Dynamic contrast-enhanced magnetic resonance imaging as a biomarker for the pharmacological response of PTK787/ZK 222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases, in patients with advanced colorectal cancer and liver metastases: Results from two phase I studies

Purpose: PTK787/ZK 222584 (PTK/ZK), an orally active inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, inhibits VEGF-mediated angiogenesis. The pharmacodynamic effects of PTK/ZK were evaluated by assessing changes in contrast-enhancement parameters of metastatic liver lesions using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in patients with advanced colorectal cancer treated in two ongoing, dose-escalating phase I studies. Patients and Methods: Twenty-six patients had DCE-MRI performed at baseline, day 2, and at the end of each 28-day cycle. Doses of oral PTK/ZK ranged from 50 to 2000 mg once daily. Tumor permeability and vascularity were assessed by calculating the bidirectional transfer constant (Ki). The percentage of baseline Ki (% of baseline Ki) at each time point was compared with pharmacokinetic and clinical end points. Results: A significant negative correlation exists between the % of baseline Ki and increase in PTK/ZK oral dose and plasma levels (P = .01 for oral dose; P = .0001 for area under the plasma concentration curve at day 2). Patients with a best response of stable disease had a significantly greater reduction in Ki at both day 2 and at the end of cycle 1 compared with progressors (mean difference in % of baseline Ki, 47%, P = .004%; and 51%, P = .006; respectively). The difference in % of baseline Ki remained statistically significant after adjusting for baseline WHO performance status. Conclusion: These findings should help to define a biologically active dose of PTK/ZK. These results suggest that DCE-MRI may be a useful biomarker for defining the pharmacological response and dose of angiogenesis inhibitiors, such as PTK/ZK, for further clinical development. © 2003 by American Society of Clinical Oncology.

Chemotaxis and chemokinesis of human prostate tumor cell lines in response to human prostate stromal cell secretory proteins containing a nerve growth factor-like protein

The migration of three human prostate tumor epithelial cell lines (TSU-pr1, PC-3, DU-145) in response to secreted protein from a human prostate stromal cell line was investigated by using the modified blind-well Boyden chamber assay. Migrated cells were quantified by spectrophotometrically measuring the concentration of crystal violet stain extracted from their nuclei. Cell number was correlated linearly with the concentration of extracted crystal violet stain. All three tumor cell lines showed intrinsic migratory ability in the absence of chemoattractants, such that approximately 1-7% of plated cells migrated across the filter of the Boyden chambers during a 5-h incubation period. Prostate tumor cell migration was significantly enhanced (3-13-fold) in response to stromal cell secretory protein in a dose-dependent manner, whereas bovine serum albumin had no effect on stimulating tumor cell migration. Immunoprecipitation of the stromal cell secreted protein with a nerve growth factor antibody partially and significantly reduced its stimulatory activity for tumor cell migration. A Zigmond-Hirsch matrix assay of tumor cell migration in response to various concentration gradients of stromal cell secreted protein demonstrated both chemotaxis and chemokinesis by all three cell lines. These results are consistent with the stromal cell secretory protein stimulation of chemokinetic tumor cell migration through the capsule of the prostate. Outside of the prostate gland metastasis of tumor cells may occur by chemotaxis to preferential sites containing chemoattractants similar to or related to maintenance factors that can substitute for components of stromal cell secretory protein.

Invasive activity and chemotactic response to growth factors by Kaposi's sarcoma cells

Kaposi's sarcoma (KS) is a relatively low grade neoplasm, classically occurring in the skin of elderly men. A more virulent and invasive form of Kaposi's sarcoma has been described in patients with acquired immune deficiency syndrome (AIDS). The origin and identification of the tumor cells in these lesions is controversial. Here we have studied the behavior of cells derived from KS lesions in an in vitro assay which measures the ability of cells to invade through a reconstituted basement membrane. In agreement with previous work, KS cells obtained under selective culture conditions were invasive showing activity comparable to that of malignant tumor cells. Normal fibroblasts, smooth muscle cells, and endothelial cells did not demonstrate invasive behavior under the same experimental conditions. To characterize further the nature of the KS cells we tested the chemotactic response of cells from the most invasive line to a variety of growth factors and compared their response to those of fibroblasts, smooth muscle, and endothelial cells. These studies suggest that normal cells respond to a unique repertoire of chemotactic factors. The chemotactic response of the KS cells most closely resembled that of smooth muscle cells and was quite distinct from endothelial cells. These results indicate that the KS-derived cultures contain invasive cells with a smooth muscle cell-like phenotype.

Genetic response to growth rate selection in pigs measured on two feeding levels

From the findings of McPhee et al. (1988), there is an expectation that selection in the growing pig for bodyweight gain measured on restricted feeding will result in favourable responses in the rate and efficiency of growth of lean pork on different levels of feeding. This paper examines this in two lines of Australian Large White pigs which have undergone 3 years of selection for high and for low growth rate over a 6-week period starting at 50 kg liveweight. Over this test period, pigs of both lines are all fed the same total amount of grower food, restricted to an estimated 80% of average ad libitum intake. 'Animal production for a consuming world': proceedings of 9th Congress of the AAAAP Societies and 23rd Biennial Conference of the ASAP and 17th Annual Symposium of the University of Sydney, Dairy Research Foundation, (DRF). Sydney, Australia.

Growth and physiological response of six Australian rainforest tree species to a light gradient

An understanding of growth and photosynthetic potential of subtropical rainforest species to variations in light environment can be useful for determining the sequence of species introductions in rainforest restoration projects and mixed species plantations. We examined the growth and physiology of six Australian subtropical rainforest tree species in a greenhouse consisting of three artificial light environments (10%, 30%, and 60% full sunlight). Morphological responses followed the typical sun-shade dichotomy, with early and late secondary species (Elaeocarpus grandis, Flindersia brayleyana, Flindersia schottiana, and Gmelina leichhardtii) displaying higher relative growth rate (RGR) compared to mature stage species (Cryptocarya erythroxyion and Heritiera trifoliolatum). Growth and photosynthetic performance of most species reached a maximum in 30-60% full sunlight. Physiological responses provided limited evidence of a distinct dichotomy between early and late successional species. E. grandis and F brayleyana, provided a clear representation of early successional species, with marked increase in Am in high light and an ability to down regulate photosynthetic machinery in low light conditions. The remaining species (F. schottiana, G. leichhardtii, and H. trifoliolatum) were better represented as failing along a shade-tolerant continuum, with limited ability to adjust physiologically to an increase or decrease in light, maintaining similar A(max) across all light environments. Results show that most species belong to a shade-tolerant constituency, with an ability to grow and persist across a wide range of light environments. The species offer a wide range of potential planting scenarios and silvicultural options, with ample potential to achieve rapid canopy closure and rainforest restoration goals.

Growth analysis and biomass partitioning of Cyperus iria in response to rice planting density and nitrogen rate

Cyperus iria is a weed of rice with widespread occurrence throughout the world. Because of concerns about excessive and injudicious use of herbicides, cultural weed management approaches that are safe and economical are needed. Developing such approaches will require a better understanding of weed biology and ecology, as well as of weed response to increases in crop density and nutrition. Knowledge of the effects of nitrogen (N) fertilizer on crop-weed competitive interactions could also help in the development of integrated weed management strategies. The present study was conducted in a screenhouse to determine the effects of rice planting density (0, 5, 10, and 20 plants pot−1) and N rate (0, 50, 100, and 150 kg ha−1) on the growth of C. iria. Tiller number per plant decreased by 73–88%, leaf number by 85–94%, leaf area by 85–98%, leaf biomass by 92–99%, and inflorescence biomass by 96–99% when weed plants were grown at 20 rice plants pot−1 (i.e., 400 plants m−2) compared with weed plants grown alone. All of these parameters increased when N rates were increased. On average, weed biomass increased by 118–389% and rice biomass by 121–275% with application of 50–150 kg N ha−1, compared to control. Addition of N favored weed biomass production relative to rice biomass. Increased N rates reduced the root-to-shoot weight ratio of C. iria. Rice interference reduced weed growth and biomass and completely suppressed C. iria when no N was applied at high planting densities (i.e., 20 plants pot−1). The weed showed phenotypic plasticity in response to N application, and the addition of N increased the competitive ability of the weed over rice at densities of 5 and 10 rice plants pot−1 compared with 20 plants pot−1. The results of the present study suggest that high rice density (i.e., 400 plants m−2) can help suppress C. iria growth even at high N rates (150 kg ha−1).

Growth kinetics and immune response of chimeric foot-and-mouth disease virus serotype `O' produced through replication competent mini genome of serotype Asia 1, 63/72, in BHK cell lines

Regular vaccinations with potent vaccine, in endemic countries and vaccination to live in non-endemic countries are the methods available to control foot-and-mouth disease. Selection of candidate vaccine strain is not only cumbersome but the candidate should grow well for high potency vaccine preparation. Alternative strategy is to generate an infectious cDNA of a cell culture-adapted virus and use the replicon for development of tailor-made vaccines. We produced a chimeric `O' virus in the backbone of Asia 1 and studied its characteristics. The chimeric virus showed high infectivity titre (>10(10)) in BHK 21 cell lines, revealed small plague morphology and there was no cross reactivity with antiserum against Asia I. The virus multiplies rapidly and reaches peak at 12 h post infection. The vaccine prepared with this virus elicited high antibody titres.

Edge-defined, film-fed growth (EFG) technique for the preparation of alpha-Al2O3 : C crystal with highly sensitive thermoluminescence response

In this work, alpha-Al2O3:C, a highly sensitive thermoluminescence dosimetry crystal, was grown by the EFG method in which a graphite heating unit and shield acted as the carbon source during the growth process. The optical, luminescent properties and dosimetric characteristics of the crystal were investigated. The as-grown crystal shows a single glow peak at 536 K, which is associated with Cr3+ ions. After annealing in H-2 at 1673 K for 80 h, the crystal shows a single glow peak at 460 K and a blue emission band at 415 nm. The thermoluminescent response of the annealed crystal shows linear-sublinear-saturation characteristics in the dose range from 5 x 10(-6) to 100 Gy.

Effects of dietary ascorbic acid supplementation on the growth performance, immune and stress response in juvenile Leiocassis longirostris Gunther exposed to ammonia

This experiment was designed to investigate the effect of dietary supplemental ascorbic acid (AA) on the feed intake, growth, serum lysozyme, hepatic superoxide dismutase (SOD) and handling stress response in Chinese longsnout catfish (Leiocassis longirostris Gunther) exposed to three levels of unionized ammonia nitrogen (UIA-N). Juvenile Chinese longsnout catfish were reared in 54 fibreglass tanks with a 3 x 3 factorial design treatment consisting of three supplemental AA levels in ascorbyl 2-monophosphate (38, 364 and 630 mg AA equivalent kg(-1) diet) and three UIA-N concentrations [0.004 (the control), 0.037 and 0.292 mg L-1]. The fish were sampled on the 11th, 32nd and 60th day. On the 62nd day, the remaining fish were subjected to an acute stress by being held in a dipnet out of water for 60 s, and sampled at 30 min post handling. The results showed that the specific growth rate (SGR) in 32 days significantly decreased with increased water UIA-N (P=0.0476) but was not affected by dietary supplemental AA (P > 0.05). After 60 days, SGR, feeding rate (FR) and feed conversion efficiency (FCE) significantly increased with increased dietary supplemental AA (P < 0.001) while remaining unaffected by water UIA-N (P > 0.05). There was no significant interaction between dietary AA and UIA-N for growth responses (P > 0.05). The serum lysozyme activity on the 11th day and the hepatic SOD activity on the 32nd day were significantly affected at high (0.292 mg L-1) water UIA-N. On the 62nd day, the increase in cortisol resulting from acute stress significantly decreased by higher UIA-N (P=0.038). It is suggested that Chinese longsnout catfish displayed an adaptive response after long-term UIA-N exposure, and AA had beneficial effects on the growth and feed intake of catfish and alleviated the negative effects of chronic ammonia stress. A chronically higher ammonia level shows a tendency to inhibit the cortisol response to another acute stressor.