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L Chen

Publications and source records attributed to L Chen.

At least 559 records · Page 31Linked to original sources
PubMed1999

MDM2 suppresses p73 function without promoting p73 degradation.

The newly identified p53 homolog p73 can mimic the transcriptional activation function of p53. We investigated whether p73, like p53, participates in an autoregulatory feedback loop with MDM2. p73 bound to MDM2 both in vivo and in vitro. Wild-type but not mutant MDM2, expressed in human p53 null osteosarcoma Saos-2 cells, inhibited p73- and p53-dependent transcription driven by the MDM2 promoter-derived p53RE motif as measured in transient-transfection and chloramphenicol acetyltransferase assays and also inhibited p73-induced apoptosis in p53-null human lung adenocarcinoma H1299 cells. MDM2 did not promote the degradation of p73 but instead disrupted the interaction of p73, but not of p53, with p300/CBP by competing with p73 for binding to the p300/CBP N terminus. Both p73alpha and p73beta stimulated the expression of the endogenous MDM2 protein. Hence, MDM2 is transcriptionally activated by p73 and, in turn, negatively regulates the function of this activator through a mechanism distinct from that used for p53 inactivation.

Apoptosis↗
PubMed1999

Association of intrinsic pICln with volume-activated Cl- current and volume regulation in a native epithelial cell.

We investigated the relationship between pICln, the volume-activated Cl- current, and volume regulation in native bovine nonpigmented ciliary epithelial (NPCE) cells. Immunofluorescence studies demonstrated the presence of pICln protein in the NPCE cells. Exposure to hypotonic solution activated a Cl- current and induced regulatory volume decrease (RVD) in freshly isolated bovine NPCE cells. Three antisense oligonucleotides complementary to human pICln mRNA were used in the experiments. The antisense oligonucleotides were taken up by the cells in a dose-dependent manner. The antisense oligonucleotides, designed to be complementary to the initiation codon region of the human pICln mRNA, "knocked down" the pICln protein immunofluorescence, delayed the activation of volume-activated Cl- current, diminished the value of the current, and reduced the ability of the cells to volume regulate. We conclude that pICln is involved in the activation pathway of the volume-activated Cl- current and RVD following hypotonic swelling.

Animals↗
PubMed1999

Mechanisms of acute cardiovascular response to periodic apneas in sedated pigs.

This study was designed to evaluate the importance of sympathoadrenal activation in the acute cardiovascular response to apneas and the role of hypoxemia in this response. In addition, we evaluated the contribution of the vagus nerve to apnea responses after chemical sympathectomy. In six pigs preinstrumented with an electromagnetic flow probe and five nonpreinstrumented pigs, effects of periodic nonobstructive apneas were tested under the following six conditions: room air breathing, 100% O2 supplementation, both repeated after administration of hexamethonium (Hex), and both repeated again after bilateral vagotomy in addition to Hex. With room air apneas, during the apnea cycle, there were increases in mean arterial pressure (MAP; from baseline of 108 +/- 4 to 124 +/- 6 Torr, P < 0.01), plasma norepinephrine (from 681 +/- 99 to 1,825 +/- 578 pg/ml, P < 0.05), and epinephrine (from 191 +/- 67 to 1,245 +/- 685 pg/ml, P < 0.05) but decreases in cardiac output (CO; from 3.3 +/- 0.6 to 2.4 +/- 0.3 l/min, P < 0.01) and cervical sympathetic nerve activity. With O2 supplementation relative to baseline, apneas were associated with small increases in MAP (from 112 +/- 4 to 118 +/- 3 Torr, P < 0.01) and norepinephrine (from 675 +/- 97 to 861 +/- 170 pg/ml, P < 0.05). After Hex, apneas with room air were associated with small increases in MAP (from 103 +/- 6 to 109 +/- 6 Torr, P < 0.05) and epinephrine (from 136 +/- 45 to 666 +/- 467 pg/ml, P < 0.05) and decreases in CO (from 3.6 +/- 0.4 to 3.2 +/- 0. 5 l/min, P < 0.05). After Hex, apneas with O2 supplementation were associated with decreased MAP (from 107 +/- 5 to 100 +/- 5 Torr, P < 0.05) and no other changes. After vagotomy + Hex, with room air and O2 supplementation, apneas were associated with decreased MAP (from 98 +/- 6 to 76 +/- 7 and from 103 +/- 7 to 95 +/- 6 Torr, respectively, both P < 0.01) but increased CO [from 2.7 +/- 0.3 to 3. 2 +/- 0.4 l/min (P < 0.05) and from 2.4 +/- 0.2 to 2.7 +/- 0.2 l/min (P < 0.01), respectively]. We conclude that sympathoadrenal activation is the major pressor mechanism during apneas. Cervical sympathetic nerve activity does not reflect overall sympathoadrenal activity during apneas. Hypoxemia is an important but not the sole trigger factor for sympathoadrenal activation. There is an important vagally mediated reflex that contributes to the pressor response to apneas.

Anesthesia↗
PubMed1999

Effects of vagotomy on cardiovascular response to periodic apneas in sedated pigs.

There are few studies investigating the influence of vagally mediated reflexes on the cardiovascular response to apneas. In 12 sedated preinstrumented pigs, we studied the effects of vagotomy during apneas, controlling for apnea periodicity and thoracic mechanical effects. Nonobstructive apneas were produced by paralyzing and mechanically ventilating the animals, then turning the ventilator off and on every 30 s. Before vagotomy, relative to baseline, apnea caused increased mean arterial pressure (MAP; +19 +/- 25%, P < 0.05), systemic vascular resistance (SVR; +33 +/- 16%, P < 0.0005), and heart rate (HR; +5 +/- 6%, P < 0.05) and decreased cardiac output (CO) and stroke volume (SV; -16 +/- 10% P < 0.001). After vagotomy, no significant change occurred in MAP, SVR, and SV during apneas, but CO and HR increased relative to baseline. HR was always greater ( approximately 14%, P < 0.01) during the interapneic interval compared with during apnea. We conclude that vagally mediated reflexes are important mediators of the apneic pressor response. HR increases after apnea termination are related, at least in part, to nonvagally mediated reflexes.

Animals↗
PubMed1999

Detection of the most common G6PD gene mutations in Chinese using amplification refractory mutation system.

Glucose-6-phosphate dehydrogenase (G6PD) is the most common human enzymopathy. To date more than 122 mutations in the G6PD gene have been discovered, among which 12 point mutations are found in the Chinese. The 2 most common mutations, G1388A and G1376T, account for more than 50% of mutations representing various regions and ethnic groups in China. Setting up a simple and accurate method for detecting these mutations is not only useful for studying the frequency of the G6PD genotypes, but also for finding new mutations. The purpose of this study was to find a simple, inexpensive and accurate method for detecting these common mutations. The amplification refractory mutation system (ARMS) method was used in this study. Samples from 28 G6PD-deficient males were investigated. The natural and mismatched amplification and restriction enzyme digestion method was used as a standard method to evaluate the nature of the point mutations. Sixteen cases were found carrying the G1388A mutation and 12 the G1376T mutation. Fourteen cases of G1388A and 10 cases of G1376T were confirmed by ARMS. Four cases were not in concordance with the results obtained by the mismatched amplification-restriction enzyme digestion. These 4 cases were then judged by direct PCR sequencing at exon 12. The DNA sequencing data supported the results obtained by ARMS. Thus we concluded that the ARMS is a rapid, simple, inexpensive and accurate method for detecting the most common G6PD gene mutations among the Chinese.

Asian People↗
PubMed1999

Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis.

Missense mutations in fibroblast growth factor receptor 3 (FGFR3) result in several human skeletal dysplasias, including the most common form of dwarfism, achondroplasia. Here we show that a glycine-to-cysteine substitution at position 375 (Gly375Cys) in human FGFR3 causes ligand-independent dimerization and phosphorylation of FGFR3 and that the equivalent substitution at position 369 (Gly369Cys) in mouse FGFR3 causes dwarfism with features mimicking human achondroplasia. Accordingly, homozygous mice were more severely affected than heterozygotes. The resulting mutant mice exhibited macrocephaly and shortened limbs due to retarded endochondral bone growth and premature closure of cranial base synchondroses. Compared with their wild-type littermates, mutant mice growth plates shared an expanded resting zone and narrowed proliferating and hypertrophic zones, which is correlated with the activation of Stat proteins and upregulation of cell-cycle inhibitors. Reduced bone density is accompanied by increased activity of osteoclasts and upregulation of genes that are related to osteoblast differentiation, including osteopontin, osteonectin, and osteocalcin. These data reveal an essential role for FGF/FGFR3 signals in both chondrogenesis and osteogenesis during endochondral ossification.

Achondroplasia↗
PubMed1999

The perceptions and practices of pediatricians: tobacco intervention.

OBJECTIVES: To investigate pediatrician self-reported intervention practices related to tobacco use and cessation. We queried about practices with three groups 1) children/adolescents who do not smoke; 2) children/adolescents who smoke; and 3) parents, and the relationship of counseling practices with the personal and professional practice-related factors of pediatricians. DESIGN: Mailed anonymous survey regarding their self-reported tobacco use prevention and cessation intervention practices. POPULATION: Random sample of 350 pediatricians in one state. RESULTS: A response rate of 75% was achieved. Pediatricians reported the greatest counseling practice in encouraging children/adolescents to not start smoking, followed by counseling adolescents who smoke. The lowest practice score was for intervening with parents who smoke. The age, gender, site of practice (eg, HMO, solo practice), and subspecialty status of the pediatricians were not related to practice. Pediatricians who reported at least some community involvement in local tobacco control efforts reported significantly higher levels of smoking cessation counseling with both children and adolescents and with parents who smoke. Pediatricians who reported previous training in counseling about tobacco issues also reported significantly higher levels of counseling of both adolescent smokers and parents who smoke but not of children and adolescents who do not smoke. Higher role perception, believing that smoking cessation counseling provided by pediatricians can be effective, and self-efficacy, were predictive of intervention with all three groups. The perceived barriers scale was not related to intervention with any group. CONCLUSIONS: Pediatricians are missing opportunities to help their patients to stop smoking and to prevent smoking initiation. Pediatricians are intervening least frequently with parents who smoke. Practices should be tailored to the specific target group.

Adolescent↗
PubMed1999

Organ selective delivery using a tissue-directed streptavidin--biotin system: targeting 5-fluorouridine via TNP-streptavidin.

Trinitrophenyl (TNP) modification of streptavidin (St) resulted in high and prolonged accumulation in mouse liver following intravenous administration of radioiodinated TNP streptavidin (TNP-St). Uptake, which is correlated with increased TNP substitution, was first observed at 2-3 h, increased to 40-50% of injected dose/gram tissue (%/g) at 24 h and slowly declined later on. A low degree of accumulation (10%/g) was observed in the spleen. TNP substitution of other proteins such as bovine serum albumin (BSA) or ovalbumin (Ova) led to a transient short-term liver uptake. The enzyme-resistance property of streptavidin and its biotin binding sites render TNP-modified streptavidin a potential targeting vehicle to the liver. 5-Fluorouridine (FUR) was attached to high molecular weight carrier carboxymethyldextran (CMdex, derived from 40 kDa dextran) and the dextran FUR conjugate was charged with 2-4 biotinyl groups (in the form of biotinyl-diaminopropionyl-tyrosine, BDT) for complexing to TNP-St. Biodistribution monitoring of the BDT-CMdex-FUR ligand, radiolabeled at the tyrosyl residue of BDT and targeted via non-radiolabeled TNP-St, showed that ligand accumulation in the liver was similar to TNP-St itself. Liver targeting of FUR was demonstrated by trace-labeling FUR with its structural analog 5,6-[3H]uridine prior to conjugation to dextran hydrazide. Specific liver accumulation of [3H] radioactivity occurred following administration of the conjugate only when complexed to TNP-St. Hepatic levels of [3H] radioactivity were in the range of 25%/g or 35% per whole liver during a period of at least 8 h, as compared to the rapid elimination of free FUR+[3H]uridine (4%/g at 20 min). [3H]-drug radioactivity disappeared at a faster rate as compared to 125I-dextran radioactivity, suggesting that metabolic processes required to generate the 5,6-[3H]uracil-containing active metabolites took place.

Animals↗
PubMed1999

Uniform connectedness and classical Gestalt principles of perceptual grouping.

We assessed whether uniform connectedness (UC; Palmer & Rock, 1994) operates prior to effects reflecting classical principles of grouping: proximity and similarity. In Experiments 1 and 2, reaction times to discriminate global letters (H vs. E), made up of small circles, were recorded. The small circles were respectively grouped by proximity, similarity of shapes, and by UC. The discrimination of stimuli grouped by similarity was slower than those grouped by proximity, and it was speeded up by the addition of UC. However, the discrimination of stimuli grouped by proximity was unaffected by connecting the local elements. In Experiment 3, similar results occurred in a task requiring discrimination of the orientation of grouped elements, except that the discrimination of stimuli grouped by UC was faster than that of those grouped by weak proximity. Experiment 4 further showed that subjects could respond to letters composed of discriminably separate local elements as fast as to those without separated local elements. The results suggest that grouping by similarity of shapes is perceived slower than grouping by UC, but grouping by proximity can be as fast and efficient as that by UC.

Adult↗
PubMed1999

Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2 expression.

BACKGROUND: The MDM2 oncogene functions as a negative feedback regulator of the p53 tumor suppressor. Abnormal expression of MDM2 in tumors may attenuate the p53-mediated growth arrest and apoptosis response, resulting in increased cell proliferation and resistance to chemotherapy. MATERIALS AND METHODS: We have developed phosphorothioate antisense oligodeoxynucleotides optimized for inhibition of MDM2 expression and investigated the role of MDM2 in a large panel of tumor cell lines. RESULTS: Inhibition of MDM2 expression in 15 tumor types containing wild-type p53 results in a significant induction of nuclear p53 accumulation. The increase in p53 level is due to prolonged half-life and is associated with an increase in p53 transcriptional activity, growth inhibition, or apoptosis. Inhibition of MDM2 expression is also sufficient to induce nuclear p53 accumulation in several cell lines with cytoplasmic p53. CONCLUSIONS: The MDM2 negative feedback loop is important for maintenance of p53 at a low level by promoting p53 degradation. Nuclear export and degradation by MDM2 may contribute to the p53 nuclear exclusion phenotype. Inhibition of MDM2 expression can effectively activate p53 in most tumor types, including those without MDM2 overexpression, and may have broad anti-tumor potential.

Apoptosis↗
PubMed1999

[Molecular characterization of glucose-6-phosphate dehydrogenase variants in four ethnic groups in Yunnan province of China].

OBJECTIVE: In order to understand the molecular evolution, race origin and the relationship between the G6PD gene structure and clinical symptoms, the authors identified the molecular characterization of glucose-6-phosphate dehydrogenase and determined the G6PD gene frequency in four ethnic groups in Yunnan province of China. METHODS: The point mutations of G6PD were detected by Mismatch-PCR/RE, SSCP,ARMS,DNA sequence and so on. G6PD gene frequency was determined by Hardy-Weinberg Law. RESULTS: G6PD G1388A, G1376T,A95G mutations were determined in Bai and Dai people for the first time and G1388A also in Harni people by DNA sequence. G6PD C1024T were detected in Dai population by Mismatch-PCR/RE. The gene frequency of G6PD in Bai population in Dali city is 0.0113, and the incidence is 1.19% which are different from those in Dai population. CONCLUSION: G6PD G1388A,G1376T, A95G and C1024T are the mutations in national minorities as well as in the Han people. The results suggest that different national minorities of China may have the same ancestor. The incidence of G6PD deficiency and the G6PD gene frequency in Bai population are different from those in Dai population. The distribution of G6PD deficiency in Yunnan is associated with the distribution of malaria epidemic in that province.

China↗
PubMed1999

MDM2 oncogene as a target for cancer therapy: An antisense approach.

The MDM2 oncogene is amplified or overexpressed in human cancers. It has also been suggested that MDM2 levels are associated with poor prognosis of several human cancers. The MDM2 oncoprotein binds to the p53 tumor suppressor protein and serves as a negative regulator of p53. The p53 tumor suppressor also has an important role in cancer therapy, with p53-mediated apoptosis being a major mechanism of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the negative regulation of p53 by MDM2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. The investigators hypothesize that, by inhibiting MDM2 expression, the MDM2 oncoprotein level will be reduced and the MDM2 negative feedback inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53-mediated therapeutic effects. The overall objective of the present study was to investigate the functions of MDM2 oncogene in tumor growth and the potential value of MDM2 as a drug target for cancer therapy. The role of MDM2 in tumor growth is determined by inhibiting MDM2 expression in in vivo models of human cancers. The in vivo synergistically therapeutic effects of MDM2 inhibition and DNA damaging agents were also evaluated. Significant in vitro antitumor activities were found in cell lines, human osteosarcoma SJSA and choriocarcinoma JAR, in a time-, concentration-, and sequence-dependent manner. Following i.p. administration of anti-MDM2 antisense oligonucleotides, in vivo antitumor activity was observed in nude mice bearing SJSA and JAR xenografts in a dose-dependent manner. Moreover, in vivo synergistically therapeutic effects of MDM2 inhibition and DNA damaging agents adriamycin and 10-hydroxycamptothecin were observed. This study should provide the basis for future development of anti-MDM2 antisense oligonucleotides as cancer therapeutic agents used alone or in combination with conventional chemotherapeutics.

Animals↗
PubMed1999

The Food and Drug Administration and atrial defibrillation devices.

CONTEXT: Atrial fibrillation is a common arrhythmia. It leads to significant morbidity and mortality, primarily from the increased incidence of stroke. The implantable atrial defibrillator, a new therapeutic option for the management of atrial fibrillation, is currently undergoing Food and Drug Administration (FDA) scrutiny for approval to market in the United States. DATA SOURCES: A review of the basic epidemiology of atrial fibrillation, as well as the current status of accepted treatment options in light of the development of the implantable atrial defibrillator, was conducted. A literature search using the terms atrial fibrillation, implantable defibrillator, Food and Drug Administration, medical devices, and medical device regulatory law was conducted using the MEDLINE and Current Contents databases. RESULTS: Currently, there is no consensus on the optimal treatment of atrial fibrillation. Despite the lack of definitive studies showing overall benefit associated with maintaining sinus rhythm in patients in atrial fibrillation, the implantable atrial defibrillator may soon reach the general market. We examine the FDA process for the evaluation of this new medical device and discuss implications for the patient, physician, industry, and health insurers. CONCLUSIONS: Current FDA approval processes for new devices are a compromise between (a) the needs for expediency and encouraging innovation by the medical device industry and (b) the need to ensure that new devices will contribute to improved patient outcomes. We suggest alternative FDA-approval processes that address these issues.

Atrial Fibrillation↗
PubMed1999

Biochemical and immunological characteristics of 4-1BB (CD137) receptor and ligand and potential applications in cancer therapy.

4-1BB (CD 137) is a member of the tumor necrosis factor receptor (TNFR) superfamily that is expressed primarily on activated T cells. Crosslinking of the 4-1BB receptor activates an intracellular signal cascade that leads to the activation of NF-kappaB and costimulation of T cell growth. Recent evidence indicates that 4-1BB may preferentially costimulate CD8+ T cell growth and induce cytolytic activity. The cytolytic activity induced by 4-1BB crosslinking is able to eradicate large, well-established, poorly immunogenic tumors and augments allogenic T cell responses in vivo. The 4-1BB/4-1BB ligand costimulatory pathway can provide an alternative T cell costimulatory pathway in the absence of CD28, but may physiologically function as a synergistic or complementary pathway to the CD28 costimulatory pathway. Only some of the basic immunological functions of 4-1BB/4-IBB ligand have been elucidated and much study is required to determine its exact role in T cell activation.

Animals↗
PubMed1999

Relationship between ventral stream for object vision and dorsal stream for spatial vision: an fMRI + ERP study.

Recent imaging studies indicated the existence of two visual pathways in humans: a ventral stream for object and form vision and a dorsal stream for spatial and motion vision. The present study was motivated by a stimulating question: Supposing shape and motion are processed separately in the two pathways, how do the respective cortical areas respond to the stimuli of "forms defined by motion"? fMRI and ERP recordings were combined in order to measure the spatiotemporal activation pattern in the two pathways responding to forms defined by motion, which were produced solely by coherent movement of random dots against a background of dynamic or static random dots. The fMRI data indicated that the stimuli of forms defined by motion indeed activated both dorsal MT/V5 and ventral GTi/GF. Furthermore, the RV curves resulting from fMRI-seeded dipole modeling indicated that each pair of dipoles located at MT/V5 or GTi/GF reached the same best-fit point; a single pair of free dipoles located near the fMRI foci of MT/V5 and GTi/GF could be identified at the corresponding best-fit point; and the source waveforms resulting from fixed dipole modeling also showed simultaneous activation of MT/V5 and GTi/GF dipoles in the time interval around the best-fit point. The present results, therefore, suggest that MT/V5 and GTi/GF appear to be activated in parallel and simultaneously responding to forms defined by motion. Such findings raise interesting issues about the hierarchical organization and the functional specialization in the two pathways.

Adult↗
PubMed1999

[Investigation on the prevalence and influencing factors to anemia in women at reproductive age].

OBJECTIVE: To investigate the prevalence of anemia in women of reproductive age and to analyze the influencing factors in anemia. METHODS: A total number of 1,529 women aged 15-49 years old including workers, farmers, cadres and students were tested with Hb and FEP and investigated through questionnaire including related influencing factors. Statistical analysis was performed using SPSS/PC statistical software. RESULTS: Mean value of Hb was 116.35 g/L (SD 14.67 g/L) in 1,529 cases and the prevalence rate of anemia was 31.2%. Majority of the anemia identified belonged to the 'iron deficiency type'. Influencing factors on anemia included occupation, education, marriage status, menstruation, status of family expenses and physical exercise. CONCLUSION: The prevalence rate of anemia in reproductive aged women was high, thus more attention should be paid. In order to lower the incidence of anemia, preventive and intervenient measurements should be conducted accordingly.

Adolescent↗