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.     

Using a cost-construction model to assess the cost of educating undergraduate medical students at the University of Texas--Houston Medical School

Spontaneous resolution of deformities after excision of facial skin lesions has been known and used for a long time by plastic surgeons. The resorption mechanism of deformity is based on natural skin expansion, and seems to be directly related to the action of the muscles of facial expression and their skin relations. Natural expansion has been shown to be effective in children. Between 1990 and 1994 excision of skin lesions, including congenital nevi, leading to postoperative deformity of the cheek, labial commissure, nose, eyelid and forehead, was performed on 35 patients, aged from 3 month to 12 years. The average follow-up is 24 months. For 26 patients (74%), natural resorption was observed 4 or 6 weeks later with good aesthetic results. For 6 patients (17%), the deformity persisted 3 or 6 months later, but did not require any further surgery. For 3 patients (9%), a second operation was necessary. Using the skins natural capacity for expansion in the treatment of facial skin defects in children is a method of reconstruction which has already been used for excision in enforced position. The platysma and muscles of facial expression by their action on skin mobilisation, allow natural expansion. A better knowledge of cutaneous biomechanical properties enables plastic surgeons to find an alternative to other classical methods.     

Evaluating generalized predictive control for a brushless DC drive

This paper proposes a new control approach for a brushless DC motor drive using the generalized predictive control (GPC) algorithm. Based on the same least-squares framework as in the controller design, we further develop the method to design an observer. The GPC algorithm uses the receding horizon approach whereby the control signals are determined by minimizing a quadratic cost function. Our study shows that the rise time and settling time of the servo system have an approximate linear relationship with the prediction horizon. Thus, it is used to tune the controller of the drive. Moreover, the control weighting factor can be used to smooth the controller output. The proposed algorithm has been implemented using a digital signal processor (DSP) and tested in real time with a prototype system. The performance and robustness of the algorithms have been evaluated both in simulation and experiment. The results show that the drive performs reasonably well despite load changes and step changes in the position setpoint. Furthermore, it is fairly robust against motor parameters change     

Off-Site Exposure to Respirable Aerosols Produced during the Disk-Incorporation of Class B Biosolids

Field experiments were conducted at a Class B biosolids land application site in central Arizona to measure, model, and source-track the off-site transport of aerosols emitted when biosolids were disk-incorporated into soils. Real-time PM10 monitoring provided time-resolved aerosol information sufficient for verifying both off-site concentration and off-site exposure time model results. Under the conditions considered and at a distance of 165?m from the aerosol source, biosolids disk-incorporation resulted in an intermittent exposure to biosolids-derived aerosol concentration between 15 and 40?μg/m3 and an inhalable biosolids dose between 2 and 8?μg. Transport modeling predicted that these doses will decrease with increasing wind speed. In addition, three DNA sequence-based biosolids source tracking methods were applied to aerosol samples and confirmed the presence of biosolids in aerosols at 5, 65, and 165?m from the aerosol source. Field measurements and modeling indicate that the nature of biosolids-derived aerosol exposure is a series of intermittent high concentration puffs, rather than a continuous low concentration.     

Efficient Spreadsheet Algorithm for First-Order Reliability Method

A new spreadsheet-cell-object-oriented algorithm for the first-order reliability method is proposed and illustrated for cases with correlated nonnormals and explicit and implicit performance functions. The new approach differs from the writers earlier algorithm by obviating the need for computations of equivalent normal means and equivalent normal standard deviations. It obtains the solution faster and is more efficient, robust, and succinct. Other advantages include ease of initialization prior to constrained optimization, ease of randomization of initial values for checking robustness, and fewer required optimization constraints during spreadsheet-automated search for the design point. Two cases with implicit performance functions, namely an asymmetrically loaded beam on Winkler medium and a strut with complex supports are analyzed using the new approach and discussed. Comparisons are also made between the proposed approach and that based on Rosenblatt transformation.