Oral topotecan given once or twice daily for ten days: a phase I pharmacology study in adult patients with solid tumors

The development of a highly sensitive method for detection of telomerase activity, telomeric repeat amplification protocol (TRAP), has provided knowledge on telomerase activity in normal and cancer tissues. Subsequent several modifications have been achieved, including an introduction of the internal standard and hybridization protection technique that leads to simplicity and improvement of reproducibility and linearity of this method, and application of TRAP to in situ analysis to identify the cells responsible for telomerase activity. As for measurement of telomere length, fluorescence in situ hybridization technique appeared to give an information of telomere length on an individual chromosome in contrast to analysis of terminal restriction fragment, a conventional method which can express mean telomere length of all chromosomes. Further methodological improvement in this field is ongoing and showing a new sight on cell mortality and immortality.     

Single agent activity of rhizoxin in non-small-cell lung cancer: a phase II trial of the EORTC Early Clinical Trials Group

In a multicentre trial of the EORTC-Early Clinical Trials Group (ECTG) we treated 31 chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) with rhizoxin, a novel tubulin-binding agent. The drug was given as an i.v. bolus injection at 2 mg m-2 once every 3 weeks in an outpatient setting. Prophylactic antiemetics were not routinely given. Of the 29 eligible patients, nine had been treated surgically and three had received radiotherapy. The main toxic effects observed were stomatitis (34% of cycles) and neutropenia (41% of cycles). Neutropenic fever was rare (3% of cycles). Twenty-seven patients were evaluable for response. There were four partial responses (15%), while 13 patients (48%) showed stabilisation of their disease. The median duration of response was 7 months (range 6.0-10.7 months) and median survival from the start of rhizoxin treatment was 6 months (range 2-14.7 months). Rhizoxin as single agent shows activity in patients with advanced NSCLC.     

Five days of oral topotecan (Hycamtin), a phase I and pharmacological study in adult patients with solid tumours

Topotecan is a specific inhibitor to topoisomerase I. An oral formulation of topotecan is available with a bioavailability of 32-44% in humans. A phase I and pharmacological study of the oral formulation of topotecan administered daily for 5 days every 21 days was performed in adult patients with solid tumours to determine the maximum tolerated dose (MTD). Adult patients with a WHO performance status < or = 2 adequate haematological, hepatic and renal functions, with malignant solid tumours refractory to standard forms were entered into the study. Pharmacokinetics were performed on days 1 and 4 of the first course using a validated high performance liquid chromatographic assay. 29 patients entered the study, all patients were evaluable for toxicity and response. The doses studied in the 29 patients were 1.2, 1.8, 2.3, 2.7 mg/m2/day and a fixed dose of 4 mg/day without surface area adjustment. A total of 109 courses were given. Dose limiting toxicity (DLT) was reached at a dose of 2.7 mg/m2/day and consisted of CTC (NCI-Common Toxicity Criteria) grade IV granulocytopenia. The regimen was well tolerated. Non-haematological toxicities were mild, including fatigue, anorexia, nausea, vomiting and diarrhoea. A significant correlation was observed between the percentage decrease in white blood cells versus the area under the curve (AUC(t)) of topotecan lactone (R = 0.76 P < 0.01) which was modelled by a sigmoidal Emax function. The correlation coefficient between the absolute topotecan dose administered and the AUC(t) was R = 0.52 (P = 0.04). Pharmacokinetics of the fixed dose of 4 mg/day were comparable to the 2.3 mg/m2/day dose. DLT in this phase I study of five daily doses of oral topotecan every 21 days was granulocytopenia. The recommended dose for phase II studies is 2.3 mg/m2/day or alternatively, a fixed dose of 4 mg/day.     

Archiving and absolute quantitation of solutes separated by single charged droplet coulomb explosion

The electrospray (ES) ion source relies on the transfer of low-volatility solutes to the gas phase as an outcome of coulomb explosion events of charged droplets generated by electrical atomization. Introduced here are two methods for archiving compounds separated by coulomb explosion of single droplets having net charge that had been levitated in an electrodynamic balance. We categorized compounds separated by the explosion as either material ejected, including progeny droplets, or the material retained in the main residue. The potential for this methodology is illustrated by (i) qualitative characterization of solute states, aqueous versus precipitated in the separated material, and (ii) absolute quantitation of solutes separated by such an event. For a droplet containing 5 x 10(7) 20-nm-diameter fluospheres, its first encountered coulomb explosion event resulted in the ejection of 1.70% of them. The capability to acquire such detailed information regarding the individual steps in the process of transferring low-volatility solutes to the gas phase in an ES ion source is essential to develop strategies for absolute quantitation in applications of ES mass spectrometry.     

Apparatus for preparing mimics of suspended particles in the troposphere and their controlled deposition onto individual lung cells in culture with measurement of downstream biological response

Inhalation exposure to particles <10 microm in size that are suspended in the troposphere (PM10) is a factor in respiratory and cardiovascular diseases. The extent of the injury, local to systemic inflammation, is dependent on the number, size, and composition of the particles to which an individual is exposed. The physical properties of and compounds on PM10 that are responsible for these adverse effects on human health are the subject of intense investigation. Here, we report a laboratory method that involved the creation of 1-120 particles per trial that were of known size and composition, followed by deposition of them directly onto individual human lung cells within a cell culture, and after an incubation period, a downstream biological response was measured. To illustrate this methodology, particles that each contained 50 pg of lipopolysaccharide were created and deposited onto individual cells over a region <0.36 mm2 within a genetically modified A549 cell culture. The biological readout was the relative expression of intercellular cell adhesion molecule 1 after 24 h of incubation using an immunocytochemistry assay. The apparatus and methodology introduced here enables studies at the interface between the relevant but diverse areas of atmospheric particle chemistry and lung cell biology to identify the chemical and physical factors of PM10 that cause/exacerbate respiratory and cardiovascular diseases by triggering various biological pathways.     

Nanocomposite bulk of mechanically milled Al-Pb samples consolidated pore-free by the high-energy rate forming technique

It is shown that pore-free bulk samples were produced by the high-energy rate forming axis-symmetrical powder compaction method for different application purposes in case of the very different, immiscible Al and Pb metal pair. The starting Al-Pb nanocomposites were made by mechanical milling of atomized Al and Pb powders either in a SPEX 9000 or a Fritsch Pulverisette 4 mill. Due to the conditions that milling was carried out in air, the PbO layer, originally existing at the surface of the atomized Pb powder, ruptured and was also dispersed in the composite. The presence of the nano PbO particles was proven by XRD and TEM (BF, DF, SAED). When the energy of milling was high, the PbO crystallites became so small that they could hardly be seen by XRD technique. Local distribution of the PbO nanoparticles was still visible in a TEM, using the process diffraction method. Both XRD and SAED proved to be useful for the evaluation of the results of the milling process and compaction.     

Coenzymes Q in lemon shark liver

Earlier studies have shown that some extracts of nonpolar lipids from lemon shark liver are able to stimulate the reticuloendothelial system (RES) of experimental animals. This communication reports the identification of the coenzymes Q as the constituents of a fraction from lemon shark liver lipid which showed intense biological activity.     

Downlink Capacity Analysis of Collaborative Crossed Timeslots in CDMA TDD Systems

Traffic asymmetry between uplink and downlink is expected to be a remarkable 3G characteristic in cellular mobile multimedia communications. CDMA system with TDD is a good solution to this traffic asymmetry. However, the level of traffic asymmetry may be significantly different from a cell to another cell. To tackle this problem and to support the traffic hot spot, crossed slots are examined. The use of crossed slots is restricted within a certain range of a cell by investigating the inter-cell interference and the maximum planned load factor. We examine the radius of inner zone and discuss the capacity of downlink crossed slots for various neighbor cell environments. Computational results show that the capacity increase in the target cell is outstanding by reducing the service range of neighbor cells. When all six neighbors reduce their service range by 20%, the capacity at target cell crossed slot is increased by 35%. Monte Carlo simulation is performed with large scale fading to verify the numerical analysis.

Occurrence of Listeria and Enterobacteriaceae in domestic refrigerators

Consumers' refrigeration practices have a significant impact on the safety and quality of foods. To determine the prevalence and the identity of microorganisms in domestic refrigerators, swab samples were taken from various locations in the refrigerators from 137 households in middle Tennessee. The swabs were inoculated into different media, and standard procedures were used to characterize the isolates. API 20E and API Listeria were used for identification of Enterobacteriaceae and Listeria spp., respectively. The Kirby-Bauer technique was used to test resistance of the isolates. Actual counts for aerobic and Enterobacteriaceae ranged from not detected to 8.53 and 8.39 log CFU per sample, respectively. Klebsiella pneumoniae (23.4%), Klebsiella oxytoca (6.8%), Klebsiella terrigena (4.0%), Enterobacter sakazakii (2.2%), and Yersinia enterocolitica (0.7%) were some of the bacteria of concern that were isolated from domestic refrigerators. Resistance to antibiotics was most common in erythromycin (39.9%), followed by ampicillin (33.8%), cefoxitin (12.8%), tetracycline (5%), streptomycin (4.0%), nalidixic acid (2.1%), kanamycin (1.4%), and colistin (0.7%). None of the isolates tested was resistant to ciprofloxacin or gentamycin. Listeria spp. were also detected in six refrigerators. These findings underline the need for greater consumer education regarding proper refrigerator cleaning and safe food handling practices.