Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Prepubertal Angus crossbred heifers (n = 24) between 8 and 10 mo of age were used to determine if progestogen treatment would enhance jugular concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) after oxytocin (OT) injections. Heifers were stratified by age and weight and allotted to randomized treatments in a 2 x 2 factorial arrangement. Heifers were treated with either a norgestomet (NOR) implant (6 mg) for 9 d or no implant (0 mg; BLK). On d 8 of NOR treatment, jugular veins were catheterized and, on d 9, blood samples were collected every 15 min for 165 min. The first four samples were used to determine basal PGFM concentrations (an indirect measure of uterine PGF2 alpha release). After collection of the fourth sample, either OT (100 IU) or saline (0 IU; SAL) was injected via the jugular catheter. After the 165-min sample was collected, NOR implants were removed. Beginning 48 h after implant removal, a second 165- min blood sampling period was initiated. Average progesterone concentrations were less than 1 ng/ml during both bleeding periods. Within treatment, PGFM concentrations were similar between the first and second sampling periods; therefore, data within treatment were combined. Basal PGFM concentrations were higher (P < .01) in NOR-treated than in BLK heifers. Oxytocin did not increase PGFM concentrations in BLK-OT heifers; however, a marked increase in PGFM was detected in the NOR-OT heifers in response to oxytocin. Average PGFM concentration was greatest (P < .0001) in NOR-OT heifers, and PGFM profiles differed (P < .0001) between NOR-OT and each of the other treatment groups. Results from this study indicate that NOR increases basal PGFM and may "condition" the uterus to respond to OT in prepubertal heifers.
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PMID:Jugular plasma concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha in prepubertal beef heifers treated with progestogen then challenged with oxytocin. 147 75

The presence of amidases cleaving the tripeptide VAL.LEU.ARG.pNA, and liberating from human plasma kininogen substance(s) able to contract uterine smooth muscle and to lower blood pressure (uterus contracting and hypotensive activity), has been demonstrated in vascular and muscle tissues from normally perfused and ischaemic areas of dog hearts. Studies were carried out on blood free preparations of coronary arteries and veins and normally perfused and ischaemic ventricle. All the tissues were found to contain both acid optimum (pH 6) and alkaline optimum (pH greater than 9) enzymes forming uterus contracting substance (UCS, bioassayed on isolated uterus of rats in oestrus), the highest levels of both activities being found in arterial tissues and the least in ventricle. Enzyme levels in ischaemic or normally perfused ventricle did not differ significantly. Gel filtration (Sephacryl, S-300) of coronary artery extracts gave one peak each of acid optimum enzyme with a molecular weight of 38,300 +/- 800 daltons and alkaline optimum enzyme with a molecular weight of 92,100 +/- 4000 daltons. Both acid and alkaline enzyme fractions cleaved the tripeptide substrate with pH optima identical to those for UCS formation. The acid optimum activity, both of UCS formation and tripeptide cleavage, was inhibited by pepstatin but not by aprotinin or soybean trypsin inhibitor (SBTI). The alkaline optimum activity was inhibited by aprotinin and SBTI but not pepstatin. Both acid and alkaline optimum enzymes released a hypotensive agent from a plasma protein substrate. The molecular weight and response to inhibitors of the acid optimum enzyme were similar to a cathepsin, and those of the alkaline optimum enzyme were similar to plasma kallikrein.
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PMID:Enzymes in normally perfused and ischaemic dog hearts which release a substance with kinin like activity. 277 62

Heavy distillate (HD), the highest-boiling coal liquid from the solvent-refined coal-II process (SRC-II), was administered by intragastric (IG) intubation to pregnant rats. Five dose levels of HD (0.09, 0.14, 0.18, 0.36 and 0.74 g kg-1), were given daily from 12 to 16 days of gestation and the rats were killed at 20 days of gestation. Maternal body weights and weights of the liver, kidneys, spleen, adrenals, thymus, ovaries and the gravid uterus were obtained. Gravid uteri were evaluated for prenatal mortality. Live fetuses were examined for malformations and weighed; fetal lungs were excised and weighed. Maternal (extragestational) weight gains and thymic weights diminished in all groups that received the SRC material. Adrenal weights were increased in all treated animals, except for those in the lowest-dose group (0.9 g kg-1). There was significant maternal mortality at 0.74 g kg-1 and increased intrauterine mortality at doses of 0.37 and 0.74 g kg-1. Placental weight was depressed, and the incidence of fetal anomalies was increased at 0.14 g kg-1 and all higher dose levels.
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PMID:Developmental toxicity following oral administration of a high-boiling coal liquid to pregnant rats. 671 82

Radiation therapy of cervix carcinoma is applied in this Institute by means of a modified Stockholm method in combination with external beam irradiation. In 1968, parametrial portals were replaced by large planparallel opposed fields extending cranially to LIII/LIV with central shielding in order to avoid overdosage in the area of intracavitary treatment. This resulted in a marked increased incidence of severe sigmoid-colon radiation lesions from 0.25% to 4%; predominantly in Stage I and II patients. Therefore two measures have been introduced: beginning in 1972 measures were taken to prevent the cranial displacement of the uterus during intracavitary treatment in order to avoid shortening the distance between the radioactive sources and the sigmoid-colon; from 1972 stereo X ray photogrammetry (SMR) was applied for dose determinations at points of the sigmoid-colon, which were seen to be located close to the applicator. When SRM data indicated that a high dose at the sigmoid-colon might occur, treatment modifications enabled prevention of radiation damage. Change of position of the applicator was the first to be considered. In the last seven years no surgical intervention had to be performed because of a sigmoid-colon lesion resulting from an unexpected high radiation dose delivered by intrauterine sources. The local recurrence rate was not increased following treatment modifications for prevention of sigmoid-colon radiation damage.
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PMID:Stereo X ray photogrammetry applied for prevention of sigmoid-colon damage caused by radiation from intrauterine sources. 710 31

In order to understand the structural features that might lead to an estrogen receptor (ER) based breast tumor imaging agent with improved uptake characteristics, we have synthesized several new analogs of 16 beta-fluoroestradiol (beta FES) and studied their tissue distribution in immature rats. The compounds we prepared were 11 beta-methoxy-beta FES (7a), 11 beta-ethyl-beta FES (7b), 17 alpha-ethynyl-beta FES (8c), 17 alpha-ethynyl-11 beta-methoxy-beta FES (8a), and 11 beta-ethyl-17 alpha-ethynyl-beta FES (8b). All of the analogs exhibit good affinity for ER, ranging at 25 degrees C from 10 to 460, with estradiol equal to 100. Measurement of their octanol/water partition coefficients by an HPLC method allowed us to estimate their level of nonspecific binding and thereby to predict their binding selectivity indices (BSI, i.e., the ratio of their ER-specific to nonspecific binding); the BSI values of three fluorine-substituted analogs exceed that of estradiol. These ligands have been labeled in the 16 beta position with fluorine-18 by the nucleophilic displacement of an alpha-disposed trifluoromethanesulfonate by [18F]fluoride ion. Reduction with lithium aluminum hydride produced the estradiol series ([18F]-7a-c), while treatment with lithium trimethylsilylacetylide afforded the ethynylated series ([18F]-8a-c). The synthesis time was 85 min for [18F]-7a-c and 120 min for [18F]-8a-c, with radiochemical yields ranging from 16 to 43%, and effective specific activities being 90-2900 Ci/mmol (3.3-107 TBq/mmol). In tissue distribution studies in immature female rats, all of the labeled analogs demonstrated ER-selective uptake in the principal target tissues, the uterus and the ovaries, and also in organs with lower titers of ER, the secondary target sites kidney, thymus, fat, and muscle. Although factors other than specific and nonspecific binding obviously affect the tissue distribution of these 16 beta-fluoroestrogens, we find that their ER-specific uptake by both the principal and the secondary target tissues correlates with their BSI values at a high level of statistical significance in most cases. The ethynylated-11 beta-methoxy analog [18F]-8a had high selectivity (uterus to blood ratio) after 3 h and exhibited the highest uterine uptake (percent injected dose/gram) of any fluorine-substituted estradiol ligand we have studied to date. This compound has been chosen for more detailed studies (to be described elsewhere), including clinical trials in human patients diagnosed with primary breast cancer.
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PMID:16 beta-([18F]fluoro)estrogens: systematic investigation of a new series of fluorine-18-labeled estrogens as potential imaging agents for estrogen-receptor-positive breast tumors. 768 51

The spatial and temporal expression of the transforming growth factor beta (TGF-beta) receptors type III, type II, and two types I (ALK-5 and Tsk 7L) and their ligands TGF-beta 1 and TGF-beta 2 in postimplantation mouse development were examined using the reverse transcription polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry. With RT-PCR, expression of the signaling TGF-beta receptors (types II and ALK-5) was shown to be absent in isolated germ layers of 6.0-7.5 days postcoitum (dpc) embryos, whereas the type III receptor and Tsk 7L were differentially expressed at these stages. In contrast, all TGF-beta receptor types were expressed at these stages in the pregnant uterus and decidua. TGF-beta 1 and TGF-beta 2 transcripts were detected before gastrulation at 6.5 dpc only in the visceral embryonic endoderm, whereas during gastrulation, at 7.5 dpc TGF-beta 1 and TGF-beta 2 mRNA was detected in all three germ layers. In situ hybridization and immunohistochemistry of the expression of the TGF-beta type II receptor confirmed the data obtained by RT-PCR. Furthermore, the type II receptor was detected in the extraembryonic ectoderm of 7.5 dpc embryos. In the embryo proper, TGF-beta type II receptor expression was detected only later in differentiating tissues and developing organs, but not in the brain and neural tube. Since the expression of the type II receptor may essentially determine whether a cell is able to respond to TGF-beta, the results are consistent with the view that TGF-beta s might be implicated in embryo implantation and organogenesis, but are not involved in gastrulation of the embryo.
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PMID:Expression of TGF-beta s and their receptors during implantation and organogenesis of the mouse embryo. 781 89

Bovine embryos, recovered from the uterus in vivo or derived from in vitro matured and in vitro fertilized oocytes, were investigated for the presence of the developmentally regulated mouse antigen TEC-3 by indirect immunofluorescence. During preimplantation embryo development TEC-3 is expressed on bovine morulae and blastocysts. It is absent from unfertilized and fertilized oocytes, and from all stages before the 32-cell stage. The finding that TEC-3 is not expressed before the onset of embryonic transcription, which occurs at the eight-cell stage in the bovine, but only when the embryonic genome is active, makes it a potential marker for studying nuclear reprogramming after nuclear transfer. Nuclear transfer embryos were made by electrical fusion of blastomeres from morulae derived in vivo with enucleated metaphase II oocytes. Indirect immunofluorescence with the TEC-03 antibody showed that the TEC-3 antigen, present on blastomeres of the morula stage embryo, disappeared after fusion and was expressed again when the nuclear transfer embryos developed to the morula and blastocyst stage. These data suggest that the bovine embryonic nucleus may be able to revert to the equivalent of an earlier developmental stage when transferred to ooplasm, and is then capable of following the normal developmental program.
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PMID:Stage-specific appearance of the mouse antigen TEC-3 in normal and nuclear transfer bovine embryos: re-expression after nuclear transfer. 812 28

We have measured in vivo the uptake of 16 alpha-[18F]estradiol (FES) by target tissues in the immature rat at increasing dose levels (obtained by dilution of [18F]FES with unlabeled estradiol). This was done to examine the binding capacity of target tissues in vivo and to determine whether the uptake in receptor-rich tissues was flow limited, as this has implications concerning the appropriateness of using receptor-rich tissues in experimental animals as models for FES uptake by receptor-poor breast tumors in humans. We also wanted to establish the dose level of the anti-estrogen tamoxifen required to block target tissue uptake of FES. We found that in untreated rats, specific uptake in the uterus saturated at c. 180 pmol/g, in the ovary at c. 54 pmol/g and in the muscle at c. 2 pmol/g. At an intermediate dose of tamoxifen (570 micrograms/kg), uptake saturated at somewhat lower levels, and at a high tamoxifen dose (1710 micrograms/kg), yet lower specific uptake was evident. In the FES titrations at low dose levels of FES, both the uterus and the ovaries, but not the muscle, showed characteristics of flow-limited uptake, i.e. the uptake-to-dose ratio reached a maximum level. This flow limitation suggests that only when receptor levels are sufficiently low will the FES uptake be related to receptor concentration. While receptor-rich tissues such as the rat uterus will show this flow limitation, the receptor concentration in most primary and metastatic human breast tumors is sufficiently low, so that the uptake should parallel receptor content. In in vivo distribution studies, target tissues (or tumors) with low receptor content will be more fully saturated and ligand more readily displaced. Also, uptake by secondary target tissues (i.e. those with a lower content of estrogen receptor, such as muscle, thymus and kidney) may be better models for assessing the effectiveness of new breast tumor imaging agents than uptake by receptor-rich tissues.
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PMID:Titration of the in vivo uptake of 16 alpha-[18F]fluoroestradiol by target tissues in the rat: competition by tamoxifen, and implications for quantitating estrogen receptors in vivo and the use of animal models in receptor-binding radiopharmaceutical development. 840 74

A cDNA (CSMK1) encoding a delayed rectifier K+ channel of the Kv1.2 class was cloned from canine colonic circular smooth muscle and expressed in Xenopus oocytes. These channels appear to be uniquely expressed in gastrointestinal muscles and may participate in the electrical slow wave activity. Functional expression of CSMK1 in Xenopus oocytes demonstrated a K+ current that activated in a voltage-dependent manner upon depolarization. This current was highly sensitive to 4-aminopyridine (IC50, 74 microM). A low-conductance K+ channel was identified in inside-out patches from oocytes injected with CSMK1. This channel displayed a linear current-voltage relation with a slope conductance of 14 pS. The channels were blocked in a concentration-dependent manner by 4-aminopyridine. Northern blot analysis demonstrated that CSMK1 is expressed in a wide variety of gastrointestinal smooth muscles. Portal vein, renal artery, and uterus do not express CSMK1, suggesting that, among smooth muscles, expression of this K+ channel may be restricted to gastrointestinal smooth muscles. CSMK1 is 91% homologous to RAK, a delayed rectifier K+ channel cloned from rat heart, but displays unique pharmacological properties and tissue distribution.
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PMID:Cloning and expression of a Kv1.2 class delayed rectifier K+ channel from canine colonic smooth muscle. 841 58

The fps/fes proto-oncogene encodes a cytoplasmic protein tyrosine kinase that is thought to participate in signaling pathways involving members of the cytokine receptor superfamily, including those for erythropoietin, granulocyte-macrophage colony-stimulating factor, leukemia inhibitory factor, oncostatin M, ciliary neurotropic factor, and interleukins 3, 4, 6, and 11. Expression of fps/fes has been detected in hematopoietic cells, vascular endothelial cells, and cell types arising from all three germ layers during early development. Here, we describe fps/fes expression in developing and adult tissues from normal mice or from transgenic animals overexpressing wild-type or activated mutant fps/fes alleles. The highest levels of fps/fes expression were seen in angioblasts of early yolk sac blood islands, chondrocytes, vascular endothelial cells, neuronal cells, and several epithelial cell types, including those of the choroid plexus and the uterus. Fps/Fes protein was concentrated in the perinuclear region of cultured neuronal, myeloid, epithelial, and vascular endothelial cells, and a chimeric Fps/Fes-green fluorescence protein colocalized with gamma-adaptin, a marker for the trans-Golgi apparatus. These observations suggest the involvement of Fps/Fes in vesicle transport processes in cells with prominent secretory functions.
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PMID:The fps/fes tyrosine kinase is expressed in myeloid, vascular endothelial, epithelial, and neuronal cells and is localized in the trans-golgi network. 880 11


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