Molecular basis for maize as a risk factor for esophageal cancer in a South African population via a prostaglandin E2 positive feedback mechanism.

The incidence of squamous cancer of the esophagus varies up to a hundredfold in different regions of the world. In Transkei, South Africa, a particularly high incidence of the disease is observed. We have previously proposed an association between a maize-rich diet and elevated levels of intragastric prostaglandin E2 production (PGE(2)). Here we investigate the molecular mechanisms by which a high-maize diet could lead to increased incidence of squamous cancer of the esophagus. We confirm that levels of PGE(2) are high (606.8 pg/ml) in the gastric fluid of individuals from Transkei. We also show that treatment of esophageal cells with linoleic acid, which is found at high levels in maize and is a precursor to PGE(2), leads to increased cell proliferation. Similarly, treatment of cells with PGE(2) or with gastric fluid from Transkeians also leads to increased proliferation. Our data suggest that the high levels of PGE(2) associated with a maize-rich diet stimulate cell division and induce the enzyme COX 2, resulting in a positive feedback mechanism that predisposes the esophagus to carcinoma.

Prospects for clinical application of electronic-nose technology to early detection of Mycobacterium tuberculosis in culture and sputum.

Ziehl-Neelsen (ZN) staining for the diagnosis of tuberculosis (TB) is time-consuming and operator dependent and lacks sensitivity. A new method is urgently needed. We investigated the potential of an electronic nose (EN) (gas sensor array) comprising 14 conducting polymers to detect different Mycobacterium spp. and Pseudomonas aeruginosa in the headspaces of cultures, spiked sputa, and sputum samples from 330 culture-proven and human immunodeficiency virus-tested TB and non-TB patients. The data were analyzed using principal-component analysis, discriminant function analysis, and artificial neural networks. The EN differentiated between different Mycobacterium spp. and between mycobacteria and other lung pathogens both in culture and in spiked sputum samples. The detection limit in culture and spiked sputa was found to be 1 x 10(4) mycobacteria ml(-1). After training of the neural network with 196 sputum samples, 134 samples (55 M. tuberculosis culture-positive samples and 79 culture-negative samples) were used to challenge the model. The EN correctly predicted 89% of culture-positive patients; the six false negatives were the four ZN-negative and two ZN-positive patients. The specificity and sensitivity of the described method were 91% and 89%, respectively, compared to culture. At present, the reasons for the false negatives and false positives are unknown, but they could well be due to the nonoptimized system used here. This study has shown the ability of an electronic nose to detect M. tuberculosis in clinical specimens and opens the way to making this method a rapid and automated system for the early diagnosis of respiratory infections.

Long remissions in hairy cell leukemia with purine analogs: a report of 219 patients with a median follow-up of 12.5 years.

BACKGROUND: Both pentostatin and cladribine have efficacy in hairy cell leukemia (HCL), but it is not known which agent achieves better results. METHODS: We reviewed a series of 219 patients with HCL, with median follow-up from diagnosis of 12.5 years (range 1.0 -34.6 yrs), treated with either pentostatin (n = 185) or cladribine (n = 34), to compare these agents and assess the potential for cure. RESULTS: Overall response to pentostatin was 96% with a complete response (CR) in 81% and a median disease-free survival (DFS) of 15 years. Response to first-line cladribine was 100% with a CR in 82% and DFS of 11+ years. The relapse rates at 5 years and 10 years were 24% and 42%, respectively, with pentostatin, and 33% and 48% with cladribine. Survival at 10 years was respectively 96% and 100%. CR rates decreased with each sequential relapse through 69% to 45% (P < or = 0.001). Patients achieving CR after first-line treatment had a significantly longer DFS (P = 0.00007) than those achieving a partial response; a similar result was seen after second-line therapy (P = 0.00001). DFS also declined with sequential treatment (P = 0.00005). CONCLUSION: We have shown equivalent efficacies for both agents in the treatment of HCL, with DFS showing no plateau. True cure in HCL remains elusive, but the addition of monoclonal antibodies may be beneficial. Our results suggest that achieving CR should remain the main goal of treatment.

On the histogenesis of Barrett's oesophagus and its associated squamous islands: a three-dimensional study of their morphological relationship with native oesophageal gland ducts.

Current hypotheses concerning the histogenesis and regression of Barrett's oesophagus are based predominantly on animal models. Our study was formulated to assess, in human tissue, the morphological relationship between oesophageal gland ducts and both Barrett's oesophagus and their associated squamous islands. Serial sections were cut through a total of 46 blocks of archived oesophageal resection tissue containing oesophageal gland ducts underlying Barrett's epithelium. Serial sections were also taken through 15 squamous islands, taken from the same archived tissue, to assess their underlying histology: 21 of the ducts opened onto overlying Barrett's epithelium; in 17 there was a relatively sharp distinction between the two cell types, at the junction, whereas in four there was continuity and a gradual morphological change between the cells of the oesophageal gland ducts and the Barrett's epithelium. All 15 squamous islands sectioned were found to be continuous with an underlying gland duct. This study suggests an interrelationship between Barrett's epithelium and oesophageal gland ducts. More definitively we confirm that squamous islands are universally associated with oesophageal gland duct epithelium. These findings are of fundamental importance for the development of more targeted management strategies for Barrett's oesophagus.

Monitoring haemodialysis using electronic nose and chemometrics.

An ever-increasing number of patients have to undergo regular renal dialysis to compensate for acute or chronic renal failure. The adequacy of the treatment has a profound effect on patients' morbidity and mortality. Therefore, it is necessary to assess the delivered dialysis dose. For the quantification of the dialysis dose, two parameters are most commonly used, namely the K(t)/V value (normalised dose of dialysis) and the urea reduction rate, yet the prescribed dialysis dose often differs from the actual delivered dialysis dose. Currently, no interactive process is available to ensure optimal treatment. The aim of this study was to investigate the potential for an "electronic nose" as a novel monitoring tool for haemodialysis. Blood samples were analysed using an electronic nose, comprising an array of 14 conducting polymer sensors, and compared to traditional biochemistry. Principal component analysis and hierarchical cluster analysis were applied to evaluate the data, and demonstrated the ability to distinguish between pre-dialysis blood from post-dialysis blood independent of the method used. It is concluded that the electronic nose is capable of discriminating pre-dialysis from post-dialysis blood and hence, together with an appropriate classification model, suitable for on-line monitoring.

Contrasting expression of thrombospondin-1 and osteopontin correlates with absence or presence of metastatic phenotype in an isogenic model of spontaneous human breast cancer metastasis.

Knowledge of the molecular mechanisms involved in metastatic spread is needed to facilitate advances in prognostic evaluation for individual patients and in the design of therapeutic interventions to inhibit the process. In an effort to establish a methodological framework for analysis of molecules and mechanisms involved in this complex multistep process, we have developed a well defined experimental system, in which the role of candidate genes can be screened and tested. By serial dilution cloning of the MDA-MB-435 breast tumor cell line and screening by orthotopic implantation into the mammary fat pad of athymic mice, we have derived a pair of breast tumor cell lines (M-4A4 and NM-2C5) that originate from the same breast tumor but have diametrically opposite metastatic capabilities. In 74% of inoculated athymic mice, clone M-4A4 metastasized consistently to the lungs, mimicking a major dissemination route of human breast cancer. Conversely, although equally tumorigenic, clone NM-2C5 did not metastasize to any distal site. We have confirmed that the cell lines originate from a single genetic source by spectral karyotyping and evaluated the expression of a number of proteins previously implicated in cellular transformation and metastasis. The ability of M-4A4 to metastasize was not associated with increased angiogenesis, as measured by immunohistochemical microvessel density analysis. However, RNA and protein analyses revealed that two secreted proteins were differentially expressed: osteopontin expression was increased approximately 30-fold in clone M-4A4 and thrombospondin-1 expression was increased approximately 15-fold in clone NM-2C5. These cell lines constitute a stable and accessible model for the identification of genes involved in the multistep process of breast tumor metastasis. Manipulation of candidate genes in these cells will permit evaluation of their functional significance in the geometric progression of breast cancer.