Prolonged tamoxifen exposure selects a breast cancer cell clone that is stable in vitro and in vivo

The effects of long-term tamoxifen exposure on cell growth and cell cycle kinetics were compared between oestrogen receptor (ER)-positive (MCF-7) and ER-negative (MDA-MB-231) cell lines. In the MCF-7 cell line, prolonged tamoxifen exposure (0.5 mumol/l for > 100 days) blocked cells in G0-G1 of the cell cycle, and slowed the doubling time of cells from 30 to 59 h. These effects corresponded to an increase in the cellular accumulation of tamoxifen over time [mean area under concentration curve (AUC) = 77.92 mumoles/10(6)/cells/day]. In contrast, in the MDA-MB-231 cell line, long-term tamoxifen exposure had no obvious effect on the doubling time, and reduced cellular tamoxifen accumulation (mean AUC = 50.50 mumoles/10(6)/cells/day) compared to the MCF-7 cells. Flow cytometric analysis of MDA-MB-231 cells demonstrated that a new tetraploid clone emerged following 56 days of tamoxifen exposure. Inoculation of the MDA-MB-231 tetraploid clone and MDA-MB-231 wildtype cells into the opposite flanks of athymic nude mice resulted in the rapid growth of tetraploid tumours. The tetraploid tumours maintained their ploidy following tamoxifen treatment for nine consecutive serial transplantations. Histological examination of the fifth transplant generation xenografts revealed that the tetraploid tumour had a 25-30 times greater mass, area of haemorrhage and necrosis, a slightly higher mitotic index and was more anaplastic than the control neoplasm. The control wildtype MDA-MB-231 tumours maintained a stable ploidy following tamoxifen treatment until the eighth and ninth transplantation, when a tetraploid population appeared, suggesting that tamoxifen treatment may select for this clone in vivo. These studies suggest that prolonged tamoxifen exposure may select for new, stable, fast growing cell clones in vitro as well as in vivo.     

Unexplained physical symptoms: outcome, utilization of medical care and associated factors

BACKGROUND: Measurement of intracardiac hemodynamic parameters has been limited to brief periods in the acute care setting. We developed and evaluated an implantable hemodynamic monitor that is capable of measuring chronic right ventricular oxygen saturation and pulmonary artery pressure. METHODS AND RESULTS: The device consists of an electronic controller placed subcutaneously and two transvenous leads placed in the right ventricle (reflectance oximeter) and pulmonary artery (variable capacitance pressure sensor). Implantation was performed in 10 patients with severe left ventricular dysfunction. Average implant pulmonary artery pressures were systolic, 52 +/- 16 mm Hg; diastolic, 29 +/- 11 mm Hg; and mean, 40 +/- 12 mm Hg. The mean right ventricular oxygen saturation at implant was 51%. Provocative maneuvers, including postural changes, sublingual nitroglycerin, and bicycle exercise, demonstrated expected changes in measured oxygen saturation and pulmonary artery pressures over time. At follow-up of 0.5 to 15.5 months, there were no significant differences between pulmonary artery pressures or oxygen saturation values transmitted from the device and simultaneous measurement with balloon flotation catheters. Four of the pulmonary artery leads dislodged and three demonstrated sensor drift, whereas two of the oxygen saturation sensors failed. Four patients died and four received transplants. Pathological study did not demonstrate injury to the right ventricular outflow tract or pulmonic valve. CONCLUSIONS: Chronic measurement of hemodynamic parameters in the outpatient setting with implantable sensor technology appears to be feasible. The devices are well tolerated without significant untoward effects, and the sensors generally function well over time, providing reliable information. Clinical usefulness remains to be established.     

Simulations of the mobile phase of polyethylene

Results are presented from atomistic molecular dynamics simulations of the mobile pseudo-hexagonal phase of polyethylene, which occurs under conditions of elevated pressure and temperature. Three different types of model are considered, all of which employ periodic boundary conditions. The first model consists of n-alkane sequences (48×-C₂₄H₄₈-) that are bonded across the simulation box boundaries to produce chains that are effectively infinite in extent. On heating, at high pressure, this system displays a rotator phase, in which the chains retain an all-trans conformation, and rotate as semi-rigid units. A second model, consisting of finite n-alkanes (48×C₂₄H₅₀) displays the same behaviour at low temperatures, but at high temperature and pressure forms a conformationally disordered rotator phase, characterised by a large proportion of gauche defects and a significant lattice expansion. The final model considered contains long n-alkanes (24×C₁₀₂H₂₀₆) which contain jog defects and each pass twice through the simulation box. This model forms a conformationally disordered rotator phase at high temperature and ambient pressure. The behaviour of the three models, in terms of the variations in chain conformation and rotational and translational dynamics, are compared. The conformationally disordered phases provide useful representations of the experimentally observed mobile phase.     

Effects of manufacturing defects on the mechanical properties of carbon fibre reinforced polyethersulphone laminates

The effects of defects on the mechanical properties of carbon fibre reinforced polyethersulphone laminates have been measured. The defects studied were cut fibre plies, omission of polymer films and local delamination produced by the inclusion of foreign matter. Of these it was found that only cut plies had a significant detrimental effect on the strength of a laminate. For specimens with two cut plies, the failure stress, tensile, flexural and compressive in the remaining continuous plies was the same as in the defect-free material, provided that the cut plies were widely separated. However the failure stresses were 15–18% lower in the continuous plies in the specimens containing two cut plies which were more closely spaced and in specimens containing four cut plies.     

The effects of a monetary alternative on marijuana self-administration

We have used a variety of methods to characterize the genome of the archaeon Methanosarcina thermophila TM-1. Pulsed-field gel analysis indicates a genome size of 2.8 Mb. We have constructed a bacterial artificial chromosome (BAC) library of M. thermophila and have used it to generate physical maps for this organism. The library is made up of 384 clones with an average insert size of 58 kb representing 8.0 genome equivalents. The utility of the library for low-resolution physical mapping was shown by identifying NotI linking clones and using these to order the NotI macrorestriction fragments of M. thermophila into a 2.8 Mb map. Hybridization of nine single copy genes and a 16S rRNA sequence to these macrorestriction fragments forms the basis for the first genetic map in this organism. High-resolution physical maps, consisting of overlapping clones, have been created using HindIII fingerprints of BAC clones. In this way, we identified a minimal path of five clones that span a 270 kb NotI fragment. The ease of manipulating BAC clones makes the BAC system an excellent choice for the construction of low-resolution and high-resolution physical and genetic maps of archaeal genomes. It also provides a substrate for future genome-sequencing efforts.     

Transconductance and mobility of Si:B delta MOSFETs

Delta-doped MOSFETs have been fabricated in MBE-grown silicon using for the first time boron as the dopant within the delta layer. Current-voltage characteristics have been measured, and secondary ion mass spectrometry (SIMS) is used to confirm the location of the delta layer and the extent of layer broadening by diffusion during processing. Precise threshold voltages of the devices are difficult to determine since the devices (which all operate in depletion mode) take several volts to switch off. Transconductances of the devices have been measured, and it is shown how analysis of these results can yield estimates of the carrier mobility for transport along the delta layers despite the uncertainty in the threshold voltage. A clear transition is observed in the results which is attributed to the formation of a parasitic surface-channel field-effect transistor, providing conclusive evidence that the devices are conducting along a delta channel for part of the measured range of applied gate biases