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.     

High char‐yielding poly[acrylonitrile‐co‐(itaconic acid)‐co‐(methyl acrylate)]: synthesis and properties

Polyacrylonitrile terpolymers of various compositions consisting of acrylonitrile (AN), itaconic acid (IA) and methyl acrylate (MA) were synthesized by solution polymerization in dimethylsulfoxide. Increase in concentration of either IA or MA retarded the overall polymerization rate and the polymer molecular weight. The system consisting of AN + MA and varying IA concentration was more prone to retardation in comparison with the system composed of AN + IA with variable MA concentration. The retardation factors were quantified. Minor quantities of MA boost the reactivity of IA in the terpolymer system. The terpolymer was richer in MA vis‐à‐vis the feed. The thermal characteristics of the terpolymer were examined as a function of its composition. In contrast to the copolymer of AN and IA requiring 1–1.5 mol% IA, the terpolymer required an IA content of approximately 2.5 mol% for optimum thermal stability. The polymer with 90 mol% AN, 2.5 mol% IA and 7.5 mol% MA exhibited reasonably good char‐forming characteristics and thermal stability. The overall crystallinity and crystallite size of the polymers were found to decrease on incorporation of the comonomers. The ‘aromatization index’ of the copolymer increased with the temperature of pyrolysis through re‐organization of the tetrahydropyridine ladder structure. Copyright © 2005 Society of Chemical Industry     

High yield formation of carbon nanotubes using a rotating cathode in open air

Carbon nanotubes (CNTs) have been synthesized using the arc discharge method with a rotating graphite disc as the cathode. Arcing was carried out in open air and without the use of catalysts. The current density was maintained constant through out the experiment, while, the rate of rotation of the cathode and atmosphere under which arcing was carried out were changed during experimentation. Characterization of the samples produced indicates that rotation of the cathode has a significant impact on the quality and yield of the process. It is proposed that rotation of the cathode drags plasma formed between two electrodes away from high temperature region. This results in a sudden quenching of the reactive plasma. The time available for nucleation and growth phenomena is significantly reduced and thus leads to the formation of highly graphitic multi walled CNTs (yield 60%) and traces of double walled CNTs.     

Serial cytological assay of micronucleus induction: a new tool to predict human cancer radiosensitivity

The role of the propeptide sequence and a disulfide bridge between sites 1 and 122 in chymotrypsin has been examined by comparing enzyme activities of wild-type and mutant enzymes. The kinetic constants of mutants devoid of the Cys1-Cys122 disulfide-linked propeptide show that this linkage is not important either for activity or substrate specificity. However this linkage appears to be the major factor in keeping the zymogen stable against non-specific activation. A comparison of zymogen stabilities showed that the trypsinogen propeptide is ten times more effective than the chymotrypsinogen propeptide in preventing non-specific zymogen activation during heterologous expression and secretion from yeast. This feature can also be transferred in trans to chymotrypsinogen; i.e. the chymotrypsin trypsin propeptide chimera forms a stable zymogen.     

Development of Anticandidal Delivery Systems: (I) Anticandidal Activities of Antifungal Agents and Synergistic Combination with Other Drugs

Susceptibility testing with antifungal agents, e. g., minimum inhibitory concentration (MIC) determination, is performed to obtain reliable data that permit selection of the most suitable agents for treatment of an infective condition. To determine the drugs that provide maximum effectiveness against oral candidiasis, the MICs of various antifungal agents were determined. Also, synergism between two chosen antifungal agents was evaluated, and the effect of benzocaine, an anesthetic, and hydrocortisone, an antiinflammatory agent, on their MICs was examined. It was observed that among all the drugs tested, clotrimazole was the most promising candidate for use as an oral local antifungal. The combination of clotrimazole and chlorhexidine resulted in a decrease in the MIC. While the addition of hydrocortisone to this combination resulted in a slight increase in the MIC, the inclusion of benzocaine resulted in a substantial decrease in the MIC of the antifungal agent combination.     

Identifying technology horizons for strategic investment decisions

Technology investment models usually assume that a known number of technologies will appear in the future, though their appearance, cost, and revenue parameters may be uncertain. In practice, however, it is not always clear how many future technologies or periods need to be considered. We introduce the concept of a technology horizon, which we define as the minimum number of future technologies and future periods that need to be considered to guarantee that the optimal decision would not change even if additional technologies or periods worth of data were to be considered. We also allow the costs and revenue of existing technologies in our model to vary depending on the latest technology introduced. Further, we allow for implementation costs, which enables us to model situations where it may cost more to leapfrog technologies than if one were to buy intervening technologies. We then provide a fast algorithm to identify such technology horizons     

Novel A-sandwich radome design for airborne applications

A novel A-sandwich hybrid variable thickness radome design, based on optimised power reflection, is presented. The radome performance parameters are evaluated accurately by a 3D ray-tracing procedure in conjunction with the aperture integration method. This design is demonstrated to be a better choice when multiple performance parameters need to be satisfied simultaneously.     

Genetic definition of a new bovine papillomavirus type 1 open reading frame, E5B, that encodes a hydrophobic protein involved in altering host-cell protein processing

We have previously observed that bovine papillomavirus type 1 (BPV-1) induces the appearance of five cellular proteins in C127 mouse fibroblasts, four of which appear to arise by altered processing of resident endoplasmic reticulum proteins. Studies of various cell lines revealed that expression of the 3' end of the BPV early region was sufficient for induction of these changes. To identify the BPV gene responsible, we have utilized the simian virus 40 (SV40)/BPV-1 recombinant virus Pava-1, which expresses the 3' end of the BPV early region behind an SV40 early promoter. C127 cells infected with Pava-1 for 48 h show the expected BPV-associated alterations, as do cells infected with Pava constructs mutated in the E5 or E2 genes. However, a mutation in the start codon of a previously ignored open reading frame extending from nucleotides 4013 to 4170 (E5B) eliminated the BPV-associated changes. Similar results were obtained with COS cells infected with the Pava mutants and C127 cells transformed by full-length mutated BPV. Despite its influence on the processing of cellular endoplasmic reticulum proteins, this mutation in E5B did not alter BPV-transforming efficiency or the ability of transformants to form colonies in soft agar. The E5B open reading frame encodes a hydrophobic 52-amino-acid polypeptide that shares structural similarities with HPV6 E5A and HPV16 E5. Speculations on a role for E5B in the viral life cycle are discussed.     

Dual frequency miniature microstrip antenna

A single-feed dual frequency compact microstrip antenna with a shorting pin is described. This new antenna configuration gives a large variation in frequency ratio of the two operating frequencies, without increasing the overall size of the antenna