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C M Lin

Publications and source records attributed to C M Lin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Cutting edge: trimolecular interaction of TCR with MHC class II and bacterial superantigen shows a similar affinity to MHC:peptide ligands.

Bacterial superantigens such as Staphylococcus aureus enterotoxin A (SEA) are very potent stimulators of T cells. They bind to the Vbeta region of the TCR and to MHC class II, stimulating T cells at nanomolar concentrations. Using surface plasmon resonance measurements, we find that binding between the individual components of the complex (TCR-class II, TCR-SEA, SEA-class II) is very weak, but that the stability of the trimolecular complex is considerably enhanced, reaching an affinity similar to that found for TCR interactions with MHC:peptide ligand. Thus, the potency of SEA in stimulation of T cells is not due to particularly strong affinities between the proteins, but to a cooperative effect of interactions in the TCR-SEA-MHC class II trimolecular complex that brings the kinetics into a similar range to binding of conventional Ags. This range may be the optimum for T cell activation.

Animals↗
PubMed1999

Effect of dietary glutamate on chemotherapy-induced immunosuppression.

Chemotherapy causes severe host immune depression and consequently increases susceptibility to infection. Dietary glutamate (GLU) serves as a stable substrate for the formation of glutamine (GLN), which is an important fuel and metabolic precursor for the immune cells. The effect of addition of GLU to a GLN/GLU-free amino acid diet upon immune response was studied in rats recovering from chemotherapy. Animals were fed a 0, 4, or 8% GLU diet and received a single intraperitoneal injection of methotrexate (MTX, 20 mg/kg BW). Two in vivo immune tests, delayed-type hypersensitivity (DTH) and popliteal lymphoproliferation (PLP), were performed 3 and 7 d after MTX treatment. Food intake and body weight decreased significantly immediately after MTX treatment and gradually recovered after 8 d with no significant difference among treatment groups. In a 23-d feeding study, no significant difference was found in the DTH response, but the PLP response increased in a GLU dose related fashion (83 and 133% increases for the 4 and 8% GLU diets, respectively). In a 44-d feeding study, the DTH response increased 61 and 83%, while the PLP response increased 191 and 382% for the 4 and 8% GLU diets, respectively. Plasma GLN, GLU, or glutathione (GSH) levels were increased by dietary GLU, but only in the immediate postprandial state. In summary, dietary GLU improves immune status of rats recovering from MTX treatment. The immune-enhancing effect of dietary GLU was dose-dependent and more pronounced after a longer duration of dietary GLU intake.

Animals↗
PubMed1999

Qualitative and quantitative differences in T cell receptor binding of agonist and antagonist ligands.

The kinetics of interaction between TCR and MHC-peptide show a general relationship between affinity and the biological response, but the reported kinetic differences between antigenic and antagonistic peptides are very small. Here, we show a remarkable difference in the kinetics of TCR interactions with strong agonist ligands at 37 degrees C compared to 25 degrees C. This difference is not seen with antagonist/positive selecting ligands. The interaction at 37 degrees C shows biphasic binding kinetics best described by a model of TCR dimerization. The altered kinetics greatly increase the stability of complexes with agonist ligands, accounting for the large differences in biological response compared to other ligands. Thus, there may be an allosteric, as well as a kinetic, component to the discrimination between agonists and antagonists.

Animals↗
PubMed1999

Towards metabolic sink therapy for mut methylmalonic acidaemia: correction of methylmalonyl-CoA mutase deficiency in T lymphocytes from a mut methylmalonic acidaemia child by retroviral-mediated gene transfer.

The pathology associated with mut methylmalonic acidaemia (MMA) is caused by systemic accumulation of methylmalonate. Therefore, removal of methylmalonate from the circulation of affected individuals by an engineered metabolic system is proposed as a potential treatment. The haematopoietic cell is a potential site for such a metabolic system because of its direct contact with the accumulated metabolite and the demonstrated safety and ease in utilizing this cell. In this study, we assessed the feasibility of developing a haematopoietic cell-based methylmalonate sink by analysing propionate/methylmalonate metabolism in a variety of haematopoietic cells. The results show that propionate metabolism and methylmalonyl-CoA mutase (MCM) activity are intact in primary T cells, EBV-B cells, and CD34+ haematopoietic stem cell-derived granulocytes, whereas they are defective in those from a mut MMA child. Moreover, normal T and EBV-B cells clear methylmalonate from the medium at a significant rate. Transduction of MCM-deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism. These results establish the basis for developing haematopoietic cell-based metabolic sink therapy for mut MMA by T lymphocyte/haematopoietic stem cell-directed gene transfer.

3T3 Cells↗
PubMed1999

Virus reduction in the preparation of intravenous immune globulin: in vitro experiments.

BACKGROUND: While immune globulins for intravenous administration (IGIV) have an excellent record with respect to virus safety, concern regarding these preparations has been raised by reports of transmission of hepatitis C virus (HCV) to patients treated with IGIV and the presence of genetic material for HCV in IGIV preparations. STUDY DESIGN AND METHODS: This in vitro study evaluated the effectiveness of several manufacturing steps, including ethanol precipitation and pasteurization, in reducing HIV and model viruses including encephalomyocarditis (EMC) virus, pseudorabies virus (PRV), bovine viral diarrhea virus (BVDV), Sindbis virus, vaccinia virus, and vesicular stomatitis virus (VSV), as well as HCV RNA, in IGIV. RESULTS: Ethanol precipitation carried out after pasteurization resulted in virus reductions (log10) of >3.97 for HIV, 1.95 for EMC virus, >5.39 for PRV, and 3.52 for BVDV. Pasteurization inactivated EMC virus by 4.52 log10 and resulted in a log10 reduction of >6.54 for HIV, >5.39 for PRV, >6.64 for BVDV, >7.78 for Sindbis virus, >5.84 for vaccinia virus, and >6.99 for VSV. All viruses except EMC virus were reduced below the limit of detection within 6 hours of the beginning of pasteurization. Cohn processing of Fraction II + III paste and the 4.5-percent alcohol precipitation step prior to pasteurization provided additional virus removal. Studies using the polymerase chain reaction technique found that HCV RNA was detectable in the starting fraction of Cohn Fraction II paste, but not in the final IGIV preparation. CONCLUSION: These findings strongly support the viral safety of IGIV prepared by this method and show a significant added measure of virus safety associated with pasteurization of this preparation.

Animals↗
PubMed1999

Evaluation of serum CA27.29, CA15-3 and CEA in patients with breast cancer.

The Truquant BR radioimmunoassay (RIA) using monoclonal antibody BR 27.29 to recognize a peptide sequence on the MUC-1 gene product for quantification of the CA 27.29 antigen in serum was used in this report to evaluate in 145 patients with breast cancer and compared the other conventional serum markers such as CA15-3 and CEA. The upper limit of normal (25 u/ml) was determined from CA27.29 values 12.4 +/- 4.1 u/ml (mean +/- 3 S.D.) for 112 female subjects apparently free of disease. The CA15-3 levels above 25 u/ml and CEA levels above 5 ng/ml were considered positive values. Thirty-seven cases of 145 patients studied had elevated CA 27.29 levels (sensitivity: 25.5%), 35 of 145 had positive CA15-3 levels (sensitivity 24.1%) and 27 of 145 patients had positive CEA levels (sensitivity: 18.6%) (p < 0.05). One hundred and ten cases of the breast cancer patients (75.8%) did not have metastatic disease. In this group CA 27.29 sensitivity was 6.4%, while CA15-3 sensitivity was 5.5% and CEA sensitivity was 4.5% (p > 0.05). Mean values were 10.2 +/- 9.2 u/ml for CA 27.29, 14.1 +/- 5.6 u/ml for CA 15-3 and 1.7 +/- 1.5 ng/ml for CEA. Thirty-five patients (24.2%) had metastatic disease. In this group CA 27.29 sensitivity was 85.7%, CA15-3 sensitivity was 82.8% and CEA sensitivity was 62.8% (p < 0.05). Mean values for CA27.29 was 152.6 +/- 131.6 u/ml, CA15-3 was 123.1 +/- 107.6 u/ml and 21.8 +/- 36.9 ng/ml of CEA. With regard to the correlation of three tumor markers with clinical stages, patients had significantly higher levels of CA27.29 than CEA, but they were similar to CA 15-3 in metastatic breast cancer. These results suggest CA27.29 to be more sensitive and specific than CEA, but that it is similar to CA15-3 for metastatic breast cancer detection and monitoring.

Adult↗
PubMed1999

Cardiogenic shock in a patient with glyphosate-surfactant poisoning.

We present a case of glyphosate-induced cardiogenic shock in a young man. The patient a 26-year-old man, presented with nausea and vomiting 4 hours after attempting suicide by drinking 150 mL of glyphosate surfactant. Cardiogenic shock with accelerated idio-ventricular rhythm on electrocardiography developed after admission. Intravenous injection of epinephrine, atropine, and calcium failed to improve the condition. Over the next 16 hours, the QRS complex gradually narrowed, sinus rhythm returned, and the hemodynamic status improved. Echocardiograms revealed diffuse left ventricular hypokinesis with markedly reduced ejection fraction while the patient was in shock; normal left ventricular function resumed the next day. In this case, the glyphosate surfactant poisoning-induced shock may have been due to transient suppression of the cardiac conduction system and contractility, rather than intravascular hypovolemia.

Adult↗
PubMed1998

Synthesis and biological evaluation of 2-acyl analogues of paclitaxel (Taxol).

The anticancer drug paclitaxel (Taxol) has been converted to a large number of 2-debenzoyl-2-aroyl derivatives by three different methods. The bioactivities of the resulting analogues were determined in both tubulin polymerization and cytotoxicity assays, and several analogues with enhanced activity as compared with paclitaxel were discovered. Correlation of cytotoxicity in three cell lines with tubulin polymerization activity showed reasonable agreement. Among the cell lines examined, the closest correlation with antitubulin activity was observed with a human ovarian carcinoma cell line.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Glutamine synthetase expression in rat lung is regulated by protein stability.

During physiological stress, the lung increases production of the amino acid glutamine (Gln) using the enzyme Gln synthetase (GS) to maintain Gln homeostasis. Glucocorticoid hormones are considered the principal mediators of GS expression during stress. However, whereas animal studies have shown that glucocorticoids increase lung GS mRNA levels 500-700%, GS activity levels rise only 20-45%. This discrepancy suggests that a posttranscriptional control mechanism(s) ultimately determines GS expression. We hypothesized that the level of GS protein in the lung is governed by the intracellular Gln concentration through a mechanism of protein destabilization, a feedback regulatory mechanism that has been observed in vitro. To test this hypothesis, Sprague-Dawley rats were treated with a Gln-free diet and the GS inhibitor methionine sulfoximine (MSO) to deplete tissue Gln levels and prevent this feedback regulation. Exposure to Gln-free chow and MSO (100 mg/kg body wt) for 6 days decreased plasma Gln levels 50% (P < 0.01) and decreased lung tissue Gln levels by 70% (P < 0.01). Although lung GS mRNA levels were not influenced by Gln depletion, there was a sevenfold (P < 0.01) increase in GS protein. A parenteral Gln infusion (200 mM, 1.5 ml/h) for the last 2 days of MSO treatment replenished lung Gln levels to 65% of control level and blunted the increase in GS protein levels by 33% (P < 0.05) compared with rats receiving an isomolar glycine solution. The acute effects of glucocorticoid and MSO administration on lung GS expression were also measured. Whereas dexamethasone (0.5 mg/kg) and MSO injections individually augmented lung GS protein levels twofold and fourfold (P < 0.05), respectively, the combination of dexamethasone and MSO produced a synergistic, 12-fold induction (P < 0.01) in lung GS protein over 8 h. The data suggest that, whereas glucocorticoids are potent mediators of GS transcriptional activity, protein stability greatly influences the ultimate expression of GS in the lung.

Animals↗
PubMed1997

Antitumor agents. 178. Synthesis and biological evaluation of substituted 2-aryl-1,8-naphthyridin-4(1H)-ones as antitumor agents that inhibit tubulin polymerization.

As part of our continuing search for potential anticancer drug candidates in the 2-aryl-1,8-naphthyridin-4(1H)-one series, we have synthesized two series of 3'-substituted 2-phenyl-1,8-naphthyridin-4(1H)-ones and 2-naphthyl-1,8-naphthyridin-4(1H)-ones. All compounds showed significant cytotoxic effects (log GI50 < -4.0; log molar drug concentration required to cause 50% growth inhibition) against a variety of human tumor cell lines of the National Cancer Institute's in vitro screen, including cells derived from solid tumors such as non-small cell lung, colon, central nervous system, melanoma, ovarian, prostate, and breast cancers. All 3'-substituted compounds demonstrated strong cytotoxic effects in almost all tumor cell lines. Introduction of an aromatic ring at the 2'- and 3'-positions also generated compounds with potent antitumor activity. Incorporation of an aromatic ring at the 3'- and 4'-positions produced compounds with reduced activity. Interestingly, introduction of a halogen at the 3'-position yielded compounds with different selectivity for the tumor cell lines tested. All 3'-halogenated compounds (29-36) and compounds 38 and 42-44 were potent inhibitors of tubulin polymerization with activities nearly comparable to those of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Active agents also inhibited the binding of [3H]colchicine to tubulin.

Antineoplastic Agents↗
PubMed1997

Synthesis of analogs of 2-methoxyestradiol with enhanced inhibitory effects on tubulin polymerization and cancer cell growth.

A new series of estradiol analogs was synthesized in an attempt to improve on the anticancer activity of 2-methoxyestradiol, a naturally occurring mammalian tubulin polymerization inhibitor. The compounds were evaluated as inhibitors of tubulin polymerization and the binding of [3H]colchicine to tubulin, as well as for in vitro cytotoxicity in human cancer cell cultures. Overall, the most potent of the new compounds were 2-(2',2',2'-trifluoroethoxy)-6-oximinoestradiol, 2-ethoxy-6-oximinoestradiol, and 2-ethoxy-6-methoximinoestradiol. These agents lacked significant affinity for the estrogen receptor. The cytotoxicities of the compounds correlated in general with their abilities to inhibit tubulin polymerization, thus supporting inhibition of tubulin polymerization as the primary mechanism causing inhibition of cell growth.

2-Methoxyestradiol↗
PubMed1997

Antitumor agents. 174. 2',3',4',5,6,7-Substituted 2-phenyl-1,8-naphthyridin-4-ones: their synthesis, cytotoxicity, and inhibition of tubulin polymerization.

Two series of 2',3',4',5,6,7-substituted 2-phenyl-1,8-naphthyridin-4-ones and 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones have been synthesized and evaluated as cytotoxic compounds and as inhibitors of tubulin polymerization. Most 2-phenyl-1,8-naphthyridin-4-ones showed potent cytotoxic and antitubulin activities, whereas 2-phenylpyrido[1,2-alpha]pyrimidin-4-ones showed no activity in either assay. In general, a good correlation was found between cytotoxicity and inhibition of tubulin polymerization in the 2-phenyl-1,8-naphthyridin-4-one series. The 2-phenyl-1,8-naphthyridin-4-ones (44-49) with a methoxy group at the 3'-position showed potent cytotoxicity against most tumor cell lines with GI50 values in the low micromolar to nanomolar concentration range in the National Cancer Institute's 60 human tumor cell line in vitro screen. Introduction of substituents (e.g. F, Cl, CH3, and OCH3) at the 4'-position led to compounds with reduced or little activity and substitution at the 2'-position resulted in inactive compounds. The effects of various A-ring substitutions on activity depend on the substitution in ring C. Compounds 44-50 were potent inhibitors of tubulin polymerization, with activity nearly comparable to that of the potent antimitotic natural products colchicine, podophyllotoxin, and combretastatin A-4. Compounds 44-49 also inhibited the binding of radiolabeled colchicine to tubulin, but the inhibition was less potent than that obtained with the natural products. Further investigation is underway to determine if substitution at the 3'-position and multisubstitutions in ring C will result in compounds with increased activity.

Animals↗
PubMed1997

Characterization of rainbow trout (Oncorhynchus mykiss) growth hormone 1 gene and the promoter region of growth hormone 2 gene.

Studies by Agellon et al. (Mol. Reprod. Dev. 1, 11-17) showed the presence of two growth hormone (rtGH1 and rtGH2) mRNA species in pituitary glands of adult rainbow trout (Oncorhynchus mykiss). In this study, we have detected rtGH1 and rtGH2 mRNAs in pituitary glands of rainbow trout from fry to 2 years of age. The level of rtGH1 mRNA is notably higher than that of rtGH2 mRNA in 10-day-old fry and 2-year-old females. These results suggest differential expression of rtGH1 and rtGH2 genes in different sexes and developmental stages. As a step toward elucidating the mechanism of differential expression of both GH genes, DNA fragments encoding rtGH1 gene and the promoter/regulatory region of rtGH2 gene were isolated and characterized. Rainbow trout GH genes span approximately 4.5 kb and are composed of six exons and five introns. The 5'-flanking region of both genes contain consensus sequences for TATA boxes and several Pit-1 binding sequences. Consensus sequences related to the cAMP response element, thyroid hormone response element, retinoic acid response element, estrogen response element (ERE), and glucocorticoid response element are present not only in the 5'-flanking region, but also in introns and exons in rtGH1 gene. These hormone response elements, except ERE, are also present in rtGH2 gene.

Animals↗
PubMed1997

Synthesis and biological evaluation of 1,1-dichloro-2,3-diarylcyclopropanes as antitubulin and anti-breast cancer agents.

Z-1,1-Dichloro-2,3-diphenylcyclopropane (1) is an effective anti-breast cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro and causes microtubule loss in breast cancer cells, leading to accumulation in the G2/M portion of the cell cycle. Aryl ring-halogenated, methoxylated and benzyloxylated derivatives of 1, as well as its E-isomer and the dichlorocyclopropyl derivative of diethylstilbestrol (DES), were synthesized and tested for their ability to inhibit, the assembly of tubulin into microtubules. Including 1, 17 cyclopropyl compounds were tested. One (Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12)) was found to be more active than 1. In addition, E-1,1-dichlorocyclopropylDES (17) was more potent than DES. The E-isomer of 1 (16) was inactive. The cytostatic activities of the compounds against MCF-7 and MDA-MB231 human breast cancer cells, and their abilities to perturb microtubules in MCF-7 cells were also evaluated. Z-Dichloro-2-(4-fluorophenyl)-3-phenylcyclopropane (5), Z-1,1-dichloro-2-(4-fluorophenyl)-3-(4-methoxyphenyl)cyclopropane (11), and Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12) were more potent than 1 against the breast cancer cells.

Animals↗
PubMed1997

Synthesis and biological activity of A-nor-paclitaxel analogues.

A number of paclitaxel analogues with a 5-membered A-ring (A-nor-paclitaxels, or (15-->1)-abeo-paclitaxels) have been prepared in order to determine whether analogues of this class might have improved bioactivity as compared with paclitaxel. Most of the compounds synthesized were less active than paclitaxel, but one analogue was equivalent to paclitaxel in a tubulin-assembly assay, and another analogue was more cytotoxic than paclitaxel in two different cell lines of the NCI screen.

Antineoplastic Agents, Phytogenic↗
PubMed1997

Expression of human phenylalanine hydroxylase activity in T lymphocytes of classical phenylketonuria children by retroviral-mediated gene transfer.

Classical phenylketonuria (PKU) is a metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. At present, T lymphocyte-directed gene therapy is the only means for which a safety record has been established. Thus, we investigated the applicability of this strategy to PKU gene therapy. We first looked for tetrahydrobiopterin (BH4) and dihydropteridine reductase (DHPR) activity, which are required for the phenylalanine hydroxylation reaction and BH4 regeneration, respectively, in T cells isolated from PKU children. We found that T cells contained a small amount of biopterin, but significant DHPR activity, and that the intracellular biopterin content could be increased by exogenous BH4 supplementation. Moreover, PKU T cells were capable of taking up phenylalanine efficiently and effluxing acquired tyrosine. Finally, a recombinant retrovirus containing the human PAH cDNA was constructed and used to transduce isolated PKU T cells. Viral-transduced T cells produced high levels of PAH activity as compared to control mock-infected T cells. These results indicate that T lymphocytes express all that is required for synthesizing/replenishing constituents of the phenylalanine hydroxylation reaction and expressing transduced phenylalanine hydroxylase cDNA.

Biopterins↗
PubMed1997

Evoked facial nerve EMG and brainstem auditory evoked potential monitoring in cerebellopontine angle tumor resection.

BACKGROUND: The preservation of normal nerve function or identification of nerve route is critical in some surgeries of cerebellopontine angle tumors. Over the last 5 years, intraoperative facial nerve electromyogram (EMG) and brainstem auditory evoked potential (BAEP) were applied for evaluation of facial nerve integrity and brainstem function in patients while undergoing resection of cerebellopontine angle (CPA) tumor. This report represents the retrospective analysis of our results. METHODS: The inhalational anesthesia with 1-1.5% isoflurane in pure O2 was used. Muscle relaxation was maintained with continuous infusion of atracurium. The degree of muscle relaxation was aimed at a T4/T1 ratio of train-of-four response more than 20% of the adductus pollicis upon ulnar nerve stimulation at the wrist. In 236 patients suffering from CPA tumor without facial palsy, the EMG of the mentalis muscle ipisilateral to the tumor was obtained through stimulation of the facial nerve. The stimulation was applied with a nerve finder, which delivered an electrical stimulation of a single 2 mamp direct current. The EMG finding was compared with the clinical result. In 198 patients, BAEP was used to monitor the brainstem function during tumor resection. In case of intact hearing the BAEP was taken ipsilateral to the operation side and in case with total hearing loss contralateral BAEP to operation side was used. For BAEP stimulation, 90 db click sound stimulation with frequency of 11.26 Hz was applied to both ears. BAEP signals were obtained and recorded at the mastoid region of either side in reference to the vertex. The EMG and BAEP signals were recorded and saved to an evoked potential monitor. RESULTS: In facial nerve EMG monitoring, there were two false positive and no false negative tests. Except for the two false positive tests, the postoperative clinical results in the other cases were compatible with the intraoperative facial nerve EMG findings. In BAEP monitoring, there were twenty-eight positive tests. CONCLUSIONS: The low incidence of false negative test suggests that facial nerve EMG is valuable in detection of facial nerve function in CPA tumor resection. Intraoperative BAEP abnormality is possibly useful in identifying postoperative brainstem dysfunction.

Adult↗