Biomedical subjects

G Li

Publications and source records attributed to G Li.

At least 307 records · Page 17Linked to original sources

PubMed2000

p53-dependent apoptosis in melanoma cells after treatment with camptothecin.

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The forces in the anterior cruciate ligament and knee kinematics during a simulated pivot shift test: A human cadaveric study using robotic technology.

PURPOSE: Although it is well known that the anterior cruciate ligament (ACL) is a primary restraint of the knee under anterior tibial load, the role of the ACL in resisting internal tibial torque and the pivot shift test is controversial. The objective of this study was to determine the effect of these 2 external loading conditions on the kinematics of the intact and ACL-deficient knee and the in situ force in the ACL. TYPE OF STUDY: This study was a biomechanical study that used cadaveric knees with the intact knee of the specimen serving as a control. MATERIALS AND METHODS: Twelve human cadaveric knees were tested using a robotic/universal force-moment sensor testing system. This system applied (1) a 10-Newton meter (Nm) internal tibial torque and (2) a combined 10-Nm valgus and 10-Nm internal tibial torque (simulated pivot shift test) to the intact and the ACL-deficient knee. RESULTS: In the ACL-deficient knee, the isolated internal tibial torque significantly increased coupled anterior tibial translation over that of the intact knee by 94%, 48%, and 19% at full extension, 15 degrees, and 30 degrees of flexion, respectively (P <.05). In the case of the simulated pivot shift test, there were similar increases in anterior tibial translation, i.e., 103%, 61%, and 32%, respectively (P <.05). Furthermore, the anterior tibial translation under the simulated pivot shift test was significantly greater than under an isolated internal tibial torque (P <.05). Under the simulated pivot shift test, the in situ forces in the ACL were 83 +/- 16 N at full extension and 93 +/- 23 N at 15 degrees of knee flexion. These forces were also significantly higher when compared with those for an isolated internal tibial torque (P <.05). CONCLUSION: Our data indicate that the ACL plays an important role in restraining coupled anterior tibial translation in response to the simulated pivot shift test as well as under an isolated internal tibial torque, especially when the knee is near extension. These findings are also consistent with the clinical observation of anterior tibial subluxation during the pivot shift test with the knee near extension.

Adult↗

PubMed2000

Expression of the novel tumour suppressor p33(ING1)is independent of p53.

A recently cloned tumour suppressor candidate, p33ING1, has been shown in vitro to collaborate with p53 to execute growth arrest and apoptosis. However, it is unclear as to how the expression of ING1 is regulated in normal and stress conditions. Using a p53-knockout mouse model, we investigated if the expression of ING1 was dependent on p53. We found that there was no difference in ING1 mRNA and protein levels between p53+/+ and p53-/- murine organs. In addition, when normal human epithelial keratinocytes (NHEK) and a keratinocyte cell line, HaCaT, which lacks wild-type p53 function, were exposed to UVB irradiation, the expression levels of ING1 were elevated in both NHEK and HaCaT cells. It is interesting, however, that UVB irradiation did not induce ING1 expression in dermal fibroblasts isolated from p53+/+ and p53-/- mice. Based on our findings, we therefore conclude that the expression of ING1 is independent of p53 status. UV induction of ING1 in keratinocytes suggests that ING1 may play a role in cellular stress response and skin carcinogenesis.

Animals↗

PubMed2000

Cerebral arteriovenous malformations associated with aneurysms--a report of 10 cases and literature review.

We analysed 10 cases of arteriovenous malformations (AVMs) associated with aneurysms and reviewed the literature in order to confirm the clinical characteristics of AVMs associated with aneurysms. The mean incidence of aneurysms in our AVM population was 9.1% and the average age was 38 years. The ratio of male to female was 1.3 to 1. The aneurysms (40-96%) were often located on a feeding artery and seldom (23%) at an arterial bifurcation. The mortality rate was 0-26% in surgically managed patients and 38-60% in conservatively treated patients. The combination of intracranial vascular lesions is not rare. Most patients presented with symptoms referable to their AVMs. Treating both lesions in a single operation is the best option. The prognoses for most patients was good.

Adolescent↗

PubMed2000

Benzene and lymphohematopoietic malignancies in China.

While this study is larger than previous investigations and includes workers with a wide range of exposures to benzene, the estimates of risk, as measured by statistical confidence intervals, are still fairly broad, and would benefit from the larger numbers that could be provided by continued follow-up of this population. Nevertheless, the study confirms earlier findings of increased risk for ANLL and aplastic anemia among benzene-exposed workers, provides the first substantial evidence that MDS is linked to benzene exposure, and provides evidence that benzene increases risk for ANLL/MDS at lower levels of exposure than had previously been demonstrated. Currently we are evaluating the potential for extending the follow-up of workers included in this study. A new study would include expanded data collection for cases of hematopoietic malignancy and related disorders and for an appropriate control series.

Adult↗

PubMed2000

Genotoxic markers among butadiene polymer workers in China.

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.

Adult↗

PubMed2000

High frequency allelic loss on chromosome 17p13.3-p11.1 in esophageal squamous cell carcinomas from a high incidence area in northern China.

Allelic loss on chromosome 17p has been reported frequently in esophageal squamous cell carcinoma (ESCC) and generally encompasses the p53 locus at 17p13.1. However, a good correlation between allelic loss on 17p and mutation of p53 has not been found. This suggests the possibility that unknown tumor suppressor genes near p53 may be involved in the development of ESCC. To evaluate this possibility, we analyzed 30 microsatellite markers covering the entire short arm of chromosome 17 in 56 ESCC patients from a high risk population in northern China, including 34 with a family history of upper gastrointestinal (UGI) cancer and 22 without a family history of any cancer. Cancer lifestyle risk factors and clinical/pathological characteristics were also collected. We found frequent allelic loss (>/=65%) at 28 of the 30 markers evaluated in these ESCC patients. The highest frequencies of allelic loss (> or =80%) were found in three smaller regions: deletion region I located at 17p13.3-p13.2 (between D17S849 and D17S1828); deletion region II located at 17p13.2-p13.1 (between D13S938 and TP53); deletion region III located at 17p13.1-p12 (between D17S804 and D17S799). A number of genes have already been identified in these deleted regions, including: OVCA1, OVCA2 and HIC-1 in deletion region I; p53 in deletion region II; ZNF18, ZNF29, ALDH3 and ALDH10 in deletion region III. These results will help us direct future testing of candidate genes and narrow the search region for major new tumor suppressor genes that may play a role in the pathogenesis of ESCC.

Adult↗

PubMed2000

Lessons from melanocyte development for understanding the biological events in naevus and melanoma formation.

Recent advances in mouse genetics have identified molecular changes that are critical for melanocyte maturation and differentiation. This review briefly summarizes the current knowledge of distinct steps in melanocyte development, and identifies for each step the most important molecules such as the growth factors stem cell factor and endothelin-3, with their respective receptors. Classical cadherins, i.e. E-cadherin, N-cadherin and P-cadherin, determine melanocyte positioning in the skin. During naevus and melanoma development, the two growth factor signalling pathways are downregulated, whereas cadherin expression shifts concomitantly with re-positioning of the naevus and melanoma cells in the skin. Loss of E-cadherin and gain of N-cadherin by melanoma cells has profound consequences for the regulatory cross-talk between various types of cells in the skin. Naevus and melanoma cells that do not express E-cadherin are resistant to control by keratinocytes and establish close communications with fibroblasts and endothelial cells. However, forced expression of E-cadherin in melanoma cells can reverse the malignant phenotype by re-establishing the control of keratinocytes over the melanoma cells. Even highly aggressive metastatic melanoma cells can be signalled to turn off the expression of genes associated with tumour invasion and metastasis, suggesting that this strategy could be utilized in the therapy of melanoma.

Animals↗

PubMed2000

Synchronization due to common pulsed input in Stein's model.

It is known that stimulus-evoked oscillatory synchronization among neurones occurs in widely separated cortical regions. In this paper we provide a possible mechanism to explain the phenomenon. When a common, random input is presented, we find that a group of neurones-of Stein's (integrate-and-fire) model type with or without reversal potentials-are capable of quickly synchronizing their firing. Interestingly the optimal average synchronization time occurs when the common input has a high coefficient of variation of interspike intervals (greater than 0.5) for this model with or without reversal potentials. The model with reversal potentials more quickly synchronizes than that without reversal potentials.

Animals↗

PubMed2000

2.9 A crystal structure of ligand-free tryptophanyl-tRNA synthetase: domain movements fragment the adenine nucleotide binding site.

The crystal structure of ligand-free tryptophanyl-tRNA synthetase (TrpRS) was solved at 2.9 A using a combination of molecular replacement and maximum-entropy map/phase improvement. The dimeric structure (R = 23.7, Rfree = 26.2) is asymmetric, unlike that of the TrpRS tryptophanyl-5'AMP complex (TAM; Doublié S, Bricogne G, Gilmore CJ, Carter CW Jr, 1995, Structure 3:17-31). In agreement with small-angle solution X-ray scattering experiments, unliganded TrpRS has a conformation in which both monomers open, leaving only the tryptophan-binding regions of their active sites intact. The amino terminal alphaA-helix, TIGN, and KMSKS signature sequences, and the distal helical domain rotate as a single rigid body away from the dinucleotide-binding fold domain, opening the AMP binding site, seen in the TAM complex, into two halves. Comparison of side-chain packing in ligand-free TrpRS and the TAM complex, using identification of nonpolar nuclei (Ilyin VA, 1994, Protein Eng 7:1189-1195), shows that significant repacking occurs between three relatively stable core regions, one of which acts as a bearing between the other two. These domain rearrangements provide a new structural paradigm that is consistent in detail with the "induced-fit" mechanism proposed for TyrRS by Fersht et al. (Fersht AR, Knill-Jones JW, Beduelle H, Winter G, 1988, Biochemistry 27:1581-1587). Coupling of ATP binding determinants associated with the two catalytic signature sequences to the helical domain containing the presumptive anticodon-binding site provides a mechanism to coordinate active-site chemistry with relocation of the major tRNA binding determinants.

Adenine Nucleotides↗

PubMed2000

On the use of schematic eye models to estimate retinal image quality.

The optical performance of the eyes of nine vertebrate species was evaluated using optical system design techniques and schematic eye models. Essential features of eyes, including the modulation transfer function (MTF) and the MTF cutoff frequency are related to the numerical aperture of the eyes. Superior resolution for in vivo imaging of photoreceptors may be achieved by dilating the iris pupil of an eye, minimizing coherence, and using short wavelength illumination. The difference of lateral and axial resolution between a small and a large eye for imaging photoreceptors in vivo.

Animals↗

PubMed2000

Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts.

In skeletal myoblasts, Ras has been considered to be a strong inhibitor of myogenesis. Here, we demonstrate that Ras is involved also in the chemotactic response of skeletal myoblasts. Expression of a dominant-negative mutant of Ras inhibited chemotaxis of C2C12 myoblasts in response to basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and insulin-like growth factor 1 (IGF-1), key regulators of limb muscle development and skeletal muscle regeneration. A dominant-negative Ral also decreased chemotactic migration by these growth factors, while inhibitors for phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase (MEK) showed no effect. Activation of the Ras-Ral pathway by expression of an activated mutant of either Ras, the guanine-nucleotide dissociation stimulator for Ral, or Ral resulted in increased motility of myoblasts. The ability of Ral to stimulate motility was reduced by introduction of a mutation which prevents binding to Ral-binding protein 1 or phospholipase D. These results suggest that the Ras-Ral pathway is essential for the migration of myoblasts. Furthermore, we found that Ras and Ral are activated in C2C12 cells by bFGF, HGF and IGF-1 and that the Ral activation is regulated by the Ras- and the intracellular Ca(2+)-mediated pathways. Taken together, our data indicate that Ras and Ral regulate the chemotactic migration of skeletal muscle progenitors.

Animals↗

PubMed2000

Transcriptional scaffold: CIITA interacts with NF-Y, RFX, and CREB to cause stereospecific regulation of the class II major histocompatibility complex promoter.

Scaffold molecules interact with multiple effectors to elicit specific signal transduction pathways. CIITA, a non-DNA-binding regulator of class II major histocompatibility complex (MHC) gene transcription, may serve as a transcriptional scaffold. Regulation of the class II MHC promoter by CIITA requires strict spatial-helical arrangements of the X and Y promoter elements. The X element binds RFX (RFX5/RFXANK-RFXB/RFXAP) and CREB, while Y binds NF-Y/CBF (NF-YA, NF-YB, and NF-YC). CIITA interacts with all three. In vivo analysis using both N-terminal and C-terminal deletion constructs identified critical domains of CIITA that are required for interaction with NF-YB, NF-YC, RFX5, RFXANK/RFXB, and CREB. We propose that binding of NF-Y/CBF, RFX, and CREB by CIITA results in a macromolecular complex which allows transcription factors to interact with the class II MHC promoter in a spatially and helically constrained fashion.

Animals↗

PubMed2000

Effects of histone tail domains on the rate of transcriptional elongation through a nucleosome.

The N-terminal tail domains of the core histones play important roles in gene regulation, but the exact mechanisms through which they act are not known. Recent studies suggest that the tail domains may influence the ability of RNA polymerase to elongate through the nucleosomal DNA and, thus, that posttranslational modification of the tail domains may provide a control point for gene regulation through effects on the elongation rate. We take advantage of an experimental system that uses bacteriophage T7 RNA polymerase as a probe for aspects of nucleosome transcription that are dominated by the properties of nucleosomes themselves. With this system, experiments can analyze the synchronous, real-time, single-passage transcription on the nucleosomal template. Here, we use this system to directly test the hypothesis that the tail domains may influence the "elongatability" of nucleosomal DNA and to identify which of the tail domains may contribute to this. The results show that the tail domains strongly influence the rate of elongation and suggest that the effect is dominated by the N-terminal domains of the (H3-H4)(2) tetramer. They further imply that tail-mediated octamer transfer is not essential for elongation through the nucleosome. Acetylation of the tail domains leads to effects on elongation that are similar to those arising from complete removal of the tail domains.

Amino Acid Sequence↗

PubMed2000

Hypoxia reduces atrial natriuretic peptide clearance receptor gene expression in ANP knockout mice.

We tested the hypotheses that hypoxic exposure is associated with exacerbated pulmonary hypertension and right ventricular (RV) enlargement, reduced atrial natriuretic peptide (ANP) clearance receptor (NPR-C) expression, and enhanced B-type natriuretic peptide (BNP) expression in the absence of ANP. Male wild-type [ANP(+/+)], heterozygous [ANP(+/-)], and homozygous [ANP(-/-)] mice were studied after a 5-wk hypoxic exposure (10% O(2)). Hypoxia increased RV ANP mRNA and plasma ANP levels only in ANP(+/+) and ANP(+/-) mice. Hypoxia-induced increases in RV pressure were significantly greater in ANP(-/-) than in ANP(+/+) or ANP(+/-) mice (104 +/- 17 vs. 45 +/- 10 and 63 +/- 7%, respectively) as were increases in RV mass (38 +/- 4 vs. 26 +/- 5 and 29 +/- 4%, respectively). NPR-C mRNA levels were greatly reduced in the kidney, lung, and brain by hypoxia in all three genotypes. RV BNP mRNA and lung and kidney cGMP levels were increased in hypoxic mice. These findings indicate that disrupted ANP expression worsens hypoxic pulmonary hypertension and RV enlargement but does not alter hypoxia-induced decreases in NPR-C and suggest that compensatory increases in BNP expression occur in the absence of ANP.

Animals↗

PubMed2000

Analysis of related factors in complications of stereotactic radiosurgery in intracranial tumors.

OBJECT: To investigate the related factors in complications of stereotactic radiosurgery for intracranial tumors. METHODS: A retrospective review of 146 patients with intracranial tumors treated with stereotactic radiosurgery was conducted. Sixty-five patients received single-dose treatment and the rest received fractionated stereotactic radiosurgery. Ninety-five patients received conventional radiotherapy in the meantime. RESULTS: Follow-up period was 18-54 months. Follow-up rate was 92.5% and 39 patients (26.7%) had different complications. The Cox statistics showed that target volume, target peripheral dose, target maximal dose, and ratio of maximal dose to peripheral dose are related to the complications. Conversely, neither type of tumor disease, gender, radiation schedule with or without conventional radiotherapy, target minimal dose, nor ratio of target peripheral isodose volume to target volume were found to be related to complications. CONCLUSION: Target volume and dose are the major factors causing complications, and the optimization of the therapeutic planning can play a significant role in reducing them.

Brain Edema↗

PubMed2000

Effect of retinoic acid on apoptosis and DNA repair in human keratinocytes after UVB irradiation.

BACKGROUND: Skin cancer is extremely common. Epidemiological studies indicated that ultraviolet radiation (UV) is the primary cause for skin cancers, and that retinoic acid (RA) is able to inhibit this UV-induced skin carcinogenesis; however, the molecular mechanism of the anti-UV action of RA is unclear. OBJECTIVE: The purpose of this study is to investigate if RA enhances the removal of UV-induced DNA damage. METHODS: The effect of RA on UV-induced apoptosis and DNA repair was investigated by ELISA apoptosis assay and CAT assay. RESULTS: Both all-trans-RA and 9-cis-RA did not promote UV-induced apoptosis nor the repair of UV-damaged DNA in human keratinocytes. Furthermore, RA did not induce the expression of p53. CONCLUSION: The inhibition of RA on skin carcinogenesis is not due to enhanced removal of UV-damaged DNA. Therefore, RA does not inhibit skin cancer development at the initiation stage, but possibly at the promotion and progression stages.

Antineoplastic Agents↗

PubMed2000

Cadherin repertoire determines partner-specific gap junctional communication during melanoma progression.

Reduced gap junction activity has long been implicated in tumorigenesis. To elucidate the potential role of intercellular communication in melanoma development, we examined gap junctional capability of melanocytic cells from various stages of tumor progression in coculture models using dye transfer assays. Normal melanocytes coupled with keratinocytes by gap junctional formation, whereas melanoma cells did not. Instead, melanoma cells communicated among themselves and with fibroblasts. This switch in communication partners coincided with a shift from E-cadherin to N-cadherin expression during melanoma development. Forced expression of E-cadherin by adenoviral gene transfer in N-cadherin-expressing melanoma cells restored gap junctional compatibility with keratinocytes. Our data suggest that (1) melanocyte transformation is associated with loss of the pre-existing gap junctional activity with keratinocytes but a concomitant gain of communication with a newly juxtaposed cell type, the fibroblasts, (2) the specificity of gap junctional formation during melanoma development is determined by the cadherin profile on the melanocytic cells and (3) the overall gap junctional activity of melanocytic cells is not reduced with transformation.

Adenoviridae↗