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Biomedical subjects

G D Chen

Publications and source records attributed to G D Chen.

At least 19 recordsLinked to original sources
PubMed2001

A genome-wide study of microsatellite instability in advanced gastric carcinoma.

BACKGROUND: Microsatellite instability (MSI) has been described in many human carcinomas, including gastric carcinomas (GCs). There are inconsistent findings regarding the association of MSI with various subsets of GC with specific clinicopathologic features. The objective of this study was to define MSI in advanced GC at a genome-wide level and to evaluate the clinical relevance of MSI in these patients. METHODS: Forty-one gastric adenocarcinomas with serosa invasion (T3) were analyzed at 59 loci that detected at least one site per arm of each autosome in human genome. The expression patterns of mismatch repair proteins hMLH1 and hMSH2 were examined by immunohistochemistry. Comparisons were made by categorizing tumors into three groups: tumors with MSI at multiple loci (at more than three loci), tumors with MSI at low level (at one to three loci), and microsatellite-stable (MSS) tumors. Clinical significance of MSI in advanced GC was evaluated. The relative rates of hypermutability of the 59 markers also were determined. RESULTS: A significant association was found between tumors with MSI at multiple loci and the expanding type of tumor growth by Ming's histologic classification (P = 0.001), whereas tumors with MSI at low level and MSS tumors are clinicopathologically indistinguishable. The 59 dinucleotide repeat markers displayed varying degrees of susceptibility toward genetic instability. The relative rates of hypermutability of these markers were consistent with a normal distribution pattern in which the frequency of unstable tumors detected at different chromosomal loci varied from 0% to 20%. CONCLUSIONS: The authors' results showed that advanced GC with MSI at multiple loci progress preferentially in an expanding mode, supporting the notion that high MSI tumors and low MSI/MSS tumors evolve through different genetic pathways. Thus, microsatellite testing may have clinical utility as a favorable prognostic marker.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Human Ca2+/calmodulin-dependent protein kinase kinase beta gene encodes multiple isoforms that display distinct kinase activity.

Ca(+2)/calmodulin-dependent protein kinases (CaMKs) are activated upon binding of Ca(+2)/calmodulin. To gain maximal activity, CaMK I and CaMK IV can be further phosphorylated by an upstream kinase, CaMK kinase (CaMKK). We previously isolated cDNA clones encoding human CaMKK beta isoforms that are heterogeneous in their 3'-sequences (Hsu, L.-S., Tsou, A.-P., Chi, C.-W., Lee, C.-H., and Chen, J.-Y. (1998) J. Biomed. Sci. 5, 141-149). In the present study, we examined the genomic organization and transcription of the human CaMKK beta gene. The human CaMKK beta locus spans more than 40 kilobase pairs and maps to chromosome 12q24.2. It is organized into 18 exons and 17 introns that are flanked by typical splice donor and acceptor sequences. Two major species of transcripts, namely the beta1 (5.6 kilobase pairs) and beta2 (2.9 kilobase pairs), are generated through differential usage of polyadenylation sites located in the last and penultimate exons. Additional forms of CaMKK beta transcripts were also identified that resulted from alternative splicing of the internal exons 14 and/or 16. These isoforms display differential expression patterns in human tissues and tumor-derived cell lines. They also exhibit a distinct ability to undergo autophosphorylation and to phosphorylate the downstream kinases CaMK I and CaMK IV. The differential expression of CaMKK beta isoforms with distinct activity further suggests the complexity of the regulation of the CaMKK/CaMK cascade and an important role for CaMKK in the action of Ca(+2)-mediated cellular responses.

Amino Acid Sequence↗
PubMed2001

NMDA receptor blockage protects against permanent noise-induced hearing loss but not its potentiation by carbon monoxide.

While a clear role has been proposed for glutamate as a putative neurotransmitter at the inner hair cell type I spiral ganglion cell synapse, the possible role of excessive glutamate release in cochlear impairment and of NMDA receptors in such a process is uncertain. The present study compares the protective effects of (+)-MK-801, an NMDA receptor antagonist, and the relatively inactive isomer (-)-MK-801 against permanent noise-induced hearing loss (NIHL). The study also asks whether (+)-MK-801 can protect against the NIHL potentiation by carbon monoxide (CO). Rats (n = 6) were exposed to 100-dB, 13.6-kHz octave-band noise for 2 h after receiving injection of (+)-MK-801 hydrogen maleate (1 mg/kg), (-)-MK-801 hydrogen maleate (1 mg/kg), or saline. Other groups of animals were exposed to the combination of noise and CO (1200 ppm) after receiving (+)-MK-801 or saline. Additional subjects received (+)-MK-801, saline or CO exposure alone. Compound action potential (CAP) threshold sensitivities were compared 4 weeks after the exposures. The results show significant protection by (+)-MK-801 against the permanent CAP threshold elevation induced by noise alone, but no protective effect of (-)-MK-801. (+)-MK-801 produced limited protection against threshold shifts induced by the combination of noise and CO. Outer hair cell (OHC) loss was not protected by (+)-MK-801 administration. The data suggest that NMDA receptor stimulation may play a role in NIHL resulting from fairly mild noise exposure. The data do not support a role for NMDA receptor stimulation in the potentiation of NIHL that results from simultaneous exposure to CO and noise.

Action Potentials↗
PubMed2001

[A study of genetic polymorphism of the STR locus D2S441 in Chinese Han population in Chengdu].

Using PCR and PAG, followed by silver staining, the tetrameric STR D2S441 locus was studied in 260 unrelated Chinese individuals living in Chengdu. 9 alleles and 26 genotypes were observed. The range of fragment size was 131 bp to 155 bp. The genotype distribution of D2S441 locus in Han population was in accordance with Hardy-Weinberg equilibrium. Family survey confirmed Mendelian inheritance of alleles. The discriminating power (Dp), observed heterozygosity (H), polymorphism information content (PIC) and power of exclusion (PE) were 0.9084, 0.7885, 0.7390 and 0.5778 respectively. The results demonstrated that this locus was highly polymorphic and could be used for forensic identification and paternity testing.

Alleles↗
PubMed2001

[Study on the construction of standard D1S549 allelic ladder via molecular cloning and its genetic polymorphism in Chinese three populations].

OBJECTIVE: To resolve the problem of the accuracy and standardization of STR-PCR typing in forensic practice, we have designed a new method to produce standard D1S549 allelic ladder. METHODS: Eight different PCR amplified D1S549 allelic fragments were isolated from the gel, eluted into the distilled water and re-amplified by PCR. The purified allelic fragments were then blunt-end subcloned individually into the pUC plasmid vectors and transfected into competent E. coli DH5 alpha cells. RESULTS: The sequencing results confirmed that the size and the construe of the inserts were correct. The recombinant plasmids DNA with 8 inserts were then used as templates for re-amplification to generate D1S549 standard ladder, with which the genetic polymorphisms of D1S549 locus in Chinese Han population in chengdu, Hui population in Gansu and Wei population in Xinjiang were studied. CONCLUSION: The results showed that the standard ladder made via this method is excellent, and D1S549 locus is robust for genetic research and forensic application.

Alleles↗
PubMed2000

Low-level toluene disrupts auditory function in guinea pigs.

Toluene appears to have adverse effects on the human auditory system, but it is difficult to estimate its potency since it is commonly present in the workplace in combination with noise exposure; workplace noise exposures are often highly variable. Studies designed to assess toluene ototoxicity specifically have been limited to high-dose studies in a single laboratory animal model, the rat. Here permanent hearing loss has been observed at concentrations of 1000 ppm toluene and greater after inhalation exposure for 5 days, 6 h/day. The OSHA threshold limit value for toluene is only 100 ppm. The current study focuses on the onset of toluene ototoxicity acutely in the guinea pig and in adducing a mechanism of effect. In this study, evidence is presented for the impairment of auditory function by toluene in the guinea pig, at a concentration substantially lower than that used for studying permanent impairment in the rat. The impaired function was correlated with reduced energy metabolism in outer hair cells. Assessment of auditory function was made using distortion product otoacoustic emissions (DPOAE) with subsequent measurement of succinate dehydrogenase (SDH) staining density in hair cells using surface preparations. Temporary disruption of auditory function in guinea pigs is seen in subjects exposed to 250, 500, and 1000 ppm toluene for 8 h/day, 5 day/week for 1 and 4 weeks. Concentrations as low as 250 ppm toluene were able to disrupt auditory function acutely in the guinea pig, and 500 and 1000 ppm toluene produced greater acute dysfunction. SDH staining suggests that reduced enzyme activity in the midfrequency region of the cochlea occurs acutely following toluene exposure. Although the auditory dysfunction progressed between 1 and 4 weeks of exposure, a permanent loss did not develop for these subjects and hair cell death was not seen. The current study identifies early evidence of auditory system impairment in the guinea pig at low toluene concentration and evidence for impairment of energy production in hair cells. While even a transient auditory impairment has implications for workplace safety, additional study on the transition from such acute effects to permanent impairment is essential.

Animals↗
PubMed2000

Succinate dehydrogenase (SDH) activity in hair cells: a correlate for permanent threshold elevations.

Hair cell loss is often used as a histological correlate of hearing loss. However, the histological and the physiological data are not always well correlated. This paper investigates the use of succinate dehydrogenase (SDH) activity in the hair cells as a marker of cellular dysfunction and so the loss of auditory sensitivity. In our previous studies, potentiation of noise-induced auditory threshold elevation by carbon monoxide (CO) was observed [Chen and Fechter, 1999; Chen et al., 1999]. However, its histological basis is still unclear. In this study, rats were exposed to 100-dB octave-band noise (center frequency=13.6 kHz, 2 h) or to the combination of the noise and CO (1200 ppm). Threshold elevation of compound action potential (CAP) and cochlear histological changes were assessed 4 weeks after exposure. The noise alone caused CAP threshold elevations with little if any or without hair cell loss. However, the SDH activity in the hair cells decreased after the exposure. The SDH reduction, especially in the inner hair cells, was well related to the loss of auditory sensitivity. The combined exposure to noise and CO caused more severe CAP threshold elevation and SDH activity reduction than did the noise alone and it also caused significant outer hair cell loss. However, across all the test frequencies, neither the hair cell loss nor the SDH reduction alone had good correlation to the reduction of the auditory sensitivity. Under this situation, CAP threshold elevation seemed to follow OHC loss at high frequencies and to follow SDH reductions in the IHCs at low frequencies, where no hair cell loss occurred.

Action Potentials↗
PubMed2000

Characterization of the ototoxicity of difluoromethylornithine and its enantiomers.

Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the essential enzyme in mammalian polyamine biosynthesis (Pasic et al., 1997, Arch. Otolaryngol. Head Neck Surg. 123[12], 1281-1286). This cancer chemotherapeutic agent has significant ototoxic potential. Because the DFMO enantiomers differ in their ability to block ODC, the present study was designed to compare the ototoxic potential of each enantiomer with the racemic form of this drug for the rat and guinea pig. Determining differential ototoxicity of the enantiomers is one preliminary step in determining the optimal form of DFMO to use in human cancer chemotherapy. Daily intubation with D,L-DFMO does not produce any auditory dysfunction in rats with doses between 200 mg/kg/day and 1. 2 g/kg/day for up to 8 weeks, despite the fact that doses of 800 and 1200 mg/kg/day depressed body weight gain. In contrast to the data observed in rats, substantial ototoxicity was observed when guinea pigs were injected ip with doses of D,L-DFMO between 500 mg/kg/day and 1 g/kg/day. D,L-DFMO produced loss of compound action potential sensitivity, but not of cochlear microphonic amplitude. This finding correlated with histological data revealing loss of both outer and inner hair cells in the cochlea with inner more affected than outer hair cells, particularly in the basal turn. Higher exposure doses (2-3 g/kg/day) resulted in significant general toxicity including impaired growth and some mortality. When the enantiomers were evaluated in the guinea pig, it was found that 1 g/kg/day D-DFMO did not produce any significant hearing impairment, whereas 1 g/kg/day of the L-enantiomer of DFMO generated a threshold shift that surpassed that of 1 g/kg/day of the D,L-DFMO treatment.

Animals↗
PubMed2000

Predicting exposure conditions that facilitate the potentiation of noise-induced hearing loss by carbon monoxide.

Hearing loss is the most common occupational disease in the United States, with noise serving as the presumed causative agent in most instances. This investigation characterizes the exposure conditions that facilitate the potentiation of noise-induced hearing loss (NIHL) by carbon monoxide (CO). Auditory function was compared in rats exposed 4 weeks earlier to noise alone, CO alone, combined exposure, and air in the exposure chamber. This interval between exposure and auditory threshold assessment was selected to permit recovery of temporary threshold shifts. The compound action potential (CAP) threshold evoked by pure tone stimuli was used as a measure of auditory sensitivity. The no adverse effect level (NOAEL) with respect to potentiation of NIHL was found to be 300 ppm CO. Potentiation of NIHL by CO increases linearly as CO concentration increases between 500 -1500 ppm. Benchmark dose software (version 1. 1B) published by the U.S. EPA National Center for Environmental Assessment was employed to determine a benchmark concentration of CO that produced either a 5-dB potentiation of NIHL or an increase in auditory threshold equivalent to 10% of the effect of noise alone. The lower bound for these benchmark concentrations were 320 and 194 ppm CO, respectively. Unlike CO dose, the relationship between noise severity and potentiation of NIHL by CO shows a nonlinear relationship. The greatest potentiation was observed at moderate noise exposures (100 dB, 2-h, octave band-limited noise, or OBN) that produce limited permanent threshold shifts. Repeated exposures to 95-dB noise for 2-h periods in combination with 1200 ppm CO also yielded potentiation of NIHL, though such effects were not observed following a single combined exposure. These results underscore the potential risk of hearing loss from combined exposure to noise and CO, and the risks associated with repeated exposure.

Action Potentials↗
PubMed2000

Neural responses to the onset of voicing are unrelated to other measures of temporal resolution.

Voice onset time (VOT) is a temporal cue that can distinguish consonants such as /d/ from /t/. It has previously been shown that neurons' responses to the onset of voicing are strongly dependent on their static spectral sensitivity. This study examined the relation between temporal resolution, determined from responses to sinusoidally amplitude-modulated (SAM) tones, and responses to syllables with different VOTs. Responses to syllables and SAM tones were obtained from low-frequency neurons in the inferior colliculus (IC) of the chinchilla. VOT and modulation period varied from 10 to 70 ms in 10-ms steps, and discharge rates elicited by stimuli whose amplitude envelopes were modulated over the same temporal interval were compared. Neurons that respond preferentially to syllables with particular VOTs might be expected to respond best to the SAM tones with comparable modulation periods. However, no consistent agreement between responses to VOT syllables and to SAM tones was obtained. These results confirm the previous suggestion that IC neurons' selectivity for VOT is determined by spectral rather than temporal sensitivity.

Animals↗
PubMed1999

Female bladder neck changes with position.

Location of the bladder neck and its dynamic motion are believed to be influenced by body position. This study was designed to evaluate factors affecting bladder neck mobility in both supine and standing positions. The parameters of 75 GSI patients and 49 controls were compared by Student's t-test. Receiver operating characteristic curves and multiple logistic regression analysis were used to analyze the effects of potential contributing factors on bladder neck mobility. We were unable to find any significant correlation between bladder neck hypermobility and GSI. We also failed to demonstrate that bladder neck hypermobility in the supine or standing position relative to previous believed risk factors, including parity, vaginal delivery, menopause, cystocele, rectocele, uterine prolapse or body mass index. In order to elucidate the pathophysiology of bladder neck mobility clearly, changes in intraabdominal pressure and gravitational direction in different positions should be evaluated carefully and scientifically in further studies.

Adult↗
PubMed1999

Estrogen receptor alpha and beta expression in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women.

OBJECTIVE: To assess the expression of messenger RNA (mRNA) for estrogen receptors alpha and beta in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. DESIGN: In vitro experiment. SETTING: Academic research environment. PATIENT(S): Sixteen consecutively seen women who underwent hysterectomy. INTERVENTION(S): Samples of anterior vaginal walls and uterosacral ligaments were obtained during hysterectomy. MAIN OUTCOME MEASURE(S): Reverse transcriptase-polymerase chain reaction analysis for estrogen receptor mRNA. RESULT(S): Messenger RNA transcripts for estrogen receptor alpha were present in all samples of vaginal walls (16/16) and uterosacral ligaments (16/16). Estrogen receptor beta mRNA was detected in all samples of vaginal walls from premenopausal women (12/12) but in none of those from postmenopausal women (0/4). Estrogen receptor beta mRNA was found in most samples of uterosacral ligaments from premenopausal women (10/12) and in some of those from postmenopausal women (2/4). CONCLUSION(S): Estrogen receptors alpha and beta were expressed in the vaginal walls and uterosacral ligaments of premenopausal and postmenopausal women. Estrogen receptor beta was absent from the vaginal walls of postmenopausal women.

Adult↗
PubMed1999

Monaural response properties of single neurons in the chinchilla inferior colliculus.

The responses of 274 inferior colliculus (IC) central nucleus neurons from 20 chinchillas were studied. Characteristic frequency (CF) increased as the IC was traversed in the dorsal-ventral direction. Most units had little or no spontaneous activity, with a mean threshold for response of about 30 dB SPL across all units. Tuning curve width varied between units, with a significant increase in Q20, with increasing CF. Peri-stimulus time histogram (PSTH) types were similar to those reported for cat inferior colliculus units. Transient, sustained, pauser, and buildup types were observed, with transient responses predominating. Response area (RA) types were also similar to those of cat IC units, with most units displaying stable best frequencies across a range of stimulus intensity levels. For a few units, excitatory RA regions were surrounded by inhibitory sidebands. Nonmonotonic discharge rate vs. stimulus intensity level functions were common in all CF ranges and for all PSTH and RA types. Mean first spike latencies, however, differed across PSTH groups, owing to the temporal definitions of these PSTH shapes. Latencies of sustained units were significantly longer than those of transient units, and buildup PSTHs showed significantly longer latencies than any other group.

Action Potentials↗
PubMed1999

Potentiation of octave-band noise induced auditory impairment by carbon monoxide.

In previous studies from our lab, broadband noise induced hearing loss has been found to be potentiated by simultaneous carbon monoxide (CO) exposure. In the present study, octave-band noise induced auditory impairment was studied with the presence of CO at levels of 1500, 1200, 700, 500 and 300 ppm and zero (noise alone). Four octave-band noises (1.2-2.4, 2.4-4.8, 4.8-9.6 and 9.6-19.2 kHz) were used. Experimental subjects (rats) were grouped for the exposure (8 h) to each noise, CO and their combinations. The compound action potential (CAP) and cochlear microphonics (CM) were recorded 4 weeks after the exposure. The noise induced elevation of the CAP threshold and the CM iso-amplitude curve were potentiated by the simultaneous CO exposure when the CO level reached 500 ppm or higher. CO exposure alone had no effect on CAP or CM. The CO potentiation can occur in any frequency region depending on the noise band. The combined exposure can also induce threshold shifts in some cases in which both the noise and the CO alone did not cause threshold shifts. The size of the potentiation shown by CAP and CM was similar, indicating a possible origin of the CO potentiation from the damage to the outer hair cells. Interestingly, the hearing loss induced by noise alone gradually recovered (partially), but the hearing loss caused by the combined exposure did not. The potentiation may be due to the reduction of the cell's ability to repair noise induced damage by CO.

Animals↗
PubMed1999

Effects of interaural time differences on the responses of chinchilla inferior colliculus neurons to consonant-vowel syllables.

The responses of 100 inferior colliculus neurons to syllables differing in voice onset time (VOT) presented binaurally were studied. As in a previous study of monaural responses (Chen et al., 1996), the responses consisted of 1-3 response 'components', referred to as release responses, VOT responses or vowel responses. The discharge rate of all response components could vary cyclically with the interaural time difference (ITD). The maximal rate often occurred at an ITD around +0.2 ms (contralateral ear leading). Response frequencies (RF) based on the periodicity of the delay curves varied with the characteristic frequency (CF) and VOT. RF also varied across response components. Overall, RF was correlated with the 'most effective frequency', the spectral component with the highest amplitude, relative to the tuning curve. VOT response latency for a given syllable could change by a few ms with ITD, but those changes were small, relative to the range of latencies observed over the entire range of VOTs. Changes in ITD produced large changes in the overall shape of the peristimulus time histogram. There was no relation between the histogram shape and perceptual consonant categories.

Animals↗
PubMed1999

Intermittent noise-induced hearing loss and the influence of carbon monoxide.

Intermittent noise causes less hearing loss than continuous noise of equal intensity. The reduction in damage observed with intermittent noise may be explained by the fact that the auditory system has time to recover between the noise phases. Simultaneous carbon monoxide (CO) exposure produces greater noise-induced hearing loss than does noise alone (Chen and Fechter, 1999). In the present study, intermittent noise (octave-band with a center frequency of 13.6 kHz, 100 dB) of a 2 h total duration but with a different duty cycle (% of noise during exposure) was used. The intermittent exposure that had a shorter noise duty cycle induced a less permanent threshold shift (PTS) than those that had a longer noise duty cycle (or less rest periods). This relation between the loss in compound action potential (CAP) sensitivity and the noise duty cycle (or rest period) was abolished by the presence of CO. The cochlear microphonic (CM) amplitude revealed similar results to those seen using the CAP. While intermittent noise that had a short noise duty cycle did not cause hair cell loss by itself, the combined exposure to noise and CO (1200 ppm) caused remarkable OHC loss in the basal turn.

Action Potentials↗
PubMed1999

Serum anti-p53 antibodies in gastric adenocarcinoma patients are associated with poor prognosis, lymph node metastasis and poorly differentiated nuclear grade.

Mutation of the p53 tumour suppressor gene often leads to the accumulation of mutant p53 protein in tumour cells. Many cancer patients develop antibodies that recognize the overexpressed p53 protein. The presence of these antibodies is, in some tumour types, associated with poor prognosis. Gastric cancer is a highly prevalent disease associated with a high rate of mortality, there is a need for improved clinical and biological markers for disease behaviour. To investigate the clinical relevance of serum anti-p53 antibodies in patients with gastric adenocarcinoma, we have examined the sera of 501 gastric cancer patients for the presence of serum antibodies against the p53 protein. By immunoblotting analysis using a cell lysate containing overexpressed p53 protein as well as affinity-purified recombinant p53 protein as antigens, we have detected anti-p53 antibodies in 11.2% (61 of 501) of gastric cancer patients, but in none of 46 cancer-free individuals. The presence of anti-p53 antibodies was tightly associated with tumours of higher nuclear grade and lymph node metastasis, and a negative association was found between the presence of anti-p53 antibodies and survival. These results suggest that a preoperative test of serum anti-p53 antibodies in gastric cancer patients can be useful to identify subset of patients who may need gastrectomy with lymph node dissection and post-operative adjuvant therapy.

Adenocarcinoma↗