Biomedical subjects

Y Guo

Publications and source records attributed to Y Guo.

At least 271 records · Page 15Linked to original sources

PubMed1999

Increased transcriptional activity of prostate-specific antigen in the presence of TNP-470, an angiogenesis inhibitor.

Prostate-specific antigen, PSA, is regarded as a reliable surrogate marker for androgen-independent prostate cancer (AIPC). Concern has been raised that investigational agents may affect PSA secretion without altering tumour growth or volume. In a phase I trial, several patients with AIPC had elevated serum PSA levels while receiving TNP-470 that reversed upon discontinuation. TNP-470 inhibits capillary growth in several angiogenesis models. These observations prompted us to determine if TNP-470, or its metabolite, AGM-1883, altered PSA secretion. Intracellular protein and transcriptional levels of PSA and androgen receptor were also determined. The highest TNP-470 concentration produced a 40.6% decrease in cell number; AGM-1883 had minimal effects on cell viability. PSA secretion per cell was induced 1.1- to 1.5-fold following TNP-470 exposure. The same trend was observed for AGM-1883. PSA and AR were transcriptionally up-regulated within 30 min after exposure to TNP-470. PSA transcription was increased 1.4-fold, while androgen receptor (AR) transcription was induced 1.2-fold. The increased PSA transcriptional activity accounts for the increased PSA secretion. Increased AR transcription was also reflected at the protein level. In conclusion, TNP-470 and AGM-1883 both up-regulated PSA making clinical utilization of this surrogate marker problematic.

Acetamides↗

PubMed1999

Computed tomography of retroperitoneal paragangliomas.

More than 10% of retroperitoneal paragangliomas are malignant. Histopathological appearance is unreliable in distinguishing benign from malignant paragangliomas. In this study the computed tomography (CT) features of retroperitoneal paragangliomas were analysed to determine if benign neoplasms could be distinguished from malignancy by their appearance at imaging. We reviewed the clinical profiles and CT scans of 27 benign and seven malignant retroperitoneal paragangliomas in 32 patients to determine the presence of any characteristic appearances of benign and malignant neoplasms. Extra-adrenal paragangliomas were more frequently malignant (50%) than adrenal neoplasms (12.5%). Benign lesions were generally smaller (average 6.1 cm) than malignant lesions (average 7.9 cm). Benign tumours were more likely to be homogeneous (46.2%) and have well-defined margins (92.3%) than malignant tumours (25 and 12.5% respectively). Larger tumours were more frequently necrotic. Malignant retroperitoneal paragangliomas infiltrated adjacent liver, pancreas, bowel, lymph nodes, blood vessels, or metastasized to bone and liver. Malignant retroperitoneal paragangliomas are frequently extra-adrenal, large and heterogeneous, with ill-defined margin and necrosis. CT is useful for delineating the location, extent and nature of these tumours. Infiltration of surrounding tissues or organs, metastases, and resectability are accurately assessed by CT.

Adolescent↗

PubMed1999

Soybean phytochemicals inhibit the growth of transplantable human prostate carcinoma and tumor angiogenesis in mice.

The objectives of our studies are to characterize the ability of dietary soybean components to inhibit the growth of prostate cancer in mice and alter tumor biomarkers associated with angiogenesis. Soy isoflavones (genistein or daidzein) or soy phytochemical concentrate inhibit the growth of prostate cancer cells LNCaP, DU 145 and PC-3 in vitro, but only at supraphysiologic concentrations, i.e., 50% inhibitory concentration (IC(50)) > 50 micromol/L. G2-M arrest and DNA fragmentation consistent with apoptosis of prostate cancer cells are also observed at concentrations causing growth inhibition. In contrast, the in vitro proliferation of vascular endothelial cells was inhibited by soy phytochemcials at much lower concentrations. We evaluated the ability of dietary soy phytochemical concentrate and soy protein isolate to inhibit the growth of the LNCaP human prostate cancer in severe combined immune-deficient mice. Mice inoculated subcutaneously with LNCaP cells (2 x 10(6)) were randomly assigned to one of the six dietary groups based on the AIN-76A formulation for 3 wk. A 2 x 3 factorial design was employed with two protein sources (20%, casein vs. soy protein) and three levels of soy phytochemical concentrate (0, 0.2 and 1.0% of the diet). Soy components did not alter body weight gain or food intake. Compared with casein-fed controls, the tumor volumes after 3 wk were reduced by 11% (P = 0.45) by soy protein, 19% (P = 0.17) by 0.2% soy phytochemical concentrate, 28% by soy protein with 0.2% soy phytochemical concentrate (P < 0.05), 30% by 1.0% soy phytochemical concentrate (P < 0.05) and 40% by soy protein with 1.0% soy phytochemical concentrate (P < 0.005). Histologic examination of tumor tissue showed that consumption of soy products significantly reduced tumor cell proliferation, increased apoptosis and reduced microvessel density. The angiogenic protein insulin-like growth factor-I was reduced in the circulation of mice fed soy protein and phytochemical concentrate. Our data suggest that dietary soy products may inhibit experimental prostate tumor growth through a combination of direct effects on tumor cells and indirect effects on tumor neovasculature.

Animals↗

PubMed1999

Endocrine biomarkers of early fetal loss in cynomolgus macaques (Macaca fascicularis) following exposure to dioxin.

This study examines the endocrine alterations associated with early fetal loss (EFL) induced by an environmental toxin, TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), in the cynomolgus macaque, a well-documented reproductive/developmental model for humans. Females were administered single doses of 1, 2, and 4 microgram/kg TCDD (n = 4 per dose group) on gestational day (GD) 12. Urinary estrogen metabolites (estrone conjugates) were monitored to establish the day of ovulation, and serum hormones (estradiol, progesterone, chorionic gonadotropin, relaxin) were measured to assess ovarian and placental endocrine status before and after treatment. EFL occurred between GDs 22 and 32 in 10 of the 12 animals treated with TCDD. The primary endocrine alterations associated with TCDD treatment were significant decreases in serum estradiol and bioactive chorionic gonadotropin concentrations (p < 0.02). Less pronounced decreases in serum progesterone (p = 0.10) and relaxin (p < 0.08) also followed TCDD treatment. In contrast, immunoreactive chorionic gonadotropin concentrations were not reduced by TCDD exposure at any level, indicating that TCDD targets specific components of the chorionic gonadotropin synthesis machinery within the trophoblast to alter the functional capacity of the hormone. These data demonstrate the value of endocrine biomarkers in identifying a toxic exposure to primate pregnancy many days before direct signs of reproductive toxicity were apparent. The increased EFL that occurred after exposure to TCDD might reflect a toxic response initially mediated via endocrine imbalance, leading to placental insufficiency, compromised embryonic circulation, and subsequent EFL.

Abortion, Spontaneous↗

PubMed1999

A lifelong, wide-range radiation biodosimeter: erythrocytes with transferrin receptors.

Rats exposed to 0.1-600 cGy x-rays developed significantly prolonged increases (1.9-11%) of normoblasts (red cell precursors) in the bone marrow as well as a subpopulation of transferrin receptor marked erythrocytes (E-Tr, 1.9-20%) in the blood. Several characteristics are shared in common by these two progenies of the hematopoietic stem cell (HSC): a heretofore unrecognized dose-response curve extending from 0.1-600 cGy composed of logarithmic and quadratic dose response segments, the joining of the segments at approximately 150 cGy, and an identical 29-wk period for one-half repair of the quantified cell damage. This suggests that both of these cells could be surrogates for assessing radiation injury. Preliminary findings suggest that this phenomenon is identifiable in humans.

Animals↗

PubMed1999

Regulation of sigma 54-dependent transcription by core promoter sequences: role of -12 region nucleotides.

The tetranucleotide core recognition sequence (TTGC) of the sigma 54 promoter -12 recognition element was altered by random substitution. The resulting promoter mutants were characterized in vivo and in vitro. Deregulated promoters were identified, implying that this core element can mediate the response to enhancer-binding proteins. These promoters had in common a substitution at position -12 (consensus C), indicating its importance for keeping basal transcription in check. In another screen, nonfunctional promoters were identified. Their analysis indicated that positions -13 (consensus G) and -15 (consensus T) are important to maintain minimal promoter function. In vitro studies showed that the -13 and -15 positions contribute to closed-complex formation, whereas the -12 position has a stronger effect on recognition of the fork junction intermediate created during open-complex formation. Overall the data indicate that the -12 region core contains specific subsequences that direct the diverse RNA polymerase interactions required both to produce RNA and to restrict this RNA synthesis in the absence of activation.

Consensus Sequence↗

PubMed1999

CCR5-Mediated human immunodeficiency virus entry depends on an amino-terminal gp120-binding site and on the conformational integrity of all four extracellular domains.

The human immunodeficiency virus type 1 coreceptor activity of CCR5 depends on certain polar and charged residues in its amino-terminal domain. Since studies of chimeric receptors have indicated that the extracellular loops of CCR5 are also involved in viral fusion and entry, we have explored the role of bulky, polar and nonpolar residues in these regions. Selected amino acids in the three extracellular loops were individually changed to alanines, and the coreceptor activities of the mutant CCR5 proteins were tested in a luciferase reporter virus-based entry assay. We found that the cysteines in the extracellular loops of CCR5 are essential for coreceptor activity. However, only minor (two- to threefold) effects on coreceptor function were noted for all of the other alanine substitutions. We also demonstrated that when the first 19 residues of the amino-terminal region were separated from the rest of CCR5, by insertion of glycine/serine spacers between proline 19 and cysteine 20, coreceptor function decreased. Together with our previous studies, these data indicate that both an amino-terminal gp120-binding site and extracellular domain geometry play a role in viral entry.

Amino Acid Substitution↗

PubMed1999

Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5.

The CC-chemokine receptor CCR5 mediates fusion and entry of the most commonly transmitted human immunodeficiency virus type 1 (HIV-1) strains. We have isolated six new anti-CCR5 murine monoclonal antibodies (MAbs), designated PA8, PA9, PA10, PA11, PA12, and PA14. A panel of CCR5 alanine point mutants was used to map the epitopes of these MAbs and the previously described MAb 2D7 to specific amino acid residues in the N terminus and/or second extracellular loop regions of CCR5. This structural information was correlated with the MAbs' abilities to inhibit (i) HIV-1 entry, (ii) HIV-1 envelope glycoprotein-mediated membrane fusion, (iii) gp120 binding to CCR5, and (iv) CC-chemokine activity. Surprisingly, there was no correlation between the ability of a MAb to inhibit HIV-1 fusion-entry and its ability to inhibit either the binding of a gp120-soluble CD4 complex to CCR5 or CC-chemokine activity. MAbs PA9 to PA12, whose epitopes include residues in the CCR5 N terminus, strongly inhibited gp120 binding but only moderately inhibited HIV-1 fusion and entry and had no effect on RANTES-induced calcium mobilization. MAbs PA14 and 2D7, the most potent inhibitors of HIV-1 entry and fusion, were less effective at inhibiting gp120 binding and were variably potent at inhibiting RANTES-induced signaling. With respect to inhibiting HIV-1 entry and fusion, PA12 but not PA14 was potently synergistic when used in combination with 2D7, RANTES, and CD4-immunoglobulin G2, which inhibits HIV-1 attachment. The data support a model wherein HIV-1 entry occurs in three stages: receptor (CD4) binding, coreceptor (CCR5) binding, and coreceptor-mediated membrane fusion. The antibodies described will be useful for further dissecting these events.

Alanine↗

PubMed1999

Inhibition of gap junction communication in alveolar epithelial cells by 18alpha-glycyrrhetinic acid.

Cultured alveolar epithelial cells exhibit gap junction intercellular communication (GJIC) and express regulated levels of connexin (Cx) 43 mRNA and protein. Newly synthesized radiolabeled Cx43 protein equilibrates with phosphorylated Cx43 isoforms; these species assemble to form both connexons and functional gap junction plaques. The saponin 18alpha-glycyrrhetinic acid (GA) rapidly and reversibly blocks GJIC at low concentrations (5 microM). Extended exposure to 18alpha-GA at higher concentrations causes inhibition of GJIC and time- and dose-dependent reductions in both Cx43 protein and mRNA expression. The latter toxic effects are paralleled by disassembly of gap junction plaques and are reversed less readily than acute effects on GJIC. These observations demonstrate 18alpha-GA-sensitive regulation of intercellular communication in epithelial cells from the mammalian lung and suggest a role for Cx43 expression and phosphorylation in acute and chronic regulation of GJIC between alveolar epithelial cells.

Animals↗

PubMed1999

Expression and regulation of protein inhibitor of neuronal nitric oxide synthase in ventilatory muscles.

In skeletal muscle fibers, nitric oxide (NO) is synthesized by neuronal NO synthase (nNOS) and regulates excitation-contraction coupling, glucose uptake, and mitochondrial respiration. Recently, a novel 89-amino acid protein, designated protein inhibitor of nNOS (PIN), has been shown to interact with and specifically inhibit nNOS activity. In this study, we investigated the distribution, localization, and regulation of PIN expression in ventilatory and limb muscles of various species. Amplified PIN cDNA from the rat diaphragm revealed an open reading frame identical to that of human PIN. Among muscles of adult rats, PIN mRNA was strongly expressed in muscles rich in type I fibers, whereas much weaker expression was evident in muscles rich in type II fibers. By comparison, PIN protein expression was not related to fiber-type distribution. Similarly, PIN protein was equally expressed among rat, mouse, and human diaphragms. Both PIN mRNA and PIN protein were expressed at much higher levels in the embryonic rat diaphragm than in adult muscle. Immunohistochemistry revealed that PIN protein was localized in close proximity to the sarcolemma and nuclei. PIN protein was also abundant in muscle spindles and axons of nerves supplying skeletal muscle fibers. We conclude that PIN is expressed in various skeletal muscle fibers and that its expression is regulated during muscle development. The localization of PIN in muscle regions containing abundant nNOS protein suggests that it plays a role in the regulation of NO synthesis in skeletal muscle fibers.

Amino Acid Sequence↗

PubMed1999

Maternal passive smoking during pregnancy and fetal developmental toxicity. Part 1: gross morphological effects.

1. Prenatal exposure of human fetus to tobacco smoke through maternal passive smoking has been epidemiologically linked to reduced birth weight, enhanced susceptibility to respiratory diseases and changes in immune system. However, no data exists indicating teratogenicity of involuntary smoking. Since sidestream smoke of cigarettes makes the most constituent of whole smoke inhaled by nonsmokers, we performed experiments to determine whether passive inhalation of sidestream smoke by rats causes malformations in newborns. 2. Pregnant 230 - 300 g Wistar rats were each placed in a 150 dm3 glass chamber with two holes, each 3 cm in diameter in two opposite walls to provide unforced exchange of fresh air. A third hole was connected to an automatic smoking machine. The head of a commercial filter blond cigarette (13 mg Tar, 0.9 mg Nicotine) was introduced to the chamber through this later hole. Cigarettes were smoked by smoking machine at the rate and volume resembling human smoking and the mainstream smoke was separately collected and discarded. Each rat thus received the sidestream smoke self-diluted in the chamber air. Experiments were performed with either 1, 2, 3 or 4 cigarettes/day during either first, second or third week of a total 21-day pregnancy period. The interval between smoking of cigarettes was 2 h. 3. COHb in blood of negative controls was about 1.2% and after exposure to 1 or 4 cigarettes were 6% and 12.2%, respectively. A dose-dependent reduction of birth weight was observed in newborns (P<0.001); bitemporal diameters and body lengths were reduced accordingly. No macroscopically visible gross anomaly could be observed. After removing the fat tissue and staining the skeleton with alizarin, a widespread ossification retardation could be observed in all exposed groups regardless of the dose. Such a retardation was not limited to a particular bone. 4. These results support epidemiologic data on developmental toxicity of passive smoking and further provide evidence on an unfavorable osteopathic effect of sidestream exposure of mother on fetal development.

Animals↗

PubMed1999

Maternal passive smoking during pregnancy and foetal developmental toxicity. Part 2: histological changes.

1. Evidence has been accumulating on the growth suppressing effects of maternal passive smoking on foetus. Reviewing all literature released during the last two decades and screening for all possible variables such as previous smoking history, maternal age and weight gain, parity and length of gestation, placental weight, and diet, we found no reason to doubt the role of passive smoking during pregnancy in the induction of growth retardation. However, no literature indicates whether these birthweight deficits might hint at other possible hidden abnormalities in tissues. To verify this question, we performed an experiment on rats. 2. We have already reported that pups born to rats with previous exposure to cigarette's sidestream smoke during pregnancy showed a significant and dose-dependent growth retardation. Those pregnant rats were exposed each in a 150 dm3 glass chamber to diluted sidestream smoke of either 1, 2, 3 or 4 commercial blond filter brand cigarettes during either first, second or third week of pregnancy. We have selected a part of each group of pups at random and examined for possible histological changes of lung, liver, stomach, kidney and intestinal tissues. 3. Compared to controls, lung tissues of newborns of smoke exposed mothers showed an enhanced incidence of apoptosis, mesenchymal changes, and hyperplasia of bronchial muscles. Pronounced abnormal changes in haematopoiesis and proliferation of bile duct cells were the most variations from norm observed in liver tissues of exposed pups. Immature glomeruli of kidney, epithelhypoplasia of stomach, and hypoplasia of intestinal villi were common among newborns of exposed mothers than among controls. 4. These results indicate that passive smoking upon pregnancy causes abnormal morphological changes in internal tissues of newborns. At present, we can draw no conclusion as to whether these histological changes will result in functional malformations or possibly late effects, although they should be expected.

Animals↗

PubMed1999

Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0).

Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To the best of our knowledge, only 19 such cases have been described in the literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2, three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one, myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF), one case each. Their median survival was 20 weeks. Here, we report the first case of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and intracellular MPO, but all lymphoid markers tested were negative. Conventional cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in addition to 15.1% with normal diploidy. However, Fluorescence in situ hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient died four weeks after diagnosis without therapy. In conclusion, these findings suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid disorders and heralds a bad prognosis. It may be a consequence of clonal evolution of trisomy 8.

Acute Disease↗

PubMed1999

Evaluation of the inhibition of other metalloproteinases by matrix metalloproteinase inhibitors.

Two series of compounds synthesized as specific matrix metalloproteinase (MMP) inhibitors have been evaluated for their inhibition of non-MMPs. In a series of substituted succinyl hydroxamic acids, some were found to be significant (IC50 < 1 microM) inhibitors of leucine (microsomal) aminopeptidase, neprilysin (3.4.24.11), and thermolysin. Macrocyclic compounds in which the alpha carbon of the succinyl hydroxamate is linked to the side chain of the P2' amino acid were found to be good inhibitors of aminopeptidase, but not of neprilysin or thermolysin. Compounds of neither series were found to be significant inhibitors of angiotensin converting enzyme or carboxypeptidase A.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1999

[The correlation between t(14;18) chromosomal translocation and hepatocarcinoma].

OBJECTIVE: To study the correlation between t(14;18) chromosomal translocation and the occurrence of hepatocarcinoma. METHODS: bcl-2/JH fusion gene in 54 cases of hepatocarcinoma including 40 cases of hepatocellular carcinoma(HCC) and 14 cases of cholangicellular carcinoma (CCC) were investigated using seminested in situ PCR. RESULTS: Bcl-2/JH fusion gene was present in 25% (10/40) HCC and negative in CCC. CONCLUSION: These findings indicated that t(14;18) chromosomal translocation might play a role in the pathogenesis of HCC but seemed to bear no relation with CCC. mbr and mcr are the two important breakpoints of bcl-2 gene in HCC.

Carcinoma, Hepatocellular↗

PubMed1999

[Effect of mutation (T1762A1764) on hepatitis B virus core promoter activity].

OBJECTIVE: With the knowledge that the substituted mutation of T1762A1764 in hepatitis B virus (HBV) core promoter (CP) region was the most common variation during chronic HBV infection, we proceed to study the role that the mutation T1762A1764 plays in effecting the core promoter. METHODS: Seven patients with fulminant hepatitis and one asymptomatic HBV carrier were investigated for screening T1762A1764 mutation by cloning and PCR products direct sequencing. PCR products containing HBV precore/core gene regulatory sequences were directly cloned into chloramphenicol acetyltransferase (CAT) expressing plasmid. CAT assay was done to compare CAT expressing level after transfecting into HepG2 cell line and transient expression. RESULTS: Results reveal that T1762A1764 mutation was the main factor that represses CAT expression in vitro. CONCLUSION: Among the several other variations within hepatitis B virus' core promoter region, T1762A1764 mutation has mainly affected the down-regulating activity of core promoter.

Adult↗

PubMed1999

Conversion of C57Bl/6 mice from a tumor promotion-resistant to a -sensitive phenotype by enhanced ornithine decarboxylase expression.

A transgenic mouse model was developed in which ornithine decarboxylase (ODC) can be overexpressed in a tissue-specific and regulated manner. Hair follicle keratinocytes were targeted by use of a bovine keratin 6 (K6) promoter/regulatory region, and regulation was accomplished by using the tetracycline-regulated transactivator/tetracycline-response element system. Double-transgenic mice carrying both transgenes (K6/tetracycline-regulatable transactivator protein (tTA) and tetracycline-response element/Odc) on a C57Bl/6 background had no obvious phenotypic abnormalities in the absence (Odc transgene-expressed) of doxycycline (a tetracycline analog) in the drinking water. However, induction of K6-driven tTA expression by the tumor promoter (12-O-tetradecanoylphorbol-13-acetate) (TPA) led to very high levels of epidermal ODC activity and robust hyperplasia, especially involving hair follicles. Both effects were abolished by inclusion of doxycycline in the drinking water to repress transgene expression. Finally, the number of papillomas that developed in a standard (7,12-dimethybenz[a]anthracene) (DMBA)/TPA protocol was greatly reduced in mice in which transgenic Odc expression was repressed by doxycycline. Our results demonstrated that the higher levels of ODC expression produced in the transgenic model in the induced versus the repressed condition make the normally promotion-resistant C57Bl/6 strain much more sensitive to the short-term and long-term (i.e., tumor-promoting) effects of TPA.

Animals↗

PubMed1999

[Mapping the gene responsible for Smith-Fineman-Myers syndrome to Xq25].

OBJECTIVE: To map and eventually identify the gene responsible for Smith-Fineman-Myers syndrome. METHODS: The short tandem repeat markers(STRs) distributed on X chromosome at 8-10cM interval were used in the initial mapping to look for the candidate region for Smith-Fineman-Myers syndrome locus and the linked marker. The additional STRs flanking the linked marker were tested to confirm the candidate region and decide the interval of disease gene. RESULTS: Thirteen DNA samples from a Chinese family with Smith-Fineman-Myers syndrome were genotyped using 20 polymorphic STRs which cover the whole X chromosome. Of 20 STRs, DXS1001 on Xq25 suggested linkage and yielded a lod score of 3.01 at straight theta = 0 additional STRs flanking DXS1001 were tested. Fourteen polymorphic STRs out of 27 confirmed that Smith-Fineman-Myers syndrome locus is linked to several markers on Xq25. Haplotype analysis placed the disease locus within a 14.6cM interval bounded by DXS8064 and DXS8050. CONCLUSION: The gene responsible for Smith-Fineman-Myers syndrome is mapped to a 14.6cM interval between DXS8064 and DXS8050 on Xq25. This result will be helpful for the identification of disease gene.

Abnormalities, Multiple↗