[Traditional Chinese medicine in comprehensive therapy of neoplasm].
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Antineoplastic Agents, Phytogenic↗
Biomedical subjects
Y Sun
Publications and source records attributed to Y Sun.
Nonatomic games on Loeb spaces.
In the setting of noncooperative game theory, strategic negligibility of individual agents, or diffuseness of information, has been modeled as a nonatomic measure space, typically the unit interval endowed with Lebesgue measure. However, recent work has shown that with uncountable action sets, for example the unit interval, there do not exist pure-strategy Nash equilibria in such nonatomic games. In this brief announcement, we show that there is a perfectly satisfactory existence theory for nonatomic games provided this nonatomicity is formulated on the basis of a particular class of measure spaces, hyperfinite Loeb spaces. We also emphasize other desirable properties of games on hyperfinite Loeb spaces, and present a synthetic treatment, embracing both large games as well as those with incomplete information.
Journal Article↗
Interleukin-13, in combination with anti-interleukin-12, increases graft prolongation after portal venous immunization with cultured allogeneic bone marrow-derived dendritic cells.
Portal venous (pv) transfusion before transplant with large numbers (100 x 10(6)) of irradiated multiple minor histoincompatible spleen cells (B10.Br) augments allogeneic skin graft survival in C3H mice. We have shown in earlier studies that this is correlated with preferential activation for production of type 2 cytokines (interleukin [IL]-4 and IL-10) and decreased production of type 1 cytokines (IL-2 and interferon [IFN] gamma). We have also shown that recombinant (r)IL-12, in association with anti-IL-10 monoclonal antibody, can reverse in vivo the graft prolongation afforded by pv immunization and the altered cytokine production that follows. Adoptive transfer of inhibition of graft rejection is possible at early times after pv immunization, using plastic adherent cells obtained from the liver of treated mice. We show below that within 4 days of pv immunization, dendritic cells (NLDC-145+) isolated from the thymus, mesenteric lymph node (MLN), and.
Adoptive Transfer↗
Apolipoprotein E-containing high density lipoprotein promotes neurite outgrowth and is a ligand for the low density lipoprotein receptor-related protein.
Presence of the epsilon4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD), although the mechanism(s) by which it confers this risk is unknown. ApoE may play a direct role in AD neuropathology by modulating neuronal structure. We previously showed that apoE3-containing beta-very low density lipoprotein (beta-VLDL) can stimulate neurite outgrowth to a significantly greater extent than apoE4-enriched beta-VLDL in a central nervous system-derived neuronal cell line and that this effect is mediated by interaction with the low density lipoprotein receptor-related protein (LRP). To determine whether similar differences exist when apoE is associated with other lipoprotein particles, the effects of high density lipoprotein (HDL) derived from plasma and cerebrospinal fluid were defined. ApoE3-enriched HDL significantly enhanced neurite outgrowth as compared with apoE4-enriched HDL, and the majority of this stimulation was blocked in the presence of the receptor-associated protein or a neutralizing antibody to LRP. We also found that cholesterol esterification in the presence of apoE-containing plasma HDL was attenuated in fibroblasts lacking LRP. Therefore, apoE-containing HDL can serve as an LRP ligand, and apoE isoform-specific effects on neurite outgrowth are observed when HDL is the carrier particle.
Apolipoproteins E↗
Identification of a factor IX binding site on the third apple domain of activated factor XI.
Activated factor XI (factor XIa) participates in blood coagulation by activating factor IX. Previous work has demonstrated that a binding site for factor IX is present on the noncatalytic heavy chain of factor XIa (Sinha, D., Seaman, F. S., and Walsh, P. N. (1987) Biochemistry 26, 3768-3775). Recombinant factor XI proteins were expressed in which each of the four apple domains of the heavy chain (designated A1 through A4) were individually replaced with the corresponding domain from the homologous but functionally distinct protease prekallikrein (PK). To identify the site of factor IX binding, the chimeric proteins were activated with factor XIIa and tested for their capacity to activate factor IX in plasma coagulation and purified protein assays. The chimera with the substitution in the third apple domain (factor XI/PKA3) had <1% of the coagulant activity of wild type factor XIa in a plasma coagulation assay, whereas the chimeras with substitutions in A1, A2, and A4 demonstrated significant activity (68-140% of wild type activity). The Km for activation of factor IX by factor XIa/PKA3 (12. 7 microM) is more than 30-fold higher than the Km for activation by wild type factor XIa or the other factor XI/PK chimeras (0.11-0.37 microM). Two monoclonal antibodies (2A12 and 11AE) that recognize epitopes on the factor XI A3 domain were potent inhibitors of factor IX activation by factor XIa, whereas antibodies against the A2 (1A6) and A4 (3G4) domains were poor inhibitors. The data indicate that a binding site for factor IX is present on the third apple domain of factor XIa.
Antibodies, Monoclonal↗
Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome.
To study the pathogenesis of central nervous system abnormalities in Down syndrome (DS), we have analyzed a new genetic model of DS, the partial trisomy 16 (Ts65Dn) mouse. Ts65Dn mice have an extra copy of the distal aspect of mouse chromosome 16, a segment homologous to human chromosome 21 that contains much of the genetic material responsible for the DS phenotype. Ts65Dn mice show developmental delay during the postnatal period as well as abnormal behaviors in both young and adult animals that may be analogous to mental retardation. Though the Ts65Dn brain is normal on gross examination, there is age-related degeneration of septohippocampal cholinergic neurons and astrocytic hypertrophy, markers of the Alzheimer disease pathology that is present in elderly DS individuals. These findings suggest that Ts65Dn mice may be used to study certain developmental and degenerative abnormalities in the DS brain.
Aging↗
Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression.
Porcine pancreatic islets were microencapsulated in alginate-polylysine-alginate capsules and transplanted intraperitoneally into nine spontaneously diabetic monkeys. After one, two, or three transplants of 3-7 x 10(4) islets per recipient, seven of the monkeys became insulin independent for periods ranging from 120 to 804 d with fasting blood glucose levels in the normoglycemic range. Glucose clearance rates in the transplant recipients were significantly higher than before the graft administration and the insulin secretion during glucose tolerance tests was significantly higher compared with pretransplant tests. Porcine C-peptide was detected in all transplant recipients throughout their period of normoglycemia while none was found before the graft administration. Hemoglobin A1C levels dropped significantly within 2 mo after transplantation. While ketones were detected in the urine of all recipients before the graft administration, all experimental animals became ketone free 2 wk after transplantation. Capsules recovered from two recipients 3 mo after the restoration of normoglycemia were found physically intact with enclosed islets clearly visible. The capsules were free of cellular overgrowth. Examination of internal organs of two of the animals involved in our transplantation studies for the duration of 2 yr revealed no untoward effect of the extended presence of the microcapsules.
Animals↗
Spectral hole burning of Eu2+ in CaF2.
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Journal Article↗
Combination chemotherapy and photodynamic therapy with N-(2-hydroxypropyl) methacrylamide copolymer-bound anticancer drugs inhibit human ovarian carcinoma heterotransplanted in nude mice.
This study characterizes the efficacy and toxicity of: (a) free Adriamycin and N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-Adriamycin conjugate (P-A); (b) free and HPMA copolymer-meso-chlorin e6 monoethylene diamine disodium salt (Mce6) conjugate (P-C) and light-induced photodynamic therapy; and (c) combinations of the HPMA copolymer conjugates (P-A and P-C) in the destruction of human epithelial ovarian carcinoma heterotransplanted in the nude mouse (OVCAR-3). Eight-week-old female nu/nu mice were injected in both flanks with 0.04-0.05 cm3 OVCAR-3 solid tumor dispersed in media. When bilateral tumors reached a minimum volume of 0.18 cm3 (one axis, 2.0-mm minimum) and demonstrated consistent growth, the experiments were initiated. Drugs were given i.v. unless otherwise noted. Tumor-bearing mice were allocated to the following protocols: (a) Adriamycin at 1 mg/kg, P-A at 30 mg/kg (2.2 mg/kg Adriamycin equivalent), and controls (n = 6 each); (b) Mce6 and light (2 h after administration: 650 nm light for 15 min to deliver 220 J/cm2) at 1.25, 2.5, 5, and 10 mg/kg (n = 6 each), 2.5 mg/kg i.p. (n = 4), and controls (n = 6); (c) P-C at 12.5, 25, and 75 mg/kg (1.5, 2.9, and 8.7 mg/kg Mce6 equivalent, respectively with light (18 h after administration; 650 nm light for 15 min to deliver 220 J/cm2), P-C at 25 mg/kg (2.9 mg/kg Mce6 equivalent) with no light administration, and controls (n = 7 each); and (d) a combination of P-A (30 mg/kg, 2.2 mg/kg adriamycin equivalent) and P-C (12.5 and 75 mg/kg, 1.5 mg/kg and 8.7 mg/kg Mce6 equivalent, respectively) with and without light (n = 7 each; 18 h after administration; 650 nm light for 15 min to deliver 220 J/cm2) and controls (n = 12). Tumor volumes and animals weights were assessed for significant differences from the treated and controls groups by Student's t test. Adriamycin (1 mg/kg) and P-A (30 mg/kg. 2.2 mg/kg Adriamycin equivalent) caused less than a 10% weight loss, and treated tumor volumes (day 10-32) were significantly less than those of controls (all P < 0.045). Mce6 (2.5-10 mg/kg i.v.), caused tumor regression in 80% of tumors and a shock syndrome in 17-83%. i.p. dosing (2.5 mg/kg) was uniformly fatal. Mce6 at 1.25 mg/kg did not show reproducible efficacy. P-C with light (25 and 75 mg/kg, 2.9 and 8.7 mg/kg Mce6 equivalent, respectively) demonstrated significant tumor destruction (P < 0.003) but not complete ablation. The combinations of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) plus P-C (12.5 and 75 mg/kg; 1.5 mg/kg and 8.7 mg/kg of Mce6 equivalent, respectively) with light resulted in tumor volumes that were significantly less than control tumor volumes and the tumor volumes of mice receiving either P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) or P-C with light (12.5 or 75 mg/kg. 1.5 or 8.7 mg/kg Mce6 equivalent, respectively) alone (all P < 0.02). P-C (75 mg/kg, 8.7 mg/kg Mce6 equivalent) added to P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) resulted in complete tumor ablation. Free Mce6 demonstrates a narrow margin of safety, which is extended by incorporation into HPMA copolymers. P-A demonstrates safety and efficacy in vivo. The combined chemotherapy and photodynamic therapy of P-A (30 mg/kg, 2.2 mg/kg Adriamycin equivalent) with P-C and light (12.5 and 75 mg/kg 1.5 and 8.7 mg/kg Mce6 equivalent, respectively) was nontoxic and allowed us to attain a significant improvement in tumor cures than those obtained by P-A or P-C with light alone.
Animals↗
Molecular cloning of the human immunodeficiency virus subtype 2 strain HIV-2UC2.
An infectious molecular clone was derived from the HIV-2UC2 isolate that previously was found to persistently infect and induce an AIDS-like disease syndrome in baboons. The molecularly cloned virus (HIV-2UC2mc) showed in vitro properties similar to those of the parental isolate with regard to T-cell tropism, cytopathicity, and the ability to infect primary baboon PBMC. Nevertheless, when inoculated into two baboons, the cloned virus showed a limited ability to replicate in these animals. DNA sequence analysis revealed a defective vpr gene in the UC2mc as well as in the pathogenic parental UC2 strain. Thus, the vpr gene is not required for the induction of disease in baboons. The attenuated infectious molecular clone of UC2 should be useful for future studies designed to map the genetic determinants of HIV-2 pathogenesis in the baboon model and to evaluate vaccine strategies.
Animals↗
Spectral hole burning in Eu3+-doped highly porous gamma -aluminum oxide.
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Journal Article↗
Proteolytic processing patterns of prosaposin in insect and mammalian cells.
Prosaposin is a multifunctional protein encoded at a single locus in humans and mice. The precursor contains, in tandem, four glycoprotein activators or saposins, termed A, B, C, and D, that are essential for specific glycosphingolipid hydrolase activities. Prosaposin appears to be a potent neurotrophic factor. To explore the proteolytic processing from prosaposin to mature activator proteins, metabolic labeling was done with human prosaposin expressed in insect cells, human fibroblasts, neuronal stem cells (NT2) and retinoic acid-differentiated NT2 neurons. In all cell types, the major processing pathway was through a tetrasaposin, A-B-C-D, from which saposin A was then removed. In mammalian cells monosaposins were derived from the trisaposin B-C-D by cleavage to the disaposins, B-C and C-D, that were processed to monosaposins. In insect cells the major end products were the disaposins, with A-B and C-D derived from the tetrasaposin, A-B-C-D, or with B-C and C-D derived from the trisaposin, B-C-D. In insect and mammalian cells, the nonsignal NH2-terminal peptide preceding saposin A (termed Nter) was usually removed prior to saposin A cleavage. In NT2-derived differentiated neurons, precursor tetrasaposins containing A-B-C-D were secreted with and without Nter. Immunofluorescence studies using prosaposin-specific antisera showed large steady state amounts of uncleaved prosaposin in Purkinje cells, cortical neurons, and other specific cell types in adult mice. These studies indicate that prosaposin processing is highly regulated at a proteolytic level to produce prosaposin, tetrasaposins, or mature monosaposins in specific mammalian cells.
Animals↗
Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes.
Macrophage stimulating protein (MSP) is a chemotactic factor for murine peritoneal macrophages. The receptor for human MSP was recently identified as the ron gene product, a transmembrane protein tyrosine kinase cloned from a human keratinocyte cDNA library. Here we report that MSP induced proliferation of murine primary keratinocytes and established keratinocyte cell lines in a concentration-dependent manner. The growth efficacy of MSP was comparable to that of epidermal growth factor and keratinocyte growth factor. In three of four cell lines tested in a chemotaxis chamber, MSP also stimulated migration of keratinocytes on a collagen type IV substratum. The action of MSP was mediated by specific binding of MSP to the STK gene product, a murine homologue of the RON MSP receptor. Binding of MSP to keratinocyte STK induced phosphorylation of the 150 kDa STK beta chain. Herbimycin A, a protein tyrosine kinase inhibitor, blocked MSP-mediated phosphorylation of the STK receptor as well as proliferation of keratinocytes, suggesting the importance of tyrosine kinase activity for transduction of the message delivered by MSP. Previously, the only known target cell for MSP was the resident peritoneal macrophage. These studies establish the keratinocyte as a new target cell for MSP. The action of MSP on keratinocytes may have implications for tissue repair, wound healing, and tumor growth.
Animals↗
Observation of a three-dimensional vortex-line liquid in a highly c-axis-oriented (Bi,Pb)2Sr2Ca2Cu3Ox silver-sheathed tape.
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Journal Article↗
The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.
We examined the ability of chemokine receptors and related G protein-coupled receptors to facilitate infection by primary, clinical HIV-1 isolates. CCR5, when expressed along with CD4, the HIV-1 receptor, allowed cell lines resistant to most primary HIV-1 isolates to be infected. CCR3 facilitated infection by a more restricted subset of primary viruses, and binding of the CCR3 ligand, eotaxin, inhibited infection by these isolates. Utilization of CCR3 and CCR5 on the target cell depended upon the sequence of the third variable (V3) region of the HIV-1 gp120 exterior envelope glycoprotein. The ability of various members of the chemokine receptor family to support the early stages of HIV-1 infection helps to explain viral tropism and beta-chemokine inhibition of primary HIV-1 isolates.
Acquired Immunodeficiency Syndrome↗
Functional organization of saposin C. Definition of the neurotrophic and acid beta-glucosidase activation regions.
Saposin C is an essential co-factor for the hydrolysis of glucosylceramide by acid beta-glucosidase in mammals. In addition, prosaposin promotes neurite outgrowth in vitro via sequences in saposin C. The regional organization of these neurotrophic and activation properties of saposin C was elucidated using recombinant or chemically synthesized saposin Cs from various regions of the molecule. Unreduced and reduced proteins were analyzed by electrospray-mass spectrometry to establish the complement of disulfide bonds in selected saposin Cs. Using saposin B as a unreactive backbone, chimeric saposins containing various length segments of saposin B and C localized the neurotrophic and acid beta-glucosidase activation properties to the carboxyl- and NH2-terminal 50% of saposin C, respectively. The peptide spanning residues 22-31 had neurotrophic effects. Molecular modeling and site-directed mutagenesis localized the activation properties of saposin C to the region spanning residues 47-62. Secondary structure was needed for retention of this property. Single substitutions of R and S at the conserved cysteines at 47 or 78 diminished but did not obliterate the activation properties. These results indicate the segregation of neurotrophic and activation properties of saposin C to two different faces of the molecule and suggest a topographic sequestration of the activation region of prosaposin for protection of the cell from adverse hydrolytic activity of acid beta-glucosidase.
Amino Acid Sequence↗
Indium (III) and gallium (III) complexes of bis(aminoethanethiol) ligands with different denticities: stabilities, molecular modeling, and in vivo behavior.
Complexes of Ga(III) and In(III) radionuclides are widely used in diagnostic imaging. In this study, the following ligands of denticities 4, 5, and 6 respectively were prepared: N,N'-bis-(2,2-dimethyl-2-mercaptoethyl) ethylenediamine (4SS), 1-carboxy-N-N'-bis(2,2-dimethyl-2- mercaptoethyl)ethylenediamine (5SS), and N,N'-bis(2,2- dimethyl-2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid (6SS). Syntheses of the two new ligands, 5SS and 6SS, are described. Equilibrium constants for their In(III) and Ga(III) complexes were determined by both direct and ligand-competitive potentiometric methods. The formation constant (KML = [ML]/[M][L]) of In(III)--6SS in 0.100 M KNO3 at 25.0 degrees C is 10(39.8), and its pM at physiological pH (7.4 with 100% excess of the ligand) is 30.9. These values are higher than those of any other previous reported ligand for In(III). The stability constants of the complexes of 4SS, 5SS, 6SS, and the analogous ligand EDDASS, N,N'-bis(2-mercaptoethyl) ethylenediamine-N,N'-diacetic acid, which does not contain gem-dimethyl groups, are compared. The thermodynamic stabilities of the In(III) complexes of all ligands except 6SS are greater than those of the corresponding Ga(III) complexes. The presence of the geminal dimethyl groups in 6SS increased the stability of the Ga(III) and In(III) complexes over those of EDDASS. The effects of the gem-dimethyl groups on complex stabilities are explained by molecular modeling. The serum stabilities and biodistributions out to 1 h postinjection of 67/68Ga and 111In chelates of 4SS, 5SS, and 6SS were measured and compared with those of EDDASS. The 67/68Ga- and 111In-ligand complexes with more donor atoms showed were more stable in serum, both in vitro and in vivo. The biodistributions of the 67/68Ga- and 111In-ligand complexes exhibited distinct trends. None of the 67/68Ga- and 111In-chelates demonstrated significant heart or brain uptake. The majority of uptake for all compounds was in the liver and kidney. The degree of clearance through the liver corresponded to the thermodynamic stability of the complex. Correlations between in vivo behavior, molecular modeling data, and thermodynamic stability of the complexes are discussed.
Animals↗
Dual roles of sphingolipids in signaling of the escape from and onset of apoptosis in a mouse cytotoxic T-cell line, CTLL-2.
In our previous study, the sphingosine-like immunosuppressant, ISP-1, was found to suppress the proliferation of an interleukin-2-dependent cytotoxic T cell line, CTLL-2, through the inhibition of serine palmitoyltransferase, which catalyzes the committed step of sphingolipid biosynthesis. Analysis of the effect of ISP-1 by flow cytometry revealed that the ISP-1-dependent decrease in cell number was not due to inhibition of the cell cycle progression of CTLL-2 cells but to the induction of apoptosis of the cells. The ISP-1-induced apoptosis was inhibited by the addition of sphingosine (2 microM), suggesting that this ISP-1-induced apoptosis is triggered by the decrease in the intracellular levels of sphingolipids caused by the inhibition of serine palmitoyltransferase. However, another interleukin-2-dependent cell line, F7, which was derived from a mouse pro-B cell line, did not show ISP-1-dependent apoptosis, indicating that the effect of ISP-1 may be specific for a certain type of T cell lineage such as CTLL-2. On the other hand, a high dose of sphingosine (5 microM) by itself induced the apoptosis of CTLL-2 cells. This sphingosine-dependent apoptosis was also observed with F7 cells. These results provide evidence that the intracellular levels of sphingolipids play an important role in the signaling of the escape from and onset of apoptosis of CTLL-2 cells.
Acyltransferases↗