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Biomedical subjects

W Zheng

Publications and source records attributed to W Zheng.

At least 325 records · Page 18Linked to original sources
PubMed1987

Lung cancer among Chinese women.

A case-control study involving interviews with 672 female lung cancer patients and 735 population-based controls was conducted to investigate the high rates of lung cancer, notably adenocarcinoma, among women in Shanghai. Cigarette smoking was a strong risk factor, but accounted for only about one-fourth of all newly diagnosed cases of lung cancer. Most patients, particularly with adenocarcinoma, were life-long non-smokers. The risks of lung cancer were higher among women reporting tuberculosis and other pre-existing lung diseases. Hormonal factors were suggested by an increased risk associated with late menopause and by a gradient in the risk of adenocarcinoma with decreasing menstrual cycle length, with a 3-fold excess among women who had shorter cycles. Perhaps most intriguing were associations found between lung cancer and measures of exposure to cooking oil vapors. Risks increased with the numbers of meals cooked by either stir frying, deep frying or boiling; with the frequency of smokiness during cooking; and with the frequency of eye irritation during cooking. Use of rapeseed oil, whose volatiles following high-temperature cooking may be mutagenic, was also reported more often by the cancer patients. The findings thus confirm that factors other than smoking are responsible for the high risk of lung cancer among Chinese women and provide clues for further research, including the assessment of cooking practices.

Adenocarcinoma↗
PubMed1987

Decreased risk of lung cancer in the cotton textile industry of Shanghai.

The relationship between lung cancer risk and work in the cotton textile industry was investigated in a large population-based case-control study in urban Shanghai, where the industry is a major employer of men and women. Personal interviews obtained occupational, smoking, and other information from 1405 newly diagnosed lung cancer cases and 1495 controls. A significantly low risk of lung cancer was associated with cotton textile employment [odds ratio (OR) = 0.7,95% confidence interval (CI) = 0.6-0.9]. In men, the decreased risk was observed among both smokers (OR = 0.7, 95% CI = 0.5-1.1) and nonsmokers (OR = 0.3, 95% CI = 0.1-1.0). In women, the risk was also decreased regardless of smoking status (OR = 0.8, 95% CI = 0.4-1.6 among smokers; OR = 0.9, 95% CI = 0.6-1.2 among nonsmokers). In both sexes, the reductions in risk tended to be greater for lung cancer cell types other than adenocarcinoma. Low risks were found regardless of occupations within the cotton textile industry; the OR for workers in textile processing who potentially had greater dust exposure was 0.8 (95% CI = 0.6-1.2), whereas the OR for those in other industry jobs was 0.7 (95% CI = 0.4-1.0). There was little difference in risk according to self-reported exposure to textile dust, and no clear trend with duration of employment or dust exposure. Reasons for the reduced risk of lung cancer in cotton textile workers without a dose response are unclear, although several methodological explanations were considered. The findings, however, appear consistent with prior epidemiological studies and are interesting in light of speculation about tumor-inhibitory factors, such as bacterial endotoxins, that are found in dusts from cotton and other fiber crops.

Adult↗
PubMed1987

Lung cancer and prior tuberculosis infection in Shanghai.

In a population-based case-control study of lung cancer in Shanghai involving interviews during 1984-86 with 1,405 cancer patients and 1,495 controls, a significant 50% elevation in the risk of lung cancer, adjusted for cigarette smoking, was observed among persons who had a history of tuberculosis. Among those diagnosed with tuberculosis within the past 20 years, the risk exceeded 2.5-fold. In males the lung cancers tended to occur on the same side as the previous tuberculosis infection. For both sexes, the effect of recent tuberculosis was most apparent for adenocarcinoma and peripheral tumours. No relationship was found between lung cancer risk and the type of tuberculosis therapy, including use of isoniazid. The findings suggest that tuberculosis may predispose to lung cancer, with the association most apparent among recent survivors of the infection.

Adenocarcinoma↗
PubMedDate not supplied

The interactions of 1,4-dihydropyridines bearing a 2-(2-aminoethylthio)methyl substituent at voltage-dependent Ca2+ channels of smooth muscle, cardiac muscle and neuronal tissues.

The Ca2+ channel antagonistic potencies of tiamdipine [2-(2-aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-6-m ethyl-4-(3- nitrophenyl)-1,4-dihydropyridine] and nifedipine [2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydrop yri dine] analogs bearing phenyl ring substituents were studied using pharmacologic and radioligand binding techniques. Additionally, analogs of tiamdipine possessing (2-aminoethylthio)methyl-, (2-acetamidoethylthio)methyl- and (2-pyrrolidinylmethylthio)methyl- groups at the C2 position of the 1,4-dihydropyridine ring have been studied. Tiamdipine and nifedipine analogs inhibited K(+)-induced contractile responses in rat tail artery. IC50 values of 4-phenyl ring substituted 2-(2-aminoethylthio)methyl tiamdipine analogs ranged from 10(-7) mol/l to 10(-8) mol/l. However, the corresponding 4-phenyl ring substituted nifedipine analogs covered a wider range of potency from 10(-6) mol/l to 10(-9) mol/l. KI values of the corresponding tiamdipine analogs for the inhibition of specific [3H]PN 200-110 [(+)-[3H]isopropyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5- methoxycarbonyl-2,6-dimethyl-3-pyridinecarboxylate] binding ranged from 10(-7) mol/l to 10(-9) mol/l in guinea pig ileal and rat heart membranes and rat brain synaptosomes. The two stereoisomers of tiamdipine and its analog 2-(2-acetamidoethylthio)methyl-3-carboethoxy-5-carbomethoxy- 6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine, and the four stereoisomers of 2-(2-pyrrolidinylmethylthio)methyl-3-carboethoxy-5-carbom eth oxy-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine showed high stereoselectivity ratios of approximately (-)/(+) = 100 and 1000 in pharmacologic and binding experiments, respectively. The inhibitory actions of 2-(2-aminoethylthio)methyltiamdipine analogs against K(+)-induced contractile responses in rat tail artery developed very slowly requiring at least 2 h for maximum effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

GABAergic inhibition shapes frequency tuning and modifies response properties in the superior olivary nucleus of the leopard frog.

The role of gamma-aminobutyric acid (GABA)ergic inhibition in shaping the excitatory frequency tuning of 74 neurons in the superior olivary nucleus of the leopard frog, Rana pipiens, was studied using iontophoretic application of the GABA(A) receptor antagonist, bicuculline methiodide. For 37 neurons, bicuculline application broadened and/or changed the configuration of the excitatory frequency-tuning curve. Results indicate that GABA-mediated inhibition not only sharpens the tuning curves of neurons but also plays a critical role in creating new frequency tuning properties in the superior olivary nucleus. Bicuculline application affected other neuronal response properties as well. Spontaneous firing rate increased 11-338% for 18 of 59 neurons. For 32 of 58 neurons there was an increase in stimulus-evoked discharge rate and a change in rate-level function. There was no qualitative effect on the discharge pattern of 60 neurons, though 2 tonically responding neurons did show an increase (> 30%) in response duration. Additional roles for GABAergic inhibition in monaural signal analysis are discussed.

Acoustic Stimulation↗
PubMedDate not supplied

Diversity and coverage of structural sublibraries selected using the SAGE and SCA algorithms.

It is often impractical to synthesize and test all compounds in a large exhaustive chemical library. Herein, we discuss rational approaches to selecting representative subsets of virtual libraries that help direct experimental synthetic efforts for diverse library design. We compare the performance of two stochastic sampling algorithms, Simulating Annealing Guided Evaluation (SAGE; Zheng, W.; Cho, S. J.; Waller, C. L.; Tropsha, A. J. Chem. Inf. Comput. Sci. 1999, 39, 738-746.) and Stochastic Cluster Analysis (SCA; Reynolds, C. H.; Druker, R.; Pfahler, L. B. Lead Discovery Using Stochastic Cluster Analysis (SCA): A New Method for Clustering Structurally Similar Compounds J. Chem. Inf. Comput. Sci. 1998, 38, 305-312.) for their ability to select both diverse and representative subsets of the entire chemical library space. The SAGE and SCA algorithms were compared using u- and s-optimal metrics as an independent assessment of diversity and coverage. This comparison showed that both algorithms were capable of generating sublibraries in descriptor space that are diverse and give reasonable coverage (i.e. are representative) of the original full library. Tests were carried out using simulated two-dimensional data sets and a 27 000 compound proprietary structural library as represented by computed Molconn-Z descriptors. One of the key observations from this work is that the algorithmically simple SCA method is capable of selecting subsets that are comparable to the more computationally intensive SAGE method.

Journal Article↗
PubMedDate not supplied

Rational combinatorial library design. 2. Rational design of targeted combinatorial peptide libraries using chemical similarity probe and the inverse QSAR approaches.

We have developed a novel strategy for rational design of targeted peptide libraries. The goal of this method is to select a subset of natural amino acids that are most likely to be present in active peptides for the synthesis of library. Two different protocols are employed where chemical structures of peptides are described either by topological indices or by a combination of physicochemical descriptors for individual amino acids. The selection of a peptide as a candidate for the targeted library is based either on its chemical similarity to a biologically active probe or on its biological activity predicted from a preconstructed quantitative structure-activity (QSAR) equation. The optimization of the library is achieved by means of genetic algorithms (GA). This method was tested by rational design of the library with bradykinin-potentiating activity. Twenty-eight bradykinin-potentiating pentapeptides were used as a training set for the development of a QSAR equation, and, alternatively, two active pentapeptides, VEWAK and VKWAP, were used as probe molecules. In each case, the frequency distribution of amino acids in the top 100 peptides suggested by the method resembles the frequency distribution of amino acids found in the active peptides. The results obtained after GA optimization also compared favorably with those obtained by the exhaustive analysis of all possible 3.2 million pentapeptides.

Algorithms↗
PubMedDate not supplied

Rational combinatorial library design. 1. Focus-2D: a new approach to the design of targeted combinatorial chemical libraries.

We describe a new computational approach, called Focus-2D, to the rational design of targeted combinatorial chemical libraries. This approach is based on the hypothesis that structurally similar compounds display similar biological activity profiles. Building blocks that are used in a combinatorial chemical synthesis are randomly assembled to produce virtual library compounds. Individual library compounds are represented by Kier-Hall topological descriptors. Molecular similarities between compounds are evaluated quantitatively by modified pairwise Euclidean distances in multidimensional descriptor space. Simulated annealing is used to search the potentially large structural space of virtual chemical libraries to identify compounds similar to lead molecules. Frequency analysis of building block composition of selected virtual compounds identifies building blocks that can be used in combinatorial synthesis of chemical libraries with high similarity to the lead molecules. We show that this method correctly identifies building found in active peptoids with adrenergic or opioid activities.

Drug Design↗
PubMedDate not supplied

Rational combinatorial library design. 3. Simulated annealing guided evaluation (SAGE) of molecular diversity: a novel computational tool for universal library design and database mining.

We have developed a novel method for molecular diversity sampling called SAGE (simulated annealing guided evaluation of molecular diversity). Compounds in chemical databases or virtual combinatorial libraries are conventionally represented as points in multidimensional descriptor space. The SAGE algorithm selects a desired number of optimally diverse points (compounds) from a database. The diversity of a subset of points is measured by a specially designed diversity function, and the most diverse subset is selected using Simulated Annealing (SA) as the optimization tool. Application of SAGE to two simulated data sets of randomly distributed points in two-dimensional space afforded diverse and representative selection as judged by visual inspection. SAGE was also applied, in comparison with random sampling, to two other simulated data sets with points distributed among many clusters. We found that SAGE sampling covered significantly more clusters than the random sampling. By defining a fraction of data points as active, we also compared SAGE with random sampling in terms of hit rates. We showed that when the percentage of active points was low, the hit rates obtained by SAGE were always higher than those obtained by random sampling. When the percentage of active points was high, the performance of SAGE, in terms of individual hit rates, depended upon the data structure. However, in all cases, SAGE performed better than random sampling when cluster hit rates were used as the criterion.

Algorithms↗
PubMedDate not supplied

QSAR modeling of datasets with enantioselective compounds using chirality sensitive molecular descriptors.

Shape descriptors used in 3D QSAR studies naturally take into account chirality; however, for flexible and structurally diverse molecules such studies require extensive conformational searching and alignment. QSAR modeling studies of two datasets of fragrance compounds with complex stereochemistry using simple alignment-free chirality sensitive descriptors developed in our laboratories are presented. In the first investigation, 44 alpha-campholenic derivatives with sandalwood odor were represented as derivatives of several common structural templates with substituents numbered according to their relative spatial positions in the molecules. Both molecular and substituent descriptors were used as independent variables in MLR calculations, and the best model was characterized by the training set q2 of 0.79 and external test set r2 of 0.95. In the second study, several types of chirality descriptors were employed in combinatorial QSAR modeling of 98 ambergris fragrance compounds. Among 28 possible combinations of seven types of descriptors and four statistical modeling techniques, k nearest neighbor classification with CoMFA descriptors was initially found to generate the best models with the internal and external accuracies of 76 and 89%, respectively. The same dataset was then studied using novel atom pair chirality descriptors (cAP). The cAP are based on a modified definition of the atomic chirality, in which the seniority of the substituents is defined by their relative partial charge values: higher values correspond to higher seniorities. The resulting models were found to have higher predictive power than those developed with CoMFA descriptors; the best model was characterized by the internal and external accuracies of 82 and 94%, respectively. The success of modeling studies using simple alignment free chirality descriptors discussed in this paper suggests that they should be applied broadly to QSAR studies of many datasets when compound stereochemistry plays an important role in defining their activity.

Ambergris↗
PubMedDate not supplied

Discordant genetic changes in ovarian and endometrial endometrioid carcinomas: a potential pitfall in molecular diagnosis.

Endometrioid carcinoma simultaneously involving ovaries as well as the uterine corpus may present a diagnostic dilemma because of the difficulty in determining whether the lesions are separate primary tumors or metastases. It has been reported that the detection of clonality using microsatellite markers may be useful in solving this dilemma. To determine the usefulness of this technique, we compared the genetic alterations in microsatellite markers present in matched pairs of ovarian tumors from 12 patients. The study includes four ovarian cancer FIGO stage I and eight stage III/IV patients, and four patients also with independent endometrial carcinoma of the uterus. DNA from paraffin-embedded tissue was extracted and amplified using a multiplex polymerase chain reaction, after which the status of microsatellite instability and loss of heterozygosity in four microsatellite loci (BAT25, BAT26, D17S250, and D5S346) were determined. In the four patients with stage I ovarian cancer, four microsatellite markers were identical in one patient and three were identical in the remaining three patients. In high-stage patients, three markers were identical in at least 4/8 cases. In three of four patients with uterine involvement, three of the four markers were identical in the uterine tumor and one of the corresponding ovarian tumors. These results suggest that genetic discordance does not indicate independent origin or metastasis of the tumor but instead a progression of genetic changes at separate sites probably due to the marked genetic instability existing in these tumors. Because of these discordant genetic changes, great caution should be taken when distinguishing between primary and metastatic tumors on the basis of microsatellite markers.

Adult↗
PubMedDate not supplied

Telomerase antisense inhibition for the proliferation of endometrial cancer in vitro and in vivo.

The objective of this study was to investigate the antitumor effect of antisense telomerase oligodeoxynucleotides to endometrial cancer cells in vitro and in vivo. Antisense oligodeoxynucleotides (ODNs) against the human telomerase transcripatse (hTERT) synthesized to serve as telomerase inhibitors. Reverse transcription-polymerase chain reaction and 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay were used to test the expression of hTERT messengerRNA (mRNA) and inhibition of cell proliferation in vitro. In vivo, antitumor effects of ODNs or combined with cisplatin were evaluated in endometrial cancer xenograft. Telomerase activity was tested by telomeric repeat amplification protocol. Antisense ODNs could inhibit proliferation of human endometrial cancer cells (HEC-1-A) in vitro, and downregulate the expression hTRET mRNA in a dose- and period-dependent manner. The tumor growth inhibitory rate of low- and high-dose ODNs were 34.20% and 89.21%, and combined group was 75.30%. Telomerase activity was downregulated to 87.32% compared to the control in the ODNs-treated xenograft tumors. Antisense oligonucleotides of hTERT effectively inhibit the growth of endometrial cancer cell line. Telomerase inhibitor might be a new strategy for chemotherapy or chemoprevention in endometrial cancer.

Animals↗
PubMedDate not supplied

Expression of monocyte chemotactic protein-1 in human endometrial cancer cells and the effect of treatment with tamoxifen or buserelin.

Monocyte chemotactic protein-1 (MCP-1) is an important determinant of macrophage infiltration in tumours. This study investigated the effect of tamoxifen and the gonadotrophin-releasing hormone agonist buserelin on MCP-1 in the human endometrial cancer cell line EFE-184. Reverse transcription polymerase chain reaction and Western blot analysis were used to determine MCP-1 mRNA and protein expression, respectively. Immunoreactive MCP-1 in the cell culture media was quantified by enzyme-linked immunosorbent assay. Tamoxifen inhibited MCP-1 mRNA and protein expression in endometrial cancer cells and inhibited MCP-1 secretion in a time- and dose-dependent manner at concentrations of 10(-7) to 10(-5) M. Buserelin had no significant effect on MCP-1 mRNA and protein expression. These results suggest that tamoxifen directly inhibits the expression of MCP-1 in this cell line by blocking the MCP-1 signalling pathways. These findings may contribute to the understanding of the mechanisms underlying the different effects of tamoxifen and gonadotrophin-releasing hormone agonists in the treatment of endometrial cancer.

Antineoplastic Agents, Hormonal↗
PubMedDate not supplied

Manganese uptake and distribution in the central nervous system (CNS).

Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have focused on distribution, excretion, and accumulation of intravenous and intraperitoneal solutions of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation state (Mn2+) and crosses the BBB via specific carriers at a rate far slower than in other tissues. Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme, glutamine synthetase (GS), represents an important regulatory target of Mn. Compared to Mn2+, Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron (Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and 3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.

Animals↗
PubMedDate not supplied

Risk factors for oral and pharyngeal cancer in Shanghai, with emphasis on diet.

A population-based case-control study of oral and pharyngeal cancer was conducted in Shanghai, China, from 1988 to 1990, in which 204 (115 male, 89 female) incident cases and 414 (269 male, 145 female) controls were interviewed. Cigarette smoking and alcohol consumption, as well as occupational exposures to asbestos and to petroleum products and the use of kerosene stoves in cooking, were associated with increased risk of oral and pharyngeal cancer. In addition, more cases than controls reported having chronic oral diseases and false teeth. Dietary intakes of 42 major foods and selected salt-preserved or deep-fried foods during the past 10 years, ignoring any recent changes, were measured by a structured quantitative food questionnaire. After adjusting for known etiological factors, risks decreased with increasing intake of fruits, particularly oranges and tangerines, and some vegetables, including dark yellow vegetables and Chinese white radish. Men in the highest tertile of intake of these fruits and vegetables had about 30-50% the risk of those in the lowest tertile, with a less pronounced effect among women. A new finding was an excess risk associated with high consumption of salt-preserved meat and fish. The findings from this study provide further evidence that dietary factors play an important role in the development of oral and pharyngeal cancer.

Adult↗
PubMedDate not supplied

Bone sialoprotein promotes bone metastasis of a non-bone-seeking clone of human breast cancer cells.

Bone sialoprotein (BSP) is a major non-collagenous protein in mineralized tissues. BSP is also implied to be involved in tumor metastasis through its unique structure. Using the human breast cancer cell line MDA-231, we established both brain-seeking and bone-seeking cell clones. The brain-seeking cells (MDA4-231BR) showed no bone metastasis in an animal model. In this experiment, MDA-231BR cells were transfected with BSP cDNA and inoculated into the hearts of nude mice. All five nude mice which received BSP-transfected MDA-231BR cells developed bone metastases, while no bone lesions were observed in the control group. Histological examination revealed invasion of tumor cells into the endosteal space and erosion of the bone margin. Some animals were crippled due to large lesions. These results suggest that BSP may impart to breast cancer cells the capacity to metastasize and thus play an important role in bone metastasis of malignant tumors.

Animals↗