Cotreatment with a novel phosphoinositide analogue inhibitor and carmustine enhances chemotherapeutic efficacy by attenuating AKT activity in gliomas

BACKGROUND: Heightened activity of the AKT signaling pathway is prominent in malignant gliomas and has been suggested to play a role in treatment resistance. Selective targeting of AKT, therefore, may increase chemosensitivity. Recently, a novel class of AKT-selective inhibitors has been described, including SH-6, a phosphatidylinositol analogue. METHODS: The effects of SH-6 on AKT signaling were tested in glioma cells, and the putative role of AKT signaling in chemoresistance was tested by attenuating AKT signaling pharmacologically and genetically. The initial characterization of SH-6 included treatment of glioma cells with increasing doses of SH-6 (0.30-30 microM) and examining the effects on AKT signaling proteins by Western blot analyses and in kinase assays with immunoprecipitated AKT1. Dose-response studies with SH-6 administered to glioma cell lines were performed using a luminescent cell-viability assay (0.1-30 microM). Studies examining the effect of carmustine, either alone or in combination with either the phosphatidylinositol 3-kinase inhibitor LY294002 or SH-6, were performed by cell viability assays and clonogenic survival assays. The effect of carmustine on AKT activity as a response to treatment also was examined. Caspase assays were used to examine the potential role of apoptosis in SH-6/ carmustine -elicited cell death. Finally, the induction of a dominant-negative AKT1 transgene was used in combination with carmustine to demonstrate the role of AKT1 in carmustine chemoresistance. RESULTS: Serum-stimulated phosphorylation of AKT1 was inhibited by SH-6 at doses > or =10 microM (>70% decrease in Threonine 308 and Serine 473 phosphorylation of AKT1). In adenosine triphosphate assays, 72 hours of treatment with SH-6 led to 50% lethal doses near 10 microM for 2 cell lines tested. SH-6 enhancement of carmustine-mediated cell death led to synergistic increases in Caspase 3/Capsase 7 activity, implicating apoptosis as the cell death mechanism. In clonogenic assays, SH-6 cotreatment with carmustine significantly decreased the number of colonies at 10 microM (P < .05) compared with carmustine alone. No decrease was observed in cells that were treated with SH-6 alone (10 microM). LY294002 (10 microM) was also able to enhance the effects of carmustine significantly in both cell lines. CONCLUSIONS: In the current study, the authors characterized the efficacy of a new class of adjuvant chemotherapeutics that show promise in enhancing the efficacy of standard chemotherapy regimens in gliomas.     

Progress in cerebral transplantation of expanded neuronal stem cells

OBJECT: Given the success and limitations of human fetal primary neural tissue transplantation, neuronal stem cells (NSCs) that can be adequately expanded in culture have been the focus of numerous attempts to develop a superior source of replacement cells for restorative neurosurgery. To clarify recent progress toward this goal, the transplantation into the adult brain of NSCs, expanded in vitro before grafting, was reviewed. METHODS: Neuronal stem cells can be expanded from a variety of sources, including embryos, fetuses, adult bone marrow, and adult brain tissue. Recent investigations of each of these expanded stem cell types have generated a large body of information along with a great number of unanswered questions regarding the ability of these cells to replace damaged neurons. Expanded NSCs offer many advantages over their primary tissue predecessors, but also may exhibit different functional abilities as grafted cells. Because expanded NSCs will most likely ultimately replace primary tissue grafting in clinical trials, this review was undertaken to focus solely on this distinct body of work and to summarize clearly the existing preclinical data regarding the in vivo successes, limits, and unknowns of using each expanded NSC type when transplanted into the adult brain. CONCLUSIONS: Embryonic stem cell-derived cells have demonstrated appropriate neuronal phenotypes after transplantation into nonneurogenic areas of the adult brain. Understanding the mechanisms responsible for this may lead to similar success with less studied adult neuronal progenitor cells, which offer the potential for autologous NSC transplantation with less risk of tumorigenesis.     

Cell replacement efforts to repair neuronal injury: a potential paradigm for the treatment of Parkinson's disease

Much has been learned from recent clinical trials exploring cell transplantation as a means to treat Parkinson's disease. Additionally, much information is being gathered in the science arena on the method of cultivation and expansion of neural stem/progenitor cells as well as catheter and cell delivery methodology. Cell replacement remains a potential promising treatment option for Parkinson's disease, however several obstacles must be overcome in order to achieve successful outcomes in future clinical trials. Hurdles include but are not limited to the identification of a reliable method of cultivation and expansion of neural stem/progenitor cells, the optimization of methods for cell delivery and the optimization of location or locations for transplantation.     

Environmental dependence of behavioral control mechanisms: effects of alcohol and information processing demands

Studies show that alcohol increases a drinker's reliance on the environmental context for the maintenance of inhibitory and activational responding. The author of the present study examined additive effects of alcohol and cognitive load on the cue dependency of inhibitory and activational mechanisms of control. Adults received 0.0 g/kg, 0.45 g/kg, and 0.65 g/kg alcohol and performed a cued go/no-go task that presented simple and complex go and no-go stimuli. Results showed that cue dependency of response inhibition increased as a function of dose, and this effect was similar across low and high cognitive load conditions. These findings are consistent with a capacity limitation account of alcohol impairment that could involve central or output stages of information processing.     

Preresponse cues reduce the impairing effects of alcohol on the execution and suppression of responses

The present study examined the effects of alcohol on the ability to execute and inhibit behavior in a context in which preliminary information signaled the likelihood that a response should be executed or suppressed. Social drinkers (N = 12) performed a cued go/no-go task that required quick responses to go targets and suppression of responses to no-go targets. Performance was tested under 3 doses of alcohol: 0.65 g/kg, 0.45 g/kg, and 0.0 g/kg (placebo). Alcohol had no effect on inhibition and execution when cues correctly signaled these actions. By contrast, alcohol impaired inhibition and execution in a dose-dependent manner when cues incorrectly signaled actions. These findings are consistent with a resource limitation account of alcohol impairment.     

Alcohol-induced impairment of behavioral control: effects on the alteration and suppression of prepotent responses

OBJECTIVE: Alcohol use in humans is associated with aggression and other socially inappropriate behaviors. These adverse effects have been attributed to an acute impairment of behavioral control, and research findings indicate that inhibitory aspects of behavioral control might be particularly vulnerable to the effects of alcohol. The present study tested the degree to which alcohol-induced impairment of behavioral control is due to a specific impairment of inhibitory mechanisms or due to a general information processing deficit. METHOD: Forty subjects (29 men) performed a cued reaction time task before and after receiving 0.65 g/kg alcohol or a placebo. Subjects performed the task under conditions that differed in the type of response needed to maintain behavioral control: response-suppression and response-alteration. RESULTS: Alcohol impairment was observed when behavioral controlwas dependent on response-suppression, but no impairment was observed when control relied on response-alteration. CONCLUSIONS: The findings point to the susceptibility of inhibitory processes by showing that alcohol can be particularly detrimental to behavioral control in situations where prepotent responses must be completely suppressed. Evidence for alcohol-induced impairment of inhibitory functions could provide important clues about basic behavioral mechanisms by which alcohol disrupts such higher order cognitive processes as working memory, learning and decision making.     

Alcohol effects on intentional behavior: dissociating controlled and automatic influences

This research examined the effect of alcohol on intentional behavior using a process dissociation procedure to separate the influences of conscious controlled processes from those of unconscious automatic processes. In 2 identical experiments, 24 male social drinkers studied a list of words before they received either 0.56 g/kg alcohol, an alcohol placebo, or soda. Participants then performed a word stem completion test that provided estimates of controlled influences and of automatic influences on their responses. The results of the 2 experiments were consistent. Comparisons among the treatments showed that alcohol reduced conscious controlled processes and left automatic processes unchanged. The findings contribute to understanding how the drug may reduce cognitive control of intentional behavior and raise important questions concerning personal and environmental factors that might mediate these effects.     

Achieving treatment goals for schoolchildren with asthma

OBJECTIVES: To identify problems in managing asthmatic children in school, which if dealt with would help reduce absenteeism and improve participation in school activities. DESIGN: A survey by questionnaire to headteachers. SETTING: Schools in Merthyr and Rhondda Cynon Taff, South Wales. SUBJECT: Asthmatic schoolchildren in areas studied. MAIN OUTCOME MEASURES: Facilities in schools to manage asthma, headteachers' perceptions of knowledge of asthma management by teachers, possession of written policies, and desire for further training. RESULTS: There are 216 schools in the area studied, with 55,166 schoolchildren. A total of 191 (88%) headteachers returned the completed questionnaire. Five hundred and twenty seven (17%) children were reported absent from school during one term because of asthma, with an average of nine days of schooling lost per asthmatic child per term (range 2-16 days). Only 76 (40%) schools allowed children to be responsible for their inhalers, and 12 (6%) schools required parents to administer inhalers. In 115 (60%) schools, headteachers believed their staff were familiar with the management of asthma. A total of 174 (91%) headteachers expressed interest in further training. CONCLUSION: This study highlights the need to train teachers and provide an agreed joint education and health policy on managing asthma in school.