Growth of human glioblastomas as xenografts in the brains of athymic rats

BACKGROUND: We have developed xenografts of human glioblastoma (GBM) and established the baseline growth parameters and histopathological features of these tumors. MATERIALS-METHODS: Cells from 4 different human GBM cell lines were injected into the right caudate-putamen of brain in athymic rats. We measured tumor weights and the estimated survival time of each rat. RESULTS-CONCLUSION: U-251 MG and U-87 MG cells produced solid intracerebral tumors with a 100% tumor take rate, while SF-767 and SF-126 cells did not grow in the brains of athymic rats. Under the conditions employed, U-87 MG tumors grew faster than U-251 MG tumors, but both types of tumors exhibited reproducible growth characteristics from animal to animal. There was heterogeneity in the growth characteristics and histologies between the 2 tumor types, indicating that these tumor models might be useful for simulating some of the heterogeneity that occurs between GBM in humans.     

Low serum levels of high-density lipoprotein cholesterol and hypolipidaemic treatment

Low serum levels of high-density lipoprotein (HDL) cholesterol is an independent risk factor for coronary artery disease. Raising HDL cholesterol should be an important therapeutic goal in patients with coronary artery disease. Fibrates can reduce the risk of cardiac events and death from coronary artery disease.     

Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?

The alignment of drug metabolism and pharmacokinetic departments with drug discovery has not produced a radical improvement in the pharmacokinetic properties of new chemical entities. The reason for this is complex, reflecting in part the difficulty of combining potency, selectivity, water solubility, metabolic stability and membrane permeability into a single molecule. This combination becomes increasingly problematic as the drug targets become more distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads available for aminergic 7-TMs, like the natural agonists, are invariably small molecular weight, water soluble and potent. Even moving to 7-TMs for which the agonist is a peptide invariably produces lead matter that is less drug-like (higher molecular weight and lipophilic). The role of drug metabolism departments, therefore, has been to guide chemistry to obtaining adequate, rather than optimal, pharmacokinetic properties for these 'difficult' drug targets. A consistent belief of many researchers is that a high value is placed on optimal, rather than adequate, pharmacokinetic properties. One measure of value is market sales, and when these are examined no clear pattern emerges. Part of the success of amlodipine in the calcium channel antagonist sector must be due to its excellent pharmacokinetic profile, but the best-selling drugs among the angiotensin antagonists and beta-blockers have a much greater market share than other agents with better pharmacokinetic properties. Clearly, many other factors are important in the successful launch of a medicine, some reflected in the manner the compound is developed and the subsequent structure of the labelling. Overall, therefore the presence of drug metabolism in drug discovery has probably contributed most by allowing 'difficult' drug targets to be prosecuted, rather than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult' target candidates become successful drugs when skilfully developed. There is no doubt that skilful development relies heavily on drug metabolism and pharmacokinetic departments, in this case those with a clinical rather than a preclinical orientation.     

Single or group housing altered hormonal physiology and affected pituitary and interstitial cell kinetics

A significant negative correlation between testicular interstitial cell tumors and pituitary tumors in control male F344 rats has been reported associated with the number of animals per cage. Change in numbers of animals per cage may cause stress and increased serum corticosteroids that can impair testosterone synthesis by interstitial cells. Eventual atrophy of interstitial cells may result in pituitary hyperfunction and tumor development. For relevant risk assessments, understanding the effect husbandry has on cellular processes is necessary. Twenty-four 6-week-old male F344 rats were housed individually, as pairs, or as trios for 13 weeks. Measured parameters included feed consumption, body and organ weights, hemograms, hormonal levels, histopathology, and cellular kinetics in the pituitary and testicle. Several caging-related differences occurred, that, although not statistically different, could be biologically significant; these included increased serum levels of estradiol, progesterone, and corticosterone; increased spermatogonial proliferation; decreased apoptosis within seminiferous tubules; and increased BrdU immunoreactivity of the interstitial cells. The statistically significant decrease in lymphocyte numbers correlated with the associated increase in corticosterone levels. This study indicates that the number of animals in a cage is associated with hormonal and cellular kinetic changes in the pituitary and testes, which could influence the incidence of tumors in these organs.     

The impact of maintenance and design for ventilation systems

Ventilation systems need to be designed to include access for cleaning and preventive maintenance. Without such access, the exhaust volume will deteriorate. Because of access difficulties and the many demands on their time, plant managers are sometimes errant in performing proper preventive maintenance. Three surveys measuring workers' exposures to methylene chloride were conducted at the same furniture stripping facility. A new ventilation system was installed for the first survey, resulting in an exhaust volume of 2900 cfm and worker exposure to methylene chloride of 59 ppm (geometric mean). Immediately after the first survey, the gasoline-powered fan was replaced by a smaller capacity electrically powered fan. Deterioration in the ventilation system was seen after seven years. Problems included clogged slots, paint chips and sawdust deposits in plenums, and a loose and frayed fan belt. The second survey indicated a reduction in exhaust volume to 1060 cfm and increased worker exposure to 330 ppm. With the smaller capacity fan still in place, the system was otherwise upgraded to allow for easier access and maintenance was performed. The third survey showed that the ventilation system performance was better (exhaust volume improved to 2080 cfm) and the worker exposures were reduced to 73 ppm. This study shows the benefits of designing for preventive maintenance and the necessity of keeping the ventilation systems clean.     

Occupation and risk of non-Hodgkin's lymphoma and chronic lymphocytic leukemia

To investigate the association between occupation and the risk of non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and to test whether the associations may vary by histological type of NHL, we analyzed data from two population-based, case-control studies of NHL performed in Kansas and Nebraska. A total of 555 incident NHL cases, 56 CLL cases, and 2380 population-based controls were included in the analysis. Information on occupation and other confounding factors was collected through telephone interviews. Study pathologists reviewed slides of tumor tissues in all cases. In men, we found an increased risk of NHL and CLL for those working in agricultural, forestry, and logging industries (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.2 to 2.1). The OR was 1.9 (95% CI, 1.4 to 2.6) for those producing crops. An increased risk was also observed for industries involving metalworking machinery and equipment (OR, 8.4; 95% CI, 1.4 to 50.6), motor vehicles and motor vehicle equipment (OR, 4.2; 95% CI, 1.3 to 13.9), and telephone communications (OR, 3.1; 95% CI, 1.2 to 8.0), and for teachers (OR, 2.5; 95% CI, 1.0 to 6.5), farmers (OR, 2.0; 95% CI, 1.5 to 2.8), and welders and solderers (OR, 2.9; 95% CI, 1.2 to 6.9). The risks for these associations increased by duration of employment and seem to vary by histological type. Work in the printing and publishing industry was also associated with an increased risk of NHL among women. These data suggest that the workers employed in these industries or occupations experienced an increased risk of NHL and CLL, and the risks associated with these industries or occupations may vary by histological type of NHL.