Biomedical subjects

Liwei Wang

Publications and source records attributed to Liwei Wang.

At least 37 records · Page 2Linked to original sources

PubMed2005

Altered expression of transcription factor Sp1 critically impacts the angiogenic phenotype of human gastric cancer.

Our recent study has shown that transcription factor Sp1 is an independent prognostic factor in gastric cancer. However, it is unclear how Sp1 impacts gastric cancer biology. Since Sp1 regulates multiple genes important to angiogenesis, we sought to evaluate the relationship between Sp1 expression and microvessel density (MVD) as well as their effects on cancer patient survival. The expression of Sp1 and status of MVD was determined using archival tissues of 86 cases of resected human gastric cancer. We found that MVD correlated highly with Sp1 expression (P < 0.001). Patients with strong Sp1 expression were 12 times more likely to have high MVD than were those with negative Sp1 expression. In univariate survival analyses, both elevated Sp1 expression (P = 0.007) and high MVD expression (P = 0.036) were associated with inferior survival. However, when Sp1 expression, MVD expression, disease stage, completeness of resection, Lauren's classification, and patient age were entered into a Cox proportional hazards model, only strong Sp1 expression (P = 0.047) and advanced stage (P < 0.01) were independently prognostic of poor survival. Furthermore, knocking down Sp1 expression significantly impaired the angiogenic potential of tumor cells in vitro and suppressed angiogenesis in vivo animal models. Therefore, we provided both clinical and experimental evidence to indicate that Sp1 might impact gastric cancer development and progression through regulating angiogenesis, a critical aspect of cancer biology.

Adenocarcinoma↗

PubMed2005

On the Euclidean distance of images.

We present a new Euclidean distance for images, which we call IMage Euclidean Distance (IMED). Unlike the traditional Euclidean distance, IMED takes into account the spatial relationships of pixels. Therefore, it is robust to small perturbation of images. We argue that IMED is the only intuitively reasonable Euclidean distance for images. IMED is then applied to image recognition. The key advantage of this distance measure is that it can be embedded in most image classification techniques such as SVM, LDA, and PCA. The embedding is rather efficient by involving a transformation referred to as Standardizing Transform (ST). We show that ST is a transform domain smoothing. Using the Face Recognition Technology (FERET) database and two state-of-the-art face identification algorithms, we demonstrate a consistent performance improvement of the algorithms embedded with the new metric over their original versions.

Algorithms↗

PubMed2005

Methylenetetrahydrofolate reductase polymorphisms/haplotypes and risk of gastric cancer: a case-control analysis in China.

Studies have suggested that low dietary folate intake is associated with an increased risk of gastric cancer. Methylenetetrahydrofolate reductase (MTHFR) is involved in folate metabolism and influences DNA methylation and nucleotide synthesis. MTHFR is highly polymorphic and the variant genotypes result in decreased MTHFR enzyme activity and lower plasma folate level. We hypothesized that three MTHFR common variants (i.e. C677T, A1298C and G1793A) and their haplotypes are associated with the risk of gastric cancer. To test this hypothesis, we genotyped these polymorphisms in a population-based case-control study of 320 incident gastric adenocarcinoma cases and 313 cancer-free controls in a Chinese population. Consistent with our previous observations, the 677TT genotype was associated with a significantly increased risk for gastric cancer (adjusted OR =1.79, 95% CI =1.02-3.15) compared with the 677CC genotype; the association was more evident for gastric cardia adenocarcinoma (adjusted OR =2.60, 95% CI =1.30-5.21). When we used the haplotype analyses and assumed MTHFR 677T, 1298C and 1793A as risk alleles, individuals with 6 variant alleles had a significantly (4.64-fold) increased risk for gastric cardia adenocarcinoma (OR =4.64, 95% CI =1.34-16.01) compared with those having 0-2 variants. These findings suggest that the MTHFR common variants and their haplotypes may play a role in the etiology of gastric cancer, particularly gastric cardia adenocarcinoma. Future studies using large sample sizes and incorporating detailed data on dietary folate intake and related serological measurements are warranted to confirm our findings.

Adenocarcinoma↗

PubMed2004

Drug release from injectable depots: two different in vitro mechanisms.

Certain poly (lactide-co-glycolide) (PLGA)/benzyl benzoate (BB) solutions can form gels when injected into buffer (depot formation) as well as upon ageing under ambient conditions. When evaluating various PLGAs in benzyl benzoate, we have found that only those that gel upon ageing also form gel depots in buffer. This indicates that depot formation in this system may be fundamentally different from the phase inversion depot formation that has been observed for PLGA in water-miscible solvents. The drug release kinetics in vitro is controlled both by diffusion and erosion, with the base form of the drug being always released faster than its salt form. This is due to base-catalyzed hydrolysis. While gel permeation chromatography (GPC) measurements show a continuous decrease in molecular weight, the rheological properties upon buffer injection show maxima, for the base drug and the salt drug. The location of the viscosity maximum with time is dependent on the nature of the drug and its concentration.

Benzoates↗

PubMed2004

Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer.

The biological and clinical behaviors of cancer are affected by multiple molecular pathways that are under the control of transcription factors. Improved understanding of how transcription factors affect cancer biology may lead to improved ability to predict clinical outcome and discovery of novel therapeutic strategies. We evaluated the relationship between Sp1 and vascular endothelial growth factor (VEGF) expression, as well as their effect on survival in 86 cases of resected human gastric cancer. The degree of VEGF expression correlated highly with Sp1 expression (P < 0.01). Patients with high Sp1 expression were 98 times more likely to have high VEGF expression compared with those with negative Sp1 expression. Clinically, negative or weak Sp1 expression was associated with early stage (IA) in gastric cancer. Strong Sp1 expression was more frequently observed among patients with stage IB-IV disease (P = 0.035). Similarly, whereas strong Sp1 expression was uncommonly observed among patients with N0 or N1 disease (19 and 16%), N2/N3 gastric cancer was associated with strong Sp1 expression (48%; P = 0.034). Strong Sp1 expression was also associated with inferior survival. The median survival duration in patients who had a tumor with a negative, weak, and strong Sp1 expression was 44, 38, and 8 months (P = 0.0075), respectively, whereas patients with strong VEGF expression had a shorter survival duration; the difference was not statistically significant. When Sp1 and VEGF expression, stage, completeness of resection, histology, and patient age were entered in a Cox proportional hazards model, strong Sp1 expression (P = 0.021) and an advanced disease stage (P < 0.001) were independently prognostic of poor survival. Given the importance of Sp1 in the expression of VEGF, our data suggest that dysregulated Sp1 expression and activation play important roles in VEGF overexpression and, thus, gastric cancer development and progression.

Aged↗

PubMed2004

Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity.

The aggressive biology of human pancreatic adenocarcinoma has been linked with overexpression of vascular endothelial growth factor (VEGF). Constitutive activation of the transcription factor Sp1 plays a critical role in VEGF overexpression. Recent studies indicated that celecoxib, a selective cyclooxygenase-2 inhibitor, exhibits potent antitumor activity. However, the underlying molecular mechanisms of this activity remain unclear. In the present study, we used a pancreatic cancer model to determine the role of Sp1 in the antitumor activity of celecoxib. Treatment of various pancreatic cancer cells with celecoxib suppressed VEGF expression at both the mRNA and protein level in a dose-dependent manner. VEGF promoter deletion and point mutation analyses indicated that a region between nucleotide -109 and -61 and its intact Sp1-binding sites were required for the inhibition of VEGF promoter activity by celecoxib. Also, celecoxib treatment reduced both Sp1 DNA binding activity and transactivating activity. This decreased activity correlated with reduced Sp1 protein and its phosphorylation as determined using Western blot analysis. Furthermore, in an orthotopic pancreatic cancer animal model, celecoxib treatment inhibited tumor growth and metastasis. The antitumor activity was consistent with inhibition of angiogenesis as determined by evaluating tumor microvessel formation, which correlated with decreased Sp1 activity and VEGF expression. Collectively, our data provide a novel molecular mechanism for the antitumor activity of celecoxib and may help further improve its effectiveness in controlling pancreatic cancer growth and metastasis.

Adenocarcinoma↗

PubMed2004

NF-kappaB activity blockade impairs the angiogenic potential of human pancreatic cancer cells.

The effect of blockade of NF-kappaB activity on human pancreatic cancer angiogenesis was determined in an orthotopic xenograft model. Highly metastatic L3.3 human pancreatic cancer cells, which expressed an elevated level of constitutive NF-kappaB activity, were transfected with a mutated IkappaBalpha (IkappaBalphaM). After implantation in the pancreas of nude mice, parental (L3.3) and control vector-transfected (L3.3-Neo) cells produced rapidly growing tumors and liver metastases, whereas IkappaBalphaM-transfected (L3.3-IkappaBalphaM) cells had decreased tumorigenicity and metastatic potential. NF-kappaB signaling blockade significantly inhibited the in vitro and in vivo expression of the major proangiogenic molecules vascular endothelial growth factor and interleukin-8 and decreased tumor vascular formation. These events were correlated with retarded tumor growth and suppression of metastasis. Collectively, these data suggest that suppression of tumorigenicity and metastasis by NF-kappaB blockade is due to impaired angiogenic potential of tumor cells.

Animals↗

PubMed2004

Evidence for peripheral plasticity in human odour response.

Of those people who are anosmic to androstenone, a proportion can acquire sensitivity to it by repeated exposure and even those who are able to smell it can lower their threshold with this treatment. Using olfactory threshold testing, intranasal electrophysiology and EEG we show for the first time that: (1) the subjects' detection threshold is proportional to the amplitude of the olfactory evoked potential (EOG) recorded inside the nose; (2) the EOG amplitude is correlated with the amplitude of the olfactory event-related potential (OERP) recorded on the scalp; and (3) with repetitive exposure, human subjects acquire a reduced threshold for androstenone and, as they do so, their EOG and OERP increase. These observations support the existence of odourant-specific plasticity in the peripheral olfactory system.

Adolescent↗

PubMed2004

Molecular basis of gastric cancer development and progression.

Gastric cancer is one of the leading causes of cancer death worldwide. Because of its heterogeneity, gastric cancer has been an interesting model for studying carcinogenesis and tumorigenesis. Various genetic and molecular alterations are found in gastric cancer that underlie the malignant transformation of gastric mucosa during the multistep process of gastric cancer pathogenesis. Although the detailed mechanisms of gastric cancer development remain uncertain, the enhancement in understanding of its molecular biology in recent years has led to a better perspective on the molecular epidemiology, carcinogenesis, and pathogenesis of gastric cancer. More importantly, it is becoming possible to use molecular markers in differential diagnosis, prognostic evaluation, and specific clinical interventions. Because multiple molecular alterations are frequently noted in gastric cancer and because its histology is complex, new technologies for studying its molecular biology are important to further evaluate gastric carcinogenesis. This review describes our current knowledge of the molecular basis of gastric cancer as it relates to molecular epidemiology, multiple molecular alterations in pathogenesis, and molecular determinants of invasion and metastasis, as well as their potential clinical applications.

Biomarkers↗

PubMed2004

A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer.

Insulin-like growth factor I receptor (IGF-IR) is critical to cell survival and growth and altered IGF-IR expression is found in many human cancers. However, its expression and potential role in gastric cancer development and progression has not been explored. The IGF-IR expression level was determined via immunohistochemistry in primary tumor and lymph node metastasis of 86 cases of resected gastric cancer. Relationships of IGF-IR expression with transcription factor Spl expression and clinicopathological features were analyzed. The impact of altered Sp1 expression on IGF-IR expression and gastric cancer biology was further determined using small inhibitory RNA for Sp1 mRNA. We found that IGF-IR was overexpressed in 62% of the tumor samples when compared with adjacent tumor-free gastric mucosa. Patients with lymph node metastases had strong expression of IGF-IR in both primary and metastatic tumor cells. IGF-IR overexpression in the primary tumor correlated with increased lymph node metastasis. Furthermore, the level of IGF-IR expression directly correlated with that of Spl, an important transcription factor for IGF-IR regulation. Knocking-down of Spl expression by small inhibitory RNA led to decreased IGF-IR expression and attenuated growth and metastasis of gastric cancer cells. Therefore, dysregulated expression of IGF-IR and/or Sp1 may contribute to the growth and metastasis of gastric cancer and potentially can be a target of therapeutic intervention.

Animals↗

PubMed2004

A new non-invasive method for recording the electro-olfactogram using external electrodes.

OBJECTIVE: The aim of this investigation was to explore the possibility of recording the electro-olfactogram (EOG) using external electrodes placed on the root of the nose on either side of the bridge and at the medial termination of the eyebrows. The EOG is considered to be the summated generator potential of olfactory receptor cells and therefore represents peripheral olfactory events. Recording of human EOG is technically difficult due to poor access to the olfactory mucosa and the nasal irritation is tolerated by few subjects. METHODS: The evoked potentials at these sites in response to two odourants, n-amyl acetate and benzaldehyde, were recorded simultaneously with the EOG, recorded conventionally with an intranasal electrode, and the olfactory event-related potential (OERP) recorded using scalp electrodes. RESULTS: The extranasal potential recorded at the root of the nose, 0.5-1 cm below the nasion, 1 cm from the ridge and ipsilateral with the stimulus, had the highest degree of correlation with the intranasal EOG. We refer to this site as N1 (left side) and N2 (right side). Further analysis demonstrated that the latency, the time constant of the rising phase and the amplitude of the evoked potential recorded at N1 also had a higher correlation coefficient with the EOG than did those potentials recorded at other sites. Statistical analysis indicated that the latency and time constant of the response recorded externally at N1 were the same as those of the EOG recorded intranasally. CONCLUSIONS: We conclude that an olfactory evoked potential, with many of the characteristics of the EOG recorded from the olfactory mucosa, can be recorded externally at a site close to the bridge of the nose. SIGNIFICANCE: This non-invasive method of recording the EOG will have benefits for the objective assessment of olfactory function.

Adult↗

PubMed2004

P53 codon 72 polymorphism and risk of gastric cancer in a Chinese population.

The p53 gene plays an important role in cell cycle control in response to DNA damage, which may increase the probability of mutations that lead to carcinogenesis. The p53 codon 72 Arg right curved arrow Pro polymorphism has been suggested to be associated with risk for different kind of cancers, but the data on gastric cancer (GC) is very limited. To evaluate the association between this polymorphism and risk of GC, we performed genotype analysis by using a polymerase chain reaction-based restriction fragment length polymorphism assay in a population-based case-control study of 324 GC patients and 317 cancer-free controls in a Chinese population. The controls were frequency-matched to the cases by age, sex and smoking status. The frequency of the p53 Arg allele was 57.4% in the cases and 54.9% in the controls, and the genotype frequencies of p53 Arg/Arg, Arg/Pro, and Pro/Pro were 29.6%, 55.6%, and 14.8%, respectively, in the cases, and 29.6%, 50.5%, and 19.9%, respectively, in the controls (p=0.207). Logistic regression analysis revealed that the p53 Arg allele (Arg/Pro and Arg/Arg genotype) was associated with a borderline significantly increased risk of gastric cancer (adjusted OR=1.44, 95% CI=0.95-2.18), particularly non-cardia gastric cancer (adjusted OR=1.67, 95% CI=1.00-2.77), compared with p53 homozygous Pro allele (Pro/Pro genotype), and the risk was significantly more evident among alcohol drinkers (adjusted OR=2.85, 95% CI=1.37-5.95). While the results suggest that the p53 codon 72 polymorphism may contribute to gastric cancer susceptibility, further larger studies are needed to substantiate our findings and to explore a possible interaction between p53 codon 72 polymorphism and alcohol in the etiology of gastric cancer.

Adult↗

PubMed2003

Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer.

The transcription factor Sp1 regulates the expression of multiple genes. However, its expression and role in human tumor development and progression remain unclear. Using immunohistochemistry, we investigated Sp1 expression patterns in 86 cases of human gastric cancer having various clinicopathologic characteristics, 57 normal gastric tissue specimens, and 53 lymph node metastases. We found that Sp1 protein was expressed predominantly in the nuclei of cells located in the mucous neck region, whereas Sp1 expression was not detected either in the cells located toward the gastric pit (foveolar differentiation) or cells of the glandular epithelium (glandular differentiation). In sharp contrast, strong Sp1 expression was detected in tumor cells, whereas no or very weak Sp1 expression was detected in stromal cells and normal glandular cells surrounding or within the tumors. We also evaluated the effect of Sp1 expression on the survival of patients who have undergone surgical resection. The median survival duration in patients who had a tumor with negative, weak, and strong Sp1 expression was 43, 37, and 8 months, respectively (P = 0.0075). Next, Sp1 expression, stage, completeness of resection, age, and sex were entered into a Cox proportional hazard model. In multivariate analysis, Sp1 (P = 0.003) and stage (P < 0.001) were independently prognostic of survival. Therefore, normal and malignant gastric tissues have unique Sp1 expression patterns. Given the importance of Sp1 in the expression of multiple molecules key to tumor cell survival, growth, and angiogenesis, its disregulated expression and activation may play important roles in gastric cancer development and progression.

Aged↗

PubMed2003

Structure formation in injectable poly(lactide-co-glycolide) depots.

Solutions of low-molecular-weight poly(lactide-co-glycolide) (PLGA) in organic solvents have been investigated as novel injectable drug depots for drug delivery over periods of weeks to months. In this paper, we investigated the structure formation in a PLGA/benzyl benzoate system, using controlled stress rheometry, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). GPC analysis demonstrated a decrease in molecular weight as a function of time and temperature, indicating degradation. Rheological experiments showed that the flow properties of PLGA/benzyl benzoate solutions were affected by a combination of degradation and gelation; the latter was also detected by an endotherm in DSC and by three-dimensional structure formation studies by rheology. Extent of degradation and gelation of PLGA were shown to depend on the solvent.

Benzoates↗

PubMed2003

Direct demonstration of negative regulation of tumor growth and metastasis by host-inducible nitric oxide synthase.

Inducible nitric oxide synthase (NOS) II expression can be induced in the tumor bed, predominantly in host cells that infiltrate and surround a tumor. However, the impact of this physiological NOS II expression in host cells on tumor growth and metastasis remains unclear because of a lack of appropriate experimental approaches. In the present study, three NOS II-null (NOS II(-/-)) tumor cell lines, KX-dw1, KX-dw4, and KX-dw7, were established and verified using Southern, Northern, and Western blot analysis, and nitric oxide production assays. Cells from these lines were then s.c. and i.v. injected into NOS II(+/+) and NOS II(-/-) C57BL/6 mice. NOS II protein expression and enzyme activity were clearly detected in the tumors that formed in NOS II(+/+) mice but not in those that formed in NOS II(-/-) mice. Consistent with the absence of NOS II expression in the tumor stroma, KX-dw1, KX-dw4, and KX-dw7 cells grew much faster and produced many more experimental lung metastases in NOS II(-/-) mice than in NOS II(+/+) mice. Therefore, physiological expression of NOS II in host cells directly inhibits tumor growth and metastasis.

Animals↗

PubMed2003

Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.

Expression of vascular endothelial growth factor (VEGF), a key angiogenic protein, has been linked with pancreatic cancer progression. However, the molecular basis for VEGF overexpression remains unclear. Immunohistochemical studies have indicated that VEGF overexpression coincides with elevated Stat3 activation in human pancreatic cancer specimens. In our study, more than 80% of the human pancreatic cancer cell lines used exhibited constitutively activated Stat3, with Stat3 activation correlated with the VEGF expression level. Blockade of activated Stat3 via ectopic expression of dominant-negative Stat3 significantly suppressed VEGF expression, angiogenesis, tumor growth, and metastasis in vivo. Furthermore, constitutively activated Stat3 directly activated the VEGF promoter, whereas dominant-negative Stat3 inhibited the VEGF promoter. A putative Stat3-responsive element on the VEGF promoter was identified using a protein-DNA binding assay and confirmed using a promoter mutagenesis assay. These results indicate that Stat3 directly regulates VEGF expression and hence angiogenesis, growth, and metastasis of human pancreatic cancer, suggesting that Stat3 signaling may be targeted for treatment of pancreatic cancer.

Adenocarcinoma↗

PubMed2003

Design and structure-based study of new potential FKBP12 inhibitors.

Based on the structure of FKBP12 complexed with FK506 or rapamycin, with computer-aided design, two neurotrophic ligands, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-Leucine ethyl ester and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester, were designed and synthesized. Fluorescence experiments were used to detect the binding affinity between FKBP12 and these two ligands. Complex structures of FKBP12 with these two ligands were obtained by x-ray crystallography. In comparing FKBP12-rapamycin complex and FKBP12-FK506 complex as well as FKBP12-GPI-1046 solution structure with these new complexes, significant volume and surface area effects and obvious contact changes were detected which are expected to cause their different binding energies-showing these two novel ligands will become more effective neuron regeneration drugs than GPI-1046, which is currently undergoing phase II clinical trail as a neurotrophic drug. Analysis of volume and surface area effects also gives a new clue for structure-based drug design.

Binding Sites↗

PubMed2003

Psychophysical evaluation of responses to pleasant and mal-odour stimulation in human subjects; adaptation, dose response and gender differences.

A psychophysical detection test was used to measure the response of human subjects to 'good' and 'bad' smells. Different intensities and frequencies of odour stimulation were delivered by an olfactometer and the responses to a group of malodours (valeric acid, skatol, butyric acid) and pleasant smells (amyl acetate, cis-3-hexenol, linalool) were compared. A mathematical model, a power equation, was used to fit the three-dimensional data plots (dose vs. stimulus frequency vs. response). The model was able to distinguish between malodours and pleasant odours on the basis of the values of parameters describing dose-response and adaptation/habituation. We show that the olfactory system adapts/habituates more rapidly to malodours than to pleasant smells, but is much more sensitive to changes in stimulation by malodours than pleasant odours. The degree of adaptation is inversely proportional to stimulus strength. The response profile for women was different to that of men for certain odours, in particular valeric acid, skatol and cis-3-hexenol. The difference lay in their sensitivity and the slope and range of the dose response. Thus, we have shown for the first time that the olfactory system adapts more readily to 'bad' smells than 'good' smells, and that it has a broader range of adaptation for bad smells. As a consequence, the olfactory system is specially responsive to changes in potential olfactory warning signals.

Adaptation, Physiological↗