The p53 tumor suppressor gene is one of the genes with greatest therapeutic potential for cancer treatment and its growth inhibitory mechanism is thought to be mediated through the activation of its downstream mediator, WAF1/Clip1. In this study, we evaluated the effect of the replication-defective recombinant adenovirus expressing wild-type p53 gene(Ad5CMV-p53) in human glioma cell lines(U-251, LG) harboring mutant-type p53. beta-galactosidase histochemistry revealed that 90% of the U-251 and 42% the of LG cells are infected with the adenovirus at a multiplicity of infection(MOI) of 25 plaque-forming units(PFU)/cell. Immunoblot analyses showed that endogenous p53 protein is expressed at a high level, and significant exogenous p53 protein expression and WAF1/Clip 1 induction peaked on day 1 and day 3 after Ad5CMV-p53 treatment. Introduction of Ad5CMV-p53 inhibited the cell rowth of U-251(85% inhibition) and LG cells(36% inhibition), and influenced cell morphology. The optimal dose of Ad5CMV-p53 for the tumor cel ls growth inhibition was MOI of 10-40 PFU/cell. These results suggest that Ad5CMV-p53 infects human glioma cells and transduces the p53 gene with high efficiency, and could be further developed for the gene therapy of human gliomas.
Adenoviridae ; beta-Galactosidase ; Brain* ; Genes, p53* ; Genes, Tumor Suppressor ; Genetic Therapy* ; Glioma* ; Humans*

Fifteen cases of diffuse axonal injury(DAI) brought about by nonmissile head injury in humans are analyzed. All cases were subjected to comprehensive clinical studies such as measurement of cerebral blood flow by SPECT, continuous intracranial pressure monitoring and multimodality evoked potentials(MEPs). In the patients with DAI, a high incidence of low cerebral perfusion and abnormal MEPs. especially auditory evoked potentials, were found, with high incidence of high velocity traffic accident injury mechanism. On the other hand, a low incidence of increased intracranial pressure was found and dehydrating agents such as glycerol and mannitol did not exert a beneficial influence upon the clinical courses or the outcomes. The outcome of the patients with DAI depended upon the duration of coma and whether or not brain stem signs were noted.
Accidents, Traffic ; Axons ; Brain Stem ; Coma ; Craniocerebral Trauma ; Diffuse Axonal Injury* ; Evoked Potentials* ; Evoked Potentials, Auditory ; Glycerol ; Hand ; Humans ; Incidence ; Intracranial Pressure* ; Mannitol ; Perfusion ; Tomography, Emission-Computed, Single-Photon

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.
Adenoviruses, Human ; Animal ; Brain Neoplasms/therapy* ; Cell Division ; Gene Therapy* ; Genetic Vectors ; Glioma/therapy* ; Human ; Mice ; Mice, Nude ; Protein p53/physiology ; Protein p53/genetics* ; Rats ; Tumor Cells, Cultured

We investigated the antineoplastic potentials of recombinant adenovirus containing wild-type p53 cDNA (Ad5CMV-p53) for malignant gliomas. In four human glioma cell lines (U-251 and LG expressing endogenous mutant p53, and U-87 and EFC-2 expressing wild-type p53) and two rat glioma cell lines (9L and C6, each expressing mutant and wild-type p53), gene transfer efficiency determined by X-gal staining and Western blotting was varied (10-99% at 10-500 multiplicity of infection, MOI). Growth inhibitory effect was drastic (>90% at 100 MOI) in U-251 cells and only moderate or minimal in other cell lines harboring wild-type p53 or low gene transfer efficiency. Ex vivo transduction of U-251 cells with Ad5CMV-p53 suppressed the in vivo tumorigenicity of the cells. Histopathologic examination for Ad5CMV-p53 toxicity to rat brains showed inflammatory reactions in half of the tested brains at 10(8) MOI. U-251 cells were inoculated intracerebrally in nude mice and injected Ad5CMV-p53 into the tumor, in which neither the tumor suppression nor the survival benefit was observed. In conclusion, heterogeneity of the cellular subpopulations of malignant glioma in p53 status, variable and insufficient gene delivery to tumor, and adenoviral toxicity to brain at higher doses may be limiting factors to be solved in developing adenovirus-p53 gene therapy for malignant gliomas.
Adenoviruses, Human ; Animal ; Brain Neoplasms/therapy* ; Cell Division ; Gene Therapy* ; Genetic Vectors ; Glioma/therapy* ; Human ; Mice ; Mice, Nude ; Protein p53/physiology ; Protein p53/genetics* ; Rats ; Tumor Cells, Cultured

The Clinical Research Center for Dementia of South Korea (CREDOS), a nation-wide clinical dementia research group, has prepared clinical practice guidelines (CPG) for dementia tailored to the Korean population. In this article, a summary of the CREDOS CPG is presented with the Korean and English version of full report included in the appendix. The CREDOS CPG in intended not only for psychiatrists and neurologists, but also internists, family physicians, and other primary care physicians involved in the prevention and early diagnosis of dementia. While our CPG for dementia mainly covers Alzheimer's disease (AD) and vascular dementia (VaD), it also includes mild cognitive impairment (MCI) and vascular MCI, which are currently known to be the preclinical stages of AD or VaD, respectively, with emphasis placed on early diagnosis. The CREDOS CPG aims to achieve the following goals by developing CPG for dementia: to establish evidence-based, objective and clear clinical standards for dementia; to improve the clinical decision-making process for patients with dementia; to provide scientific and systematic scales to aid in the work of dementia specialists; to suggest comprehensive and systematic healthcare services tailored to each dementia subtype. The CREDOS CPG focuses on diagnosis and evaluation of clinical practice available domestically, and provides useful concepts of dementia. Its emphasis is on etiologies and epidemiology, diagnostic criteria and evaluation, neuropsychological tests, behavioral and psychological symptoms, the activities of daily living, laboratory tests, and brain imaging.
Activities of Daily Living ; Alzheimer Disease ; Appendix ; Delivery of Health Care ; Dementia ; Dementia, Vascular ; Early Diagnosis ; Humans ; Mild Cognitive Impairment ; Neuroimaging ; Neuropsychological Tests ; Physicians, Family ; Physicians, Primary Care ; Psychiatry ; Republic of Korea ; Weights and Measures