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Biomedical subjects

Y Cao

Publications and source records attributed to Y Cao.

At least 271 records · Page 15Linked to original sources
PubMed1998

CD8+ T cells inhibit immunoglobulin E synthesis in low responder SJL/J mice.

In an effort to examine the basis for low IgE responsiveness of SJL/J strain mice, we analysed the profiles of cytokines, such as interleukin-2 (IL-2), IL-4 and interferon-gamma (IFN-gamma), in SJL/J and A.SW/SnJ mice following immunization. Splenocytes of ovalbumin (OVA)-immunized SJL/J mice, secreted significantly higher levels of IL-4 and lower levels of IFN-gamma than those of A.SW/SnJ mice. A time-course analysis of cytokine expression in in vitro cultures of spleen cells indicated that the levels of IL-4 and IL-2 remained persistently high throughout in the cultures of SJL/J splenocytes as opposed to those of A.SW/SnJ. Depletion of CD4+ T cells in vivo suppressed the production of IL-2, IL-4 and IFN-gamma suggesting that CD4 T cells are the producers of most cytokines in both SJL/J and A.SW/SnJ mice. Depletion of CD8+ T cells in vivo not only induced productive epsilon transcript but also enhanced IgE production in SJL/J mice. Moreover, CD8 depletion in SJL/J mice led to decreased production of IFN-gamma, resulting in a net decrease in the ratio of IFN-gamma to IL-4. A similar shift in the IFN-gamma/IL-4 ratio was found in splenocytes of SJL/J mice following irradiation, which is known to enhance IgE synthesis in these mice. Taken together, it is concluded that low IgE responsiveness in SJL/J mice is not due to a defect in IL-4 production per se. Increased IFN-gamma production by the CD8+ T cells inhibits class switch and suppresses IgE antibody production in SJL/J mice.

Animals↗
PubMed1998

Physiological factors affecting protein expression of flavin-containing monooxygenases 1, 3 and 5.

1. The mouse and rat exhibit substantial differences in the gender expression of flavin-containing monooxygenase (FMO) forms. Hepatic FMO1 is gender-dependent in both species, selective to the male in rat, female in mouse. Human FMO1 is nearly undetectable. FMO3 in mouse is gender-specific to the female, but gender-independent in rat and man. FMO5 is gender-independent for mouse, rat and man. 2. Gender differences in substrate metabolism do not reflect overall FMO or isoform differences. Methimazole, imipramine and thiobenzamide are much better substrates for FMO1 than for FMO3 or FMO5. 3. Activities of microsomal samples toward these substrates reflect the relative abundance of FMO1. Hepatic samples show a 3-fold greater activity toward methimazole in the female mouse and male rat. Human microsomal samples show minimal activity. 4. Developmentally, FMO1 and FMO5 are expressed in foetuses as early as gestation days 15 and 17 and equally between genders until puberty. FMO3 is not found until 2 weeks post-partum and is found equally in the male and female until 6 weeks post-partum when it becomes undetectable in the male. 5. An event takes place after birth but before puberty that confers the ability to produce FMO3. The developmental pattern observed for mouse FMO3 is similar to human FMO3.

Adult↗
PubMed1998

Longitudinal and cross-sectional analysis of cytotoxic T lymphocyte responses and their relationship to vertical human immunodeficiency virus transmission. ARIEL Project Investigators.

The ARIEL Project for the Prevention of HIV Transmission from Mother to Infant was established to evaluate virologic and immunologic parameters during vertical transmission. To determine the strength and breadth of the cytotoxic T lymphocyte (CTL) response and its correlation with human immunodeficiency virus (HIV) transmission, a cross-sectional study was done of 31 HIV-infected pregnant women, of whom 15 transmitted and 16 did not transmit HIV to their infants. The precursor frequencies of CTL specific for HIV-1 gag, pol, nef, and env from 5 different isolates of the clade B of HIV-1 were determined by limiting dilution analysis. Results showed that variable levels of HIV-specific CTL response were present in HIV-infected pregnant women during and after pregnancy. In addition, CTL precursor frequencies specific for pol and nef were higher during pregnancy in nontransmitters than in transmitters. Thus, CTL responding to different HIV antigens may not be contributing equally to the prevention of vertical transmission.

Adult↗
PubMed1998

Preponderance of slightly deleterious polymorphism in mitochondrial DNA: nonsynonymous/synonymous rate ratio is much higher within species than between species.

We estimated synonymous (dN) and nonsynonymous (dS) substitution rates for protein-coding genes of the mitochondrial genome from two individuals each of the species human, chimpanzee, and gorilla. The genes were analyzed both separately and in a combined data set. Pairwise sequence comparisons suggest that the dN/dS rate ratios are about 5-10 times higher in within-species comparisons than in between-species comparisons. This result is confirmed by a more rigorous likelihood ratio test, which rejected the null hypothesis that the dN/dS rate ratios are identical within and between species. The likelihood models account for the genetic code structure, transition/transversion rate ratio, and codon usage bias and are expected to produce more reliable results than the commonly used contingency test. Separate analyses of different genes show that the dN/dS rate ratios are higher within species than between species for all 13 mitochondrial genes, with the difference being statistically significant for all except three small or slowly evolving genes. Furthermore, in conserved genes, nonsynonymous rates within species tend to be higher than the between-species rates by a greater proportion than in fast-changing genes. Our findings confirm and extend earlier results obtained from smaller data sets and suggest the operation of slightly deleterious mutations throughout the mitochondrial genome in the hominoids. Implications of the results for evolutionary studies and, in particular, for studies of the origin of modern humans, are discussed.

Adenosine Triphosphatases↗
PubMed1998

The complete mitochondrial DNA sequence of the shark Mustelus manazo: evaluating rooting contradictions to living bony vertebrates.

A remarkable example of a misleading mitochondrial protein tree is presented, involving ray-finned fishes, coelacanths, lungfishes, and tetrapods, with sea lampreys as an outgroup. In previous molecular phylogenetic studies on the origin of tetrapods, ray-finned fishes have been assumed as an outgroup to the tetrapod/lungfish/coelacanth clade, an assumption supported by morphological evidence. Standard methods of molecular phylogenetics applied to the protein-encoding genes of mitochondria, however, give a bizarre tree in which lamprey groups with lungfish and, therefore, ray-finned fishes are not the outgroup to a tetrapod/lungfish/coelacanth clade. All of the dozens of published phylogenetic methods, including every possible modification to maximum likelihood known to us (such as inclusion of site heterogeneity and exclusion of potentially misleading hydrophobic amino acids), fail to place the ray-finned fishes in a biologically acceptable position. A likely cause of this failure may be the use of an inappropriate outgroup. Accordingly, we have determined the complete mitochondrial DNA sequence from the shark, Mustelus manazo, which we have used as an alternative and more proximal outgroup than the lamprey. Using sharks as the outgroup, lungfish appear to be the closest living relative of tetrapods, although the possibility of a lungfish/coelacanth clade being the sister group of tetrapods cannot be excluded.

Animals↗
PubMed1998

Searching for the closest living relative(s) of tetrapods through evolutionary analyses of mitochondrial and nuclear data.

The phylogenetic relationships of the African lungfish (Protopterus dolloi) and the coelacanth (Latimeria chalumnae) with respect to tetrapods were analyzed using complete mitochondrial genome DNA sequences. A lungfish + coelancanth clade was favored by maximum parsimony (although this result is dependent on which transition:transversion weights are applied), and a lungfish + tetrapod clade was supported by neighbor-joining and maximum-likelihood analyses. These two hypotheses received the strongest statistical and bootstrap support to the exclusion of the third alternative, the coelacanth + tetrapod sister group relationship. All mitochondrial protein coding genes combined favor a lungfish + tetrapod grouping. We can confidently reject the hypothesis that the coelacanth is the closest living relative of tetrapods. When the complete mitochondrial sequence data were combined with nuclear 28S rRNA gene data, a lungfish + coelacanth clade was supported by maximum parsimony and maximum likelihood, but a lungfish + tetrapod clade was favored by neighbor-joining. The seeming conflicting results based on different data sets and phylogenetic methods were typically not statistically strongly supported based on Kishino-Hasegawa and Templeton tests, although they were often supported by strong bootstrap values. Differences in rate of evolution of the different mitochondrial genes (slowly evolving genes such as the cytochrome oxidase and tRNA genes favored a lungfish + coelacanth clade, whereas genes of relatively faster substitution rate, such as several NADH dehydrogenase genes, supported a lungfish + tetrapod grouping), as well as the rapid radiation of the lineages back in the Devonian, rather than base compositional biases among taxa seem to be directly responsible for the remaining uncertainty in accepting one of the two alternate hypotheses.

Animals↗
PubMed1998

Effect of glutamine on methotrexate efficacy and toxicity.

OBJECTIVE: To examine the effect of oral glutamine (GLN) on the efficacy and toxicity of methotrexate (MTX). SUMMARY BACKGROUND DATA: The use of high-dose chemotherapy regimens is limited by the severity of their toxicities. Oral GLN has been shown to decrease the gut toxicity seen with MTX treatment while enhancing its tumoricidal effect. METHODS AND RESULTS: Studies were done in laboratory rats and in breast cancer outpatients. Fischer 344 rats were randomized to 48 hours of prefeeding with GLN (1 g/kg/day) or an isonitrogenous amount of glycine. Rats were killed 24 hours after receiving a 20-mg/kg intraperitoneal dose of MTX. In the GLN group, there was a threefold increase in total MTX in the tumor as compared with the control group, and this increase was in both the diglutamated and pentaglutamated MTX. Inversely, there was a significant decrease in the total polyglutamated MTX in the gut in the GLN group. Given the results of this preclinical study, the authors performed a phase I trial. Nine patients diagnosed with inflammatory breast cancer received GLN (0.5 g/kg/day) during MTX neoadjuvant therapy, escalating from doses of 40 mg/m2 to 100 mg/m2 weekly for 3 weeks, followed by a doxorubicin-based regimen. No toxicity of oral GLN was detected. No patient showed any sign of chemotherapy-related toxicity. One patient had a grade I mucositis. Except for one, all patients responded to the chemotherapy regimen. Median survival was 35 months. CONCLUSIONS: These studies suggest that GLN supplementation is safe in its administration to the tumor-bearing host receiving MTX. By preferentially increasing tumor retention of MTX over that of normal host tissue, GLN may serve to increase the therapeutic window of this chemotherapeutic age.

Adult↗
PubMed1998

Genotypic and phenotypic characterization of human immunodeficiency virus type 1 variants isolated from patients treated with the protease inhibitor nelfinavir.

Nelfinavir mesylate (formerly AG1343) is a potent and selective inhibitor of human immunodeficiency virus (HIV) protease approved for the treatment of individuals infected with HIV. Nucleotide sequence analysis of protease genes from plasma HIV type 1 (HIV-1) RNA revealed a unique aspartic acid (D)-to-asparagine (N) substitution at residue 30 (D30N) in 25 of 55 patients treated with nelfinavir for a median of 13 weeks. Although the appearance of D30N was occasionally associated with concurrent or sequential emergence of other changes (e.g., at residues 35, 36, 46, 71, 77, and 88), genotypic changes associated with phenotypic resistance to other protease inhibitors were not observed (e.g., at residues 48, 50, 82, and 84) or were only rarely observed (e.g., at residue 90). In phenotypic assays, viral isolates with high-level resistance to nelfinavir remained susceptible to indinavir, saquinavir, ritonavir, and amprenavir (formerly VX-478/141W94). Similar results were observed in phenotypic assays utilizing HIV-1 NL4-3, which contained the D30N substitution alone or in combination with substitutions at other residues (e.g., residues 46, 71, and 88). These data indicate that the initial pathway of resistance to nelfinavir is unique and suggest that individuals failing short courses of nelfinavir-containing regimens may respond to regimens containing other protease inhibitors.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Use of coreceptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type 1 is rare in vitro.

We have tested a panel of pediatric and adult human immunodeficiency virus type 1 (HIV-1) primary isolates for the ability to employ the following proteins as coreceptors during viral entry: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CXCR4, Bonzo, BOB, GPR1, V28, US28, and APJ. Most non-syncytium-inducing isolates could utilize only CCR5. All syncytium-inducing viruses used CXCR4, some also employed V28, and one (DH123) used CCR8 and APJ as well. A longitudinal series of HIV-1 subtype B isolates from an infected infant and its mother utilized Bonzo efficiently, as well as CCR5. The maternal isolates, which were syncytium inducing, also used CXCR4, CCR8, V28, and APJ.

Adult↗
PubMed1998

Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines.

We have studied 18 participants in phase I/II clinical trials of recombinant gp120 (rgp120) subunit vaccines (MN and SF-2) who became infected with human immunodeficiency virus type 1 (HIV-1) during the course of the trials. Of the 18 individuals, 2 had received a placebo vaccine, 9 had been immunized with MN rgp120, and seven had been immunized with SF-2 rgp120. Thirteen of the 18 infected vaccinees had received three or four immunizations prior to becoming infected. Of these, two were placebo recipients, six had received MN rgp120, and five had received SF-2 rgp120. Only 1 of the 11 rgp120 recipients who had multiple immunizations failed to develop a strong immunoglobulin G antibody response to the immunogen. However, the antibody response to rgp120 was transient, typically having a half-life of 40 to 60 days. No significant neutralizing activity against the infecting strain was detected in any of the infected individuals at any time prior to infection. Antibody titers in subjects infected despite vaccination and in noninfected subjects were not significantly different. Envelope-specific cytotoxic T-lymphocyte responses measured after infection were infrequent and weak in the nine vaccinees who were tested. HIV-1 was isolated successfully from all 18 individuals. Sixteen of these strains had a non-syncytium-inducing (NSI) phenotype, while two had a syncytium-inducing (SI) phenotype. NSI strains used the CCR5 coreceptor to enter CD4+ cells, while an SI strain from one of the vaccinees also used CXCR4. Viruses isolated from the blood of rgp120 vaccinees were indistinguishable from viruses isolated from control individuals in terms of their inherent sensitivity to neutralization by specific monoclonal antibodies and their replication rates in vitro. Furthermore, genetic sequencing of the env genes of strains infecting the vaccinees did not reveal any features that clearly distinguished these viruses from contemporary clade B viruses circulating in the United States. Thus, despite rigorous genetic analyses, using various breakdowns of the data sets, we could find no evidence that rgp120 vaccination exerted selection pressure on the infecting HIV-1 strains. The viral burdens in the infected rgp120 vaccine recipients were also determined, and they were found to be not significantly different from those in cohorts of placebo-vaccinated and nonvaccinated individuals. In summary, we conclude that vaccination with rgp120 has had,to date, no obvious beneficial or adverse effects on the individuals we have studied.

AIDS Vaccines↗
PubMed1998

Persistent antibody responses but declining cytotoxic T-lymphocyte responses to multiple human immunodeficiency virus type 1 antigens in a long-term nonprogressing individual with a defective p17 proviral sequence and no detectable viral RNA expression.

Long-term nonprogressor AD-18 has been infected with human immunodeficiency virus type 1 (HIV-1) for at least 16 years. During the past 5 years, he has had undetectable levels of plasma viremia, and HIV-1 cannot be isolated from him. Sequencing of proviral DNA indicates that the only HIV-1 sequences that can be identified in AD-18 have gross defects in the p17-encoding regions of the gag gene (Y. Huang, L. Zhang, and D. D. Ho, Virology 240:36-49, 1998). However, AD-18 has strong, sustained antibody responses to several HIV-1 antigens, including p17. Cytotoxic T-lymphocyte responses to Env and Gag antigens have gradually diminished over the past 4 years, at a time when the titers of antibodies to the same proteins have remained stable. We discuss what these observations might mean for the generation and maintenance of immunological memory.

Dendritic Cells↗
PubMed1998

Modulation of t1alpha expression with alveolar epithelial cell phenotype in vitro.

T1alpha is a recently identified gene expressed in the adult rat lung by alveolar type I (AT1) epithelial cells but not by alveolar type II (AT2) epithelial cells. We evaluated the effects of modulating alveolar epithelial cell (AEC) phenotype in vitro on T1alpha expression using either soluble factors or changes in cell shape to influence phenotype. For studies on the effects of soluble factors on T1alpha expression, rat AT2 cells were grown on polycarbonate filters in serum-free medium (MDSF) or in MDSF supplemented with either bovine serum (BS, 10%), rat serum (RS, 5%), or keratinocyte growth factor (KGF, 10 ng/ml) from either day 0 or day 4 through day 8 in culture. For studies on the effects of cell shape on T1alpha expression, AT2 cells were plated on thick collagen gels in MDSF supplemented with BS. Gels were detached on either day 1 (DG1) or day 4 (DG4) or were left attached until day 8. RNA and protein were harvested at intervals between days 1 and 8 in culture, and T1alpha expression was quantified by Northern and Western blotting, respectively. Expression of T1alpha progressively increases in AEC grown in MDSF +/- BS between day 1 and day 8 in culture, consistent with transition toward an AT1 cell phenotype. Exposure to RS or KGF from day 0 prevents the increase in T1alpha expression on day 8, whereas addition of either factor from day 4 through day 8 reverses the increase. AEC cultured on attached gels express high levels of T1alpha on days 4 and 8. T1alpha expression is markedly inhibited in both DG1 and DG4 cultures, consistent with both inhibition and reversal of the transition toward the AT1 cell phenotype. These results demonstrate that both soluble factors and alterations in cell shape modulate T1alpha expression in parallel with AEC phenotype and provide further support for the concept that transdifferentiation between AT2 and AT1 cell phenotypes is at least partially reversible.

Animals↗
PubMed1998

Summary report on the ISOBM TD-6 workshop: analysis of 20 monoclonal antibodies against Sialyl Lewisa and related antigens. Montreux, Switzerland, September 19-24, 1997.

The ISOBM TD-6 Workshop is the first international workshop on monoclonal antibodies against the Sialyl Lewisa (SLea) antigen. Eight research groups participated in a blind study to characterize the epitope binding, relative affinity and performance in immunoradiometric assays, of a panel of 20 monoclonal antibodies. The antibodies were tested against a diverse panel of neoglycoconjugates, purified antigens and human serum pools from gastrointestinal malignancies. Epitope specificities were determined for the majority of antibodies in the panel. Cross-reactivity with related saccharide structures was noted in several antibodies. Overall, the results of the TD-6 Workshop show further development of SLea immunoassays may yield yet more specific assays for the detection and management of gastrointestinal and other malignancies.

Antibodies, Monoclonal↗
PubMed1998

Immunohistochemical characterization of a panel of 56 antibodies with normal human small intestine, colon, and breast tissues.

The epithelial mucin MUC1 is heavily but differently glycosylated depending on the origin and developmental status of the tissue, which greatly influences the reactivity of monoclonal antibodies (MAbs). A partial characterization of their epitopes is possible by mild, carbohydrate-specific periodate oxidation of tissue sections prior to immunostaining. Using this strategy, we have evaluated 56 MAbs submitted to the ISOBM TD-4 (MUC1) Workshop. Paraffin sections from normal human small intestine, colon and breast were immunostained at different defined antibody concentrations either directly or after oxidation with 20 mM periodate at pH 5 for 30 min (PO). In addition, monolayers of T-47D breast cancer cells without PO treatment were examined in immunofluorescence. The array of observed reactivities allowed us to classify the MAbs as follows. Fourteen antibodies were found to detect MUC1 largely independent of the degree of glycosylation, and are therefore classified as pan-MUC1 MAbs (Group A). Twenty-four MAbs were nonreactive with one or more types of the examined epithelia, but became reactive after PO of the tissue sections. We have called these differentiation-dependent MUC1 MAbs (Group B). They might be especially valuable in histological tumour diagnosis. According to their differential staining behaviour towards untreated small intestine, colon, and breast tissue sections, we divided these MAbs into 4 subtypes (Group B1 through Group B4). A further group of six MAbs detected PO-sensitive carbohydrate epitopes (Group C). A seventh antibody apparently also belongs to Group C by immunohistological criteria, although its corresponding epitope was not PO-sensitive. Three further MAbs are still unclear in their specificity, and another 2 are not MUC1-specific (Group D). Six preparations were found nonreactive with the examined tissues; 4 of these were also negative with T-47D cells. Generally, a broad spectrum of different immunohistological patterns has emerged which appears to be widely independent of the type of epitope (sequence versus conformational, length of sequence) and the relative affinities determined in vitro.

Antibodies, Monoclonal↗
PubMed1998

Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis.

BACKGROUND AND PURPOSE: Studies of cerebral activation of motor function after ischemic stroke may enhance our understanding of the underlying mechanisms of motor functional recovery, including the role of the noninfarcted hemisphere. METHODS: Eight right-handed recovering hemiparetic or hemiplegic patients were studied using functional MRI. Results were evaluated for each patient to consider individual variability in original functional organization, neuroanatomy, infarct size and extent, treatment, age, and sex. The results were also pooled as a group for comparison with a control group of eight right-handed normal subjects. RESULTS: In six of eight stroke patients, extended activation in ipsilateral sensorimotor cortex was observed during paretic hand movements. Bilateral activation of the primary sensorimotor cortex was recorded in three of these six patients; ipsilateral activation alone was recorded in the remaining three patients. Only two patients had mild synkinesia. Furthermore, in two male patients, the paretic hand movements activated extended areas of ipsilateral premotor and dorsolateral prefrontal cortex, when compared with normal subjects. In two patients with left frontal infarction, profound activation in the right supramarginal gyrus and in the right premotor cortex was observed during the ipsilateral paretic hand movements. CONCLUSIONS: Synkinesia alone cannot explain the extent of ipsilateral activation in primary sensorimotor cortex. The explanation offered for our findings is that preexisting uncrossed motor neural pathways may be accessed or recruited to compensate for damage to the crossed motor pathways after ischemic stroke.

Adult↗
PubMed1998

Comparative study of the use of poly(glycolic acid), calcium alginate and pluronics in the engineering of autologous porcine cartilage.

New cartilage formation has been successfully achieved by technology referred to as tissue engineering. Polymers and hydrogels such as poly(glycolic acid), calcium alginate, and poly(ethylene) and poly(propylene) hydrogels have been used as cell carriers to regenerate cartilage in the nude mouse model. The next step toward human applications of engineered cartilage is to demonstrate their potential in immunocompetent animal models. This study compared the suitability of three polymers for generating tissue engineered elastic cartilage using autologous cells in an immuno-competent porcine animal model. Auricular cartilage was obtained from pigs. Chondrocytes were isolated onto fiber based poly(glycolic acid) (PGA) scaffolds or suspended in calcium alginate or pluronic F127 gel at constant concentrations. Chondrocyte-polymer constructs were either implanted (PGA) or injected (calcium alginate and pluronic) as autologous implants subcutaneously into the pigs from which the cells had been isolated. Specimens were harvested and analyzed grossly and historically after 6 weeks in vivo. All explants demonstrated cartilage formation to a variable degree. When using PGA or calcium alginate, the overall histological appearance of the tissue formed is that of fibrocartilage with thick bundles of collagen dispersed in the tissue. When using pluronics as scaffold, histologic features resemble those of native elastic cartilage, showing a more organized arrangement of the cells, which seems to correlate to functional properties as elastin presence in the tissue engineered cartilage. Elastic cartilage engineered in an immunocompetent animal model varies with the type of polymer used. The behavior of the cell-polymer constructs is not fully understood and outcome seems to be related to several factors, including inflammatory reaction. Further studies with similar models are needed to determine the feasibility of engineering tissue generated from different cell-polymer constructs prior to human application.

Alginates↗
PubMed1998

MRI of the occipital cortex, red nucleus, and substantia nigra during visual aura of migraine.

The authors report a patient with migraine in whom they measured brain oxygenation indirectly during a visual aura by means of T2-weighted MRI. An aura of left homonomous quadrantanopia was accompanied by increased T2-weighted contrast intensity of bilateral regions in the occipital cortex, and the red nucleus and substantia nigra bilaterally. The mechanisms of these changes remain to be determined, but in this patient the migraine aura was associated with probable hyperoxia and not cerebral ischemia.

Adult↗