The tetravalent guanylhydrazone CNI-1493 blocks the toxic effects of interleukin-2 without diminishing antitumor efficacy

The use of interleukin 2 (IL-2) as an antineoplastic agent has been limited by the serious toxicities that accompany the doses necessary for a tumor response. Elevation of nitric oxide (NO) and tumor necrosis factor (TNF) both have been implicated in IL-2 toxicities. CNI-1493, a tetravalent guanylhydrazone, is an inhibitor of macrophage activation including the synthesis of TNF and other cytokines. Doses of CNI-1493 as low as 1 mg/kg/day conferred complete protection against fatal toxicity of IL-2 with IL-2 doses tenfold higher than the safely tolerated level in Sprague–Dawley rats. Moreover, typical pathologic changes in the lungs, kidneys, and the liver caused by IL-2 infusion were blocked by cotreatment with CNI-1493. When animals bearing established hepatomas were given IL-2 and CNI-1493 combination therapy, 10 of 10 hepatomas regressed from 1 cm3 to <1 mm3. Intracytoplasmic TNF levels were increased in normal tissues from IL-2 treated animals, and treatment with CNI-1493 maintained TNF at control levels. The degree of apoptosis measured by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining of tumors following IL-2 therapy was not reduced compared with IL-2 cotreated with CNI-1493. In contrast, apoptosis in the liver and lung parenchyma following IL-2 therapy was blocked completely by cotreatment with CNI-1493. Taken together, these data showed that low and infrequent doses of CNI-1493 markedly protected animals from IL-2 systemic toxicities whereas not affecting tumor response to IL-2 therapy. With the protection afforded by CNI-1493 treatment, IL-2 therapy dose levels could be increased to provide significant antitumor effects in animals with established hepatomas.

Structural changes in hemoglobin during adsorption to solid surfaces: Effects of pH, ionic strength, and ligand binding

We have studied the adsorption of two structurally similar forms of hemoglobin (met-Hb and HbCO) to a hydrophobic self-assembled methyl-terminated thiol monolayer on a gold surface, by using a Quartz Crystal Microbalance (QCM) technique. This technique allows time-resolved simultaneous measurements of changes in frequency (f) (c.f. mass) and energy dissipation (D) (c.f. rigidity/viscoelastic properties) of the QCM during the adsorption process, which makes it possible to investigate the viscoelastic properties of the different protein layers during the adsorption process. Below the isoelectric points of both met-Hb and HbCO, the ΔD vs. Δf graphs displayed two phases with significantly different slopes, which indicates two states of the adsorbed proteins with different visco-elastic properties. The slope of the first phase was smaller than that of the second phase, which indicates that the first phase was associated with binding of a more rigidly attached, presumably denatured protein layer, whereas the second phase was associated with formation of a second layer of more loosely bound proteins. This second layer desorbed, e.g., upon reduction of Fe3+ of adsorbed met-Hb and subsequent binding of carbon monoxide (CO) forming HbCO. Thus, the results suggest that the adsorbed proteins in the second layer were in a native-like state. This information could only be obtained from simultaneous, time-resolved measurements of changes in both D and f, demonstrating that the QCM technique provides unique information about the mechanisms of protein adsorption to solid surfaces.

The roles of prefrontal brain regions in components of working memory: Effects of memory load and individual differences

Using an event-related functional MRI design, we explored the relative roles of dorsal and ventral prefrontal cortex (PFC) regions during specific components (Encoding, Delay, Response) of a working memory task under different memory-load conditions. In a group analysis, effects of increased memory load were observed only in dorsal PFC in the encoding period. Activity was lateralized to the right hemisphere in the high but not the low memory-load condition. Individual analyses revealed variability in activation patterns across subjects. Regression analyses indicated that one source of variability was subjects’ memory retrieval rate. It was observed that dorsal PFC plays a differentially greater role in information retrieval for slower subjects, possibly because of inefficient retrieval processes or a reduced quality of mnemonic representations. This study supports the idea that dorsal and ventral PFC play different roles in component processes of working memory.

Covert attention accelerates the rate of visual information processing

Whenever we open our eyes, we are confronted with an overwhelming amount of visual information. Covert attention allows us to select visual information at a cued location, without eye movements, and to grant such information priority in processing. Covert attention can be voluntarily allocated, to a given location according to goals, or involuntarily allocated, in a reflexive manner, to a cue that appears suddenly in the visual field. Covert attention improves discriminability in a wide variety of visual tasks. An important unresolved issue is whether covert attention can also speed the rate at which information is processed. To address this issue, it is necessary to obtain conjoint measures of the effects of covert attention on discriminability and rate of information processing. We used the response-signal speed-accuracy tradeoff (SAT) procedure to derive measures of how cueing a target location affects speed and accuracy in a visual search task. Here, we show that covert attention not only improves discriminability but also accelerates the rate of information processing.