Comparative analysis of MAPK and PI3K/AKT pathway activation and inhibition in human and canine melanoma.

The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations.

Topical chlorhexidine diphosphanilate (WP-973) in burn wound sepsis.

We studied the diphosphanilate salt of chlorhexidine (WP-973), as a 2% cream, for therapeutic activity in two rat models of fatal burn wound infection. Control treatments were infection and placebo cream; infection only; infection and 1% sulfadiazine silver; and burning only. Activity against Pseudomonas aeruginosa or Proteus mirabilis was tested in surface-inoculated rats with 20% scalds. Treatments were initiated 24 hours or four hours, respectively, after inoculation. Pseudomonas-infected rats were treated once a day for ten days. Proteus-infected rats were treated once a day for five days. In these experimental models, chlorhexidine diphosphanilate was equal to silver sulfadiazine, an established topical chemotherapeutic agent. In vitro activity was examined using bacteremia isolates from 65 burned patients. Using agar diffusion trench plates, chlorhexidine diphosphanilate was active against all strains. No evidence of cross-resistance between sulfonamide and chlorhexidine diphosphanilate or its components was observed.

Mechanisms of in vitro sensitivity to sulfadiazine silver.

Sulfonamide-resistant organisms have been reported as a frequent consequence of the clinical use of sulfadiazine silver. At this burn center, sulfonamide resistance occurred in more than 80% of gram-negative isolates. We tested the requirement for the individual antimicrobial activities of sulfadiazine and silver for the vitro activity of sulfadiazine silver. The sulfadiazine component is not necessary for in vitro sensitivity. In vitro sensitivity to sulfadiazine silver does not consistently predict the presence of therapeutic activity in Pseudomonas aeruginosa-infected rats with burns. We describe an example of a transferable multiple-antibiotic resistance plasmid that contains selectable sulfonamide resistance. The use of sulfadiazine silver can, therefore, lead to the selection of organisms that are resistant not only to sulfonamides but to antibiotics of clinical consequence, and this possible risk must be considered in electing to use the agent.

Span of apprehension in hyperactive boys.

The spans of apprehension of hyperactive and normal boys were compared with a forced-choice letter-recognition task developed by Estes (1965). This task provides an estimate of the span which is relatively insensitive to either memory or motivational influences. The span size was the same for both groups when visual "noise" was absent. In the presence of noise, span size for the hyperactive boys decrease. Moreover, as the number of noise letters increased, the reduction in span size observed for the hyperactive boys increased. It is argued that this increasing reduction in span size represents a true deficit in attention.

Effect of noise distractibility on the spans of apprehension of hyperactive boys.

Denton and McIntyre (1978), using a forced-choice letter-recognition procedure, demonstrated increasing reductions in the spans of apprehension of hyperactive as compared to normal boys when a signal letter was embedded within an increasing number of noise letters. In the present study, the effect of variations in the amount of physical signal-noise similarity and noise redundancy upon the spans of apprehension of hyperactive and normal boys was compared to determine whether noise letters act as more potent distractors for the hyperactive boys. Results indicated the spans of both groups were effected equivalently by variations in signal-noise similarity and noise redundancy. No evidence for a distractibility explanation was obtained.