Randomized clinical trial comparing self-expanding metallic stents with plastic endoprostheses in the palliation of oesophageal cancer.

BACKGROUND: There is little evidence of the clinical and cost effectiveness of self-expanding metallic stents in the palliation of oesophageal cancer. The aims of this randomized trial were to evaluate the immediate and medium-term clinical outcomes following palliative intubation, examine patient quality of life, and evaluate costs and benefits from the perspective of the health service. METHODS: Fifty patients with inoperable oesophageal cancer were randomly allocated a metallic stent (n = 25) or plastic endoprosthesis (n = 25). Patients were followed up monthly until death. RESULTS: There was no significant difference in procedure-related complications or mortality rate between the two groups. There was a trend towards significance in favour of metallic stents with respect to quality of life and survival (median survival 62 versus 107 days for plastic prosthesis and metallic stent respectively). The cost of the initial placement of metallic stents was significantly higher than that of plastic endoprostheses ( pound 983 versus pound 296). After 4 weeks, cost differences were no longer significant. CONCLUSION: Metallic stents may contribute to improved survival and quality of life in patients with oesophageal cancer. Although initially more expensive, this cost difference does not last beyond 4 weeks. A larger trial involving approximately 300 patients would be required to detect a quality of life benefit of the magnitude observed in this trial.

Protein N-glycosylation: molecular genetics and functional significance.

Protein N-glycosylation is a metabolic process that has been highly conserved in evolution. In all eukaryotes, N-glycosylation is obligatory for viability. It functions by modifying appropriate asparagine residues of proteins with oligosaccharide structures, thus influencing their properties and bioactivities. N-glycoprotein biosynthesis involves a multitude of enzymes, glycosyltransferases, and glycosidases, encoded by distinct genes. The majority of these enzymes are transmembrane proteins that function in the endoplasmic reticulum and Golgi apparatus in an ordered and well-orchestrated manner. The complexity of N-glycosylation is augmented by the fact that different asparagine residues within the same polypeptide may be modified with different oligosaccharide structures, and various proteins are distinguished from one another by the characteristics of their carbohydrate moieties. Furthermore, biological consequences of derivatization of proteins with N-glycans range from subtle to significant. In the past, all these features of N-glycosylation have posed a formidable challenge to an elucidation of the physiological role for this modification. Recent advances in molecular genetics, combined with the availability of diverse in vivo experimental systems ranging from yeast to transgenic mice, have expedited the identification, isolation, and characterization of N-glycosylation genes. As a result, rather unexpected information regarding relationships between N-glycosylation and other cellular functions--including secretion, cytoskeletal organization, proliferation, and apoptosis--has emerged. Concurrently, increased understanding of molecular details of N-glycosylation has facilitated the alignment between N-glycosylation deficiencies and human diseases, and has highlighted the possibility of using N-glycan expression on cells as potential determinants of disease and its progression. Recent studies suggest correlations between N-glycosylation capacities of cells and drug sensitivities, as well as susceptibility to infection. Therefore, knowledge of the regulatory features of N-glycosylation may prove useful in the design of novel therapeutics. While facing the demanding task of defining properties, functions, and regulation of the numerous, as yet uncharacterized, N-glycosylation genes, glycobiologists of the 21st century offer exciting possibilities for new approaches to disease diagnosis, prevention, and cure.

Molecular dissection of the genetic targets of ALG7 in the serpentine receptor-mediated signal transduction pathway in yeast.

These initial studies show that deregulated expression of ALG7 affects diverse cellular functions crucial to development, including proliferation, differentiation, and morphogenesis. Furthermore, the data suggest multiple genetic targets for ALG7 and provide the basis for future dissection of these developmentally relevant pathways.

Deregulation of the first N-glycosylation gene, ALG7, perturbs the expression of G1 cyclins and cell cycle arrest in Saccharomyces cerevisiae.

The evolutionarily conserved ALG7 gene encodes the dolichol-P-dependent N-acetylglucosamine-1-P transferase (GPT) and functions by initiating the dolichol pathway of protein N-glycosylation. In Saccharomyces cerevisiae, ALG7 has been shown to play a role in cell proliferation. The yeast alpha-factor-induced cell cycle arrest in G1 occurs, in part, by downregulation of CLN1 and CLN2. The function of ALG7 in G1 arrest was examined in alg7 mutants containing diminished GPT activity. In wild type, CLN1 and CLN2 mRNAs were rapidly downregulated, while in alg7 mutants, these transcripts were only transiently repressed before becoming greatly augmented. Analyses of DNA contents and budding indices showed that alg7 mutants resumed cycling when wild type cells remained arrested. Thus, deregulation of ALG7 interferes with cell cycle arrest by preventing a sustained downregulation of CLN1 and CLN2 mRNAs. These results provide a molecular insight into the role of ALG7, and protein N-glycosylation in general, in proliferation.