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Biomedical subjects

G Chen

Publications and source records attributed to G Chen.

At least 685 records · Page 38Linked to original sources
PubMed1995

Positive correlation between cellular glutathione and acquired cisplatin resistance in human ovarian cancer cells.

While multiple changes are frequently found to be associated with cisplatin resistance in a variety of tumor cell lines, a cause-effect relationship of these alterations with the resistant phenotype has not been established. In order to identify the resistance-relevant determinants, a series of cisplatin-resistant sublines with different degrees of resistance to cisplatin was developed in a human ovarian carcinoma cell line (O-129). Three derived resistant cell lines displayed 2.1-fold (O-129/DDP4, low), 4.1-fold (O-129/DDP8, moderate) and 6.3-fold (O-129/DDP16, high) resistance, respectively, to cisplatin, compared with the sensitive parental line O-129. While the activity of poly(ADP-ribose) polymerase, an enzyme proposed to be involved in DNA repair, was elevated in all three resistant lines, a significant karyotypic change was observed only in the high-resistance line with the karyotype alteration from near diploidy to heteroploidy. The moderate (4.1-fold) and high (6.3-fold) DDP resistance was associated with a slow proliferation rate in drug-free medium, but cellular glutathione level was highly correlated with DDP sensitivity in all four cell lines. Taken together, the present studies establish that while many changes at cellular level can occur with development of cisplatin resistance, only elevation of intracellular glutathione concentration appears to be related to the resistance phenotype in these human ovarian cancer cells.

Cell Division↗
PubMed1995

Treatment of human hepatocellular carcinoma by fibroblast-mediated human interferon alpha gene therapy in combination with adoptive chemoimmunotherapy.

The therapeutic effect of the fibroblast-mediated human interferon (IFN alpha) gene therapy in combination with interleukin-2 (IL-2) activated killer cells (AK)/doxorubicin (i.e., adoptive chemoimmunotherapy) on nude mice bearing the human hepatocellular carcinoma (HCC) was investigated. A fibroblast cell clone (NIH3T3-IFN alpha+) secreting 1024 U/ml human IFN alpha was obtained from 14 positive clones by BMGNeo-IFN alpha DNA transfection, G418-resistant selection, limiting dilution and assay of IFN alpha activity. After i.p. implantation of NIH3T3-IFN alpha+ encapsulated into collagen, serum human IFN alpha activity could be detected from 12 h to day 15 with a peak at 72 h. AK were prepared from human peripheral mononuclear cells costimulated in vitro by IL-2 and inactivated human SMMC 7721 HCC cells. When the NIH3T3-IFN alpha+ cells were i.p. implanted into the HCC-bearing nude mice, the grown of HCC was inhibited and the survival time of the mice was extended. The growth of HCC was inhibited more obviously when AK was i.v. injected and IL-2 was i.p. injected after the NIH3T3-IFN alpha+ cells had been implanted. The best therapeutic effect was achieved when NIH3T3-IFN alpha+ cells were used in combination with IL-2/AK/doxorubicin. All these results suggested that the fibroblast-mediated human IFN alpha gene therapy could be used to treat the human hepatocellular carcinoma effectively and that when used in combination with IL-2-based adoptive chemoimmunotherapy, the therapeutic effect would be better.

3T3 Cells↗
PubMed1995

Human cones appear to adapt at low light levels: measurements on the red-green detection mechanism.

Recent physiological evidence suggests that cones do not light adapt at low light levels. To assess whether adaptation is cone-selective at low light levels, the red-green detection mechanism was isolated. Thresholds were measured with a large test flash, which stimulated the L and M cones in different fixed amplitude ratios, on different colored adapting fields. Thresholds were plotted in L and M cone contrast coordinates. The red-green mechanism responded to an equally-weighted difference of L and M cone contrast on each colored field, demonstrating equivalent, Weberian adaptation of the L and M cone signals. The L and M cone signals independently adapted for illuminance levels as low as 60 effective trolands (e.g. M-cone trolands). Since this adaptation is entirely selective to cone type, it suggests that the cones themselves light-adapt. The red-green detection contour on reddish fields was displaced further out from the origin of the cone contrast coordinates, revealing an additional sensitivity loss at a subsequent, spectrally-opponent site. This second-site effect may arise from a net "red" or "green" signal that represents the degree to which the L and M cones are differently hyperpolarized by the steady, colored adapting field. Such differential hyperpolarization is compatible with equivalent, Weberian adaptation of the L and M cones.

Adaptation, Ocular↗
PubMed1995

Use of voltage-sensitive dyes and optical recordings in the central nervous system.

Understanding the spatio-temporal features of the information processing occurring in any complex neural structure requires the monitoring and analysis of the activity in populations of neurons. Electrophysiological and other mapping techniques have provided important insights into the function of neural circuits and neural populations in many systems. However, there remain limitations with these approaches. Therefore, complementary techniques which permit the monitoring of the spatio-temporal activity in neuronal populations are of continued interest. One promising approach to monitor the electrical activity in populations of neurons or on multiple sites of a single neuron is with voltage-sensitive dyes coupled with optical recording techniques. This review concentrates on the use of voltage-sensitive dyes and optical imaging as tools to study the activity in neuronal populations in the central nervous system. Focusing on 'fast' voltage-sensitive dyes first, several technical issues and developments in optical imaging will be reviewed. These will include more recent developments in voltage-sensitive dyes as well as newer developments in optical recording technology. Second, studies using voltage-sensitive dyes to investigate information processing questions in the central nervous system and in the invertebrate nervous system will be reviewed. Some emphasis will be placed on the cerebellum, but the major goal is to survey how voltage-sensitive dyes and optical recordings have been utilized in the central nervous system. The review will include optical studies on the visual, auditory, olfactory, somatosensory, auditory, hippocampal and brainstem systems, as well as single cell studies addressing information processing questions. Discussion of the intrinsic optical signals is also included. The review attempts to show how voltage-sensitive dyes and optical recordings can be used to obtain high spatial and temporal resolution monitoring of neuronal activity.

Central Nervous System↗
PubMed1995

Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups.

OBJECTIVE: To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN: Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS: In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS: At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.

Acyltransferases↗
PubMed1995

Antimicrobial metabolites from a bacterial symbiont.

Two types of antibiotics, namely, indoles and dithiolopyrrolones, have been isolated and identified from Xenorhabdus bovienii A2. Compounds 1 and 2 showed strong activity against Cryptococcus neoformans, compounds 3 and 4 showed strong activity against Botrytis cinerea, and compounds 1, 3, and 4 showed significant activity against Phytophthora infestants (2 was not tested). In addition, two lower homologues of xenorhabdins 5 and 6, namely, 6-(N-3'-methylbutanamido)-4,5-dihydro-1,2-dithiolo[4,3-b]pyr rol-5- one [7] and 6-(N-butanamido)[4,5-dihydro-1,2-dithiolo[4,3-b]pyrrol-5-one [8], have been isolated and characterized for the first time.

Animals↗
PubMed1995

Alterations in cyclic AMP generation and G protein subunits following transient ischemia in gerbil hippocampus.

We examined alterations in the cyclic AMP generating system and G protein subunits in gerbil hippocampus following 10 min of transient ischemia. In hippocampal slices, basal and isoproterenol- and forskolin-stimulated cyclic AMP accumulations were markedly increased at 6 and 24 h after ischemia. Interestingly, both the inhibition of forskolin-stimulated cyclic AMP and the potentiation of beta-adrenoceptor-stimulated cyclic AMP by a gamma-aminobutyric acidB receptor agonist were attenuated at these time points. Ischemia did not affect the immunolabeling of any of the G protein alpha subunits; only that of beta subunits was significantly decreased, by 28.2%, 4 days after ischemia. In contrast, pertussis toxin-catalyzed [32P]ADP ribosylation declined progressively during the late recirculation period, reaching a significant reduction (25.4%) at 6 h after ischemia. These results suggest that ischemia affects the heterotrimeric conformation (alpha beta gamma) of Gi/Go during the recirculation period, thereby leading to increased cyclic AMP production. Because cyclic AMP-dependent protein kinase A modulates the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-kainate receptor channels, postischemic sensitization of the cyclic AMP generating system may contribute to neuronal degeneration in the hippocampus.

Adenosine Diphosphate Ribose↗
PubMed1995

Studies on morphological typing of argyrophilic nucleolar organizer regions.

Morphological typing of argyrophilic nucleolar organizer regions (AgNOR) in 300 cases of malignant tumors and 140 cases of benign lesions was analyzed and five morphological types of AgNOR were described in detail. In malignant tumors, the diffuse type (78%) was the most frequently seen, and in benign lesions, the nucleolar type (92.85%); the difference was thus highly significant (P < 0.001). The intranucleolar and aggregate types were not observed in benign lesions. There was no obvious difference in the proportion of the mixed type in benign and malignant lesions (P > 0.05). The relationship between grade of malignancy and morphological typing of AgNOR and its clinical significance are discussed.

Humans↗
PubMed1995

Cyclosporin A in fat emulsion carriers: experimental studies on pharmacokinetics and tissue distribution.

In the commercially available intravenous formulation of Cyclosporin A (Sandimmun), polyoxyethylated castor oil (Cremophor EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.

Animals↗
PubMed1995

Identification of two pigments and a hydroxystilbene antibiotic from Photorhabdus luminescens.

Two yellow pigments were isolated for the first time from the entomopathogenic bacterium Photorhabdus luminescens in liquid culture and were identified as the anthraquinone derivatives 3,8-dimethoxy-1-hydroxy-9,10-anthraquinone (minor) and 1,3-dimethoxy-8-hydroxy-9,10-anthraquinone (major). A known antibiotic, 3,5-dihydroxy-4-isopropylstilbene, was also detected and for the first time showed strong fungicidal activity against several fungi of medical and agricultural importance.

Anthraquinones↗
PubMed1995

Use of Tl-201 to detect untreated pediatric Hodgkin disease.

PURPOSE: To evaluate the usefulness of thallium-201 scintigrams in depiction of supradiaphragmatic lymphadenopathy associated with newly diagnosed Hodgkin disease in pediatric patients. MATERIALS AND METHODS: Thallium-201 and gallium-67 scans of the chest and neck were obtained in 33 consecutive patients. Mediastinal, cervical, supraclavicular, and axillary lymph node activity was evaluated by independent raters, and results were compared in a blinded fashion with those on chest computed tomographic (CT) scans. RESULTS: Gallium and thallium scans demonstrated similar accuracy in depiction of CT-defined mediastinal masses. The kappa statistic indicated moderate to strong agreement with CT results. Similarly, there was no statistically significant difference between the accuracy of thallium and gallium scans in depiction of extramediastinal lymphadenopathy. CONCLUSION: Thallium scintigraphy is effective for depiction of lymphadenopathy in pediatric patients with untreated Hodgkin disease. Serial thallium studies may provide an alternative to gallium scans in monitoring response to treatment.

Adolescent↗
PubMed1995

TNF modulates endothelial properties by decreasing cAMP.

Tumor necrosis factor-alpha (TNF-alpha), a monokine that contributes to vascular dysfunction accompanying the host response to gram-negative sepsis, has been shown to increase vascular permeability in vivo and to diminish the barrier function of cultured endothelial cell (EC) monolayers. The studies reported here indicate that a mechanism through which TNF alters EC barrier function involves a reduction in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) content, due in part to increased cyclic nucleotide phosphodiesterase (CNPDE) activities. TNF increased the diffusional transit of [3H]sorbitol, [3H]inulin, and 125I-labeled albumin across confluent bovine aortic EC monolayers. This effect of TNF was both time and dose dependent and occurred in parallel with a fall in EC cAMP. cAMP analogues, such as dibutyryl cAMP (DBcAMP), prevented TNF-induced perturbation of EC barrier function. TNF also mediated another important alteration in the EC phenotype, in that both mRNA and activity of the anticoagulant cofactor thrombomodulin were reduced after exposure of EC to TNF and were normalized by the addition of DBcAMP. EC monolayers exposed to TNF-alpha showed increased cAMP levels when exposed to 3-isobutyl-1-methylxanthine, a nonspecific CNPDE inhibitor. Ion exchange chromatography of cytosol derived from TNF-treated EC consistently showed an approximately 245% increase in phosphodiesterase (PDE) IV (high-affinity, cAMP-specific PDE) activity as identified by rolipram inhibition. PDE II activity was increased by 150% after TNF-alpha treatment of early passage EC, which was identified by cGMP-activated hydrolysis of cAMP. Western and Northern analyses, as well as activity studies, revealed that TNF treatment did not change the amount of PDE IV protein or mRNA but rather increased the specific activity of the isozyme, suggesting that a posttranslational modification had occurred. These data indicate that activation of EC CNPDE activity and decreased intracellular cAMP may represent a mechanism by which TNF increases EC permeability and promotes a procoagulant EC phenotype.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1995

GABA receptors precede glutamate receptors in hypothalamic development; differential regulation by astrocytes.

1. The developmental changes in gamma-aminobutyrate (GABA)-, glutamate-, and glycine-mediated currents in cultured embryonic neurons (n = 134) from rat hypothalamus were studied with the use of whole cell voltage-clamp recording. 2. GABA-evoked currents were detected in neurons cultured from 15-day embryos (E15) a few hours after plating. Every neuron studied from the time of plating at E15 to 2 wk later responded to GABA (30 microM). The peak and steady-state currents evoked by GABA increased by four- to fivefold within 2 wk in culture. The time constants of the desensitization of GABA currents did not change during this period. The properties of the responses to GABA were not altered by different culture densities or substrates. 3. Glycine activated receptors that were pharmacologically distinct from GABA receptors on hypothalamic neurons. The glycine responses increased by > 50-fold within 2 wk in culture. The percentage of cells responding to glycine (500 microM) was 20% at 0 days in vitro (DIV), and increased to 100% at 6 DIV. Astrocytes increased both the amplitude of glycine-mediated currents and the percentage of cells responding to glycine. 4. Glutamate-mediated currents developed later than GABA-mediated currents. The percentage of cells responding to glutamate (500 microM) increased within the 1st wk, from 20% on the day of plating to 100% after 6 DIV. Both the peak currents and the steady-state currents mediated by glutamate increased by 20-fold during the 2 wk in culture. Both the amplitude of the responses to glutamate and the percentage of cells responding to glutamate were increased by growing neurons either on an astrocyte substrate or in high-density cultures. 5. The currents and conductance changes elicited by GABA were greater than those generated by glutamate or glycine throughout the period examined. This difference was particularly evident in younger cells. After 3 days in vitro, GABA (30 microM) elicited a mean current of 1,648 pA, whereas glutamate (500 microM) only elicited a 266-pA current, and glycine (500 microM) elicited a 278-pA current from neurons growing on an astrocyte layer. 6. The expression of amino acid receptors was heterogeneous among hypothalamic neurons in younger cultures. Whereas all neurons expressed GABA receptors, some developing neurons did not express detectable glutamate receptors or glycine receptors. 7. Each of the three amino acid-evoked currents increased from E15 (1 DIV) to E20 (1 DIV), indicating an intrinsic development in the expression of the amino acid receptors in vivo. The GABA, glutamate, and glycine currents at E15, 10 DIV were similar to the currents at E20, 5 DIV (both 25 days after conception), suggesting parallel developmental patterns for amino acid receptor expression in vitro and in vivo. 8. Together, these data suggest that GABA may play a major role in early development because hypothalamic neurons are more sensitive to GABA than to either glutamate or glycine. However, glutamate and glycine receptors appear more sensitive to regulation by the local environment than GABA receptors because culture density and the astrocyte substrate have greater inductive effects on glutamate and glycine receptors than on GABA receptors.

Animals↗
PubMed1995

Viral, host and environmental risk factors for hepatocellular carcinoma: a prospective study in Haimen City, China.

To identify specific environmental, viral, and genetic risk factors for hepatocellular carcinoma (HCC) and the interaction of such factors, we are conducting a prospective study in a high-incidence area of China. Questionnaires were completed and biosamples collected by 60,984 men ages 30-64 years, at study entry. Within 2.5 years, 183 deaths from HCC had occurred. Each HCC case was matched with 5 controls and compared for items on the questionnaire. In addition to chronic hepatitis B virus (HBV) infection, the significant risk factors were: occupation (peasant), corn consumption (in the 1970s), family history of HCC, and history of an episode of acute hepatitis as an adult. HBV, consumption of aflatoxins, a genetic factor, and possibly a second hepatitis virus infection contribute to the risk of HCC.

Adult↗
PubMed1995

Observation and quantitation of exocytosis from the cell body of a fully developed neuron in Planorbis corneus.

We have discovered a neuronal system that releases neurotransmitter via exocytosis from the cell body. In the large dopamine cell of the pond snail Planorbis corneus, depolarization induces rhythmic release of dopamine from the cell body. When a stimulant is applied extracellularly or intracellularly in situ to the cell body, transient dopamine concentration packets that appear in a bursting pattern are observed. Dopamine release is calcium dependent and release is on the time scale expected for exocytosis (2 to 4 msec rise times). Quantitation of individual events reveals an average of 818,000 molecules per exocytotic event. As many as 89,000 individual exocytotic events have been observed following a single stimulation of one cell. Neurotransmitter exocytosis from the neuronal cell body appears to represent an alternative form of neurocommunication to synaptic transmission.

Animals↗
PubMed1995

Dihydrofolate reductase binding and cellular uptake of nonpolyglutamatable antifolates: correlates of cytotoxicity toward methotrexate-sensitive and -resistant human head and neck squamous carcinoma cells.

Several mechanisms have been demonstrated to be independently involved in methotrexate (MTX) resistance, including increased dihydrofolate reductase (DHFR) activity, decreased membrane transport, and decreased conversion to noneffluxing polyglutamates by folylpolyglutamate synthetase. We conducted the present study to test the hypothesis that nonpolyglutamatable antifolates with an N delta-hemiphthaloyl-L-ornithine side chain could be more potent than MTX against MTX-sensitive and -resistant human carcinoma cells via tighter DHFR binding, more efficient cellular uptake, the ability to bypass defective polyglutamation, or a combination. Two nonpolyglutamatable antifolates, N alpha-(4-amino-4-deoxypteroyl)-N delta-hemiphthaloyl-L-ornithine (PT523) and the new B-ring analogue N alpha-[4-[N-(2,4-diamino-5-chloroquinazolin-6-yl)methyl]amino] benzoyl-N delta-hemiphthaloyl-L-ornithine (PT619), were tested as inhibitors of purified recombinant human DHFR and were found to bind somewhat better to the enzyme than MTX as determined by competitive radioligand binding assay. PT523 and PT619 were 9- and 14-fold, respectively, more active than MTX as inhibitors of parental SCC25 human and neck squamous carcinoma cell growth in 72-hr cultures. Moreover, there was an even greater increase in relative potency against two previously described MTX-resistant cell lines with an increased DHFR content and a decreased ability to convert MTX to polyglutamates: SCC25/R1 (selected with MTX) and SCC25/CP (selected with cisplatin but collaterally resistant to MTX). Both PT523 and PT619 very efficiently inhibited [3H]MTX uptake by SCC25 cells in a 1-hr assay, with PT523 being 11-fold more potent and PT619 being 17-fold more potent than MTX. Greater inhibition of [3H]MTX uptake with PT523 and PT619 than with MTX was also observed in SCC25/R1 and SCC/CP cells. However, the increase in activity of PT523 and PT619 relative to MTX in uptake experiments was less than that in growth-inhibition assays, especially for SCC25/CP cells. This suggested that additional cytotoxicity determinants may exist in these resistant cells.

Antimetabolites, Antineoplastic↗
PubMed1995

[Clinical and immunophenotyping features of CD34-positive acute nonlymphoblastic leukemia].

Antigen CD34 and other markers of cell membrane were investigated in cells from 43 patients with primary acute nonlymphoblastic leukemia (ANLL) by immunofluorescence test. The blast cells of 13 patients (30.2%) expressed antigen CD34. The patients with positive CD34 were no significantly different from the remaining 30 patients with negative CD34 with respect to age, serum lactate dehydrogenase (LDH), hemoglobin, white blood cell count, platelet count and the proportion of blast cells in blood and bone marrow, but their blasts were more likely to express HLA-DR, CD38, CD7 and lack of CD15 antigen. These patients had FAB M1 or M5a morphologic characteristics and lower complete remission (CR) rate. This result demonstrated that CD34 positive ANLL is poorly differentiated.

Adolescent↗