PubMed Health⌕ Search

Biomedical subjects

D R Hinton

Publications and source records attributed to D R Hinton.

At least 127 records · Page 7Linked to original sources
PubMed1994

Lovastatin induces growth inhibition and apoptosis in human malignant glioma cells.

The competitive HMG-CoA reductase inhibitor lovastatin has been shown to suppress growth and induce morphological changes in a variety of non-glioma tumor cell lines. This study assesses the effects of this agent on the growth and survival of the human malignant glioma cell lines A172 and U87-MG. The response to the drug was investigated using a cell proliferation assay which revealed significant dose-dependent growth inhibition. Treatment with as little as 100 nM lovastatin over a period of 72 hours led to DNA degradation into nucleosome-sized fragments characteristic of apoptosis. Our data suggest that HMG-CoA reductase inhibitors such as lovastatin merit further investigation as potential therapeutic agents for the treatment of malignant gliomas.

Apoptosis↗
PubMed1994

Protein kinase C inhibitors induce apoptosis in human malignant glioma cell lines.

Previous work has demonstrated the importance of the protein kinase C (PKC) system in regulating glioma growth, and has led to clinical trials utilizing PKC inhibitors as adjuncts in the therapy of patients harboring malignant gliomas. This study was performed to explore the possibility that inhibition of PKC in gliomas was triggering an apoptosis signal. Glioma cell lines were treated with PKC inhibitors staurosporine (10 nM), and tamoxifen (10 microM). DNA from cells treated with each of these drugs exhibited a 'ladder' pattern of oligonucleosome-sized fragments characteristic of apoptosis, thus suggesting that in glioma cells, these drugs may be cytocidal in action.

Alkaloids↗
PubMed1994

Transforming growth factor-beta regulates human retinal pigment epithelial cell phagocytosis by influencing a protein kinase C-dependent pathway.

BACKGROUND: Transforming growth factor-beta (TGF-beta) plays an important role in the pathogenesis of many ocular diseases, including proliferative vitreoretinopathy. We examined the effect of TGF-beta on the phagocytosis of rod outer segments by retinal pigment epithelium (RPE), which is a major function of RPE, and investigated the dependence of this effect on the protein kinase C (PKC) pathway. METHODS: Phagocytotic uptake of fluoresceinated bovine rod outer segments was determined by flow cytometry. RPE cells were treated with TGF-beta 1 or TGF-beta 2 and their effects on phagocytosis were examined. The effects of various PKC inhibitors (calphostin C, staurosporine, and extended exposure to phorbol 12-myristate 13-acetate, PMA) and a stimulator (brief exposure to PMA) on RPE phagocytosis was evaluated. RESULTS: Both TGF-beta 1 and TGF-beta 2 up-regulated RPE phagocytosis and PMA abolished the up-regulating effect of TGF-beta. In contrast, PKC inhibition by staurosporine and calphostin C resulted in increased phagocytosis. A combination of TGF-beta and PKC inhibitor treatment did not produced any additive effect on phagocytosis. CONCLUSION: We concluded that TGF-beta up-regulates human RPE phagocytosis, but that this effect is counteracted by PKC activation. It is possible that this TGF-beta-induced effect is due, in part, to a negative modulation of the PKC-dependent pathway.

Alkaloids↗
PubMed1994

Giant infectious intracavernous carotid artery aneurysm presenting as intractable epistaxis.

Infectious intracavernous carotid artery aneurysms usually present with ophthalmoplegia and/or signs of cavernous sinus thrombosis. We report an unusual case in which a patient with AIDS presented with intractable epistaxis secondary to rupture of a giant infectious intracavernous carotid artery aneurysm. Culture of the aneurysm grew mycobacterium avium intracellulare (MAI). The patient was treated successfully by excision of the aneurysm and reconstruction of the internal carotid artery with a saphenous vein interposition graft.

AIDS-Related Opportunistic Infections↗
PubMed1994

Exogenous tat protein activates central nervous system-derived endothelial cells.

Tat protein, an HIV gene product known to be secreted extracellularly, was tested to determine its role in the dissemination of HIV into the central nervous system (CNS). Tat was shown to activate human CNS-derived endothelial cells (CNS-EC) by the increase in the expression of E-selectin, the synthesis of IL-6, and the secretion of plasminogen activator inhibitor-1 (PAI-1). Tat also functioned synergistically with tumor necrosis factor alpha (TNF). AIDS brains stained for tat in situ, demonstrated positive cells. These data suggest that secreted tat protein may increase leukocyte binding, and alter the blood-brain barrier permeability to enhance dissemination of HIV-infected cells into the CNS.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Somataglycan-S: a neuronal surface proteoglycan defines the spinocerebellar system.

The formation and maintenance of functionally specific neuronal networks may depend on specific proteoglycans localized to the surface membranes of a subset of neurons. Monoclonal antibody (MAb) 6A2 labeled a distinct subset of CNS neurons: the somas and proximal dendrites of cells making up the spinocerebellar and reticular systems. These pathways contribute to proprioceptive and exteroceptive functions. Ultrastructurally, MAb 6A2 immunoreactivity was distributed focally along the cell surface membranes and the adjacent extracellular space. On western blots of immunoaffinity-purified preparations from cerebellar homogenates, a major, broad band of approximately 400 kDa is labeled by MAb 6A2. Increased electrophoretic mobility of the purified antigen after digestion with chondroitinase ABC and keratanase suggests that the antigen is a proteoglycan bearing chondroitin sulfate and keratan sulfate glycosaminoglycans. Unsulfated N-acetyl-galactosamine residues linked to unsaturated uronic acid constituted the initial disaccharide in the chondroitin sulfate glycosaminoglycan chains. N- and O-linked oligosaccharides on the core protein were detected by the biotinylated lectins wheat germ agglutinin and Jacalin, respectively, and by MAb anti-HNK-1. Lyase and glycosidase digests result in a 280-kDa band. This proteoglycan, somataglycan-S, may provide a key to the role of glycoconjugates in determining neuronal diversity and system specificity.

Animals↗
PubMed1994

Surgical implications of magnetic resonance-enhanced dura.

The purpose of this study was to assess tissue changes responsible for dural enhancement of magnetic resonance imaging (MRI) and its clinical implications. A prospective surgical, histopathological, and MRI study was performed in 73 patients with various types of disease, including meningiomas (n = 29), craniofacial tumors with possible direct intracranial extension (n = 21), gliomas and brain metastasis in close proximity to the dura mater (n = 9), and a variety of nonneoplastic processes (n = 14). Contrast-enhanced MRI was obtained within 5 days before surgery and in some cases within 3 days after surgery as well. Histopathological examination of the dural specimens was performed in all 59 patients with neoplasia and in selected patients with nonneoplastic processes. Dural invasion was noted in 18 of 29 meningiomas, 15 of 21 craniofacial neoplasms, 3 of 5 gliomas, and 3 of 4 brain metastases. In these patients invasion was focal and in direct continuity with the tumors. MRI disclosed that dura invaded by the tumor had a break in the continuity of enhancement, or that there was no discernible enhancement. Association between patterns of dural enhancement and tumor invasion of dura was statistically significant (P < 0.001). The thickened-enhanced portion of the dura represented reactive changes. Postoperative enhancement was seen as early as 24 hours after surgery and was shown histologically to be associated with vasodilation and reactive changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1994

Hypericin: a potential antiglioma therapy.

Hypericin, a polycyclic aromatic dione isolated from plants, is presently being clinically evaluated as an antiviral agent in the treatment of human immunodeficiency virus (HIV) infection. In addition, it is known to be a potent protein kinase C inhibitor. To evaluate its potential as an inhibitor of glioma growth, an established (U87) and low-passage glioma line (93-492) were treated with hypericin in tissue culture for a period of 48 hours after passage. Hypericin inhibited the glioma growth in a dose-related manner, with a marked inhibition of growth in the low-micromolar concentration range (e.g., in line U87 and low-passage line 93-492, a concentration of hypericin of 10 mumol/L produced 62 and 76% decreases in [3H]thymidine uptake, respectively). Because the reported inhibitory effects of protein kinase C are enhanced by visible light, [3H]thymidine uptake was measured in both the presence and the absence of visible light. In glioma line A172, the presence of light slightly increased the inhibitory effect of hypericin. Moreover, an apoptosis (i.e., programmed cell death) assay was performed to determine whether the treatment of glioma cells with hypericin was cytostatic or cytocidal. Cells were harvested, and purified deoxyribonucleic acid (DNA) was analyzed by agarose gel electrophoresis. DNA from cells treated with hypericin for 48 hours exhibited a classical "ladder" pattern of oligonucleosome-sized fragments characteristic of apoptosis. These data suggest that the proven safe drug hypericin may have potential as an antiglioma agent; we suggest clinical trials.

Anthracenes↗
PubMed1994

Cytokine expression in radiation-induced delayed cerebral injury.

Radiation-induced delayed brain injury is a well-documented complication of both standard external beam radiation (teletherapy) and interstitial brachytherapy; however, the cause of this damage has not been determined. Cytokines and growth factors are important regulatory proteins controlling the growth and differentiation of normal and malignant glial cells, which have been implicated in the tissue response to radiation injury. Six snap-frozen brain biopsies showing radiation injury were obtained from four patients harboring malignant gliomas who underwent either postoperative external beam and/or stereotactic interstitial brachytherapy at standard dosages. The specimens showed variable amounts of gliosis, tissue necrosis, calcification, inflammation, and vascular proliferation and hyalinization. Frozen tissue sections were examined for the presence of infiltrating lymphocytes, macrophages, cytokines, and other immunoregulatory molecules by the use of a panel of specific monoclonal and polyclonal antibodies. All specimens showed diffuse T cell infiltration with both CD4+ and CD8+ cells. Infiltrating activated macrophages (CD11c+, HLA-DR+) were prominent in five of six cases. Tumor necrosis factor-alpha and interleukin-6 immunoreactivity was prominent in four of six cases and was predominately localized to macrophages. Transforming growth factor-beta astrocytic and macrophage immunoreactivity was present at moderate levels in all cases. This study suggests that in radiation necrosis, interleukin-1 alpha, tumor necrosis factor-alpha, and interleukin-6 are expressed, predominately by infiltrating macrophages.

Adult↗
PubMed1994

Multifocal inflammatory leukoencephalopathy associated with levamisole and 5-fluorouracil: case report.

Levamisole and 5-fluorouracil have now become the standard chemotherapeutic regimen for patients with Stage III colon carcinoma. A case of multifocal inflammatory leukoencephalopathy secondary to levamisole alone or combination of levamisole and 5-fluorouracil is reported. Magnetic resonance imaging with gadolinium demonstrated multifocal contrast-enhancing frontal, parietal, occipital, and periventricular white matter lesions. A stereotactic biopsy revealed reactive gliosis and macrophage infiltration, without evidence of metastatic tumor. Despite continuation of 5-fluorouracil, resolution of contrast-enhancing lesions on magnetic resonance imaging without further neurological sequelae occurred when levamisole was stopped. The patient died with evidence of systemic metastasis 6 months later. Autopsy examination of the brain revealed multifocal demyelinating lesions, with no evidence of metastatic tumor. Immunoperoxidase studies of demyelinated lesions demonstrated infiltrating macrophages strongly positive for Class II antigens, interleukin-6, and interleukin-1 alpha. Surrounding astrocytes were positive for granulocyte macrophage colony-stimulating factor. Small numbers of perivascular T cells were present. This patient represents the first autopsy documented case of levamisole associated multifocal inflammatory leukoencephalopathy.

Aged↗
PubMed1994

Dexamethasone induced proliferation of cultured retinal pigment epithelial cells.

Dexamethasone (DEX) is a glucocorticoid that is widely used after vitreoretinal surgery and may have mitogenic properties. This study was initiated to determine if human cultured retinal pigment epithelium (RPE) cells express glucocorticoid receptor and proliferate in response to DEX stimulation. Glucocorticoid receptor mRNA was detected in RPE cells by means of reverse transcriptase polymerase chain reaction. To determine the effect of DEX on RPE cell proliferation in vitro, we cultured human RPE cells with various concentrations for DEX for 5 days and determined the effects on cell number and incorporation of tritiated thymidine. DEX treatment with a DEX dose of 1 microgram/ml in the presence or absence of serum resulted in a maximal 2-3 times increase in cell number. Autoradiography after thymidine incorporation revealed a greater than 2-fold increase in incorporating cells at this same dose. These results indicate that DEX causes cultured human RPE cells to proliferate and suggest that it may have a growth factor-like action.

Cell Count↗
PubMed1994

Collagen gel contraction induced by retinal pigment epithelial cells and choroidal fibroblasts involves the protein kinase C pathway.

Contraction of intraocular fibrous membranes is an important feature in the pathogenesis of retinal detachment in proliferative vitreoretinopathy (PVR). Collagen gel contraction is a useful in vitro model of membrane contraction in PVR. We studied the role of protein kinase C (PKC) in collagen gel contraction induced by bovine choroidal fibroblasts and retinal pigment epithelial (RPE) cells. Collagen gels embedded with the cells were formed in culture dishes and gel contraction was evaluated. The PKC stimulator, phorbol 12-myristate 13-acetate (PMA), and the protein phosphatase 1 and 2A inhibitor, okadaic acid (OA), were used to evaluate the role of the PKC-mediated phosphorylation system in this gel contraction. Fifteen min incubation with PMA stimulated gel contraction, but 180 min incubation had no effect. Choroidal fibroblast- but not RPE cell-induced gel contraction was stimulated by OA. These effects were inhibited by the broad spectrum protein kinase inhibitor staurosporine and the specific PKC antagonist calphostin C. Transforming growth factor-beta (TGF-beta)1 and TGF-beta 2, which are known to be present in eyes with PVR, were evaluated to determine their effect on gel contraction. Both TGF-beta 1 and 2 had a stimulatory effect on contraction of gels seeded with choroidal fibroblasts and RPE cells, but staurosporine and calphostin C inhibited this TGF-beta-induced gel contraction. These results indicate that activation of PKC/protein phosphorylation is an important factor in gel contraction caused by choroidal fibroblasts and RPE cells, and that TGF-beta-induced gel contraction is mediated at least in part via the PKC pathway.

Animals↗
PubMed1994

Effect of TGF-beta on interferon-gamma-induced HLA-DR expression in human retinal pigment epithelial cells.

PURPOSE: Retinal pigment epithelial (RPE) cells express human leukocyte antigen (HLA)-DR (class II) antigens when stimulated with interferon gamma (IFN-gamma) and may be capable of local antigen presentation. The authors examined the effect of transforming growth factor-beta (TGF-beta), a cytokine normally found in the eye, on the expression of these immunoregulatory molecules in vitro and attempted to determine the mechanism by which this cytokine acts. METHODS: Human RPE cells were cultured in the presence of IFN-gamma and then stained immunohistochemically for HLA-DR antigens. TGF-beta 1 or TGF-beta 2 was added simultaneously with IFN-gamma or after 3 days of IFN-gamma treatment. In parallel experiments, RPE cells were pretreated with 4-phorbol-12 myristate-13 acetate (PMA), staurosporine, or calphostin C before stimulation with IFN-gamma or TGF-beta. Quantitative analysis was performed by fluorescence-activated cell sorting. RESULTS: IFN-gamma induced HLA-DR expression on RPE cells. Both TGF-beta 1 and TGF-beta 2 were able to inhibit this effect. These inhibitory effects of TGF-beta were augmented by pretreatment with either PMA or calphostin C. Pretreatment of the cells with PMA before stimulation with IFN-gamma downregulated HLA-DR expression. Staurosporine pretreatment suppressed HLA-DR expression by IFN-gamma-stimulated RPE cells, but this was not additive with TGF-beta. CONCLUSIONS: The authors conclude that TGF-beta 1 and TGF-beta 2 strongly inhibit the IFN-gamma-induced upregulation of class II antigens on human RPE cells. The modulation of these IFN-gamma and TGF-beta effects by calphostin C, staurosporine, and PMA treatment suggests involvement of the protein kinase C pathway.

Cells, Cultured↗
PubMed1994

Intercellular gap formation induced by thrombin in confluent cultured bovine retinal pigment epithelial cells.

PURPOSE: Thrombin is formed at the site of intraocular hemorrhage and may be important in the development of progressive retinal damage. The authors observed that thrombin-treated bovine retinal pigment epithelial (RPE) cell cultures develop intercellular gaps and initiated this study to examine in detail the effects of thrombin on RPE cell morphology, adhesion, and cytoskeleton. METHODS: Confluent cultures of bovine RPE cells were incubated for various times (0 to 24 hours) with alpha-thrombin (0.1 to 100 U/ml) or enzymatically inactive thrombin. Intercellular gaps were quantitated by light microscopy in ten representative fields (magnification X400) as number of gaps per field (gaps/f). RPE cytoskeleton was studied using immunofluorescent staining for vinculin and F-actin. The mechanism of thrombin-induced RPE cell gap formation was studied by preincubation with specific drugs, including a protein kinase inhibitor (staurosporine), protein kinase C inhibitors (H-7 and calphostin C), cyclic adenosine monophosphate (cAMP) inducer (forskolin), and cytoskeleton-disrupting agents (cytochalasin B or colchicine). RESULTS: Intercellular gaps (20 to 80 microns in diameter) were markedly increased in number in thrombin-treated cultures in a dose-dependent and time-dependent manner and were associated with an alteration in the distribution of F-actin and vinculin. Whereas control cultures showed 3.3 +/- 2.4 gaps/f, incubation with 8 U/ml of alpha-thrombin for 3 hours resulted in 44.8 +/- 15.3 gaps/f. These changes were most prominent shortly after the 3-hour coincubation, but the cultures did return to their original confluent state within 24 hours. Cultures treated with an enzymatically inactive thrombin showed fewer intercellular gaps than those treated with enzymatically active thrombin but had significantly more intercellular gaps than control cultures. Thrombin-induced intercellular gap formation was blocked by preincubation with forskolin (14.6 +/- 7.1 gaps/f), staurosporine (10.2 +/- 5.0 gaps/f), or H-7 (24.5 +/- 9.8 gaps/f). CONCLUSIONS: Exposure to an enzymatically active thrombin results in formation of intercellular gaps between cultured RPE cells. Inhibition of this phenomenon by protein kinase inhibitors and by a cAMP inducer suggests that this effect is mediated, at least in part, through protein kinase C- and cAMP-dependent pathways. Thrombin generation associated with intraocular hemorrhage may thus result in direct damage to the RPE monolayer, possibly via the same pathway(s).

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Dural invasion by craniofacial and calvarial neoplasms: MR imaging and histopathologic evaluation.

The authors prospectively correlated results of magnetic resonance (MR) imaging and histologic examination of the dura in 17 patients with craniofacial and calvarial neoplasms and possible intracranial extension. Contrast material-enhanced MR imaging revealed dural enhancement in 14 patients and no enhancement in three. In four cases, the dura deep to the tumor appeared as a continuous band of enhancement and there was a thin unbroken hypointense zone between the dura and the tumor. Histologic examination in these four patients revealed only dural inflammation without neoplastic spread. In 10 patients, there was a break in the continuity of the enhancement of the underlying dura or a portion of the dura and overlying enhancing tumor could not be separated on MR images. The hypointense zone was focally absent in nine of these cases, and in all 10 there was invasion of the dura by adjacent tumor. Among the other three patients, in whom dural enhancement was not discernible, one had dural invasion by tumor while the other two did not.

Adult↗
PubMed1993

Differential effects of tumor necrosis factor-alpha on proliferation, cell surface antigen expression, and cytokine interactions in malignant gliomas.

Tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by astrocytes in vivo and in vitro, was tested for its effects on two malignant astrocytoma cell lines (A-172, U-87). Both lines were immunoreactive for glial fibrillary acidic protein, vimentin, Class I antigens, and interleukin-6. The lines differed in their expression of Class II and intercellular adhesion molecule-1 (ICAM-1) antigenic determinants: A-172 cells were negative for both Class II and ICAM-1 antigens, while U-87 cells were intensely positive for Class II and weakly positive for ICAM-1. When these astrocytoma cell lines were exposed to TNF-alpha, A-172 growth was stimulated while U-87 growth was inhibited. Furthermore, in U-87 cells, TNF-alpha enhanced both ICAM-1 and interleukin-1 beta (IL-1 beta) expression, and decreased immunoreactivity for transforming growth factor-beta (TGF-beta) protein. In contrast, in the presence of TNF-alpha, A-172 cells remained negative for IL-1 beta and TGF-beta, but showed an increased expression of ICAM-1. These results demonstrate that TNF-alpha can induce changes in growth rate, cytokine production, and surface antigen expression in malignant astrocytomas; however, the nature of these changes is dependent on the specific characteristics of these malignant astrocytomas. The resultant variability in the immunological microenvironment of these tumors may reflect differences in their growth potential.

Antigens, Neoplasm↗
PubMed1993

Clinical and radiographic response in a minority of patients with recurrent malignant gliomas treated with high-dose tamoxifen.

Previous work has demonstrated the importance of the Protein Kinase C (PKC) signal transduction system in regulating the growth rate of malignant gliomas in vitro. Tamoxifen inhibits PKC in a minority of malignant gliomas within the micromolar concentration range in vitro, a property distinct from its estrogen receptor blockade effect. Tamoxifen was administered orally in very high dosages to 11 patients (9 males:2 females, age range 26-73, mean 45 years) with malignant gliomas (anaplastic astrocytoma or glioblastoma multiforme) who had failed treatment with external beam radiation therapy (and additional chemotherapy in 2). The dosage administered was estimated to be that necessary to achieve tissue concentrations within the low micromolar range, shown necessary to inhibit PKC in these tumors in vitro, and is approximately 5 times that used for standard antiestrogen therapy. Tumor reduction on radiographic images (MRI and PET [18FdG uptake]) with clinical improvement occurred in 3 patients; halting of tumor progression clinically and radiographically occurred in an additional patient. Of the remaining seven patients, three patients had marked and rapid progression of their disease despite treatment (dead after 3, 4, and 6 months respectively). Complications of treatment included a deep venous thrombosis requiring anticoagulation in one patient, nausea in one patient, and "hot-flashes" in a third patient. Tumor biopsy and measurement of tamoxifen and its active metabolite within the tumor of one patient (non-responder) showed levels within the middle of the in vitro therapeutic range. Follow-up of alive patients ranges from 4-18 months (mean 10 months). These encouraging preliminary results in a minority of these patients suggests some potential for this type of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗