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J M Hoffman

Publications and source records attributed to J M Hoffman.

At least 109 records · Page 6Linked to original sources
PubMed1992

Serum-induced sensitization of cyclic AMP accumulation in C62B rat glioma cells.

Exposure of C62B rat glioma cells to fresh medium containing fetal bovine serum induced a sensitization of the subsequent ability of isoproterenol and forskolin to stimulate cyclic AMP accumulation, compared to cells exposed to fresh medium without serum. Isoproterenol stimulation was typically increased by 2- to 4-fold and forskolin stimulation by 3- to 5-fold. Sensitization occurred rapidly, was rapidly reversible and appeared to result from an increase in maximal stimulation. A commercial preparation of albumin, purified chromatographically so as to retain bound lipids and other factors, was able to mimic the effect of serum. In contrast to the effects of serum, exposure of cells to phorbol 12-myristate, 13-acetate induced little or no change in forskolin stimulation but a marked desensitization of isoproterenol stimulation that was due primarily to a decrease in potency. Neither the protein kinase C inhibitor staurosporine or overnight exposure to phorbol 12-myristate, 13-acetate to down-regulate protein kinase C prevented serum-induced sensitization. Pertussis toxin almost completely blocked serum-induced sensitization, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in mediating the effects of serum. Sensitization was poorly retained in membrane adenylate cyclase assays. Studies with the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, direct assays of cyclic AMP degradation by intact cells and assays of phosphodiesterase activity in cell lysates all indicated that degradation of cyclic AMP was decreased in serum-pretreated cells. Thus, both increased cyclic AMP synthesis and decreased cyclic AMP degradation may contribute to sensitization in these cells.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Studies of primary central nervous system lymphoma with fluorine-18-fluorodeoxyglucose positron emission tomography.

Primary CNS lymphoma is a rare and highly malignant primary brain tumor. Ten patients with biopsy-proven primary CNS lymphoma were studied with 18F-2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) to demonstrate the findings in patients with this tumor. The accumulation of FDG in primary CNS lymphoma is similar to that seen in anaplastic gliomas and is significantly more prominent than in low grade astrocytomas (p = 0.001). Steroid therapy substantially reduced the amount of FDG uptake in the one case studied both before and after its administration. The difference in FDG uptake between steroid-treated and untreated cases of primary CNS lymphoma, however, did not reach statistical significance (p = 0.40). Primary CNS lymphoma, like gliomas, suppresses the metabolism of both contiguous and distant but functionally linked areas of the brain. This study thus shows that the metabolic behavior of primary CNS lymphoma, as monitored by FDG-PET, resembles that of malignant glial tumors.

Adult↗
PubMed1992

The effects of carbidopa administration on 6-[18F]fluoro-L-dopa kinetics in positron emission tomography.

Carbidopa (L-alpha-hydrazino-alpha-methyl-b-(3,4-dihydroxyphenyl) propionic acid is a known inhibitor of aromatic amino acid decarboxylase. In both humans and monkeys, we studied the effects of carbidopa on plasma and brain kinetics of 6-[18F]fluoro-L-DOPA (FDOPA), an analog of L-DOPA used for PET studies of the central dopaminergic system. Pretreatment with carbidopa resulted in increases in the plasma levels of FDOPA and 3-O-methyl-6-[18F]fluoro-L-DOPA (3-OMFD). Total striatal and cerebellar activities measured with PET were also increased. Furthermore, increases observed in the specific striatal activity (striatum minus cerebellum total activity) were correlated with increases in the plasma FDOPA curve. Carbidopa pretreatment did not affect the influx rate constant (K) for FDOPA from plasma to striatum in humans as determined by Patlak graphical analysis. Thus, an increase in measured striatal tomographic activity was secondary to the increase in plasma FDOPA levels rather than as a result of changes in the FDOPA influx rate constant.

Adult↗
PubMed1991

Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity.

Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-[( (4,7-Dimethyl-1,3-benzoxazol-2-yl) methyl]amino ]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,639) and 3-[[ (4,7-dichloro-1,3-benzoxazol-2-yl) methyl]amino]-5-ethyl-6-methylpyridin-2(1H)-one (L-697,661), two compounds within this series, had HIV-1 RT IC50 values in the range of 20-800 nM, depending upon the template-primer used. The most potent inhibition was obtained with rC.dG and dA.dT as template--primers. With rC.dG, reversible slow-binding non-competitive inhibition was observed. [3H]L-697,639 bound preferentially to enzyme-template-primer complexes. This binding was magnesium-dependent and saturable with a stoichiometry of 1 mol of [3H]L-697,639 per mol of RT heterodimer. Displacement of [3H]L-697,639 was seen with phosphonoformate. In human T-lymphoid-cell culture, L-697,639 and L-697,661 inhibited the spread of HIV-1 infection by at least 95% at concentrations of 12-200 nM. Synergism between 3'-azido-3'-deoxythymidine or dideoxyinosine and either of these compounds was also demonstrated in cell culture. Based upon their specificity for HIV-1 RT activity, template-primer dependence on potency and ability to displace [3H]L-697,639; a tetrahydroimidazo [4,5,1-jk] [1,4]-benzodiazepin-2(1H)-thione derivative R82150 and the dipyridodiazepinone BI-RG-587 appear to inhibit RT activity by the same mechanism as the pyridinones.

Antiviral Agents↗
PubMed1991

Differential effects of pertussis toxin on insulin-stimulated phosphatidylcholine hydrolysis and glycerolipid synthesis de novo. Studies in BC3H-1 myocytes and rat adipocytes.

Insulin-induced increases in diacylglycerol (DAG) have been suggested to result from stimulation of de novo phosphatidic acid (PA) synthesis and phosphatidylcholine (PC) hydrolysis. Presently, we found that insulin decreased PC levels of BC3H-1 myocytes and rat adipocytes by approximately 10-25% within 30 s. These decreases were rapidly reversed in both cell types, apparently because of increased PC synthesis de novo. In BC3H-1 myocytes, pertussis toxin inhibited PC resynthesis and insulin effects on the pathway of de novo PA-DAG-PC synthesis, as evidenced by changes in [3H]glycerol incorporation, but did not inhibit insulin-stimulated PC hydrolysis. Pertussis toxin also blocked the later, but not the initial, increase in DAG production in the myocytes. Phorbol esters activated PC hydrolysis in both myocytes and adipocytes, but insulin-induced stimulation of PC hydrolysis was not dependent upon activation of PKC, since this hydrolysis was not inhibited by 500 microM sangivamycin, an effective PKC inhibitor. Our results indicate that insulin increases DAG by pertussis toxin sensitive (PA synthesis de novo) and insensitive (PC hydrolysis) mechanisms, which are mechanistically separate, but functionally interdependent and integrated. PC hydrolysis may contribute importantly to initial increases in DAG, but later sustained increases are apparently largely dependent on insulin-induced stimulation of the pathway of de novo phospholipid synthesis.

Adipose Tissue↗
PubMed1991

6-[18F]fluoro-L-dopa metabolism in MPTP-treated monkeys: assessment of tracer methodologies for positron emission tomography.

6-[18F]Fluoro-L-DOPA (FDOPA) is an L-DOPA analog that is used to assess the functional integrity of central dopaminergic systems in vivo with positron emission tomography (PET). FDOPA metabolites from putamen of normal and MPTP-treated monkeys were characterized to correlate FDOPA metabolism changes with those of the endogenous dopamine system. In MPTP-lesioned putamen, 6-[18F]fluorodopamine and dopamine levels were less than 2% those of controls. Increases in endogenous dopamine metabolism were reflected by similar increases in 6-[18F]fluorodopamine metabolites. These results suggest that changes in the central dopamine system biochemistry can be monitored in vivo with FDOPA and PET.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1991

Identification of early recurrence of primary central nervous system tumors by [18F]fluorodeoxyglucose positron emission tomography.

As aggressive neurosurgery and adjuvant therapy have become standard care for most patients with primary central nervous system (CNS) tumors, limitations of posttreatment neuroimaging techniques have become more apparent. Interpretation of computed cranial tomography (CT) and magnetic resonance imaging (MRI) in patients with brain tumors is complicated by changes related to surgery, corticosteroids, radiation, and chemotherapy. We investigated the role of 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (FDG-PET) in these difficult diagnostic situations by obtaining FDG-PET scans in 5 patients following temporal lobectomy for epilepsy, in 5 patients with recurrent anaplastic gliomas before and after corticosteroid therapy, and in 5 patients after the development of histologically confirmed radionecrosis. We also obtained postoperative FDG-PET scans in 32 consecutive patients undergoing initial resection of a primary brain tumor. Our results indicate that glucose uptake as detected by FDG-PET scanning with [18F]fluorodeoxyglucose is not increased in the postoperative period; is not affected by steroid therapy; and accurately predicts early recurrence of tumor, supplementing other predictors of tumor behavior, including extent of resection, histological diagnosis, and postoperative CT. Thus PET using [18F]fluorodeoxyglucose can contribute to the optimum management of patients with primary brain tumors.

Adult↗
PubMed1991

Reversible neurotoxicity following hyperfractionated radiation therapy of brain stem glioma.

Two patients with brain stem gliomas were treated with hyperfractionated radiation therapy (HFR) (7,020 and 7,560 cGy, respectively). Despite initial clinical improvement during irradiation, both patients demonstrated clinical deterioration approximately 3 weeks after completion of radiotherapy. Cranial magnetic resonance imaging (MRI) revealed a progressive increase in distribution of abnormal brain stem signal consistent with either tumor or edema. 18FDG positron emission tomography (PET) was obtained in one patient and demonstrated a hypermetabolic lesion at diagnosis and a hypometabolic lesion at the time of clinical deterioration postirradiation. Management with a tapering dose of dexamethasone alone resulted in marked clinical (both patients) and radiographic (one patient) improvement, allowing reduction or discontinuation of this medication. These results suggest that patients with brain stem tumors demonstrating clinical and radiographic evidence of progressive tumor shortly after completion of HFR should be initially managed conservatively with dexamethasone, since these findings may be manifestations of reversible radiation-related neurotoxicity.

Adolescent↗
PubMed1991

Kinetics and modeling of L-6-[18F]fluoro-dopa in human positron emission tomographic studies.

Kinetics of L-3,4-dihydroxy-6-[18F]fluorophenylalanine (FDOPA) in striatum and cerebellum were measured in 10 normal human subjects with positron emission tomography (PET) from 0 to 120 min after an intravenous bolus injection of the tracer. The time course of the arterial plasma concentrations of the tracer and its metabolites was also assayed biochemically. FDOPA compartmental models that are based on biochemical information were investigated for their consistency with the measured striatal and cerebellar tissue kinetics. A modeling approach was also developed for separating plasma FDOPA and metabolite time-activity curves from the measured total 18F time-activity curve in plasma. Results showed that a model consisting of three separate compartments for tissue FDOPA, tissue 6-[18F]fluorodopamine (FDA) and its metabolites, and tissue L-3,4-dihydroxy-6-[18F]fluoro-3-O-methylphenylalanine (3-OMFD) could describe adequately the striatal kinetics in humans. Based on this model, the FDOPA transport constant across the blood-brain barrier (BBB) (K1), the FDOPA decarboxylation rate constant (k3), and the turn-over rate constant of FDA and its metabolites (k4) could be estimated by model fitting to the tissue kinetics and were found for the normal subjects to be 0.031 +/- 0.006 ml/min/g (mean +/- SD), 0.041 +/- 0.015/min, and 0.004 +/- 0.002/min, respectively. About 50% of the FDOPA that crossed the BBB from plasma to striatum was decarboxylated. The decarboxylation constant with respect to plasma FDOPA (K3) was 0.015 +/- 0.003 ml/min/g. The BBB transport corresponded to a permeability-surface area product of 0.032 ml/min/g for FDOPA. For 3-OMFD, the BBB transport was 1.7 times faster. The effects of tissue heterogeneity on the FDOPA kinetics and on the estimated model parameters were also investigated. The usefulness and implications of these findings for interpretation of PET FDOPA studies are discussed.

Adult↗
PubMed1991

Modelling approach for separating blood time-activity curves in positron emission tomographic studies.

A modelling approach is developed to generate the full time course of an injected radiotracer and its labelled metabolites in plasma/blood, based on measurements of the total radioactivities in withdrawn plasma/blood samples. A compartmental model is used to describe the conversion of an injected tracer to its metabolites in the body. The model equation is formulated with the total radioactivity concentration curve as the input function. The utility and characteristics of the approach in quantitative positron emission tomographic (PET) studies are shown with two examples. In the first example, using the tracer 6-[18F]fluoro-L-dopa (FDOPA), the approach is shown to derive the full time course of plasma FDOPA and its metabolites. In the second example of dynamic 15O oxygen PET, the approach is used to solve a deconvolution problem to give separated time-activity curves of 15O oxygen and 15O water in blood. The modelling approach improves the separation of blood/plasma time-activity curves and leads to better quantitative interpretation of PET results.

Dihydroxyphenylalanine↗
PubMed1991

Functional brain imaging and Alzheimer-type dementia.

Alzheimer disease is a common neurodegenerative disorder consisting of memory impairment and intellectual function that produces not only profound disabilities in the patient, but a significant cost to society as well. The biochemical basis for Alzheimer disease is not completely understood, but both positron-emission tomography and single-photon-emission computed tomography provide insights into the in vivo biochemistry associated with this disease. Both techniques show characteristic brain abnormalities, which consist of reductions in temporal-parietal metabolism that progress in severity and extent as the disease itself shows clinical progression. Such noninvasive biochemical assays may ultimately prove to be of assistance in clinical management, and are clearly helpful in understanding the pathophysiologic mechanisms associated with the production of this disease.

Alzheimer Disease↗
PubMed1991

Viral resistance to human immunodeficiency virus type 1-specific pyridinone reverse transcriptase inhibitors.

Human immunodeficiency virus type 1 (HIV-1)-specific pyridinone reverse transcriptase (RT) inhibitors prevent HIV-1 replication in cell culture (M. E. Goldman, J. H. Nunberg, J. A. O'Brien, J.C. Quintero, W. A. Schleif, K. F. Freund, S. L. Gaul, W. S. Saari, J. S. Wai, J. M. Hoffman, P. S. Anderson, D. J. Hupe, E. A. Emini, and A. M. Stern, Proc. Natl. Acad. Sci. USA 88:6863-6867, 1991). In contrast to nucleoside analog inhibitors, such as AZT, which need to be converted to triphosphates by host cells, these compounds act directly to inhibit RT via a mechanism which is noncompetitive with respect to deoxynucleoside triphosphates. As one approach to define the mechanism of action of pyridinone inhibitors, we isolated resistant mutants of HIV-1 in cell culture. Serial passage in the presence of inhibitor yielded virus which was 1,000-fold resistant to compounds of this class. Bacterially expressed RTs molecularly cloned from resistant viruses were also resistant. The resistant RT genes encoded two amino acid changes, K-103 to N and Y-181 to C, each of which contributed partial resistance. The mutation at amino acid 181 lies adjacent to the conserved YG/MDD motif found in most DNA and RNA polymerases. The mutation at amino acid 103 lies within a region of RT which may be involved in PPi binding. The resistant viruses, although sensitive to nucleoside analogs, were cross-resistant to the structurally unrelated RT inhibitors TIBO R82150 (R. Pauwels, K. Andries, J. Desmyter, D. Schols, M. J. Kukla, H. J. Breslin, A. Raeymaeckers, J. Van Gelder, R. Woestenborghs, J. Heykanti, K. Schellekens, M. A. C. Janssen, E. De Clercq, and P. A. J. Janssen, Nature [London] 343:470-474, 1990) and BI-RG-587 (V. J. Merluzzi, K. D. Hargrave, M. Labadia, K. Grozinger, M. Skoog, J. C. Wu, C.-K. Shih, K. Eckner, S. Hattox, J. Adams, A. S. Rosenthal, R. Faanes, R. J. Eckner, R. A. Koup, and J. L. Sullivan, Science 250:1411-1413, 1990). Thus, these nonnucleoside analog inhibitors may share a common binding site on RT and may all make up a single pharmacologic class of RT inhibitor. This observation may have important implications for the clinical development of these compounds.

Amino Acid Sequence↗
PubMed1991

Interrelated effects of insulin and glucose on diacylglycerol-protein kinase-C signalling in rat adipocytes and solei muscle in vitro and in vivo in diabetic rats.

The effects of insulin and glucose, alone and combined, on diacylglycerol (DAG), protein kinase-C (PKC), and glucose transport were compared in rat adipocytes and solei incubated in medium containing 0-20 mM glucose. In both tissues insulin rapidly stimulated [3H]DAG production from [3H]glycerol; extracellular glucose masked this effect in adipocytes, but not in solei. [3H]Glucose was avidly converted to DAG in adipocytes, and this conversion was enhanced by insulin. In contrast, [3H]glucose was poorly converted to DAG in solei. Glucose alone (5-20 mM) stimulated PKC translocation in adipocytes, but not in solei. Insulin stimulated PKC translocation in both tissues at all glucose concentrations. However, glucose modulated this effect of insulin in adipocytes by 1) decreasing cytosolic PKC and the absolute amount of PKC translocated, and 2) promoting apparent turnover of membrane PKC. In contrast, in solei, glucose did not affect PKC levels or translocation responses to insulin. In keeping with DAG-PKC signalling, the relative glucose transport effects of insulin were influenced by extracellular glucose in adipocytes, but not in solei. These results suggest that 1) glucose-induced PKC translocation requires metabolism of glucose to DAG; 2) glucose activates DAG-PKC signalling in adipocytes, but not in solei; 3) insulin activates DAG-PKC signalling in both tissues at all glucose levels; and 4) glucose may modulate the effects of insulin on DAG-PKC signalling in adipocytes, but not in solei. Consistent with in vitro results, in solei taken directly from diabetic rats, membrane PKC was decreased, and cytosolic PKC was increased, presumably reflecting diminished PKC translocation due to hypoinsulinemia. In contrast, in adipose tissue, cytosolic PKC was decreased, presumably reflecting hyperglycemia-induced PKC translocation. Accordingly, DAG levels were increased in adipose tissue, but not in solei, in diabetic rats, and insulin increased DAG in both tissues.

Adipose Tissue↗
PubMed1991

Serum-induced sensitization of cyclic AMP accumulation in 1321N1 human astrocytoma cells.

Exposure of 1321N1 human astrocytoma cells to fresh medium containing fetal bovine serum induced a marked increase in the subsequent ability of isoproterenol and forskolin to stimulate cAMP accumulation in intact cells, compared with cells exposed to fresh medium without serum. This "sensitization" of cAMP accumulation by serum was dose dependent, occurred rapidly, was maintained in the continuing presence of serum, and reversed rapidly upon removal of serum. Preliminary characterization of the sensitizing factor(s) in serum has been performed, but the factor(s) remain to be identified. Sensitization appeared to result from an increase in maximal response and not from changes in the potency of isoproterenol or forskolin. The protein kinase C inhibitor staurosporine inhibited serum-induced sensitization. Furthermore, down-regulation of protein kinase C almost completely eliminated the subsequent ability of serum to induce sensitization, indicating involvement of protein kinase C in the serum effect. Pretreatment of cells with pertussis toxin also markedly reduced subsequent sensitization induced by serum, suggesting involvement of a pertussis toxin-sensitive guanine nucleotide-binding protein in the pathway for serum-induced sensitization. The rate of cAMP degradation was not changed in sensitized cells, but some increase in adenylyl cyclase activity was retained in broken cell preparations from sensitized cells, suggesting increased synthesis of cAMP by adenylyl cyclase as the mechanism for sensitization.

1-Methyl-3-isobutylxanthine↗
PubMed1991

The effect of metabolic milieu on cardiac PET imaging using fluorine-18-deoxyglucose and nitrogen-13-ammonia in normal volunteers.

Cardiac PET imaging using 13N-ammonia and 18FDG was performed on 17 normal volunteers in the glucose-loaded and fasted states. PET images (glucose-loaded and fasted) were subjected to qualitative visual analysis using the descriptors: image quality, FDG blood-pool activity, ammonia lung field activity, and clinical interpretability. Glucose-loaded studies had better image quality, diminished FDG blood-pool activity, and were more often clinically interpretable compared to fasted studies. Dietary state did not affect 13N-ammonia study parameters. Using a semi-quantitative region of interest method, 18FDG myocardial activity was homogeneous and significantly affected by dietary state (2.48 +/- 1.0 fold increase in myocardial-to-blood pool ratio in glucose-loaded versus fasted states). Serum glucose, insulin, and free-fatty acid concentrations responded physiologically to glucose loading and fasting but showed no correlation with myocardial 18FDG uptake. PET imaging using 13N-ammonia and 18FDG appears optimal in the glucose-loaded state.

Adult↗
PubMed1991

Clinical application of PET for the evaluation of brain tumors.

The combination of FDG and PET has demonstrated clinical utility in the evaluation of patients with brain tumors. At the time of diagnosis, FDG PET provides information concerning the degree of malignancy and patient prognosis. After therapy, FDG PET is able to assess persistence of tumor, determine degree of malignancy, monitor progression, differentiate recurrence from necrosis, and assess prognosis. Other studies using PET provide information that may be clinically useful. Determination of tumor blood flow and permeability of the blood-brain barrier may help in the selection of appropriate therapy. Amino acid imaging using 11C-methionine is being evaluated in patients with brain tumors and provides different information than FDG imaging.

Brain Neoplasms↗