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.     

Predeployed secure key distribution mechanisms in sensor networks: current state-of-the-art and a new approach using time information

In this article we survey a number of predeployed secure key distribution (PSKD) schemes proposed in the technical literature. We also propose a new time-based PSKD (TPSKD), which operates under the assumption of loose time synchronization, and discuss the performance of the scheme. Since the TPSKD scheme uses time information, which would typically already be available in sensor nodes, the cost of the scheme?s implementation is low.     

Field observations on the occurrence of new indicators of disinfection efficiency

This paper summarizes studies on the presence of acid-fast and yeast organisms in wastewater and water treatment plants and in surface water. These organisms were found to satisfy three of Bonde's criteria for indicator organisms: presence whenever pathogens are likely to be present; resistance at least equal to that of pathogens; and lack of regrowth in the post-treatment environment. This, plus prior data, indicates that these organisms are at least as acceptable as indicators of disinfection efficiency than the coliform group.     

Real-Time Three-Dimensional Occupancy Grid Modeling for the Detection and Tracking of Construction Resources

Awareness of the construction environment can be improved by automatic three-dimensional (3D) sensing and modeling of job sites in real time. Commercially available 3D modeling approaches based on range scanning techniques are capable of modeling static objects only, and thus cannot model dynamic objects in real time in an environment comprised of moving humans, equipment, and materials. Emerging prototype video range cameras offer an alternative by facilitating affordable, wide field of view, dynamic object tracking at frame rates better than 1?Hz (real time). This paper describes a methodology to model, detect, and track the position of static and moving objects in real time, based on data obtained from video range cameras. Experiments with this technology have produced results that indicate that video rate 3D data acquisition and analysis of construction environments can support effective modeling, detection, and tracking of project resources. This approach to job site awareness has inherent value and broad application. In combination with effective management practices and other sensing techniques, this technology has the potential to significantly improve safety on construction job sites.     

Evidence for distinct signaling mechanisms in two mammalian olfactory sense organs

In mammals, olfactory stimuli are detected by sensory neurons at two distinct sites: the olfactory epithelium (OE) of the nasal cavity and the neuroepithelium of the vomeronasal organ (VNO). While the OE can detect volatile chemicals released from numerous sources, the VNO appears to be specialized to detect pheromones that are emitted by other animals and that convey information of behavioral or physiological importance. The mechanisms underlying sensory transduction in the OE have been well studied and a number of components of the transduction cascade have been cloned. Here, we investigated sensory transduction in the VNO by asking whether VNO neurons express molecules that have been implicated in sensory transduction in the OE. Using in situ hybridization and Northern blot analyses, we found that most of the olfactory transduction components examined, including the guanine nucleotide binding protein alpha subunit (G-alpha-olf), adenylyl cyclase type III, and an olfactory cyclic nucleotide-gated (CNG) channel subunit (oCNC1), are not expressed by VNO sensory neurons. In contrast, VNO neurons do express a second olfactory CNG channel subunit (oCNC2). These results indicate that VNO sensory transduction is distinct from that in the OE but raise the possibility that, like OE sensory transduction, sensory transduction in the VNO might involve cyclic nucleotide-gated ion channels.     

Role of hepatic resection in surgery for bilateral intrahepatic stones

The effect of phenylephrine-induced reflex parasympathetic stimulation on QT interval and its dispersion was studied in 16 healthy subjects with a history of paroxysmal supraventricular tachycardia, both during sinus rhythm and during atrial pacing. Results demonstrate that rapid reflex parasympathetic stimulation does not influence QT interval duration or QT dispersion, and also emphasize the inappropriateness of Bazett's formula, the need for comparison of QT intervals during identical heart rates, and the importance of analyzing all 12 leads of a standard electrocardiogram when assessing the effects of various interventions on the QT interval.     

Wall-bounded laminar sink flows

Summary The laminar flow near an infinite plane wall perpendicular to a line sink of constant strength is investigated in the limit of large Reynolds numbers. Self-similarity requires that fluid is issuing from the boundary layer. The inviscid flow outside the boundary layer is governed by the Euler equations. A one-parametric set of solutions to the Euler equations with appropriate boundary conditions is given. Uniqueness of the inviscid flow solution is obtained from matching with the boundary layer expansion. The solution of the boundary-layer equations is given both in closed form and numerically. It is found that at the edge of the boundary layer the vorticity decays algebraically.Dedicated to Prof. Dr. Dr. h. c. Franz Ziegler on the occasion of his 60th birthday     

Seeking the truth about ad hoc join costs

In this paper, we re-examine the results of prior work on methods for computing ad hoc joins. We develop a detailed cost model for predicting join algorithm performance, and we use the model to develop cost formulas for the major ad hoc join methods found in the relational database literature. We show that various pieces of “common wisdom” about join algorithm performance fail to hold up when analyzed carefully, and we use our detailed cost model to derive op timal buffer allocation schemes for each of the join methods examined here. We show that optimizing their buffer allocations can lead to large performance improvements, e.g., as much as a 400% improvement in some cases. We also validate our cost model's predictions by measuring an actual implementation of each join algorithm considered. The results of this work should be directly useful to implementors of relational query optimizers and query processing systems. Edited by M. Adiba. Received May 1993 / Accepted April 1996     

Dependence on the motif YIPP for the physical association of Jak2 kinase with the intracellular carboxyl tail of the angiotensin II AT1 receptor

Angiotensin II is the effector molecule of the renin-angiotensin system. Virtually all of its biochemical actions are mediated through a single class of cell-surface receptors called AT1. These receptors contain the structural features of the seven-transmembrane, G-protein-coupled receptor superfamily. Angiotensin II, acting through the AT1 receptor, also stimulates the Jak/STAT pathway by inducing ligand-dependent Jak2 tyrosine phosphorylation and activation. Here, we show that a glutathione S-transferase fusion protein containing the carboxyl-terminal 54 amino acids of the rat AT1A receptor physically binds to Jak2 in an angiotensin II-dependent manner. Deletional analysis, using both in vitro protocols and cell transfection analysis, showed that this association is dependent on the AT1A receptor motif YIPP (amino acids 319-322). The wild-type AT1A receptor can induce Jak2 tyrosine phosphorylation. In contrast, an AT1A receptor lacking the YIPP motif is unable to induce ligand-dependent phosphorylation of Jak2. Competition experiments with synthetic peptides suggest that each of the YIPP amino acids, including tyrosine 319, is important in Jak2 binding to the AT1A receptor. The binding of the AT1A receptor to the intracellular tyrosine kinase Jak2 supports the concept that the seven-transmembrane superfamily of receptors can physically associate with enzymatically active intracellular proteins, creating a signaling complex mechanistically similar to that observed with growth factor and cytokine receptors.