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S Chiu

Publications and source records attributed to S Chiu.

At least 37 records · Page 2Linked to original sources
PubMed1994

Nuclear structure and the microdistribution of radiation damage in DNA.

Evidence for the roles of proteins and metal ions in the microheterogeneity of DNA damage is reviewed. Decondensation of chromatin in hypotonic buffers markedly sensitizes the DNA to radiation, while treatment of nuclei with hypertonic buffers strips the DNA of histones and other nuclear proteins and enhances the radiosensitivity of the DNA with respect to double-strand break (dsb) formation. Addition of the radical scavenger DMSO reduces the yield of strand breaks, but dehistonized chromatin remains approximately 2.5 times more sensitive to radiation than does native chromatin at 0.1 M DMSO. DNA-protein crosslink (DPC) formation is relatively unaffected by the removal of the majority of histones from chromatin. Most DPC form at or near the nuclear matrix, and matrix is stabilized and radiosensitized by Cu++. To elucidate the role of Cu++, the induction of dsb and DPC by gamma-radiation has been compared with that by hydroxyl radical from Fe(++)-EDTA, or Cu++ catalysed Fenton reactions. Data comparing the size of DNA fragments produced, the effect of expanding or dehistonizing chromatin, and the effects of radical scavengers suggest that gamma-radiation and Fe(++)-EDTA produce dsb at open chromatin sites, whereas Cu(++)-generated dsb are similar to radiation-induced DPC in their location at the nuclear matrix. Both metal ions appeared to produce damage by site-specific generation of hydroxyl radicals. The nuclear matrix, the proteinaceous skeleton which anchors chromosomal loops and provides sites for DNA replication and transcription, binds metal ions and matrix-attachment DNA regions (MARs) consisting of 300 + bp of AT-rich DNA. The interaction of cloned MARs with isolated nuclear matrices has been found to be hypersensitive to crosslinking upon gamma-irradiation, in comparison with associations formed by similarly sized DNA fragments lacking MAR sequences. Thus, the non-random distribution of radiation damage is partially explained by the protection of DNA afforded by histones and chromatin structure and partially by the hypersensitivity of DNA-nuclear matrix associations.

Binding Sites↗
PubMed1994

Prolactin receptor mRNA localization in the hypothalamus by in situ hybridization.

Prolactin receptors may mediate the action of prolactin in the brain to influence behavior and neuroendocrine secretions. We recently demonstrated prolactin receptor gene expression in the anterior and medial basal hypothalamus and not in the cortex by the reverse transcription-polymerase chain reaction. In this paper, we localize the prolactin receptor gene expression to individual cells with in situ hybridization. Several steps in the in situ hybridization method were modified to increase sensitivity by using (i) probes complementary to the coding sequence of the extracellular binding domain common to both long and short prolactin receptor, (ii) more stringent hybridization and wash conditions to reduce background and (iii) higher specific activity, more complex and saturating amounts of probe. We detected prolactin receptor gene expression in cells of the periventricular area of the preoptic nucleus, medial preoptic nucleus, supraoptic nucleus, rostral arcuate nucleus and choroid plexus. Cortical brain tissue, which has been demonstrated previously by reverse-transcription polymerase chain reaction to be lacking in prolactin receptor mRNA, did not have any detectable signal for the receptor mRNA and was used as an indication of background levels of signal. The mean area of silver grains over labeled cells in periventricular area of the preoptic nucleus, medial preoptic nucleus, supraoptic nucleus, arcuate nucleus, lateral ventromedial nucleus was at least 10 times greater than the background in the cortex of the same brain section.

Animals↗
PubMed1993

Assessment of gene expression and peptide secretion from individual cells.

We have developed an assay that allows one to monitor gene expression in and peptide secretion from individual cells. By combining the reverse hemolytic plaque with in situ hybridization, investigators can quantitate simultaneously the level of gene expression and the level of secretion of a peptide. The method can be used in any system in which an appropriate antibody for the reverse hemolytic plaque assay and probes complementary to the mRNA of interest are available. It can be used to monitor the level of mRNA and secretion of the peptide product, or expression of one gene and the secretion of another peptide. In this paper we will describe the major steps of the method. We have used the pituitary lactotroph as a model to demonstrate the power of this technique. However, we believe that this method may be an important approach to answer many questions regarding the cellular and molecular mechanisms that regulate the coupling of peptide secretion and gene expression at the single cell level.

Animals↗
PubMed1993

High- and low-affinity states of dopamine D1 receptors in schizophrenia.

Using SKF-38393/[3H]SCH-23390 dopamine D1 receptor agonist/antagonist competition binding technique, we showed that schizophrenics distinguished from the neuro-psychiatric and normal controls by exhibiting a significant increase in the density of the low-affinity state, and a concomitant enhancement in the binding affinity of the high-affinity state of D1 dopamine receptors in caudate nucleus. The results suggest that perturbation in dynamic equilibrium of high- and low-affinity states of D1 receptors underlies the pathogenesis of schizophrenia.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1993

Efficacy of ganciclovir in combination with zidovudine against cytomegalovirus in vitro and in vivo.

In cultured MRC-5 cells, ganciclovir (GCV) alone had good activity against both the established AD169 strain (IC50 8 and 9 microM) and a clinical isolate (IC50 14 microM) of human cytomegalovirus (CMV), while 3'-azido-3'-deoxythymidine (AZT) was relatively inactive [IC50 508 and > 800 (AD169 strain); > 800 microM (clinical isolate)]. When reductions in plaques were compared against reductions in the cellular metabolism of MTT at all GCV and AZT combination concentrations using an improved 3-dimensional linear regression analysis, AZT had an additive effect on the antiviral activity of GCV against the AD169 strain and potentiated the antiviral activity of GCV against the clinical isolate. Calculations showed that, in the presence of 50 microM AZT, the anti-CMV activity of GCV was unchanged for the AD169 strain, whereas the activity of GCV was increased approximately 5-10-fold for the clinical isolate. An increase in GCV efficacy for the AD169 strain first became apparent at 100 microM AZT with an approximately 3-fold increase in activity. In Swiss-Webster mice, the anti-CMV activity of GCV against murine CMV was unaffected when administered in combination with AZT. GCV given alone subcutaneously had an ED50 of 6 mg/kg which was unaffected by daily intraperitoneal doses of 320 mg/kg AZT. These results suggest that AZT will not adversely affect the efficacy of GCV against CMV in HIV-positive, non-neutropenic patients.

Animals↗
PubMed1993

Three-dimensional dosimetry for radioimmunotherapy treatment planning.

Absorbed-dose calculations for radioimmunotherapy are generally based on tracer imaging studies of the labeled antibody. Such calculations yield estimates of the average dose to normal and target tissues assuming idealized geometries for both the radioactivity source volume and the target volume. This work describes a methodology that integrates functional information obtained from SPECT or PET with anatomical information from CT or MRI. These imaging modalities are used to define the actual shape and position of the radioactivity source volume relative to the patient's anatomy. This information is then used to calculate the spatially varying absorbed dose, depicted in "colorwash" superimposed on the anatomical imaging study. By accounting for individual uptake characteristics of a particular tumor and/or normal tissue volume and superimposing resulting absorbed-dose distribution over patient anatomy, this approach provides a patient-specific assessment of the target-to-surrounding normal tissue absorbed-dose ratio. Such information is particularly important in a treatment planning approach to radioimmunotherapy, wherein a therapeutic administration of antibody is preceded by a tracer imaging study to assess therapeutic benefit.

Brain Neoplasms↗
PubMed1992

Detection of prolactin receptor (PRL-R) mRNA in the rat hypothalamus and pituitary gland.

Prolactin receptor (PRL-R) mRNAs exist in several tissues where prolactin is known to act including the liver, testes, prostate, ovary, mammary gland, adrenal gland and kidney. PRL also acts at the level of the hypothalamus and pituitary gland to feed back and regulate its own secretion and the secretion of other anterior pituitary hormones. Therefore, we hypothesized that PRL-R mRNA would exist in these target tissues as well. Total RNA was extracted from rat anterior and medial basal hypothalamus, anterior and posterior pituitary gland, cerebral cortex, skeletal muscle and liver. After reverse transcribing total RNA with Murine-MLV reverse transcriptase and random or oligo(dT) pmers, the polymerase chain reaction (PCR) was performed. PCR products were then analyzed by ethidium bromide staining. Using primers that flanked the coding region for the extracellular binding domain we detected PRL-R mRNA in the anterior and medial basal hypothalamus, anterior and posterior pituitary gland, as well as in the liver, but not in the cerebral cortex or skeletal muscle. In addition, when we used primers that distinguish the long and short forms of the PRL-R mRNA, both forms of the PRL-R mRNA were detectable in the same tissues. Our data suggest that PRL may feed back at the level of the hypothalamus and pituitary gland through the same short and/or long PRL-R mRNA that mediate PRL action in the peripheral tissues.

Animals↗
PubMed1991

Lymphangiosarcoma associated with lymphedema in a man with Maffucci's syndrome.

A man with Maffucci's syndrome and lifelong lymphedema in the right lower extremity had a lymphangiosarcoma in the same extremity. Despite amputation of the limb and radiotherapy, he died several months later of pulmonary metastases. Malignancies of vascular origin rarely have been reported in this syndrome. Our patient's features suggest that lymphedema may predispose patients with Maffucci's syndrome to the development of lymphangiosarcoma.

Adult↗
PubMed1986

L-prolyl-L-leucyl-glycinamide analogues--a new class of peptide antihypertensives.

Accumulating evidence suggests that there is an increase in the density (maximum binding sites) of striatal dopamine receptors in the central nervous system of spontaneously hypertensive rats (SHR). A tripeptide of hypothalamic origin, PLG (L-Prolyl-L-Leucyl-Glycinamide) has been found to have modulatory effect on the dopamine receptors in the central nervous system of rats. Two analogues of PLG with cyclic amino-acid residues, L-Prolyl-L-Leucyl-(-)-thiazolidine-2-carboxamide and L-Prolyl-L-Leucyl-(+)-thiazolidine-2-carboxamide, have shown antihypertensive effect at the established phase of hypertension in 16-week old SHRs at a dose of 35 mg/kg per day per 7 days i.p. It was also observed from studies of radioligand [3H]-spiroperidol binding that the laevo-isomer of the PLG analogue has down-regulated the up-regulated dopamine receptors. Our findings confirm the role of central dopaminergic pathways in the pathogenesis of hypertension in SHR.

Animals↗
PubMed1985

Brain adenylate cyclase activity in the amphetamine sensitized rat.

Behaviour was augmented in rats by treatment with 10 mg/kgm d-amphetamine twice a day for 10 days. A greater activation of adenylate cyclase was found in dopamine rich areas of these rats brains than in normal controls when the enzyme was tested with sodium fluoride and quanylimidodiphosphate. These results parallel similar findings in the brains of schizophrenics obtained at post mortem and support the use of amphetamine sensitization in rats as a model for schizophrenia.

Adenylyl Cyclases↗
PubMed1984

Differential changes in central serotonin and dopamine receptors in spontaneous hypertensive rats.

Functional significance of central dopaminergic and serotonergic mechanism in relation to the pathogenesis of hypertension, was assessed in the brain of hypertensive rat (SHR) models. In the mesolimbic area, dopamine receptors were found to be significantly enhanced in the SHR as compared with the normotensive control, whereas serotonin receptors in the hippocampus and frontal cortex were not significantly altered in the SHR. Our results, coupled with our previous finding on the enhanced 3H-spiroperidol binding in the striatum support the hypothesis that supersensitivity of central dopamine receptors may contribute towards the development of hypertension.

Animals↗