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Biomedical subjects

J D Chen

Publications and source records attributed to J D Chen.

At least 91 records · Page 5Linked to original sources
PubMed1997

The nuclear receptor corepressor SMRT inhibits interstitial collagenase (MMP-1) transcription through an HRE-independent mechanism.

Nuclear receptors inhibit synthesis of collagenase-1 (matrix metalloproteinase-1; MMP-1), an enzyme that degrades interstitial collagens and contributes to joint pathology in rheumatoid arthritis. SMRT (Silencing Mediator for Retinoid and Thyroid hormone receptors) mediates the repressive effect of nuclear receptors at hormone responsive elements (HREs), prompting us to investigate whether this co-repressor could also regulate transcription of MMP-1, which lacks any known HREs. We find that primary synovial fibroblasts express SMRT. When over-expressed by transient transfection, SMRT inhibits MMP-1 promoter activity induced by interleukin-1 (IL-1), phorbol phorbol myristate acetate (PMA) or v-Src. SMRT apparently inhibits MMP-1 gene expression by interfering with one or more transcriptional elements clustered in a region between -321 and +63. We conclude that SMRT negatively regulates MMP-1 synthesis through a novel, HRE-independent mechanism that involves proximal regions of the MMP-1 promoter.

Animals↗
PubMed1997

RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2.

Steroids, thyroid hormones, vitamin D3, and retinoids are lipophilic small molecules that regulate diverse biological effects such as cell differentiation, development, and homeostasis. The actions of these hormones are mediated by steroid/nuclear receptors which function as ligand-dependent transcriptional regulators. Transcriptional activation by ligand-bound receptors is a complex process requiring dissociation and recruitment of several additional cofactors. We report here the cloning and characterization of receptor-associated coactivator 3 (RAC3), a human transcriptional coactivator for steroid/nuclear receptors. RAC3 interacts with several liganded receptors through a mechanism which requires their respective ligand-dependent activation domains. RAC3 can activate transcription when tethered to a heterologous DNA-binding domain. Overexpression of RAC3 enhances the ligand-dependent transcriptional activation by the receptors in mammalian cells. Sequence analysis reveals that RAC3 is related to steroid receptor coactivator 1 (SRC-1) and transcriptional intermediate factor 2 (TIF2), two of the most potent coactivators for steroid/nuclear receptors. Thus, RAC3 is a member of a growing coactivator network that should be useful as a tool for understanding hormone action and as a target for developing new therapeutic agents that can block hormone-dependent neoplasia.

Amino Acid Sequence↗
PubMed1997

Potent antitumour activity of a new class of tumour-specific killer cells.

Two approaches to the antibody-directed targeting of toxic or cytolytic activity and augmentation of cellular immune responses have been explored for tumour immunotherapy, but so far success has been limited. Obstacles facing immunotherapy are the limited accessibility of antibodies or antibody conjugates to solid tumours and the difficulty in obtaining tumour-specific cytotoxic lymphocytes. Here we generate a new class of tumour-specific killer cells by genetically modifying lymphocytes to produce and secrete a targeted toxin against an oncoprotein overexpressed on breast and other tumour cells. The transduced lymphocytes were shown to have potent and selective cytotoxicity to tumours in culture and nude mouse models. The potent in vivo antitumour activity is probably a result of the migration of the lymphocytes to tumours as a targeted toxin carrier, and production and accumulation of the targeted toxins inside tumours as a producer. Our approach, which has features of both antibody-directed and cell-mediated immunotherapy, may have application in a gene therapy context.

ADP Ribose Transferases↗
PubMed1997

Neurobehavioral effects of occupational exposure to low-level organic solvents among Taiwanese workers in paint factories.

At six paint factories in northern Taiwan, 325 workers participated in a detailed evaluation that included medical and occupational questionnaires, blood sampling, neurobehavioral tests, vibratory perception threshold tests, and thermal perception threshold tests. Because of cultural differences, a Chinese test battery was modified from the Neurobehavioral Evaluation System 2. Eleven tests were performed: finger tapping, continuous performance, associated learning, symbol-digit, pattern comparison, pattern memory, visual digit span, switch attention, associated delayed recognition, mood scales, and vocabulary. Air concentrations of organic solvents were measured by passive personal samplers and analyzed by gas chromatography. Results showed that major solvents to which the workers were exposed were toluene, xylene, n-hexane, methyl iso-butyl ketone, and n-butyl acetate. The exposure index (EI) was classified by different exposure patterns and different air concentrations in the breathing zone as follows: EI 0, nonexposure; EI 1, low exposure; and EI 2, high exposure (the medians of 8-hr hygienic effects were 0, 0.03, and 0.25, respectively). Because of their diverse socioeconomic status and demographic characteristics, the workers were divided into two groups for additional analysis: one group comprised white-collar workers, including technicians and administrative staff, and the other comprised blue-collar workers. By using multiple linear regression analysis controls for age, sex, education, and alcohol intake, significant associations were found between increased exposure to solvent mixtures and performance on some neuropsychologic tests. In the blue-collar group, significantly prolonged response latencies were observed in the tests of continuous performance, pattern comparison, and pattern memory. Among white-collar workers, significant impairment was observed in the continuous performance test. All three tests involved visual attention and perceptual (speed and memory) functions. It was concluded that these may be the earliest neurotoxic signs of occupational exposure to low-level organic solvents in paint manufacturing workers.

Adolescent↗
PubMed1997

Classification of normal and abnormal electrogastrograms using multilayer feedforward neural networks.

A neural network approach is proposed for the automated classification of the normal and abnormal EGG. Two learning algorithms, the quasi-Newton and the scaled conjugate gradient method for the multilayer feedforward neural networks (MFNN), are introduced and compared with the error backpropagation algorithm. The configurations of the MFNN are determined by experiment. The raw EGG data, its power spectral data, and its autoregressive moving average (ARMA) modelling parameters are used as the input to the MFNN and compared with each other. Three indexes (the percent correct, sum-squared error and complexity per iteration) are used to evaluate the performance of each learning algorithm. The results show that the scaled conjugate gradient algorithm performs best, in that it is robust and provides a super-linear convergence rate. The power spectral representation and the ARMA modelling parameters of the EGG are found to be better types of the input to the network for this specific application, both yielding a percent correctness of 95% on the test set. Although the results are focused on the classification of the EGG, this paper should provide useful information for the classification of other biomedical signals.

Algorithms↗
PubMed1997

Impaired gastric myoelectrical activity in patients with chronic renal failure.

Dysmotility and delayed emptying of the stomach have been reported in patients with chronic renal failure (CRF). The aim of this study was to investigate whether gastric myoelectrical activity was impaired in patients with CRF using electrogastrography. The electrogastrogram (EGG) was recorded in 24 symptomatic patients with CRF (15 with diabetes) and 12 normal subjects. Two 30-min EGG recordings before and after a test meal were analyzed using spectral analysis methods. It was found that patients with CRF showed a significantly lower percentage of normal 2-4 cpm slow waves in both fasting and fed states in comparison with healthy controls (in fasting state: 88.9 +/- 2.5% vs 67.4 +/- 6.6%/63.2 +/- 7.0%, P < 0.01; in fed state: 89.6 +/- 1.8% vs 64.6 +/- 6.2%/62.0 +/- 8.3%, P < 0.01; controls vs diabetic patients/nondiabetic patients). Both patient groups showed a significantly higher prevalence of the abnormal EGG, which was defined as the percentage of 2-4 cpm slow waves lower than 70% (fasting state: 8% vs 60%/56%, P < 0.01/0.05; fed state: 0% vs 53%/56%, P < 0.005/0.002; controls vs diabetic patients/nondiabetic patients). No significant difference was observed in the regularity of the gastric slow waves between the two patient groups. The healthy controls showed a significant increase in the dominant power and frequency of the EGG after the test meal. However, this increase was absent in the two patient groups. It was concluded that patients with chronic renal failure have abnormal gastric myoelectrical activity, including impaired regularity of the gastric slow wave and a failed increase in the power of the EGG at 3 cpm. Electrogastrography is an attractive noninvasive method for the study of gastric motility in patients with severe chronic renal failure.

Adult↗
PubMed1997

What can be measured from surface electrogastrography. Computer simulations.

The aims of this study were to investigate the detectability of the propagation of the gastric slow wave from the cutaneous electrogastrogram (EGG) and the patterns of the EGG when the gastric slow waves are uncoupled. A mathematical model was established based on the volume conductor theory to simulate the transfer of the serosal gastric slow wave from the stomach to the abdominal surface. A number of computer simulations were conducted using the model, and the periodic cross-correlation function was used to estimate the phase shift between the four channels. It was found that the propagation of the gastric slow wave was detectable from the multichannel EGG signals. The detectability of the propagation was, however, associated with a number of factors, such as the thickness of the abdominal wall and the propagation velocity of the serosal slow wave. The amplitude of the EGG was found to be associated with the coupling/uncoupling and propagation velocity of the gastric slow wave. The amplitude of the EGG increased when the propagation velocity of the gastric slow wave increased. The amplitude of the EGG was substantially decreased when the gastric slow waves were uncoupled. The uncoupling of the gastric slow wave at a frequency of 3 cpm produced dysrhythmias in the EGG, including tachygastria, bradygastria, and arrhythmia. The power spectra of simulated different positional EGG signals showed similar patterns when the gastric slow wave was coupled and different and unpredictable patterns when the gastric slow wave was uncoupled. In conclusion, multichannel EGG recordings may be necessary to obtain more information on gastric slow waves from the abdominal electrodes. The propagation and coupling or uncoupling of the gastric slow wave may be detected from multichannel EGG recordings.

Computer Simulation↗
PubMed1997

Inactivation of HIV-1 chemokine co-receptor CXCR-4 by a novel intrakine strategy.

CXC-chemokine receptor (CXCR)-4/fusin, a newly discovered co-receptor for T-cell line (T)-tropic HIV-1 virus, plays a critical role in T-tropic virus fusion and entry into permissive cells. The occurrence of T-tropic HIV viruses is associated with CD4-positive cell decline and progression to AIDS, suggesting that the T-tropic HIV-1 contributes to AIDS pathogenesis. In this study, we used a novel strategy to inactivate CXCR-4 by targeting a modified CXC-chemokine to the endoplasmic reticulum (ER) to block the surface expression of newly synthesized CXCR-4. The genetically modified lymphocytes expressing this intracellular chemokine, termed "intrakine", are immune to T-tropic virus infection and appear to retain normal biological features. Thus, this genetic intrakine strategy is uniquely targeted at the conserved cellular receptor for the prevention of HIV-1 entry and may be developed into an effective treatment for HIV-1 infection and AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis.

BACKGROUND: Recently, several studies have shown an alteration in bowel function during sleep in patients with irritable bowel syndrome (IBS), and a recent study also suggests a remarkable increase in rapid eye movement (REM) sleep. These studies have suggested that an alteration in CNS function may play an important role in the pathogenesis of IBS. AIMS: To confirm the presence of an alteration in REM sleep in patients with IBS and to assess the relation between sleep and a non-invasive measure of gastric functioning, the electrogastrogram (EGG). PATIENTS: Ten patients with IBS and 10 age and sex matched normal volunteers. METHODS: All subjects slept one night in the sleep laboratory and underwent polysomnographic monitoring to determine sleep patterns, and recording of the EGG from surface electrodes. RESULTS: The IBS group had a notable and significant increase in the percentage and duration of REM sleep (p < 0.05). The control group had a decrease in the amplitude of the dominant EGG frequency from waking to non-REM sleep (p < 0.05), and a subsequent increase in the amplitude from non-REM to REM sleep (p < 0.05). No such changes were noted in the patients with IBS. CONCLUSIONS: Results confirmed the enhancement of REM sleep in patients with IBS and suggested an intrinsic alteration in autonomic and CNS functioning in patients with IBS.

Adult↗
PubMed1997

Patterns of gastric myoelectrical activity in human subjects of different ages.

The aim of this study was to investigate the developmental change of gastric myoelectrical activity in humans. Five groups of healthy subjects were studied, including 10 preterm newborns, 8 full-term newborns, 8 full-term infants (ages 2-6 mo), 9 children (ages 4-11 yr), and 9 adults. Gastric myoelectrical activity was recorded using surface electrogastrography for 30 min before and 30 min after a test meal in each subject. Spectral analysis methods were applied to compute the parameters of the electrogastrogram (EGG). The results showed that the percentage of 2- to-4-cycles/min (cpm) slow waves was 26.6 +/- 3.9% in the preterm newborns, 30.0 +/- 4.0% in full-term newborns, 70 +/- 6.1% in 2- to 6-mo-old infants (P < 0.001 compared with newborns), 84.6 +/- 3.2% in 4- to 11-yr-old children (P < 0.03 compared with infants), and 88.9 +/- 2.2% in the adults (P > 0.05 compared with children). In conclusion, gastric slow waves are absent at birth, and there is a maturing process after birth. Age-matched controls are necessary for the interpretation of EGG data from neonates and infants, whereas EGG data in children are the same as in adults.

Adult↗
PubMed1997

Characterization of receptor interaction and transcriptional repression by the corepressor SMRT.

SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) and N-CoR (nuclear receptor corepressor) are two related transcriptional corepressors that contain separable domains capable of interacting with unliganded nuclear receptors and repressing basal transcription. To decipher the mechanisms of receptor interaction and transcriptional repression by SMRT/N-CoR, we have characterized protein-protein interacting surfaces between SMRT and nuclear receptors and defined transcriptional repression domains of both SMRT and N-CoR. Deletional analysis reveals two individual nuclear receptor domains necessary for stable association with SMRT and a C-terminal helix essential for corepressor dissociation. Coordinately, two SMRT domains are found to interact independently with the receptors. Functional analysis reveals that SMRT contains two distinct repression domains, and the corresponding regions in N-CoR also repress basal transcription. Both repression domains in SMRT and N-CoR interact weakly with mSin3A, which in turn associates with a histone deacetylase HDAC1 in a mammalian two-hybrid assay. Far-Western analysis demonstrates a direct protein-protein interaction between two N-CoR repression domains with mSin3A. Finally we demonstrate that overexpression of full-length SMRT further represses basal transcription from natural promoters. Together, these results support a role of SMRT/N-CoR in corepression through the utilization of multiple mechanisms for receptor interactions and transcriptional repression.

Amino Acid Sequence↗
PubMed1997

Evidence of a retinoid signaling alteration involving the activator protein 1 complex in tumorigenic human bronchial epithelial cells and non-small cell lung cancer cells.

Retinoids, including retinol and retinoic acid derivatives, inhibit the growth of normal human bronchial epithelial (HBE) cells. Using a lung carcinogenesis model consisting of normal, immortalized, and tumorigenic HBE cells, we showed previously that, compared to normal HBE cells, the tumorigenic HBE cell line 11701 is resistant to the growth-inhibitory effects of all-trans-retinoic acid (t-RA). Retinoid receptor function is preserved in tumorigenic 11701 cells, suggesting that other retinoid signaling components are altered. The activator protein 1 (AP-1) complex is a component of the retinoid signaling pathway and has demonstrated importance in cellular growth and differentiation. Therefore, we investigated whether AP-1 is involved in a retinoid signaling defect in tumorigenic 11701 cells and in retinoid-resistant non-small cell lung cancer (NSCLC) cell lines. We found that t-RA treatment inhibited AP-1 transcriptional activity in normal HBE cells but not in tumorigenic 11701 cells nor in the NSCLC cell lines Calu-1, Calu-6, SKMES-1, and ChaGo K1. We sought mechanisms for this retinoid signaling alteration involving AP-1 in tumorigenic 11701 cells. Basal AP-1 transcriptional activity; AP-1 DNA-binding activity; and the mRNA levels of c-fos, the AP-1 coactivator Jun activation domain-binding protein 1, and the retinoid receptor corepressor, the silencing mediator for retinoid and thyroid hormone receptors (SMRT), were lower in tumorigenic 11701 cells than in normal HBE cells. Transient transfection of tumorigenic 11701 cells with c-fos or CREB binding protein, which is a coactivator of AP-1 and retinoid receptors, enhanced basal AP-1 transcriptional activity but did not alter the effects of t-RA on AP-1 transcriptional activity. These findings provide evidence of a retinoid signaling alteration involving AP-1 in tumorigenic 11701 and NSCLC cells. Furthermore, the inhibitory effect of t-RA on AP-1 transcriptional activity was not restored in tumorigenic 11701 cells by transfection of c-fos, silencing mediator for retinoid and thyroid hormone receptors, Jun activation domain-binding protein 1, or CREB-binding protein, suggesting the involvement of other transcriptional coregulators in this retinoid signaling defect.

Blotting, Northern↗
PubMed1997

Electrical stimulation of acupuncture points enhances gastric myoelectrical activity in humans.

OBJECTIVE: Acupuncture is known to enhance gastric motility. Electrical acustimulation has been shown to reduce gastric tachyarrhymia in vection-induced motion sickness. The aim of this study was to investigate the effect of electrical stimulation of acupuncture points on gastric myoelectrical activity in healthy humans. METHODS: Nine healthy native Chinese were studied. Gastric myoelectrical activity was recorded using surface electrogastrography (EGG). The EGG recording was made in the fasting state, in a study period during which acupuncture points were electrically stimulated continuously, and in a recovery period after stimulation. The percentage of regular slow waves was assessed by computing the percentage of 2 to 4 cycles per minute slow waves in the EGG. RESULTS: Electrical stimulation significantly increased the percentage of regular slow waves, which was sustained in the recovery period. The increase of the regular slow wave activity resulted from the normalization of arrhythmia. CONCLUSION: Electrical stimulation of acupuncture points may enhance the regularity of gastric myoelectrical activity and may be an option for treatment of gastric dysrhythmia.

Acupuncture Points↗
PubMed1996

Intra- and extracellular immunization against HIV-1 infection with lymphocytes transduced with an AAV vector expressing a human anti-gp120 antibody.

Recently, we developed a novel anti-HIV-1 approach by transducing an anti-gp120 antibody gene into lymphocytes, resulting in the resistance to HIV-1 infection by the combined intra- and extracellular binding activities of the neutralizing antibody. To extend this study, we improved the co-expression of the heavy and light chains of the Fab105 fragment of the anti-gp120 antibody F105 by using an internal ribosome entry site (IRES) sequence. The Fab105 expression cassette was then cloned into an adeno-associated virus (AAV) shuttle vector, and encapsidated recombinant AAV-Fab105 vectors were produced. The Fab105 antibody gene was shown to be transduced into human lymphocytes by using the recombinant AAV viruses. The transduced lymphocytes were able to produce and secrete the Fab105 fragments, while maintaining their normal morphology, growth rates, and responsiveness to mitogen stimulation. The infection of several primary HIV-1 patient isolates was effectively blocked in the transduced lymphocytes. This study indicates that the combined intra- and extracellular immunization approach may be useful for the treatment of HIV-1-infected patients.

Antibodies↗
PubMed1996

SMRT isoforms mediate repression and anti-repression of nuclear receptor heterodimers.

Transcriptional repression represents an important component in the regulation of cell differentiation and oncogenesis mediated by nuclear hormone receptors. Hormones act to relieve repression, thus allowing receptors to function as transcriptional activators. The transcriptional corepressor SMRT was identified as a silencing mediator for retinoid and thyroid hormone receptors. SMRT is highly related to another corepressor, N-CoR, suggesting the existence of a new family of receptor-interacting proteins. We demonstrate that SMRT is a ubiquitous nuclear protein that interacts with unliganded receptor heterodimers in mammalian cells. Furthermore, expression of the receptor-interacting domain of SMRT acts as an antirepressor, suggesting the potential importance of splicing variants as modulators of thyroid hormone and retinoic acid signaling.

Alternative Splicing↗
PubMed1996

Abnormal gastric myoelectrical activity and delayed gastric emptying in patients with symptoms suggestive of gastroparesis.

Gastric myoelectrical activity modulates gastric motor activity. Abnormalities in gastric myoelectrical activity may be associated with gastric motility disorders. The aim of this study was to investigate the correlation of gastric myoelectrical activity with gastric emptying in symptomatic patients with and without gastroparesis. Ninety-seven patients with symptoms suggestive of gastroparesis participated in the study. Gastric myoelectrical activity was recorded using surface electrogastrography. The electrogastrogram (EGG) was recorded for 30 min in the fasting state and for 120 min after a solid test meal. Gastric emptying of the solid meal was simultaneously monitored for 120 min. Patients with delayed gastric emptying showed a significantly lower percentage of normal gastric slow waves (P < 0.03) and a significantly reduced increase of the dominant power in the postprandial EGG (P < 0.02). Postprandial EGG parameters were found to be able to predict delayed emptying of the stomach. Postprandial gastric dysrhythmia predicts delayed gastric emptying with an accuracy of 78%, while the abnormality in postprandial EGG power predicts delayed gastric emptying with an accuracy of 75%. All patients with abnormalities in both the rhythmicity and the power had delayed gastric emptying. Patients with delayed gastric emptying have a lower percentage of normal gastric slow waves in the EGG and a lower postprandial increase in the dominant power. Abnormalities in the postprandial EGG seem to be able to predict delayed emptying of the stomach. However, a normal EGG does not seem to guarantee normal emptying of the stomach.

Adolescent↗
PubMed1996

Role of sham feeding in postprandial changes of gastric myoelectrical activity.

The aim of this study was to evaluate the role of sham feeding in postprandial changes of gastric myoelectrical activity. Eighteen asymptomatic healthy volunteers (10 men, 8 women; mean age: 31), with no history of gastrointestinal disease were studied. Gastric myoelectrical activity was recorded for 30 min at baseline, 30 min after sham feeding, and 1 hr after eating, using surface electrogastrography. The electrogastrogram (EGG) was analyzed by spectral analysis. It was found that the changes of postprandial EGG parameters were significantly correlated with those after sham feeding (EGG dominant power: r = 0.6, P < 0.01; dominant frequency: r = 0.8, P < 0.001; percentage of regular slow waves: r = 0.7, P < 0.003). We concluded that intrinsic gastric electrical activity can be altered by sham feeding and the cephalic phase of digestion plays an important role in the postprandial response of gastric myoelectrical activity.

Adult↗