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)

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

FES is a non-receptor protein tyrosine kinase expressed in hematopoietic progenitors and differentiated myeloid cells. It has recently been implicated in granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and erythropoietin signal transduction. To better understand the role played by FES in normal and neoplastic hematopoiesis, we used cell fractionation techniques to examine the subcellular localization of FES in myeloid cells and cell lines. FES was observed in the nuclear, granular and plasma membrane fractions of primary human neutrophils and the myeloid leukemia cell line, HL-60. The nuclear localization was confirmed by immunocytochemistry of neutrophils.
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PMID:Human c-FES is a nuclear tyrosine kinase. 770 Jun 50

Transcripts coding for transcription factors (RB, P53, FOS, MYC, MYB, ERBA, REL), growth factors (FGF1, FGF2, INT2, TGFA, TGFB, PDGF, IGF1, IGF2), interleukins, (IL1, IL2, IL3, IL4, IL6, TNF), growth-factor receptors or cytosolic protein kinases (RAF, PIM, FES, MET, SRC, ROS, TRK, KIT, CSFR, IGFR, PDGFR, EGFR, NEU) were quantified in cultured human mammary fibroblasts from normal tissues, benign tumours, carcinomas and post-radiation fibrosis lesions by slot-blot autoradiography and image analysis. The effects of a differentiating agent (cholera toxin) and of a tumour promoter (12-O-tetradecanoyl-phorbol-13-acetate) were also examined. The drugs modulated the levels of the anti-oncogene transcripts (RB, P53) and of ERBA, REL, RAF, MET, ROS, TRK, CSFR, EGFR, NEU, FGF1, INT2, IGF1, IL1, IL2, IL4 and IL6. Apart from this variation, there were multiple differences in gene expression among normal and pathological cells (concerning all but P53, TGFB and interleukin transcripts) and between sub-types defined by the presence of alpha-sm-actin (myofibroblasts) or EDB-fibronectin (RAF, ROS, FES, KIT, IGFR, NEU, INT2, TGFB, PDGF, IGFs, ILs). It appears, therefore, that mammary stroma progress irreversibly along with the epithelium during tumoral development, and that breast cancer is not only a multi-gene but also a multi-tissue phenotype.
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PMID:Quantitative variation of proto-oncogene and cytokine gene expression in isolated breast fibroblasts. 776 44

It is unknown whether the catecholamine (CAT) response to acute exercise and prolonged training in humans with spinal cord injury (SCI) is similar to that of neurologically intact man. Plasma samples were collected from seven subjects with chronic SCI (level of injury C5-T7) at rest and during voluntary arm-crank ergometry (ACE) before and after 6 months of training with functional electrical stimulation cycle ergometry (FES-CE). Similar plasma collections were made during one FES-CE exercise training session after 6 months of training. Norepinephrine (NE) and epinephrine (EPI) were measured by HPLC. After FES-CE training, resting NE decreased 37% (950 +/- 150 vs 1510 +/- 350 pmol.l-1 pretraining); resting EPI decreased 80% (54 +/- 10 vs 163 +/- 32 pmol.l-1 pretraining) (P < 0.05 by paired t-tests). No significant changes were observed in group means after training for the CAT response to submaximal ACE; however, five of seven subjects exhibited greater increments in plasma NE with ACE after FES-CE training. Acute FES-CE exercise elicited a 55-844% increase in NE, and a 35-350% increase in EPI above resting values with power outputs eliciting heart rates of 90-146 bpm. These data provide evidence for a systemic CAT response in subjects with SCI during acute FES-CE and reduced resting CAT following 6 months of training with FES-CE.
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PMID:Catecholamine response to exercise and training in individuals with spinal cord injury. 779 64

Protein tyrosine kinases have been implicated in tumor initiation and progression. Here we used Northern blotting to study expression of their genes in cultured normal melanocytes and 19 melanoma cell lines from different stages of tumor progression. We detected transcripts for 2 cytoplasmic (ABL and FES) and 6 receptor (ECK, ERB-B2, FGF-R4, IGFI-R, KDR and TIE) kinases but not for receptors RET or TRK-A. Genes for ECK, FGF-R4 and TIE were expressed ectopically in melanomas (not in normal melanocytes). Similarly, ECK protein was detected by immunoblotting in metastatic melanomas but not in normal melanocytes. ECK mRNA levels tended to increase again during late melanoma progression. ECK and TIE mRNAs were also detected in highly metastatic variant cells but not in the corresponding poorly metastatic parental lines. Conversely, FES and KDR gene expression was lost in most advanced primary and metastatic melanomas. These findings suggest positive and negative roles for specific tyrosine kinases during progression.
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PMID:Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. 781 45

Estrogen receptors are expressed in several brain areas of various animal species, and steroid hormones exert physiologic and biochemical effects on the central nervous system. The aim of the present study was to evaluate in female adult rats, the suitability of 16 alpha [18F]fluoro-17 beta-estradiol ([18F]FES), a selective estrogen receptor ligand, for the in vivo assessment of brain estrogen receptors. This was considered to be a preliminary step in evaluating the potential usefulness of [18F]FES for studies of cerebral estrogen receptors with positron emission tomography (PET) in nonhuman primates and human subjects. We evaluated (a) the time course of the metabolic degradation of [18F]FES in blood; (b) the time course of distribution of the tracer in discrete cerebral areas; (c) the inhibitory effect of increasing doses of cold estradiol on cerebral [18F]FES uptake; and (d) the possibility of in vivo quantification of estrogen receptor binding parameters using both equilibrium and dynamic kinetic analyses. We quantified [18F]FES binding to estrogen receptors using both equilibrium and dynamic kinetic analyses. The results of this study indicate that [18F]FES is a suitable tracer for the measurement of estrogen receptors in the pituitary and hypothalamus, using either the equilibrium or the kinetic analysis. However, [18F]FES is inadequate for the in vivo investigation of estrogen binding sites in brain areas with low receptor density, such as the hippocampus.
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PMID:Systemic and cerebral kinetics of 16 alpha [18F]fluoro-17 beta-estradiol: a ligand for the in vivo assessment of estrogen receptor binding parameters. 786 Jun 63

Incidence and prevalence rates of both anorexia nervosa and bulimia among adolescents have steadily increased during the past decade. The purpose of this study was to examine the relationship of gender and family environment to the risk of developing anorexia nervosa or bulimia in adolescents. The Family Environment Scale (FES; Moos & Moos, 1981) and the Setting Conditions for Anorexia Nervosa Scale (SCANS; Slade, Phil, & Dewey, 1986) were used to measure select components of family environment and risk of developing anorexia nervosa or bulimia, respectively. Data were collected from 393 students attending a private secondary boarding school located in central New Jersey. Subjects represented 35 states and 25 countries, had a mean age of 16.3 years, were predominantly Caucasian (75.6%) with a Catholic (27.5%) or Protestant (26.5%) affiliation, and reported a family income in excess of $50,000 (63.9%). Multiple regression using a unique approach revealed a significant relationship between family environment and the risk of developing anorexia nervosa or bulimia in adolescents (p < .01). The FES subscale of expressiveness was the only subscale found to have a significant relationship with the risk of developing anorexia nervosa or bulimia. Female subjects displayed a greater risk than did males (p < .01). Finally, no significant interaction was found between family environment and gender on the risk of developing anorexia nervosa or bulimia in adolescents. Simple correlation of the FES subscales was conducted by means of Pearson product moment and results indicated that lower cohesion, expressiveness, and organization were significantly associated with greater eating disorder risk (p < .01). Lower independence was significantly associated with increased eating disorder risk, but to a lesser degree (p < .05). Greater conflict (p < .01) and control (p < .05) were significantly associated with greater eating disorder risk.
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PMID:The relationship of gender and family environment to eating disorder risk in adolescents. 789 93

It has recently been demonstrated that mutations in the gene for Bruton's tyrosine kinase (BTK) are responsible for X-linked agammaglobulinemia. Southern blot analysis and sequencing of cDNA were used to document deletions, insertions, and single base pair substitutions. To facilitate analysis of BTK regulation and to permit the development of assays that could be used to screen genomic DNA for mutations in BTK, we determined the genomic organization of this gene. Subcloning of a cosmid and a yeast artificial chromosome showed that BTK is divided into 19 exons spanning 37 kilobases of genomic DNA. Analysis of the region 5' to the first untranslated exon revealed no consensus TATAA or CAAT boxes; however, three retinoic acid binding sites were identified in this region. Comparison of the structure of BTK with that of other nonreceptor tyrosine kinases, including SRC, FES, and CSK, demonstrated a lack of conservation of exon borders. Information obtained in this study will contribute to our understanding of the evolution of nonreceptor tyrosine kinases. It will also be useful in diagnostic studies, including carrier detection, and in studies directed towards gene therapy or gene replacement.
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PMID:The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. 792 35

To examine our hypothesis that family experiences would be associated with attitudes toward marriage, we administered the Family Environment Scale (FES; Moos & Moos, 1986) and a Marriage Attitudes Questionnaire (MAQ; adapted from Long, 1987) to 40 unmarried college students. Correlational analyses indicated that for the conflict subscale of the FES, only two of the six marital expectation questions approached significance. However, family expressiveness (another subscale of the FES) was significantly correlated with three of the marital expectation questions and approached significance with a fourth question. These results indicated that higher expressiveness in the family was significantly related to positive attitudes toward marriage. We concluded that family dynamics need to be studied from multiple perspectives to identify factors that influence marital expectations.
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PMID:Family dynamics and attitudes toward marriage. 793 94

We present a case of FES (fat embolism syndrome) with very serious neurologic signs (convulsions, deep coma, decerebrate response to noxious stimuli), without lung lesions. Nuclear magnetic resonance imaging revealed vascular alterations of the cerebral hemisphere, truncus, and cerebellum. The patient recovered without neurologic sequelae.
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PMID:Neurologic symptoms in fat embolism syndrome: case report. 801 21


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