Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning

Camptothecins are a new class of anticancer drugs that target DNA topoisomerase I; current efforts are directed toward elucidating optimal combinations of these drugs with other antineoplastic agents. A rationale for the use of sequential therapy involving the combination of camptothecins with topoisomerase II-targeting drugs, such as etoposide, has arisen from observations of increased topoisomerase II protein levels in cell lines resistant to camptothecin. In an effort to understand potential mechanisms of resistance to this strategy, we developed a U-937 cell subline, denoted RERC, that is capable of surviving exposure to sequential topoisomerase poisoning. The RERC cells are 200-fold resistant to camptothecin, 8-fold resistant to etoposide, and 10-fold hypersensitive to cisplatin compared to the parental U-937 cells. Biochemical analyses indicate that the resistant phenotype involves alterations in both topoisomerase I and topoisomerase IIalpha. Topoisomerase I catalytic activity in the resistant cells is similar to that of the parental line but is resistant to camptothecin. Moreover, the resistant cells express a single mRNA species of topoisomerase I that codes for a mutation in codon 533. In addition, topoisomerase IIalpha protein levels are decreased 10-fold in the resistant line, coincident with a two-fold decrease in the expression of topoisomerase IIalpha mRNA. Collectively, these results indicate that resistance to sequential topoisomerase poisoning may involve a reduction in total cellular topoisomerase activity.     

The Michigan benchmark: towards XML query performance diagnostics

We propose a micro-benchmark for XML data management to aid engineers in designing improved XML processing engines. This benchmark is inherently different from application-level benchmarks, which are designed to help users choose between alternative products. We primarily attempt to capture the rich variety of data structures and distributions possible in XML, and to isolate their effects, without imitating any particular application. The benchmark specifies a single data set against which carefully specified queries can be used to evaluate system performance for XML data with various characteristics.     

Effects of GABA compounds injected into the subpallidal regions of rat brain on nucleus accumbens evoked hyperactivity.

The effects of administration of γ-aminobutyric acid (GABA) compounds into the ventral pallidum and substantia innominata on the locomotor hyperactivity induced by the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene (ADTN) in the nucleus accumbens were investigated in rats. Hyperactivity induced by ADTN was antagonized by the GABA receptor agonists muscimol, isoguvacine, and baclofen. The compounds were equally effective in both subpallidal regions. In contrast, the GABA antagonists picrotoxin and bicuculline injected into subpallidal sites had no effects on accumbens—evoked hyperactivity, although by themselves both antagonists caused a mild and transient locomotor stimulation. It is suggested that GABA receptors in the subpallidal areas are involved in locomotor stimulation elicited from the nucleus accumbens. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of stochastic approaches to the transportation problem:a case study

The objective of this case study is to provide insight to practitioners about the methodology of using the space-time autoregressive integrated moving average (STARIMA) class of models to formulate stochastic demand of the transportation problem. While providing insight, two other methods-expected value (EV) and stochastic approximation (SA)-are also employed to formulate demand. A comparative evaluation of the methods using brewery data for the distribution of four products from five production plants to 64 distribution centers is presented. It is shown that the demand characterized by the STARIMA approach results in a lower total cost of transportation. This occurs because the STARIMA approach results in better forecasts. Based upon the case study, the cost analysis indicated that the STARIMA method when used without (with) updating resulted in a 9.49% (10.5%) increase in the Company's net profit as compared with the SA method. Similarly, the STARIMA approach when used without (with) updating resulted in an 11.36% (12.37%) increase in the net profit as compared with the EV method. For the STARIMA approach, computations for a large size problem are shown to be identical to those of the deterministic transportation problem given the demand forecasts. Extra computation effort for producing STARIMA forecasts are easily justified in terms of the increased profit margin     

Analysis of a simple successive interference cancellation scheme ina DS/CDMA system

Compensating for near/far effects is critical for satisfactory performance of DS/CDMA systems. So far, practical systems have used power control to overcome fading and near/far effects. Another approach, which has a fundamental potential in not only eliminating near/far effects but also in substantially raising the capacity, is multiuser detection and interference cancellation. Various optimal and suboptimal schemes have been investigated. Most of these schemes, however, get too complex even for relatively simple systems and rely on good channel estimates. For interference cancellation, estimation of channel parameters (viz. received amplitude and phase) is important. We analyze a simple successive interference cancellation scheme for coherent BPSK modulation, where the parameter estimation is done using the output of a linear correlator. We then extend the analysis for a noncoherent modulation scheme, namely M-ary orthogonal modulation. For the noncoherent case, the needed information on both the amplitude and phase is obtained from the correlator output. The performance of the IC scheme along with multipath diversity combining is studied     

Influence of curing at different relative humidities upon compound reactions and porosity in Portland cement paste

The reduction in relative humidity within drying concrete depends mainly on the depth from the exposed surface, exposure duration, temperature and environmental humidity; this limits hydration and coarsens pore structure, thus impairing durability. OPC paste, of 0.59 water/cement ratio, was cured for 2 days and then exposed to controlled relative humidity environments. After 14 and 90 days exposure, hydration of the individual compounds was measured using quantitative X-ray diffraction and thermogravimetry. Methanol adsorption was used to monitor porosity and gel formation. Even a small drop in relative humidity below 95% r.h. significantly limited cement hydration. Gel porosity increased with amount of hydration and, for a given level of hydration, decreased with drying. Curing below 80% r.h. produced a coarsened pore structure with a large-diameter porosity three times greater than that obtained with saturated curing.     

Pseudoexstrophy

Pseudoexstrophy is a rare, mild exstrophy variant which involves the major musculoskeletal defects of the exstrophy complex without any associated defect in the urinary system. A case is reported presenting at birth as an umbilical positional anomaly. Differential diagnosis and management are reviewed.     

Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs

The present study was undertaken to determine the effects of chronic sinoaortic (baroreceptor) denervation (SAD) on the hemodynamic and sympathetic alterations that occur in the pacing-induced model of congestive heart failure. Two groups of dogs were examined: intact (n = 9) and SAD (n = 9). Both groups of dogs were studied in the control (prepace) state and each week after the initiation of ventricular pacing at 250 beats/min. After the pacemaker was turned off, hemodynamic and plasma norepinephrine levels returned toward control levels in the prepaced state and after 1 and 2 wk of pacing. However, by 3 wk all hemodynamic and norepinephrine levels remained relatively constant over the 10-min observation period with the pacemaker off. With the pacemaker off, left ventricular end-diastolic pressure went from 2.7 +/- 1.4 (SE) mmHg during the prepace state to 23.2 +/- 2.9 mmHg in the heart failure state in intact dogs (P < 0.01). Left ventricular end-diastolic pressure increased to 27.1 +/- 2.2 mmHg from a control level of 4.2 +/- 1.9 mmHg i SAD dogs (P < 0.0003). Mean arterial pressure significantly decreased in intact and SAD dogs. Resting heart rate was significantly higher in SAD dogs and increased to 135.8 +/- 8.9 beats/min in intact dogs and 136.1 +/- 6.5 beats/min in SAD dogs. There were no significant differences in the hemodynamic parameters between intact and SAD dogs after pacing. Plasma norepinephrine was significantly lower in intact than in SAD dogs before pacing (197.7 +/- 21.6 vs. 320.6 +/- 26.6 pg/ml; P < 0.005). In the heart failure state, plasma norepinephrine increased significantly in both intact (598.3 +/- 44.2 pg/ml) and SAD (644.0 +/- 64.6 pg/ml) groups. There were no differences in the severity or the magnitude of the developed heart failure state in SAD vs. intact dogs. We conclude from these date that the arterial baroreflex is not the sole mechanism for the increase in sympathetic drive in heart failure.