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T Liu

Publications and source records attributed to T Liu.

At least 415 records · Page 23Linked to original sources
PubMed1993

Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia.

Cytokine-induced neutrophil chemoattractant (CINC), originally identified as a chemoattractant in rat kidney epithelial cells, is related to human 'gro' and murine 'KC'. The proteins encoded by these genes belong to the chemokine alpha superfamily, most of which have neutrophil chemotactic activity. Since brain chemokines may play a significant role in neutrophil accumulation in cerebral ischemia which can contribute to the extent of tissue injury in stroke, we examined the expression of CINC mRNA in the cerebral cortex of rats subjected to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Significant CINC mRNA expression was observed in the ipsilateral (ischemic) cortex from 6 h (17.3 +/- 3.7%, n = 6, P < 0.05) to 24 h (32.1 +/- 3.7%, n = 5, P < 0.01) with a peak at 12 h (43.9 +/- 3.7%, n = 6, P < 0.01) after MCAO. Five days post-MCAO, CINC mRNA levels were no longer elevated. No significant CINC mRNA expression was observed in the contralateral (control) cortex. These studies suggest that message for the neutrophil chemoattractant CINC is induced early in brain tissue subjected to ischemia, and therefore supports the possibility that brain-derived chemokines support the infiltration of circulating inflammatory cells following focal stroke.

Animals↗
PubMed1993

A phase I clinical trial of murine monoclonal antibody D612 in patients with metastatic gastrointestinal cancer.

In a phase I study, 21 patients with metastatic adenocarcinoma of the gastrointestinal tract received the murine monoclonal antibody D612. This antibody is directed at a M(r) 48,000 antigen restrictively expressed on tumors of the gastrointestinal tract and to a limited degree on normal gastrointestinal mucosa. Patients received total doses of 10-180 mg/m2 administered as single or multiple doses of 1-100 mg/m2 over an 8-day period. Dose-limiting toxicity was secretory diarrhea. A single dose of 100 mg/m2 exceeded guidelines for maximal tolerated dose. Higher total doses were achieved in subsequent patients by using repeated administration of lower doses. Three of five patients receiving 60 mg/m2 for 3 doses (180 mg/m2 total dose) experienced grade 3 diarrhea and could not complete the prescribed course. The dose of 40 mg/m2 administered on days 1, 4, and 8 (total dose, 120 mg/m2) has been selected as the dose for phase II studies. The pharmacokinetics of D612 is best described by a one-compartment model with a mean t1/2 of 48 +/- 3 h (SEM). Eighteen of 21 patients developed human anti-mouse antibody (HAMA). Patients who developed high levels of HAMA demonstrated a more rapid clearance of the day 8 dose than those who developed low levels of HAMA. In all patients studied, a component of HAMA was directed at the D612 variable region. With one exception, serum from all patients with detectable antibody to the D612 variable region demonstrated anti-paratope reactivity. Thirty-four % of known metastatic sites demonstrated uptake of radiolabeled D612. There were no objective antitumor responses in this phase I trial. The antitumor effect of D612 in vitro has been shown to be potentiated by interleukin 2 and recombinant human macrophage colony-stimulating factor. A phase II study of D612 administered in combination with cytokines that enhance human effector function is presently ongoing.

Adenocarcinoma↗
PubMed1993

Studies of the dimerization and domain structure of gamma delta resolvase.

gamma delta Resolvase is a site-specific recombinase (20.5 kDa) that catalyzes the resolution of a negatively supercoiled plasmid to a catenated pair of circular DNA products (Reed, R. R. (1981) Cell 25, 713-719). Cross-linking experiments and size exclusion high pressure liquid chromatography analysis of isolated fragments corresponding to specific proteolytic cleavage indicate that the intact enzyme and the large fragment exist in a monomer-dimer equilibrium (KDdimer = 8.0 microM, intact enzyme; KDdimer = 0.1 microM, large fragment) and that the small fragment, which displays DNA binding specificity, is a monomer. Dimerization is further supported by line width comparisons in one-dimensional NMR spectra and determinations of the correlation time of the protein. The one-dimensional proton NMR spectra spectroscopy spectra indicate that the overall structure of the two isolated fragments is highly similar to the structure present in the domains of the intact enzyme. The rotational correlation time of resolvase, determined from relaxation data obtained from each domain, indicates that the small domain has a limited degree of additional motion with respect to the large domain of the enzyme. The monomer-dimer equilibrium and small domain mobility may assist in the binding of resolvase to palindromic-type sites with variable spacers and in subunit exchange during catalysis.

Chromatography, High Pressure Liquid↗
PubMed1993

Relationship between circadian-dependent toxicity of 5-fluorodeoxyuridine and circadian rhythms of pyrimidine enzymes: possible relevance to fluoropyrimidine chemotherapy.

Previous studies in experimental animals and patients have suggested a circadian variation in host toxicity following administration of 5-fluorodeoxyuridine (FdUrd) although the biochemical mechanisms are not fully understood. Thymidine kinase (TK; EC 2.7.1.21), the initial enzyme in the thymidine-phosphorylation pathway, is the first enzyme in the anabolism of FdUrd. Dihydropyrimidine dehydrogenase (DPD; EC 1.3.1.2), is the rate-limiting enzyme in the pyrimidine catabolic pathway and has been shown to be the key enzyme in FdUrd catabolism. The present study examined the relationship between the suggested circadian variation in FdUrd toxicity and potential circadian variations in the activity of these enzymes. Initial studies in Sprague-Dawley rats confirmed that the time of FdUrd administration affected death rate and other drug-related toxicities including loss of body weight, diarrhea, and bone marrow suppression, with the least toxicity and highest survival rate being observed in rats receiving FdUrd at 12:00 noon and 4:00 p.m. and the greatest toxicity and lowest survival rate at 12:00 midnight and 4:00 a.m. Statistical analysis revealed a circadian pattern in FdUrd toxicity (Cosinor analysis, P < 0.001). In subsequent studies with the same species, we simultaneously measured TK and DPD activities in several tissues at various times over 24 h. Under standardized light conditions (lights on, 6:00 a.m. to 6:00 p.m.; lights off, 6:00 p.m. to 6:00 a.m.), with sampling at 4-h intervals (4:00 and 8:00 a.m.; 12:00 noon; 4:00 and 8:00 p.m., and 12:00 midnight), a circadian variation in TK activity was observed (P < 0.0001, Cosinor analysis) in bone marrow, intestinal mucosa, liver, and spleen. In the same group of animals, a circadian pattern of DPD activity in liver and bone marrow was also observed (Cosinor analysis, P < 0.0001) that was inverse compared to the circadian variation in TK activity (Pearson correlation analysis, P < 0.05). Further statistical analysis indicated that the observed circadian variation in FdUrd toxicity was correlated with the circadian variation of TK activity and inversely correlated with DPD activity (Pearson correlation analysis, P < 0.05). Based on the above data, we conclude that the circadian pattern of TK and DPD activity may explain the observed circadian variation in toxicity as the time of FdUrd administration is varied. These results may be useful in the design of improved chemotherapeutic regimens using time-modified administration of FdUrd.

Animals↗
PubMed1993

A mathematical model of the kinetics and tissue distribution of 2-fluoro-beta-alanine, the major catabolite of 5-fluorouracil.

2-Fluoro-beta-alanine (FBAL) is the major metabolite of 5-fluorouracil (FUra), one of the most widely used anticancer drugs. It has been suggested previously that FBAL and/or its metabolites may have a role in the hepatotoxicity, neurotoxicity and cardiotoxicity resulting from FUra chemotherapy. Studies in patients and experimental animals have demonstrated that FBAL has a prolonged elimination compared with the parent drug, FUra. In the present manuscript, a mathematical model is developed for the kinetics and tissue distribution of FBAL. This model is based on recently published data from a study of the pharmacokinetics and disposition of FBAL in rats (Zhang et al., Drug Metab Dispos 20: 113-119, 1992). Satisfactory agreement was achieved between predicted and measured values, permitting an accurate evaluation of the kinetic and distribution parameters for FBAL. This model indicates that: (1) FBAL accumulates in several tissues including brain, heart, spleen, and enterohepatic system; and (2) enterohepatic circulation of FBAL and its bile acid conjugates has an important role in FBAL kinetics and distribution as demonstrated by a model in which enterohepatic circulation parameters were deleted.

Animals↗
PubMed1993

Circadian rhythm of rat spleen cytoplasmic thymidine kinase.

The activity of thymidine kinase (TK, EC 2.7.1.21), the first enzyme of the thymidine phosphorylation pathway, was measured at various times over a 24-hr period in the spleens of Sprague-Dawley rats that had been housed under standardized conditions of light and dark for at least 4 weeks before the study. Spleen cytoplasmic TK activity was assayed with [2-14C]thymidine as substrate. Under "normal" light conditions (lights on 6:00 a.m.-6:00 p.m. and lights off 6:00 p.m.-6:00 a.m.), a circadian variation of TK activity was observed (P < 0.0001), Cosinor analysis) with peak activity (1.98 nmol product/hr/mg protein) at 1:00 a.m. (19 hr after light onset, HALO) and trough activity (0.40 nmol product/hr/mg protein) at 1:00 p.m. (7 HALO). Maximum enzyme activity exceeded minimum activity by approximately 5-fold. Reversing the light-dark cycle resulted in a corresponding shift in TK activity. Under these "reverse" conditions (lights on 6:00 p.m.-6:00 a.m. and lights off 6:00 a.m.-6:00 p.m.), a circadian variation in TK activity was also observed (P < 0.0001, Cosinor analysis) with peak activity (1.14 nmol product/hr/mg protein) at 12:00 noon (18 HALO) and trough activity (0.32 nmol/hr/mg protein) at 12:00 a.m. (6 HALO). Maximum enzyme activity exceeded minimum activity by approximately 4-fold. In summary, this study demonstrated for the first time that TK activity varies over a 24-hr period in association with the light-dark cycle.

Animals↗
PubMed1993

Antigen processing mutant T2 cells present viral antigen restricted through H-2Kb.

Cytotoxic T lymphocytes (CTL) recognize foreign antigens as short peptides presented by class I molecules of the major histocompatibility complex (MHC). T2 cells are profoundly defective in the presentation of endogenously synthesized antigens to CTL due to a deletion of MHC class II-encoded genes for transporters associated with antigen presentation (TAP1/TAP2). Surprisingly, we here demonstrate that T2 cells, after infection with Sendai virus, are readily killed by H-2Kb restricted CD8+ T cells. In contrast to classical class I-mediated antigen presentation, the presentation of Sendai virus antigen in T2Kb cells is brefeldin A (BFA) insensitive. The present findings may suggest the presence of an alternative pathway for MHC class I-mediated antigen presentation in T2 cells.

Animals↗
PubMed1993

Distribution of spin-trapping compounds in rat blood and brain: in vivo microdialysis determination.

Microdialysis was utilized to determine blood and brain distribution of spin-trapping nitrone compounds in the rat following intraperitoneal administration. In vivo quantitation by high-pressure liquid chromatography (HPLC) analysis, in vitro calibration of microdialysis probes, optimum perfusion rate, and the relationship of microdialysis sample recovery to tissue levels were evaluated in detail. The microdialysis sampling and HPLC analysis provided on-line, within-animal pharmacokinetic time-course determinations. At equimolar concentrations, 150 mg/kg alpha-phenyl-N-tert-butyl nitrone (PBN) or 165 mg/kg alpha-4-pyridyl-N-oxide N-tert-butyl nitrone (POBN) reached a similar, steady-state venous blood concentration of 224 +/- 21 microM and 210 +/- 10 microM, respectively. The POBN steady-state brain concentration was 149 +/- 9 microM, a significantly (p < .05) lower concentration than in the blood. In contrast, the brain concentration of PBN was 331 +/- 25 microM, significantly (p < .05) higher than its concentration in the blood. The increased brain distribution/penetration of PBN was attributed to its greater lipophilicity as measured by its octanol/water partition coefficient. All microdialysis results were validated by direct measurement of blood and brain levels at steady-state using conventional extraction procedures and assays. Also, the amount of tissue/cell bound versus unbound nitrones was determined by comparing the microdialysis "dialyzable" fraction with the total amount from whole tissue extracts. These data demonstrate that on-line determinations of nitrone spin-trap brain penetration/levels can be carried out accurately using in vivo microdialysis. The implication of these results for potential use of the microdialysis technique for detection of free radical products in in vivo animal models is discussed.

Animals↗
PubMed1993

The time of administration of 3'-azido-3'-deoxythymidine (AZT) determines its host toxicity with possible relevance to AZT chemotherapy.

3'-Azido-3'-deoxythymidine (AZT) is the drug most widely used in the treatment of AIDS. Its major drug-related toxicity is bone marrow suppression, which limits the dose of AZT that can be used. It is essential that AZT be phosphorylated for antiviral effect. We have recently demonstrated that thymidine kinase (TK), the initial enzyme in AZT anabolism, follows a circadian pattern in rat bone marrow. The present study was undertaken to determine whether AZT toxicity is related to the time of its administration and whether the variation in toxicity is correlated with the circadian variation in TK activity. Male Sprague-Dawley rats were housed under standardized conditions of light and dark (lights on 0600 to 1800 and lights off 1800 to 0600) for 4 weeks. The animals were randomly divided into seven groups; six groups were administered AZT by intraperitoneal injection at the same dose of 750 mg/kg of body weight at various times (0400, 0800, 1200, 1600, 2000, and 2400), and one group was used as a control. AZT-related toxic effects, including bone marrow toxicity, differed significantly among the treatment groups, depending on the time of AZT administration (by analysis of variance and Cosinor analysis, P < 0.001). The least toxicity was observed in rats receiving AZT at 1600 (10 h after light onset [10 HALO], in late sleep span) and the greatest toxicity was observed in those injected at 0400 (22 HALO, in late activity span). To verify these results, we administered AZT by intraperitoneal injection at an approximately 50% lethal dose (1,500 mg/kg) to two groups of rats, one at 1200 (6 HALO, in the middle of the sleep span) and the other at 2400 (18 HALO, in the middle of the activity span). AZT lethality was significantly higher in rats receiving AZT at 2400 (18 HALO, in the middle of the activity span). Further statistical analysis demonstrated that the variation in AZT toxicity was correlated with the circadian variation in TK activity in bone marrow of the same species (peak activity at 0400 [22 HALO, in late activity span] and trough activity at 1600 [10 HALO, in late sleep span]), suggesting that the circadian variation in TK activity may be the biochemical basis for the observed circadian variation in AZT toxicity. These results may be useful in the design of improved AZT chemotherapeutic regimens.

Analysis of Variance↗
PubMed1993

Acute liver rejection: evaluation with cell-directed MR contrast agents in a rat transplantation model.

Enhancement patterns with gadolinium (4s)-4-(4-ethoxybenzyl)-3,6,9-tris (carboxylatomethyl)-3,6,9-triazaundecandioic acid (EOB) diethylenetriaminepentaacetic acid (DTPA), a hepatocyte-directed magnetic resonance (MR) contrast agent, and superparamagnetic iron oxide particles (SPIO), a Kupffer cell-directed contrast agent, were compared at MR imaging in rat models of allogeneic and syngeneic liver transplantation. Light and electron microscopy were performed to monitor the morphologic changes in these livers and revealed typical findings in acute rejecting liver (allogeneic transplants) and normal architecture in syngeneic transplants. Liver enhancement with Gd-EOB-DTPA at MR imaging was delayed and prolonged with transplantation, and even more with rejection, but the level of enhancement when compared with that of control rats remained unaffected. Uptake of SPIO was decreased in the acutely rejecting livers but was normal in the syngeneic transplantation model. Enhanced MR imaging with cell-directed contrast agents depicted decreased phagocytotic activity in acute transplant rejection and enabled the excretory function of hepatocytes to be monitored. Additionally, Gd-EOB-DTPA may be applied advantageously for detection of focal lesions in transplanted livers.

Acute Disease↗
PubMed1993

Interleukin-1 beta mRNA expression in ischemic rat cortex.

BACKGROUND AND PURPOSE: Interleukin-1 beta is a proinflammatory cytokine produced by blood-borne and resident brain inflammatory cells. The present study was conducted to determine if interleukin-1 beta mRNA was produced in the brain of rats subjected to permanent focal ischemia. METHODS: Rat interleukin-1 beta cDNA, synthesized from stimulated rat peritoneal macrophage RNA by reverse transcription and polymerase chain reaction and cloned in plasmid Bluescript KS+, was used to evaluate the expression of interleukin-1 beta mRNA in cerebral cortex from spontaneously hypertensive rats and normotensive rats subjected to permanent middle cerebral artery occlusion. Interleukin-1 beta mRNA was quantified by Northern blot analysis and compared with rat macrophage RNA standard. To correct for gel loading, blots were also analyzed with cyclophilin cDNA, which encodes an abundant, conserved protein that was unchanged by the experimental conditions. RESULTS: Interleukin-1 beta mRNA produced in the ischemic zone was significantly increased from 6 hours to 120 hours, with a maximum of 211 +/- 24% of interleukin-1 beta reference standard, ie, 0.2 ng stimulated rat macrophage RNA, mRNA compared with the level in nonischemic cortices (4 +/- 2%) at 12 hours after ischemia (P < .01; n = 6). Interleukin-1 beta mRNA at 12 hours after ischemia was markedly elevated in hypertensive rats over levels found in two normotensive rat strains. Neurological deficits were also apparent only in the hypertensive rats. CONCLUSIONS: Brain interleukin-1 beta mRNA is elevated acutely after permanent focal ischemia and especially in hypertensive rats. These data suggest that this potent proinflammatory and procoagulant cytokine might have a role in brain damage following ischemia.

Animals↗
PubMed1993

Calmodulin and the contractile vacuole complex in mitotic cells of Dictyostelium discoideum.

In amoebae of the eukaryotic microorganism Dictyostelium discoideum, calmodulin is greatly enriched on membranes of the contractile vacuole complex, an osmoregulatory organelle. Antibodies specific for Dictyostelium calmodulin were used in the present study to immunolocalize the contractile vacuole complex in relation to the Golgi complex (detected with wheat germ agglutinin) and the microtubule organizing center (MTOC, detected with anti-tubulin antibodies). Cells were examined throughout the cell cycle. Double-staining experiments indicated that the contractile vacuole complex extended to the MTOC in interphase cells, usually, but not always, overlapping the Golgi complex. In metaphase and anaphase cells, the Golgi staining became diffuse, suggesting dispersal of Golgi membranes. In the same mitotic cells, anti-calmodulin antibodies labeled numerous small cortical vacuoles, indicating that the contractile vacuole complex had also become dispersed. When living mitotic cells were examined, the small cortical vacuoles were seen to be active, implying that all parts of the Dictyostelium contractile vacuole complex possess the ability to accumulate fluid and fuse with the plasma membrane. In contrast to observations reported for other types of cells, anti-calmodulin antibodies did not label the mitotic spindle in Dictyostelium. Despite this difference in localization, it is possible that vacuole-associated calmodulin in Dictyostelium cells and spindle-associated calmodulin in larger eukaryotic cells might perform a similar function, namely, regulating calcium levels.

Animals↗
PubMed1993

[Peripheral lymphocyte subsets in patients with Vogt-Koyanagi-Harada syndrome (VKH)].

The peripheral lymphocyte subsets were analyzed in 37 patients with VKH and 32 normal controls by indirect fluorescein assay, using monoclonal antibodies. The percentages of OKT3+, OKT4+, and OKT8+ T-cells in active patients were found to differ insignificantly from those in quiescent patients, as were those in patients of the VK type from those in patients of the Harada type (P > 0.05), whereas the percentage of OKT4+ was significantly higher, that of OKT8+ was lower, and the OKT4/OKT8 ratio was higher in the recurrent patients than in the controls (P < 0.01). There was statistical difference in the ratio of OKT4/OKT8 between the recurrent and the non-recurrent patients (P < 0.01), while the ratio differed insignificantly between the two types of recurrent patients. The results suggested that the recurrence of VKH could be related with imbalance between the T-cell subsets.

Adolescent↗
PubMed1993

Direct localization comparison of murine and chimeric B72.3 antibodies in patients with colon cancer.

To compare radiolocalization of murine B72.3 (m-B72.3) and mouse/human chimeric B72.3 (ch-B72.3) antibodies, five patients with biopsy confirmed adenocarcinoma of the colon received both radiolabeled antibodies 4 or 7 days before laparotomy. Following antibody administration, preoperative gamma camera images showed localization to sites of disease in four of the five patients. Autoradiography of resected specimens showed that both labeled antibodies localized specifically to the tumor with only minimal amounts in normal tissues. Radioactivity from each isotope in biopsy specimens of tumor and normal tissues was quantitated by scintillation gamma counting. Comparison of the percentages of injected activities for each antibody in resected tumor and normal tissue yields tumor to normal tissue radiolocalization ratios of 2.7-13.3 and 0.9-6.3 for murine and chimeric antibodies, respectively. The higher ratios for murine antibody were due to lower normal tissue levels, reflecting its faster clearance from the circulation, whereas the quantitative uptake of labeled antibody was always greater with the chimeric antibody. The chimera to murine antibody ratios in tumor of 1.1-2.7 suggest modest enhancement of tumor localization with chimeric antibody because of its longer half-life.

Aged↗