Cytotoxic effects of topotecan combined with various anticancer agents in human cancer cell lines

BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic effects produced by combinations of TPT and other antineoplastic agents in experiments involving multiple human cancer cell lines of diverse histologic origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), alone and in combination with TPT, were measured in clonogenic (i.e., colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer cell lines were used in these assays. The data were analyzed by the median effect method, primarily under the assumption that drug mechanisms of action were mutually nonexclusive (i.e., completely independent of one another). For each level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was calculated. A CI less than 1 indicated synergy (i.e., the effect of the combination was greater than that expected from the additive effects of the component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 indicated antagonism (the effect of the combination was less than that expected from the additive effects of the component agents). RESULTS: When the mechanisms of drug action were assumed to be mutually nonexclusive, virtually all CIs for combinations of TPT and either antimetabolites or antimicrotubule agents revealed cytotoxic effects that were less than additive. The CIs calculated at low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were less than additive; in most cases, however, nearly additive or even synergistic effects were observed with these same drug combinations at high levels of cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results obtained with combinations of TPT and cisplatin varied according to the cell line examined. With A549 cells, less than additive effects were seen at low-to-intermediate levels of cytotoxicity, and more than additive effects were seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT cytotoxicity appears to be enhanced more by combination with certain DNA-damaging agents than by combination with antimetabolites or antimicrotubule agents. Interactions between TPT and other drugs can vary depending on the cell type examined. Further investigation is required to determine the basis of the observed effects and to determine whether these in vitro findings are predictive of results obtained in vivo.     

Men, medicine and machines

PURPOSE: To examine the management and possible causes of primary valve malfunction of the Krupin eye valve with disk. METHODS: The authors reviewed the results of 113 patients undergoing implantation of the Krupin eye valve with disk and identified eight patients with primary valve malfunction requiring surgical revision. RESULTS: Valve revision involved manipulation (n = 1 case), explantation of the malfunctioning valve and implantation of a new valve (n = 2), and amputation of the valve (n = 5). Six of eight patients had final intraocular pressures of < 21 mmHg on one or no medications at a mean interval of 15.9 months (range 5-36) after surgical revision. Transient postoperative hypotony was noted in three patients and chronic hypotony with loss of light perception in one patient. One explanted valve was examined and found to have partially fused leaflets. CONCLUSIONS: Surgical revision in cases of primary valve malfunction of the Krupin eye valve with disk may be accomplished relatively safely with an acceptable level of postoperative complications. The etiology of primary valve malfunction may be related to the sterilization process and prolonged storage before implantation.     

Water-Quality Monitoring in Anguilla

Anguilla is a UK overseas (non-independent) territory in the Caribbean. It is a small middle-income island with a population of 13 000, and recent statistics indicate that it is more dependent on tourism than any other country or territory in the world. Rapid population growth and development have placed more emphasis on the need for human health and environmental protection. For the first time, a systematic water-quality monitoring programme has been developed, based on the realities of the local situation, e.g. low resource base, limited capabilities, dependence on household rainwater catchment, storage cisterns, and a poor water-supply network. Development of the programme incorporated the key themes of pragmatic, realistic, incremental, responsive, and consultative approaches.     

Analysis of a stiffener intersection eccentricity in a steel containment

Containment structures have several regions in which the continuity of the cylindrical pressure boundary is interrupted, e.g., shell penetrations, discontinuous stiffeners, and changes in the shell thickness. Significant strain concentrations can occur in these areas of discontinuity. The Sandia National Laboratories 1:8-scale steel containment equipment hatch was analyzed as an example of an eccentricity at a stiffener intersection.A portion of the as-built 1:8-scale model was modeled with the ANSYS general purpose finite element program using triangular, thin shell finite elements. The overall size of the model was determined from Saint-Venant type considerations of the stress field around the hatch. Shell elements were used to model the ring and formed stiffeners. Geometric and material nonlinear behavior were included. The model was loaded using discrete load steps up to a pressure of 165 psig. At this pressure, the maximum strain was 19.7 percent in the formed stiffener near its intersection with the ring stiffener. The finite element solution demonstrated the very localized nature of the strain field near the ring/formed stiffener intersection.In an attempt to reduce analysis costs, a small portion of the 1:8-scale model immediately surrounding the ring/formed stiffener intersection was selected for further analysis. Two smaller models, a ring/formed stiffener intersection and a ring/circular stiffener intersection, were studied. The models were significantly smaller than the regions used previously. A comparison of the two intersection models showed that the circular stiffener is a more efficient configuration.     

Structural characterisation of apatite coatings

The current, most frequently employed, commercial route to produce hydroxyapatite prosthetic coatings is plasma spraying. However, this has several important limitations especially for textured surfaces. Low temperature methods of coating fabrication such as cathodic electrodeposition are attractive alternatives. However, quantitative characterisation of the phase composition of thin electrodeposited coatings can be problematic. An X-ray diffraction method, which provides quantitative compositional information without reference to external or internal standards, is introduced and validated. The method can also be applied when Bragg peaks from the supporting substrate are apparent within the data and preferred orientation can be tolerated. This method has been used to examine in detail the microstructure of electrodeposited coatings which are compared directly with those formed by a commercial plasma spraying process.We show that, unlike the plasma sprayed coatings, the electrodeposited material consists of a single crystalline phase (hydroxyapatite) and a significantly reduced amorphous phase. The electrodeposited coatings also possess significantly more microstrain and a smaller crystallite size than the corresponding plasma sprayed material.     

Characteristics of Milk Powders Produced by Spray Freeze Drying

Skim and whole milk powders were manufactured at lab scale by spray freeze drying (SFD), using liquid nitrogen as the cryogen. The polydispersity of droplet/particle sizes was limited using an encapsulator nozzle to atomize the feed. Particle morphology was examined using a scanning electron microscope. Samples were compared with equivalent spray-dried powders in tests of wettability and dissolution in water. The spray freeze-dried powders were found to be highly porous, with a uniform structure of pores throughout the entire particles. When tested in water, SFD skim milk powders wetted roughly three times as fast as industrially spray-dried agglomerated skim milk powders and were observed to dissolve rapidly by breaking down into smaller particles.     

System requirements for Ka-band Earth-satellite propagation data

Accurate estimates of the propagation impairments that affect link quality and availability and determine signal interference fields are essential for the reliable design of telecommunication systems and the efficient use of the electromagnetic spectrum. Recent announcements by commercial entities of their intent to use Ka-band spectrum to supply satellite services have heightened interest in propagation data and models for these frequencies. This paper provides a brief overview of Ka-band Earth-satellite systems and requirements in relation to the need for specific types of propagation data     

An extended panel of hamster-human hybrids for chromosome 2q

A hamster-human hybrid containing only the q arm of chromosome 2 has been used to construct a panel of hybrids bearing reduced regions of chromosome 2 using the technique of irradiation fusion gene transfer. The human chromosome 2 carried the Ecogpt gene and all hybrids were selected using this marker. The integrated Ecogpt gene was localized to the region 2q33-34, resulting in the selective retention of this region in the hybrids. These data were combined with another previously constructed panel of hybrids containing regions of 2q, which were enriched for the region 2q36-37. The combined hybrid panel is useful for the mapping of new markers to defined regions of chromosome 2 and for the cloning of genes located on 2q by a positional strategy.