Extracellular matrix proteins and tumor angiogenesis.

Tumor development is a complex process that relies on interaction and communication between a number of cellular compartments. Much of the mass of a solid tumor is comprised of the stroma which is richly invested with extracellular matrix. Within this matrix are a host of matricellular proteins that regulate the expression and function of a myriad of proteins that regulate tumorigenic processes. One of the processes that is vital to tumor growth and progression is angiogenesis, or the formation of new blood vessels from preexisting vasculature. Within the extracellular matrix are structural proteins, a host of proteases, and resident pro- and antiangiogenic factors that control tumor angiogenesis in a tightly regulated fashion. This paper discusses the role that the extracellular matrix and ECM proteins play in the regulation of tumor angiogenesis.

The role of dysregulated glucose metabolism in epithelial ovarian cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic cancer and also one of the most poorly understood. Other health issues that are affecting women with increasing frequency are obesity and diabetes, which are associated with dysglycemia and increased blood glucose. The Warburg Effect describes the ability of fast-growing cancer cells to preferentially metabolize glucose via anaerobic glycolysis rather than oxidative phosphorylation. Recent epidemiological studies have suggested a role for hyperglycemia in the pathogenesis of a number of cancers. If hyperglycemia contributes to tumour growth and progression, then it is intuitive that antihyperglycemic drugs may also have an important antitumour role. Preliminary reports suggest that these drugs not only reduce available plasma glucose, but also have direct effects on cancer cell viability through modification of molecular energy-sensing pathways. This review investigates the effect that hyperglycemia may have on EOC and the potential of antihyperglycemic drugs as therapeutic adjuncts.

Characterization of novel inhibitors of cyclin-dependent kinases.

In epithelial cells progression through the G1 phase of the cell cycle and preparing the cell for the S phase is regulated by cyclin D1-cdk4. Cells that express the retinoblastoma protein (pRb) are dependent on cyclin D1-cdk4 activity for their proliferation while cells that do not express pRb are not. Overexpression of cyclin D1 and/or cdk4, and loss of expression of p16 (the natural inhibitor of cyclin D1-cdk4 activity), have been implicated in several cancers. These data suggest that the aberrant activity of cyclin D1-cdk4 correlates with the tumor phenotype. Hence, blocking cyclin D1-cdk4 activity may prove to be an effective anticancer therapy for pRb(+) tumors. In this paper, we report the identification of four novel compounds that selectively inhibit cyclin D1-cdk4 activity to various degrees. We further demonstrate that two of these compounds also selectively inhibit the target, pRb(+) tumor cells. The implications of these discoveries and their utility as anticancer agents are discussed.

Amperometric responses to acetylene, ethylene, and methane by a Clark-type oxygen electrode.

Hydrogen-conditioned Clark electrodes exposed to successive acetylene samples displayed a decreasing curvilinear response. Slight electrode responses are also effected by saturated ethylene solutions. Thus, amperometric measurements of hydrogen or carbon monoxide in the aqueous environment by these electrodes are perturbated by the presence of acetylene and to a much lesser extent by ethylene. Methane-saturated solutions induced no electrode response.

Amperometric response to carbon monoxide by a Clark-type oxygen electrode.

Hydrogen-conditioned Clark-type electrodes responded amperometrically to carbon monoxide but to a lesser extent than to hydrogen. They lost sensitivity over time at a concentration-dependent rate when exposed to H2 or CO. Maximum electrode current produced by pure CO was 0.45 microA at the optimum polarizing voltage of 0.60 V; electrode sensitivities to H2 and CO were 15 and 1.8 nA, respectively, in 1 microM solutions. These electrodes also responded weakly to acetylene and ethylene. Caution is suggested in interpretation of H2 measurements made with these electrodes if all components of the reaction milieu are not known.

Expression of hydrogenase activity in free-living Rhizobium japonicum.

A medium is described on which selected Rhizobium japonicum strains express hydrogenase (H(2) uptake) activity under free-living conditions. Low concentrations of carbon substrates, decreased oxygen tension, and the quantity of combined nitrogen in the medium were major factors influencing hydrogenase expression. Hydrogenase activity was dependent upon a preincubation period in the presence of H(2) under conditions such that the cells did not exhibit nitrogenase activity. H(2) uptake rates were easily measured amperometrically in aerobically or anaerobically prepared suspensions from free-living cultures. Six R. japonicum strains that formed nodules with the ability to utilize H(2) oxidized this gas when grown in free-living cultures. In comparison six randomly chosen strains forming nodules that lost H(2) in air either showed no or low capacity to take up H(2) under free-living conditions. The reduction of triphenyltetrazolium chloride in an agar medium was used to detect strains capable of oxidizing H(2). This method has enabled us to isolate a spontaneous R. japonicum mutant strain that has lost the ability to utilize H(2). This mutant strain forms nodules that evolve H(2) but other symbiotic characteristics appear normal. This strain will be useful in evaluating the importance of the hydrogenase system in the nitrogen-fixing process of legumes.

Phytoplankton uptake and excretion of assimilated nitrate in a small Canadian shield lake.

Nitrate uptake in the epilemnetic waters of a small eutrophic Canadian Shield lake was studied by using a 15N method during summer stratification. Concurrent with inhibition of primary production, 3-(3,4-dichlorophenyl)-1,1-dimethylurea inhibited NO3- assimilation. Nitrate up to 1 mg of N/liter did not affect the rate of primary production during 3 h of incubation. The NO3- fertilizer added to the lake weekly was consumed through algal assimilation in about 3 days. Excretion of the photoassimilated NO3- as dissolved organic nitrogen represented a significant portion of the nutrient incorporated by the cells. Only 40% of the NO3- -15N which disappeared could be accounted for in the particulate fraction. Although the rest was presumably excreted, only 15% of the 15N label was accounted for as cationic dissolved organic nitrogen by isotope assays. These excreted organic forms were predominantly serine and glycine in the dissolved free amino acid fraction. Bacteria as well as algae might be expected to contribute to and modify the extracellular nitrogen pool.

Aquatic acetylene-reduction techniques: solutions to several problems.

Previous methods of performing aquatic acetylene-reduction assays are described and several problems associated with them are discussed. A refinement of these older techniques is introduced and problems that it overcomes are also discussed. A depth profile of nitrogen fixation (C2H4 production), obtained by the refined technique, is shown for a fertilized Canadian Shield lake in the Experimental Lakes Area of northwestern Ontario.