Conduct of phase I trials in children with cancer

PURPOSE AND METHODS: Future progress in the care of children with cancer requires appropriate evaluations of promising new agents for pediatric indications, beginning with well-conducted phase I trials. This report summarizes current guidelines for the conduct of pediatric phase I trials and represents a consensus between American and European investigators. The primary objective of pediatric phase I trials is to define safe and appropriate doses and schedules of new agents that can subsequently be used in phase II trials to test for activity against specific childhood malignancies. Prioritization of agents for evaluation in children is critical, since many more investigational agents are evaluated in adult patients than can be systematically evaluated in children. Considerations used in prioritizing agents include activity in xenograft models, novel mechanism of action, favorable drug-resistance profile, and activity observed in adult trials of the agent. RESULTS AND CONCLUSION: Distinctive characteristics of pediatric phase I trials, in comparison to adult phase I trials, include the necessity for multiinstitutional participation and their higher starting dose (typically 80% of the adult maximum-tolerated dose [MTD]), both of which reflect the relative unavailability of appropriate patients. The application of uniform eligibility criteria and standard definitions for MTD and dose-limiting toxicity (DLT) help to assure that pediatric phase I trials are safely conducted and reliably identify appropriate doses and schedules of agents for phase II evaluation. Where possible, pediatric phase I trials also define the pharmacokinetic behavior of new agents in children.     

A new flux and stator resistance identifier for AC drive systems

The effect of stator resistance on AC drive performance is analyzed for flux vector and indirect field-oriented controllers. A new technique-the back electromagnetic force (BEMF) detector-for reducing the adverse effects of stator resistance on field-oriented control is presented and evaluated through simulation and experimental results. The BEMF detector is shown to reduce the impact of the stator resistance variations and also provide an estimate of the stator resistance. The detector is compatible with most control strategies and with or without position feedback     

Wasserbindungskapazit?t und Makrostruktur von Apfelgewebepartikeln

Zusammenfassung Haufwerke aus trockenen Apfelgewebepartikeln mit mittleren Partikelvolumina zwischen 0,3 und 5 mm³ können bis zu 80 g/g Wasser aufnehmen. Der überwiegende Teil dieses Wassers ist in makrocapillaren Haufwerks- und Partikelhohlräumen eingelagert und nur durch sehr geringe Kräfte gebunden. Bereits bei Einwirkung eines Gasdrucks von 2 kPa werden die Partikelhaufwerke stark entwässert. Die Wasserbeladung sinkt auf 20-15 g/g. Die Rehydratation einzelner getrockneter Apfelgewebepartikel ist vom Ausmaß der bei der Zerkleinerung eingetretenen Gewebezerstörung abhängig und kann durch eine der Trocknung vorgelagerte Entwässerung mit Ethanol verbessert werden. Vorentwässerte Partikel mit einem hohen Ethanolgehalt schrumpfen bei der Trocknung im geringeren Ausmaß und besitzen eine hohe Porosität. Solche Partikel binden im rehydratisierten Zustand bis zu 30 g/g Wasser. Nicht mit Ethanol behandelte Partikel binden unter 11 g/g Wasser.

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Water binding capacity and macrostructure of apple tissue particles

Samples (bulk materials) of dry apple tissue particles in a range of particle volume from 0.3 to 5 mm³ can absorb up to 80 g/g water. Most of this water is included in macrocapillary bulk and particle spaces and is bound by very small forces. An external gas pressure of 2 kPa decreases the water content to 20-15 g/g. The rehydration properties of single apple tissue particles depend on the degree of tissue disintegration and can be improved by a dehydration treatment with ethanol before drying. Such pre-dehydrated particles with a high ethanol concentration in the liquid phase show little shrinkage during the drying process and have a high porosity. They retain up to 30 g/g water after rehydration. The water uptake of non-ethanol-treated particles is less than 11 g/g.

     

Compliance-based and defiance-based intervention strategies and psychological reactance in the treatment of free and unfree behavior.

These studies investigated the use of restraining paradoxical interventions with high- and low-reactant subjects in the treatment of either procrastination or test anxiety. Study 1 compared a restraining intervention with a nonparadoxical-intervention group and a control group in the treatment of procrastination. Subjects received two 30-min interviews in which either a restraining directive or a nonparadoxical directive was given. All subjects improved their procrastination behavior. High-reactant subjects were less satisfied with their procrastination and had less expectation for change. Subjects who received the nonparadoxical treatment showed a greater expectation for change than those who received the paradoxical treatment. Study 2 compared a restraining intervention with a reframing intervention for either procrastination or test anxiety. Results showed no significant main effects for treatment for either procrastination or anxiety. All subjects decreased their anxiety. Low-reactant subjects exhibited less anxiety after treatment than high-reactant subjects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Three generations of cyclosporine a formulations: an in vitro comparison

When the microemulsion formulation of the critical dose drug cyclosporine A (CsA) (Sandimmun Optoral) was introduced in the mid-1990s, it became clear that this new formulation improves the oral bioavailability of CsA and has a positive influence on its pharmacokinetic variability. Previous studies with the original CsA formulation (Sandimmun) showed that the size of the emulsion droplets and concomitant food intake has an effect on the absorption of CsA from the small intestine when orally administered. It was suggested that these effects might have an influence on the drugs' pharmacokinetic parameters.In this study, we focused on the two above-mentioned aspects and compared the first and second generations of CsA products (Sandimmun, Sandimmun Optoral) to generic CsA formulations by analyzing the contents of cyclosporine A gel capsules with respect to their emulsion droplet and micelle sizes using photon correlation spectroscopy (PCS). We tried to discern any differences in droplet size between different generations of CsA formulations, primarily the second and third generation, through simple physical tests. Because a high fat content food may influence the absorption of CsA, we also determined the distribution of CsA between hydrophilic and lipophilic phases using high-performance liquid chromatography analysis.It became clear that when compared under simple physical conditions, established cyclosporine formulations and new generic products show significant differences in droplet size and distribution between an aqueous phase and a high fat content food. Whether these differences are of clinical relevance remains to be investigated.     

Heat and mass transfer during the coffee drying process

For a better comprehension of heat and mass transfer during the coffee drying process and optimization of the industrial application transport coefficients and coffee properties were determined. Heat transfer coefficients were measured for different air velocities and were found to follow the known dimensionless equations for the flow surrounding a sphere. Thermal conductivities and effective diffusion coefficients were measured as a function of moisture content as well as volume and densities of the coffee beans. The mentioned properties depend directly on the humidity of the coffee beans rather than on the drying conditions. Sorption behaviour was investigated and temperature dependent parameters for the Guggenheimer–Anderson–deBoer-isotherm (GAB) were determined according to the Arrhenius relationship.     

An Engineered Mannoside Presenting Platform: Escherichia coli Adhesion under Static and Dynamic Conditions

The study of the adhesion mechanisms of pathogens to host tissues has gained increased interest as bacterial adhesion is involved in the early stages of surface colonization and infection. Here we describe a platform to study the specific binding of the bacterium Escherichia coli (E. coli) K‐12 strain to molecularly well‐defined surfaces mimicking cellular interfaces. This approach uses a poly(ethylene glycol) brush interface, which displays synthetic determinants of the high mannose N‐linked glycans in a range of densities (3.8 × 10⁴–1.6 × 10⁵ mannosides µm^?2) for the investigation of multivalent interactions with bacteria. The bacterial attachment is mediated by specific interactions between the adhesive protein FimH located on the tip of the bacterial type 1 pili and the mannosylated surfaces. With synthetically engineered mannoses, it is found that the number of strongly adhering bacteria is co‐regulated by many structural physical parameters. Beyond the dependency on carbohydrate density, higher numbers of E. coli attach to the branched trimannose Man(α1–3)(Man(α1–6))Man compared to the monomannose, while larger oligomannoses exposing Man(α1–2) Man at their non reducing end show low binding capacity. The linker used between the mannose moiety and PEG is also affecting the binding efficacy of E. coli. The (hydrophobic) propyl linker results in higher bacteria numbers in comparison to the (hydrophilic) tri(EG), likely a consequence of additional stabilization of the binding complex by hydrophobic interactions. Furthermore, differences are observed in bacteria attachment between stagnant and flow conditions that depend on the type of mannose ligand. Finally, a photolithographic resist lift‐off combined with site‐selective assembly of the glycopolymers is used to produce micropatterns with bacteria colonies confined to defined areas and at controlled colony numbers.     

Validation of the performance of a GMO multiplex screening assay based on microarray detection

A new screening method for the detection and identification of GMO, based on the use of multiplex PCR followed by microarray, has been developed and is presented. The technology is based on the identification of quite ubiquitous GMO genetic target elements first amplified by PCR, followed by direct hybridisation of the amplicons on a predefined microarray (DualChip^® GMO, Eppendorf, Germany). The validation was performed within the framework of a European project (Co-Extra, contract no 007158) and in collaboration with 12 laboratories specialised in GMO detection. The present study reports the strategy and the results of an ISO complying validation of the method carried out through an inter-laboratory study. Sets of blind samples were provided consisting of DNA reference materials covering all the elements detectable by specific probes present on the array. The GMO concentrations varied from 1% down to 0.045%. In addition, a mixture of two GMO events (0.1% RRS diluted in 100% TOPAS19/2) was incorporated in the study to test the robustness of the assay in extreme conditions. Data were processed according to ISO 5725 standard. The method was evaluated with predefined performance criteria with respect to the EC CRL method acceptance criteria. The overall method performance met the acceptance criteria; in particular, the results showed that the method is suitable for the detection of the different target elements at 0.1% concentration of GMO with a 95% accuracy rate. This collaborative trial showed that the method can be considered as fit for the purpose of screening with respect to its intra- and inter-laboratory accuracy. The results demonstrated the validity of combining multiplex PCR with array detection as provided by the DualChip^® GMO (Eppendorf, Germany) for the screening of GMO. The results showed that the technology is robust, practical and suitable as a screening tool.     

Plant-derived polyphenols attenuate lipopolysaccharide-induced nitric oxide and tumour necrosis factor production in murine microglia and macrophages

Lipopolysaccharides released during bacterial infections induce the expression of pro-inflammatory cytokines and lead to complications such as neuronal damage in the CNS and septic shock in the periphery. While the initial infection is treated by antibiotics, anti-inflammatory agents would be advantageous add-on medications. In order to identify such compounds, we have compared 29 commercially available polyphenol-containing plant extracts and pure compounds for their ability to prevent LPS-induced up-regulation of NO production. Among the botanical extracts, bearberry and grape seed were the most active preparations, exhibiting IC(50) values of around 20 mug/mL. Among the pure compounds, IC(50) values for apigenin, diosmetin and silybin were 15, 19 and 12 muM, in N-11 murine microglia, and 7, 16 and 25 muM, in RAW 264.7 murine macrophages, respectively. In addition, these flavonoids were also able to down-regulate LPS-induced tumour necrosis factor production. Structure-activity relationships of the flavonoids demonstrated three distinct principles: (i) flavonoid-aglycons are more potent than the corresponding glycosides, (ii) flavonoids with a 4'-OH substitution in the B-ring are more potent than those with a 3'-OH-4'-methoxy substitution, (iii) flavonoids of the flavone type (with a C2=C3 double bond) are more potent than those of the flavanone type (with a at C2-C3 single bond).     

Comparative studies of a real-time PCR method and three enzyme-linked immunosorbent assays for the detection of central nervous system tissues in meat products

The removal of certain central nervous system (CNS) tissues (part of the bovine spongiform encephalopathy risk material) from the food chain is one of the highest priority tasks associated with avoiding contamination of the human food chain with the agent of bovine spongiform encephalopathy. A recently developed real-time PCR assay and three commercially available enzyme-linked immunosorbent assays (ELISAs) for the detection of CNS tissues in minced meat and three types of heat-treated sausages were evaluated. Bovine brain was used for spiking of internal reference material, and its detectability was examined during storage times of 12 months (for frozen minced meat and liver sausage) and 24 months (for sausages treated with medium and high heat). The real-time PCR method and both ELISA kits detected 0.1% CNS tissue in frozen minced meat and 0.1 or 1% CNS tissue in heat-treated meat products. The detectability of the amplified mRNA target region with the PCR assay was similar to the detectability of antigen by the ELISAs. Because the real-time PCR method also can be used to distinguish cattle, ovine, and caprine CNS tissues from porcine CNS tissues, it seems to be suitable as a routine diagnostic test for the sensitive and specific detection of CNS tissues in meat and meat products.