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Biomedical subjects

S Green

Publications and source records attributed to S Green.

At least 343 records · Page 19Linked to original sources
PubMed1990

Carboplatin therapy in advanced endometrial cancer.

A phase II study of the effectiveness and toxicity of carboplatin in the treatment of metastatic or locally advanced endometrial cancer was carried out by the Southwest Oncology Group. Thirty-two patients were registered in the study and 23 were fully evaluable for response and toxicity. Carboplatin was administered in a dose of 400 mg/m2 at 28-day intervals without concomitant hydration if blood counts had recovered sufficiently. There were seven responses (two complete and five partial responses) among the 23 evaluable patients, for an overall response rate of 30%. Four (two of two complete responders and two of five partial responders) of the seven responding patients remain alive at 839+ to 987+ days from the start of therapy. The two complete responders and one of the partial responders had small-volume disease, which may have contributed to their prolonged survival. Myelosuppression was the most prominent toxicity encountered. Seventeen of 27 patients evaluable for toxicity developed platelet counts of less than 75 X 10(3)/muL during therapy, but no hemorrhagic complications were encountered. Leukopenia was less prominent, with only nine of 27 patients developing white blood cell counts of less than 3.0 X 10(3)/microL. No important nephrotoxicity or neurotoxicity was observed. Emesis occurred in ten of 27 patients but was not dose-limiting. No unexpected toxicities were encountered. Carboplatin appears to be an active agent in the treatment of endometrial carcinoma.

Aged↗
PubMed1989

Combination chemotherapy and high-dose cyclophosphamide intensification for poor prognosis breast cancer. A Southwest Oncology Group Study.

Thirty-seven patients with poor prognosis, metastatic breast cancer were treated with 5-fluorouracil, vinblastine, and Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) (FUVA) induction chemotherapy. All 26 patients (74%) with responsive or stable disease after induction chemotherapy received intensification with high-dose cyclophosphamide (120 mg/kg). Continued responders received additional FUVA as consolidation. The response rate to induction therapy was 54% (with complete response [CR] in 11%). With intensification, three patients (11%) showed improved response (partial response [PR] in one, PR to complete response [CR] in two); however, six patients (23%) progressed within 2 months of cyclophosphamide intensification, three within 1 month. The overall response rate to all three phases of the study was 69%, with CR in 23%. The median survival of all patients entered in this study was 15 months. For cyclophosphamide intensification, major toxicity consisted of leukopenia with fever requiring broad-spectrum antibiotics in 27%. The authors conclude that a single cycle of high-dose cyclophosphamide intensification in metastatic breast cancer does not result in significantly improved responses or prolonged survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

A physiologically based model of creatine kinase-MB release in reperfusion of acute myocardial infarction.

To gain insight into the altered kinetics of creatine kinase-MB (CK-MB) release after reperfusion, a physiologically based model with first-order CK-MB appearance and disappearance functions was postulated. This biexponential model is based on the assumption that reperfusion reestablishes nutritive blood flow, providing direct access of interstitial CK-MB to the bloodstream. This is in contrast to persistent coronary artery occlusion, in which no direct access to nutritive flow is present. The accuracy of this model was examined in 8 dogs reperfused after 2 hours of coronary artery occlusion. The fit to observed values was excellent, with a mean r2 of 0.97 +/- 0.05. In agreement with the biexponential model, the initial increase in CK-MB activity was abrupt and rapid. The same degree of accuracy was found in 21 patients with angiographic evidence of reperfusion after thrombolytic therapy (mean r2 0.97 +/- 0.02). The appearance characteristics were similar to the animal model, with an abrupt and rapid increase in CK-MB activity. When compared with 5 patients with persistent occlusion, ka, the rate constant of the appearance function, clearly distinguished patients with reperfusion (chi-square = 20.6, p less than 0.0001), whereas considerable overlap was present in the time to peak CK-MB (time to peak less than 12 hours, chi-square = 3.6, difference not significant). Alterations of CK-MB release in reperfusion can be accurately modeled with the biexponential model. The characteristics of this model suggest that early identification of reperfusion by serial CK-MB assay is possible.

Animals↗
PubMed1989

Chimeric receptors used to probe the DNA-binding domain of the estrogen and glucocorticoid receptors.

Steroid hormone receptors activate specific gene transcription by binding as hormone-receptor complexes to short DNA enhancer-like elements termed hormone response elements. The DNA-binding domain (termed region C) is a highly conserved 66-amino acid region that contains two subregions (CI and CII) analogous to the "zinc fingers" of transcription factor IIIA. Using chimeric estrogen receptors, we show that this region, and in particular the NH2-terminal zinc finger, defines the target gene specificity of the receptor. We suggest that receptor recognition of the hormone response element 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 hormone response element and protein-DNA interaction is stabilized through nonspecific DNA binding and dimer interactions contributed by the second zinc finger.

Binding Sites↗
PubMed1989

The transcriptional activation function located in the hormone-binding domain of the human oestrogen receptor is not encoded in a single exon.

Using GAL4 chimeric receptors, we have reported previously that the hormone-binding domain (HBD) of the human oestrogen receptor (hER) contains an hormone-inducible transcription activation function. We have extended that study here to show that this activation function represents the major activating domain in the hER in HeLa cells. In addition, we have expressed the various exons encoding the hER HBD as GAL4 fusion proteins and have shown that none contain a discrete activation function. Thus the activating domain of the hER HBD appears to be different from the recently characterized 'simple' activating domains, such as acidic 'blob' or amphipathic helix, and more likely corresponds to a protein surface created from dispersed elements and dependent upon the three-dimensional folding of the HBD.

Binding Sites↗
PubMed1989

Morbidity among employees engaged in the manufacture or formulation of chlorpyrifos.

The prevalence of selected illnesses and symptoms during 1977-85 was compared between 175 employees potentially exposed to the organophosphate insecticide chlorpyrifos and 335 matched controls with no history of exposure to organophosphates. Subjects were subdivided into three exposure intensity groups on the basis of job title and air monitoring data for dose response testing. This classification scheme was shown roughly to correlate with plasma cholinesterase inhibition in the workers. No statistically significant differences in illness or prevalence of symptoms were observed between the exposed and unexposed groups or among the three exposure subgroups. Potentially exposed employees did report symptoms of dizziness and of malaise and fatigue relatively more often than subjects from the comparison group; however, further analyses by exposure level, process area, or time did not support a relation with exposure. No cases of peripheral neuropathy were seen among the exposed workers. Although the sample size was small and the statistical power limited, the cumulative exposures likely to have been experienced by this workforce exceed those to be expected for individuals using the product as recommended. The absence of exposure related adverse effects, including neurological impairment, is reassuring.

Chemical Industry↗
PubMed1989

Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study.

Four hundred forty-one women with operable breast cancer with histologically positive axillary nodes were randomized to receive either combination cyclophosphamide (60 mg/m2 orally everyday for 1 year); fluorouracil (300 mg/m2 intravenously [IV] weekly for 1 year); methotrexate (15 mg/m2 IV weekly for 1 year); vincristine (0.625 mg/m2 IV for 10 weeks); prednisone (30 mg/m2 orally days 1 to 14, 20 mg/m2 days 15 to 28, 10 mg/m2 days 29 to 42) (CMFVP) or single-agent melphalan (L-PAM) (5 mg/m2 orally every day for 5 days every 6 weeks for 2 years) chemotherapy after a modified or radical mastectomy between January 1975 and February 1978. Patients were stratified according to menopausal status and number of positive nodes (one to three, more than three nodes) before randomization. Seventy-eight patients were ineligible, most (56) because they were registered more than 42 days from surgery. Maximum duration of follow-up is 12 years, with a median of 9.8 years. The treatment arms were balanced with respect to age, menopausal status, and number of positive nodes. Among eligible patients, disease-free survival and survival were superior with CMFVP (P = .002, .005, respectively). At 10 years, 48% of patients treated with CMFVP remain alive and disease-free and 56% remain alive, compared with 35% alive and disease-free and 43% alive on the L-PAM arm. Disease-free survival and survival were significantly better with CMFVP compared with L-PAM only in premenopausal patients and patients with four or more positive nodes. Both regimens were well tolerated, although toxicity was more severe and more frequent with CMFVP. We conclude that after 10 years of follow-up, adjuvant combination chemotherapy with CMFVP is superior to single-agent L-PAM in patients with axillary node-positive primary breast cancer. The major advantage is in premenopausal women and in patients with more than three positive axillary nodes.

Age Factors↗
PubMed1989

Phosphorylation on tyrosine of in vitro synthesized human estrogen receptor activates its hormone binding.

Hormone binding controls the activity of estradiol receptor. The in vitro synthesized human receptor binds hormone with high affinity and low efficiency (1-4% of the maximal binding). We now report that phosphorylation on tyrosine of the synthetic receptor by an extensively purified calf uterus kinase increases hormone binding towards maximal levels without change in affinity. This is the first direct demonstration that a newly synthesized hormone receptor acquires ligand binding through phosphorylation. The use of in vitro synthesized proteins as substrates for enzymes which cause functional modifications of proteins is very promising because it is easy to identify the modified domains and residues by using deleted and point mutated proteins. Experiments with two estradiol receptor deletion mutants, one which lacks the N-terminal half of the receptor and binds hormone independently from the N-terminal half of the receptor, the other which lacks the C-terminal half of the receptor and contains the domain required to recognize the estradiol responsive elements, show that tyrosine phosphorylation occurs exclusively within or near the hormone binding domain of the receptor.

Amino Acids↗
PubMed1988

Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light.

Trichothiodystrophy (TTD) is an autosomal recessive disorder characterized by brittle hair with reduced sulfur content, ichthyosis, peculiar face, and mental and physical retardation. Some patients are photosensitive. A previous study by Stefanini et al. (Hum. Genet., 74: 107-112, 1986) showed that cells from four photosensitive patients with TTD had a molecular defect in DNA repair, which was not complemented by cells from xeroderma pigmentosum, complementation group D. In a detailed molecular and cellular study of the effects of UV light on cells cultured from three further TTD patients who did not exhibit photosensitivity we have found an array of different responses. In cells from the first patient, survival, excision repair, and DNA and RNA synthesis following UV irradiation were all normal, whereas in cells from the second patient all these responses were similar to those of excision-defective xeroderma pigmentosum (group D) cells. With the third patient, cell survival measured by colony-forming ability was normal following UV irradiation, even though repair synthesis was only 50% of normal and RNA synthesis was severely reduced. The excision-repair defect in these cells was not complemented by other TTD cell strains. These cellular characteristics of patient 3 have not been described previously for any other cell line. The normal survival may be attributed to the finding that the deficiency in excision-repair is confined to early times after irradiation. Our results pose a number of questions about the relationship between the molecular defect in DNA repair and the clinical symptoms of xeroderma pigmentosum and TTD.

Cell Survival↗
PubMed1988

The development of lacquer cracks in pathologic myopia.

We examined three patients with pathologic myopia who had mild visual symptoms and subretinal hemorrhages. None had subretinal neovascularization. In all three patients, lacquer crack lesions of the choroid appeared shortly after clearing of the subretinal hemorrhages. The lacquer cracks were always more extensive than the preceding hemorrhages. These findings support the theory that mechanical stretching and rupture of the Bruch's membrane-pigment epithelium-choriocapillaris complex is the cause of these lesions. Fluorescein angiography helped differentiate these subretinal hemorrhages from those caused by subretinal neovascularization.

Adult↗
PubMed1988

Intermolecular potential for thermal H2O-He collisions.

Theoretical potentials for rotational excitation of H2O by He were constructed via several methods, all of which start with a large basis set SCF interaction. The semiempirical Hartree-Fock with damped dispersion (HFD) model adds a damped long-range attraction with parameters adjusted to fit experimental total differential cross sections. Purely ab initio potentials add correlation energies obtained via perturbation theory (MP2 and MP4) or a variational method (ICF1). Scattering calculations were performed on all surfaces to compare with available beam scattering and pressure broadening data and to assess sensitivity of state-to-state rates to uncertainties in the potential. From comparison with the limited experimental data, the ICF1 surface appears to be marginally better than the MP4 surface. Thermal rates calculated from this surface should be accurate to better than 50%, at least for the larger, more important rates.

Chemical Phenomena↗
PubMed1988

The hormone-binding domains of the estrogen and glucocorticoid receptors contain an inducible transcription activation function.

We have constructed novel chimeric receptors, GAL-ER and GAL-GR, consisting of the DNA-binding domain of the yeast transcription factor GAL4 joined to the C-terminal region containing the hormone-binding domain of either the human estrogen (hER) or human glucocorticoid (hGR) receptor. Stimulation of transcription by GAL-ER and GAL-GR from GAL4-responsive reporter genes was hormone dependent, and the activation function has been localized to the hER or hGR region. Both chimeric receptors recognized GAL4-responsive elements only in the presence of hormone or anti-hormone, yet solely the hormone was capable of stimulating transcription. These and additional results suggest that the hormone plays at least a dual role. First, the hormone, or anti-hormone, is responsible for receptor "transformation" allowing the recognition of responsive DNA elements. Second, the hormone, but not the anti-hormone, can induce a transcription activation function present in the region that contains the hormone-binding domain.

DNA↗
PubMed1988

The yeast UASG is a transcriptional enhancer in human HeLa cells in the presence of the GAL4 trans-activator.

The yeast trans-activator protein GAL4, when expressed in HeLa cells, stimulates transcription from several class B (II) eukaryotic promoters containing GAL4 binding sites either as the full UASG or as synthetic 17-mers. The characteristics of this activation are indistinguishable from those of the SV40 enhancer. Transcription was similarly stimulated from either complex promoter regions containing multiple upstream elements or from a simple promoter region composed of only a TATA box. Addition of a 17-mer GAL4 binding site to the SV40 enhancer resulted in a synergistic enhancement of transcription in the presence of GAL4. Furthermore, chimeras of the human estrogen receptor DNA binding domain and either GAL4 or GCN4 activating "acidic" regions can activate a promoter region controlled by an estrogen-responsive enhancer. Together, these data indicate that the molecular mechanisms responsible for transcriptional enhancement have been conserved from yeast to man.

Animals↗
PubMed1988

Expression of human estrogen receptor mutants in Xenopus oocytes: correlation between transcriptional activity and ability to form protein-DNA complexes.

The human estrogen receptor (hER) is a trans-acting regulatory protein composed of a series of discrete functional domains. We have microinjected an hER expression vector (HEO) into Xenopus oocyte nuclei and demonstrate, using Western blot assay, that the hER is synthesized. When nuclear extracts from oocytes were prepared and incubated in the presence of a 2.7 kb DNA fragment comprising the 5' end of the vitellogenin gene B2, formation of estrogen-dependent complexes could be visualized by electron microscopy over the estrogen responsive element (ERE). Of crucial importance is the observation that the complex formation is inhibited by the estrogen antagonist tamoxifen, is restored by the addition of the hormone and does not take place with extracts from control oocytes injected with the expression vector lacking the sequences encoding the receptor. The presence of the biologically active hER is confirmed in co-injection experiments, in which HEO is co-introduced with a CAT reporter gene under the control of a vitellogenin promoter containing or lacking the ERE. CAT assays and primer extensions analyses reveal that both the receptor and the ERE are essential for estrogen induced stimulation of transcription. The same approach was used to analyze selective hER mutants. We find that the DNA binding domain (region C) is essential for protein--DNA complex formation at the ERE but is not sufficient by itself to activate transcription from the reporter gene. In addition to region C, both the hormone binding (region E) and amino terminal (region A/B) domains are needed for an efficient transcription activation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗