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Timothy Ryken, Bruce Frankel, Sharon Longo and Zita Sibenaller


An experimental model of the fas and fas ligand (fasL) interaction in malignant glioma was developed.


Using plasmid-based delivery, 36B10 rat glioma cells were modified to express fas (36B10-fas), and a delivery fibroblast cell line was modified to produce fasL, resulting in the FR-fasL cell line. Evaluation of fas expression was performed with flow cytometry and expression of fasL confirmed by Western blot analysis. Once the cell lines were created and partially characterized, fas-induced cytotoxicity was evaluated using an antibody-mediated assay for 36B10-fas that demonstrated significant toxicity at 24 and 48 hours. To evaluate the potential for activating the fas molecule by using cell-mediated delivery, coculture cytotoxicity studies were performed with a target cell line (36B10-fas) and effector cell line (FR-fasL). Using a series of culture ratios, increasing cytotoxicity was noted, suggesting that activation of the transfected fas receptor by fasL expression on the carrier cell was occurring.


Based on their experiments, the authors describe a model for evaluating the interaction of fas and fasL in a cellular model of malignant glioma.

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Gentian Toshkezi, Michele Kyle, Sharon L. Longo, Lawrence S. Chin and Li-Ru Zhao


Traumatic brain injury (TBI) is a major cause of long-term disability and death in young adults. The lack of pharmaceutical therapy for post–acute TBI recovery remains a crucial medical challenge. Stem cell factor (SCF) and granulocyte colony–stimulating factor (G-CSF), which are 2 key hematopoietic growth factors, have shown neuroprotective and neurorestorative effects in experimental stroke. The objective of this study was to determine the therapeutic efficacy of combined treatment (SCF + G-CSF) in subacute TBI.


Young-adult male C57BL mice were subject to TBI in the cortex of the right hemisphere. After TBI induction, mice were randomly divided into 2 groups: a vehicle control group and an SCF + G-CSF treatment group. Mice without TBI served as sham operative controls. Treatment was initiated 2 weeks after TBI induction. SCF (200 μg/kg) and G-CSF (50 μg/kg) or an equal volume of vehicle solution was subcutaneously injected daily for 7 days. A battery of neurobehavioral tests for evaluation of memory and cognitive function (water maze and novel object recognition tests), anxiety (elevated plus maze test), and motor function (Rota-Rod test) was performed during the period of 2–9 weeks after treatment. Neurodegeneration and dendritic density in both hemispheres were determined through histochemistry and immunohistochemistry at 11 weeks posttreatment.


Water maze testing showed that TBI-impaired spatial learning and memory was restored by SCF + G-CSF treatment. The findings from the elevated plus maze tests revealed that SCF + G-CSF treatment recovered TBI-caused anxiety and risk-taking behavior. There were no significant differences between the treated and nontreated TBI mice in both the Rota-Rod test and novel object recognition test. In the brain sections, the authors observed that widespread degenerating neurons were significantly increased in both hemispheres in the TBI-vehicle control mice. TBI-induced increases in neurodegeneration were significantly reduced by SCF + G-CSF treatment in the contralateral hemisphere, making it no different from that of the sham controls. Dendritic density in the frontal cortex of the contralateral hemisphere was significantly reduced in the TBI-vehicle control mice, whereas SCF + G-CSF–treated TBI mice showed significant increases of the dendritic density in the same brain region. SCF + G-CSF–treated TBI mice also showed a trend toward increasing dendritic density in the contralateral hippocampus.


SCF + G-CSF treatment in the subacute phase of TBI restored TBI-impaired spatial learning and memory, prevented posttraumatic anxiety and risk-taking behavior, inhibited TBI-induced neurodegeneration, and enhanced neural network remodeling. These findings suggest the therapeutic potential of hematopoietic growth factors for brain repair in the subacute phase of TBI.

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Bruce Frankel, Sharon L. Longo, Gerard S. Rodziewicz and Charles J. Hodge Jr.

Object. Available therapies for Cushing's disease are often inadequate or involve the risk of significant morbidity. Accordingly, the need arises for the development of novel treatments, especially for cases caused by corticotroph hyperplasia, a condition difficult to treat using standard therapies. In this study, the authors investigated the use of phosphorothioate antisense oligonucleotides as a potential treatment for Cushing's disease.

Methods. Corticotrophs, obtained from a patient with Cushing's disease in whom pathological findings showed multifocal areas of corticotroph adenoma and hyperplasia, were grown in tissue culture. By assessing cell viability and using immunoradiometric assay techniques, it was determined that these cells grew autonomously and secreted adrenocorticotropic hormone (ACTH) in vitro. A fully phosphorothioated antisense oligonucleotide was constructed to be complementary to the first 25 bp of the region coding for ACTH in exon 3 of the proopiomelanocortin precursor. After incubation of the corticotrophs with liposome-coated phosphorothioate antisense oligonucleotides, a greater than 90% decrease in ACTH release was noted on Days 3 and 6, compared with nonsense-treated controls (p < 0.05).

Conclusions. Antisense oligonucleotides may prove to be a useful adjunct in treating Cushing's disease by targeting one of its fundamental problems, ACTH hypersecretion.