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S Green

Publications and source records attributed to S Green.

At least 361 records · Page 20Linked to original sources
PubMed1988

The N-terminal DNA-binding 'zinc finger' of the oestrogen and glucocorticoid receptors determines target gene specificity.

Steroid hormone receptors activate specific gene transcription by binding as hormone-receptor complexes to short DNA enhancer-like elements termed hormone response elements (HREs). We have shown previously that a highly conserved 66 amino acid region of the oestrogen (ER) and glucocorticoid (GR) receptors, which corresponds to part of the receptor DNA binding domain (region C) is responsible for determining the specificity of target gene activation. This region contains two sub-regions (CI and CII) analogous to the 'zinc-fingers' of the transcription factor TFIIIA. We show here that CI and CII appear to be separate domains both involved in DNA binding. Furthermore, using chimaeric ERs in which either the first (N-terminal) (CI) or second (CII) 'zinc finger' region has been exchanged with that of the GR, indicates that it is the first 'zinc finger' which largely determines target gene specificity. We suggest that receptor recognition of the HRE is analogous to that of the helix-turn-helix DNA binding motif in that the receptor binds to DNA as a dimer with the first 'zinc finger' lying in the major groove recognizing one half of the palindromic HRE, and that protein-DNA interaction is stabilized through non-specific DNA binding and dimer interactions contributed by the second 'zinc finger'.

Amino Acid Sequence↗
PubMed1988

Genomic organization of the human oestrogen receptor gene.

The oestrogen receptor (ER) is a ligand-activated transcription factor composed of several domains important for hormone binding, DNA binding and activation of transcription. We show here that the human ER gene is greater than 140 kb in length, split into eight exons and that the positions of these introns have been highly conserved when compared with the chicken progesterone receptor and are remarkably similar to those of one of the chicken thyroid hormone receptor genes. The N-terminal A/B region, which is not conserved between the different members of the nuclear receptor family, is almost entirely encoded within a single exon. Notably each of the putative 'zinc fingers' of the receptor DNA-binding domain is encoded separately, and the hormone-binding domain is assembled from five exons. In addition, we find that the ER isolated from the human breast cancer cell line MCF-7 contains a Gly-400----Val mutation present in the hormone-binding domain.

Amino Acid Sequence↗
PubMed1988

Structure and function of the pS2 gene and estrogen receptor in human breast cancer cells.

The role of estrogen in the growth of human breast cancers has been investigated at two levels. First, we have studied the pS2 gene, whose transcription is stimulated by estrogen in the human breast cancer cell line, MCF-7. The pS2 gene product is a small, secreted polypeptide currently of unknown function, but with structural features similar to some growth factors. The expression of the pS2 gene has so far been detected only in MCF-7 cells and some breast cancer biopsies. Preliminary studies indicate that pS2 is a potential marker for hormone-dependent breast cancer. Ongoing studies will continue to focus on the implicated role of pS2 in the estrogen-mediated growth of breast cancers and its possible use as a marker for estrogen-dependent tumors. Second, we have analyzed the structure and function of the human ER. The receptor stimulates pS2 gene transcription by interacting with an ERE in the 5'-flanking region of that gene. A mutational analysis of the receptor protein has localized a DNA-binding domain, which determines target gene specificity, and a hormone-binding domain. These domains appear to be the only two regions of the receptor which are absolutely required for the transcription-activating function of the ER in transfection assays with reporter plasmids. The N-terminal region of the protein (regions A and B), which is necessary for increasing the efficiency of gene expression using the pS2 ERE, but not a vitellogenin ERE, may also play a role in transcription activation. Further progress in the characterization of the ER functional domains will require studies on target genes in a more physiological chromatin environment, as well as detailed physical analyses of receptor structure.

Amino Acid Sequence↗
PubMed1988

A phase II evaluation of cisplatin in unresectable diffuse malignant mesothelioma: a Southwest Oncology Group Study.

Cisplatin was given intravenously to 35 evaluable patients with unresectable malignant mesothelioma on Southwest Oncology Group (SWOG) Study 8418. Five patients (14.3%) achieved partial response with median response duration of six months (range 2-12 months); eleven patients (31.4%) had stable disease of median duration of 5.5. months (range 2-21 months). Median survival for all patients was 7.5 months, 9 months for responders. Toxicity was as expected except that 12 patients (34.2%) discontinued cisplatin because of side effects. Cisplatin has moderate activity in mesothelioma and further studies with platinum analogues should be pursued.

Adult↗
PubMed1988

Effect of dietary fibre and caecectomy on the excretion of endogenous amino acids from adult cockerels.

1. Eight diets based on maize starch and sucrose were prepared, containing ground maize husks or semi-purified wood cellulose, with 30, 60, 90 or 120 g fibre source/kg diet dry matter (DM). 2. The diets were precision-fed to 12 caecectomised and 12 intact adult male domestic fowls. The quantities of amino acids and faecal N excreted over the 48 h following each feeding were measured. 3. Diet had no influence on the quantities of endogenous amino acids or endogenous faecal N excreted. 4. A proportion of the amino acids and N of the maize husks and of endogenous origin appeared to be degraded or retained in the caeca of intact birds.

Amino Acids↗
PubMed1988

Collisional excitation of interstellar water.

Rates for rotational excitation of water molecules in collisions with He atoms have been obtained from a new, accurate theoretical interaction potential. Rates among the lowest 40 ortho levels are given for kinetic temperatures to 1400 K and among the lowest 29 para levels for kinetic temperatures to 800 K.

Energy Transfer↗
PubMed1988

Evaluation of cis-platinum and DTIC combination chemotherapy in disseminated melanoma. A Southwest Oncology Group Study.

The development of disseminated melanoma is associated with an extremely poor prognosis. Use of a variety of chemotherapy agents alone and in combination has yielded response rates of only 10-30%. Surgery and radiation therapy play a useful role in palliative treatment, but have little or no value in the treatment of disseminated disease. In order to evaluate the response of disseminated malignant melanoma to combination chemotherapy with cis-platinum and 5-(3,3-dimethyl-1-triazeno) imidazole-4-carboxamide (DTIC), a phase II pilot study was developed and conducted at Oregon Health Sciences University. Thirty patients were treated from January 1983 to October 1986 and evaluated. There were two complete responses (7%) and nine partial responses (30%) for a total response rate of 37%. The median duration of response was 31 weeks. This response rate is higher than has been previously achieved with DTIC and cis-platinum, or with other drugs alone or in combination. Severe (grade 3) renal, neurologic, and hematologic toxicity was seen in four of 30, three of 30, and ten of 30 patients, respectively.

Adult↗
PubMed1988

Closure of defects from pressure sores requiring proximal femoral resection.

Proximal femoral resection (i.e., modified Girdlestone procedure) is often required in the paraplegic with an infection or dislocation of the hip joint. A philosophy and technique for dealing with this difficult problem are presented. The technique involves using an external osseous fixator to stabilize the femur and allow healing of the flap used to fill the defect.

Adult↗
PubMed1988

Air or oxygen as driving gas for nebulised salbutamol.

The effects of nebulised salbutamol driven by compressed air or oxygen were compared in a randomised crossover study during 27 attacks of acute asthma. Arterial oxygen saturation fell by 2-6% during or after treatment in 10 cases: seven with compressed air, two with oxygen, and one with both driving gases. Hypoxaemia occurred in younger children and in those who fell asleep, but was not related to the level of arterial oxygen saturation before treatment or the size of the response to bronchodilator therapy. More children fell asleep with compressed air nebulisation. Arterial oxygen saturation improved and heart rates remained stable during treatment when oxygen was the driving gas. After treatment, however, arterial oxygen saturation fell and heart rates rose to values that were similar to those after treatment with compressed air. The falls in arterial oxygen saturation we observed, though comparatively small, would be clinically important on the steep part of the oxygen dissociation curve, and our results emphasise that families with home nebulisers should seek medical advice early when their children develop severe asthma. The benefits of using oxygen as the driving gas during nebulisation were transient, and in severe asthma treatment with oxygen needs to be continued after the nebulised salbutamol has been given.

Acute Disease↗
PubMed1988

Clinical effectiveness of dermatomal evoked cerebrally recorded somatosensory responses.

Among 129 patients with spine pain and radiculopathy in both the cervical and lumbar region, there were significant differences between the upper and lower extremity DSER groups, noting the higher number of normal studies by our criteria in the upper extremities as compared to the lower extremities. This difference may be due to the intertwining of the "nerve circuitry" of the input pathways. It appears that the dermatomal somatosensory evoked response is a study of low sensitivity and of high specificity.

Adult↗
PubMed1988

Research activities in toxicology and toxicological requirements of the FDA for food and color additives.

The Center for Food Safety and Applied Nutrition of the Food and Drug Administration has published guidelines for the safety assessment of direct food and color additives. These guidelines are to be updated beginning in 1988. The safety of a food and color additive must be established prior to marketing by an evaluation of probable exposure of consumers and appropriate toxicological information. "Safe" and "safety" are defined as a reasonable certainty that a substance is not harmful under the intended conditions of use. A number of tests are used in determining the safety of food additives. Some of these are: subchronic toxicity studies, chronic toxicity studies, carcinogenicity, reproduction, teratogenicity, and occasionally short-term tests for carcinogenicity. The Center also has a research program in toxicology which in part focuses on diet/toxicity interaction and risk assessment. Examples of such activities are investigation of the teratogenicity of textured vegetable protein and of the potential of zinc to prevent or ameliorate such effects, the development of whole rat embryo cultures as a model to investigate the mechanisms by which teratogens may act, and a program in pharmacokinetics and molecular toxicology to aid in studying assumptions underlying risk assessment.

Food Additives↗
PubMed1988

Sepsis of the hip in paraplegic patients.

For the treatment of chronic sepsis of the hip in paraplegic patients, we adopted three measures: (1) a Girdlestone procedure, (2) transposition of the vastus lateralis muscle into the void that was left by the removal of the femoral head and neck and the acetabular wall, and (3) external fixation to prevent unrestrained motion of the femoral shaft, which might damage the transposed muscle. The hip joint was spanned by a posterior pelvic-femoral skeletal external fixator. Nine patients, all of whom had thoracic-level paraplegia, were treated in this manner. The fixator was kept in place for three to six weeks while the patients were cared for in the prone position. All of the infections were fully healed by twelve weeks postoperatively. In two patients, the wound drained at the edge of the flap for a short time.

Adult↗
PubMed1987

Functional domains of the human estrogen receptor.

Two domains of the human estrogen receptor, responsible for hormone binding (region E) and tight nuclear binding (region C), are essential for the receptor to activate efficiently the transcription of estrogen-responsive genes. Region D, which joins the DNA- and hormone-binding domains, can be altered without affecting activation. Deletion of the N-terminal domain (region A/B) has no effect on activation of a reporter gene containing a vitellogenin estrogen-responsive element (ERE) and the HSV-tk promoter, whereas it severely impairs activation of the human pS2 gene promoter. Deletion of most or all of the hormone-binding domain leads to only about 5% constitutive transcriptional activity, yet these mutants appear to bind efficiently to an ERE in vivo. Apparently, region C recognizes the ERE of target genes, and the hormone-binding domain plays an essential role for efficient activation of transcription.

Cell Line↗
PubMed1987

Evidence that the amygdala is involved in benzodiazepine and serotonergic effects on punished responding but not on discrimination.

Interactions between the benzodiazepines (BZs) chlordiazepoxide (CDP) and midazolam (MDZ), the BZ antagonist R0 15-1788, the inverse BZ receptor agonists CGS 8216 and FG 7142, gamma-aminobutyrate (GABA), serotonin (5-HT), the 5-HT2 antagonist methysergide and the putative 5-HT agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) were investigated using peripheral and intra-amygdaloid treatments. A multiple schedule consisting of rewarded, nonrewarded (Time out: TO) and conflict periods was used to compare in parallel effects on successive discrimination between rewarded and nonrewarded periods and punished responding. The three components were presented in both a fixed order (Experiment 1) and a random order (Experiments 2 and 3). Intra-amygdaloid treatments with GABA and the BZs selectively increased rates of punished responding. CDP given systemically, on the other hand, increased both TO and conflict rates, suggesting an additional impairment of discrimination, which was more marked in the random than the fixed order condition. R0 15-1788, CGS 8216 and FG 7142 given by both routes counteracted the anti-conflict effects of CDP given centrally or systemically. However increases in TO rates induced by IP CDP were antagonized only by IP treatments with these compounds. The two inverse agonists, but not R0 15-1788, also counteracted increases in punished responding which were found after intra-amygdaloid GABA infusions. In Experiments 2 and 3 where baseline rates of pressing in Conflict periods were sufficiently high to detect decreases, CGS 8216 and FG 7142 reduced responding below control level, suggesting a specific anxiogenic activity. Evidence for effects of R0 15-1788 by itself was inconclusive. 5-HT injected into the amygdala also reduced punished responding below control level, whereas methysergide increased it with both central and peripheral treatment. Effects of 8-OH-DPAT varied according to route of administration. With IP treatment Conflict rates were increased, but after amygdaloid infusion both TO and Conflict rates were marginally reduced below control level, with a more consistent depression of punished responding. These results provide evidence that effects of BZs on punished responding are mediated by a GABAergic system which includes the lateral/basolateral amygdala, but which does not participate in BZ-induced disruption of discrimination. They also indicate that the antagonistic effects of CGS 8216 and FG 7142 involve a decrease in GABA transmission, and that these compounds may also be anxiogenic.(ABSTRACT TRUNCATED AT 400 WORDS)

Amygdala↗
PubMed1987

Are the effects of benzodiazepines on discrimination and punishment dissociable?

Studies have shown that benzodiazepines (BZs) both disrupt discrimination and increase resistance to punishment. Using a delayed response task, we provide evidence that effects of BZs on discrimination cannot be fully explained by deficits in either short or long term memory, or by intolerance for delay of reward. A schedule with rewarded, nonrewarded (Time out: TO) and conflict components was used to investigate effects in rats of compounds active at the BZ receptor on successive discrimination and punished responding in parallel. The GABA transaminase inhibitor ethanolamine-O-sulphate exerted additive effects with chlordiazepoxide (CDP) on punished but not TO responding. Both GABA and CDP injected into the amygdala selectively increased conflict rates, but with peripheral treatment CDP also increased TO rates. Two inverse BZ agonists, CGS 8216 and FG 7142 antagonzied the anti-conflict effects of GABA and CDP, given within the amygdala or peripherally, but the increase in TO rates induced by systemic CDP was counteracted only by peripheral treatments. These compounds also reduced rates of conflict responding below baseline, consistent with anxiogenic activity. Effects of the BZ antagonist Ro 15-1788 were broadly similar to those of the inverse agonists, except that it did not antagonise the anti-conflict action of intra-amygdaloid GABA, nor significantly reduce punished responding at the single dose used. We conclude from these results that the anti-conflict effects of BZs are mediated by a GABAergic amygdaloid mechanism, but that the same mechanism is not involved in BZ effects on discrimination.

Amygdala↗