days 12 and 15 in the mouse. It selects for intercellular interactions that reproduce the erythroid developmental process and endow it with robustness to external perturbations. This analysis predicts that negative autoregulatory interactions arise between early erythroblasts of similar maturation stage. By studying embryos mutant for the death receptor FAS, or for its ligand, FASL, and by measuring the rate of FAS-mediated apoptosis in vivo, we show that FAS and FASL are pivotal negative regulators of fetal erythropoiesis, in the manner predicted by the computational model. We suggest that apoptosis in erythroid development mediates robust homeostasis regulating the number of red blood cells reaching maturity

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997–2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival

LED excitation of an on-chip imaging flow cytometer for bead-based immunoassay

A green LED is demonstrated to generate a uniform square illumination pattern for an on-chip imaging flow cytometer system. The proposed system is used to perform the detection of a bead-based immunoassay for a sepsis biomarker, procalcitonin

Assessing the validity and acceptability of DietPhone as a dietary measurement tool in adolescent girls

sch_die69pub1707pubOCE