Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

Gliomas represent a wide spectrum of brain tumors characterized by their high invasiveness, resistance to chemoradiotherapy, and both intratumoral and intertumoral heterogeneity. Recent advances in transomics studies revealed that enormous abnormalities exist in different biological layers of glioma cells, which include genetic/epigenetic alterations, RNA expressions, protein expression/modifications, and metabolic pathways, which provide opportunities for development of novel targeted therapeutic agents for gliomas. Metabolic reprogramming is one of the hallmarks of cancer cells, as well as one of the oldest fields in cancer biology research. Altered cancer cell metabolism not only provides energy and metabolites to support tumor growth, but also mediates the resistance of tumor cells to antitumor therapies. The interactions between cancer metabolism and DNA repair pathways, and the enhancement of radiotherapy sensitivity and assessment of radiation response by modulation of glioma metabolism are discussed herein.     

One-trial cocaine-induced behavioral sensitization in preweanling rats: Role of contextual stimuli.

Using a one-trial procedure, preweanling rats exhibit robust sensitization regardless of whether drug pretreatment and testing occur in the same or different environments. The purpose of the present study was to determine whether one-trial context-specific and context-independent sensitization of preweanling rats could be dissociated by varying the pretreatment dose of cocaine, by varying the pretreatment drug, or by minimizing interoceptive cues. In Experiments 1a and 1b, rats were pretreated with a broad dose range of cocaine (0–40 mg/kg) before placement in a novel activity chamber or the home cage. In Experiment 2, rats were pretreated with a locomotor-enhancing drug (e.g., methylphenidate, U50,488, or MK-801) before placement in a novel activity or anesthesia chamber. In Experiment 3, rats were anesthetized with isoflurane before cocaine administration to minimize the effects of interoceptive and injection cues. In all experiments, rats were challenged with cocaine on the test day (24 hr later), with locomotion being measured in activity chambers. Results showed that (a) the pretreatment dose of cocaine (10–40 mg/kg) did not differentially affect context-specific and context-independent sensitization; (b) cross-sensitization between methylphenidate and cocaine was observed in the context-specific condition, but not when using a context-independent procedure; and (c) sensitization was evident if injection and interoceptive cues were minimized. One possibility is that associative processes do not modulate the one-trial sensitization of preweanling rats. Alternatively, “unitization” may cause preweanling rats to treat the different environments as equivalent, thus permitting robust sensitization even when drug pretreatment and testing occur in different environments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Surface evaluation of carbon fibre composites using wavelet texture analysis

Strong and lightweight fibre reinforced polymeric composites now dominate the aerospace, marine and low-volume automotive sectors. The surface finish on exterior composite panels is of critical importance for customer satisfaction. This paper describes the application of wavelet texture analysis (WTA) to the task of automatically classifying the surface finish of Carbon Fibre Reinforced Plastic (CFRP) samples into two quality grades. Automatic classification was successful for all but four samples out of 14,400 classification trial configurations, representing 403,200 sample classification attempts (28 attempts per configuration). This work establishes the principle of WTA as a basis for automatic surface finish classification of composite materials.     

Changes in blood lead of a recreational shooter

We have measured the concentration and isotopic composition of lead in blood over a 15-month period for a subject who undertook recreational shooting in outdoor and indoor firing ranges on an irregular basis. We have also measured the isotopic composition in cast lead, Cu-jacketed and Teflon-coated bullets, propellant and primer from which he assembled the cartridges. Blood lead concentration increased from 3.2 to 6.7 microg/dl with use of dominantly cast lead bullets in the outdoor range. In two intervals when no firing was undertaken for 3-4 months, the blood lead concentrations either decreased towards a baseline value in the case where only Cu-jacketed bullets were fired or remained elevated when dominantly cast lead bullets were fired. The propellants contained <2 ppm Pb and contribute negligibly to blood lead. The isotopic composition of the primer used for all bullets was consistent with a source from the US. The bullets were of different materials and made in Australia and the US, with lead from sources of different geological age and hence different isotopic signatures. Variations in blood lead concentration and isotopic composition appear most strongly influenced by the bullets. Although more expensive, the use of Cu-jacketed bullets, non-lead primers and well-ventilated indoor firing ranges would lessen the health impacts of recreational shooting.     

Carbon dioxide effects on luminol and 1,10-phenanthroline chemiluminescence

Luminol and 1,10-phenanthroline are widely used chemiluminescent (CL) reagents for the analysis of a wide range of metals and inorganic and organic complexes. While the fundamental mechanism for luminol and 1,10-phenantholine chemiluminescence is understood, the analytical application of these reagents is largely empirical and often poorly described mechanistically. For example, CL signals observed from metal-luminol systems are strongly dependent on the pH of the sample, even though the final pH of the reaction mixture is controlled to a narrow range by a buffer. Other investigators report significant changes in CL signal due to freshness and the acidity of reagents. Our work shows that many of these effects are due to dissolved CO2 present or formed in the analytical system. The hypothesis that carbon dioxide plays a pivotal role in enhancing luminol CL is supported by direct manipulation of CO2(aq) concentrations by the addition of CO2(g) or carbonic anhydrase. In contrast, Cu(II) analysis using the CL reagent 1,10-phenanthroline is completely quenched in the presence of CO2(aq). A plausible mechanism for these observations involves the reaction between superoxide, produced in these analytical systems, and CO2(aq) to form the peroxycarbonate radical, *C04-. The formation of *CO4- has very important analytical implications since this species appears to enhance or quench the CL signal from luminol and 1,10-phenanthroline, respectively.     

Electrokinetic stacking injection of neutral analytes under continuous conductivity conditions

In capillary electrokinetic chromatography, neutral analytes can be injected by electroosmotic flow directly from a sample matrix into a separation buffer containing an electrokinetic vector with an opposite mobility. Analytes are injected at the velocity of electroosmotic flow but are retained at the interface of the sample matrix co-ion and separation buffer micelle zones as analyte/micelle complexes. A simple electrokinetic chromatography system containing sodium dodecyl sulfate as the micellar agent with borate as the buffering electrolyte included in the separation buffer and in the sample matrix to provide continuous conductivity was investigated. Concentrations of the micelle, methanol, and borate in the separation buffer were explored to increase maximum injection length of neutral analytes. Reducing the analyte velocity in the separation buffer without substantially decreasing the velocity of the analyte during injection from the sample vial allowed greatly extended sample plug injection lengths. It is presently possible to inject sample solvent volumes equivalent to approximately 7 effective capillary lengths (180 cm) with a 50-microm-i.d. capillary (24.5 cm effective capillary length), total volume of sample injection approximately 3.5 microL Equations describing the injection process and maximum injection lengths for this mode of stacking in electrokinetic capillary chromatography are introduced. The result of this work leads to a postulated generalization of electrokinetic stacking injection maximums for electrophoretic processes, and the concept of orthogonal analyte stacking/injection systems is discussed.     

Ethics,data-dependent designs,and the strategy of clinical trials: time to start learning-as-we-go?

The seeds of modern clinical trials were unwittingly sown with the first use of randomization in a 1920s agricultural field experiment. The historical development of trials is briefly reviewed here, as are multifarious pressures and problems faced by those involved with clinical trials today. These challenges include recruitment difficulties, the emerging role of patient support groups, and legal threats over informed consent, to name three. Fundamentally, they reflect an overall shift towards patient-centred, individual ethics. I suggest many problems may be overcome by increased implementation of hitherto neglected, data-dependent designs for clinical trials. Over a dozen arguments against their use are countered, primarily through ethical considerations. Benefits and costs of refining clinical trials strategy are explored hypothetically under enhanced use of such 'learn-as-you-go' designs, in contrast to traditional, equal-allocation, fixed-sample-size and frequentist-based designs. These latter methods mirror crop field trials in which one cannot make scientific progress until after gathering objective data at harvest time. Some attempts to alleviate certain problems, such as Zelen randomization to boost recruitment, or over-reliance on 'large and simple trials' to detect moderate-sized treatment effects, are discussed and found inadequate. A proposal for wider discussion is made to assist the selective introduction of 'small and complex trials,' which could simultaneously expedite medical research, satisfy the concerns of regulators, statisticians, and doctors alike, and help address the growing demands of 21st-century patients.     

Designing consumer interfaces for experiential tasks: an empirical investigation

In the early adoption phase of business-to-consumer (B2C) ecommerce, the tasks that proved most conducive to online consumer interaction typically were goal-directed, being clear in sequence and structure. A key challenge in ecommerce is the ability to design interfaces that support experiential tasks in addition to goal-directed tasks. Most of the ecommerce research on interface design, however, has focused on goal-directed tasks and has not addressed experiential tasks. Based on the literature from interface metaphors and mental models, this paper explores the use of tangible attributes derived from the physical business domain as a technique for designing an interface that effectively supports experiential tasks. A laboratory experiment was designed and conducted to test the impact of two types of interfaces and business domain familiarity when completing an experiential task. Because consumers need to retain and recall information to evaluate products/services or to make brand associations, retention/recall of information was measured on both the day of the treatment and after a 2-day lag. Results revealed that the interface based upon the business domain metaphor stimulated higher levels of retention and recall of information and thus provided the desired support for experiential tasks. Further, users with weaker domain familiarity showed the greatest improvement in retention and recall, particularly after a 2-day lag, when using the interface with the business domain metaphor design.     

Method for repetitive measurement of the electrostatic chargingtendency of liquid dielectrics

The construction of an apparatus for the measurement of the electrostatic charging tendency (ECT) of a dielectric liquid is described. A sealed reciprocating piston arrangement permits a liquid to be repetitively passed through a charge separating element. The use of a gold element is shown to minimize the effects of moisture and control temporal effects. The system is evaluated by testing samples of transformer oil drawn from the field. In general, the new system ranks the oils in the same way as a conventional assessment against a paper filter, although anomalies have been found which are an impediment to adoption