Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Administration of large amounts of synthetic peptides based on the Arg-Gly-Asp (RGD) sequence has been shown to suppress tumor metastasis. To overcome the rapid degradation of peptides in the circulation, an RGD mimetic, L-arginyl-6-aminohexanoic acid (NOK), was synthesized and conjugated with phosphatidylethanolamine (PE) (NOK-PE) for liposomalization. Cell adhesion assays revealed that B16BL6 murine melanoma cells adhered to immobilized NOK-PE. This adhesion was inhibited by addition of either soluble RGDS or NOK at similar concentration in a dose-dependent manner. Administration of NOK-PE liposomes (equivalent to ca. 500 microg RGD peptides) via the tail vein completely inhibited lung colonization of B 16BL6 cells. The same dose of soluble NOK was not effective in inhibition of the tumor metastasis. In addition, injection of NOK-PE liposomes via the tail vein inhibited spontaneous lung metastasis of B16BL6 cells from the primary tumor site in the hind footpad. These results suggest that NOK, a structural mimetic of RGD, is capable of suppressing metastasis by blockade of the binding of the integrins present on tumor cells to the RGD-containing extracellular matrix.
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PMID:Liposomes modified with a synthetic Arg-Gly-Asp mimetic inhibit lung metastasis of B16BL6 melanoma cells. 1119 43

Fibroblast growth factors are structurally related proteins associated with cell growth, differentiation, migration, wound healing, angiogenesis, and oncogenesis. At the cellular level, their function is mediated by transmembrane tyrosinekinase receptors, fibroblast growth factor receptors. Four genes encoding fibroblast growth factor receptors have been identified, and mutations in three of these, FGFR1, FGFR2, and FGFR3, can cause different congenital, autosomal dominant disorders affecting the craniofacial and skeletal development: craniosynostosis and chondrodysplasias. The craniosynostosis syndromes: Apert syndrome, Beare-Stevenson syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Muenke syndrome, Pfeiffer syndrome and Saethre-Chotzen syndrome can be caused by mutation in either FGFR1, FGFR2, or FGFR3. Saethre-Chotzen syndrome can also be caused by mutation in a functionally related gene, ACS. The same mutation can cause different syndromes, and the same syndrome can be caused by mutations in different genes. The chondrodysplasias: achondroplasia, hypochondroplasia, and thanatophoric dysplasia are all caused by mutations in FGFR3.
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PMID:[The molecular genetic background of hereditary craniosynostoses and chondrodysplasias]. 1157 61

Soluble ErbB (sErbB) growth factor receptors are being investigated as cancer biomarkers. Gonadotropic and steroid hormones have been shown to modulate the expression of ERBB family members in vivo. Accordingly, the range of sErbB1 values and their relationship to gonadotropic and steroid hormones need to be established in healthy subjects to provide a baseline for future clinical studies. We assayed sera from healthy men and women to determine p110 sErbB1 concentrations by acridinium-linked immunosorbent assay (ALISA). Follicle-stimulating hormone (FSH), estradiol, and testosterone concentrations were measured using the ACS:180 Immunoassay Analyzer. Luteinizing hormone (LH) and progesterone concentrations were quantified using the Access Immunoassay System. Unadjusted for age, p110 sErbB1 concentrations in healthy men and women do not differ significantly. However, sErbB1 concentrations show a strong age-gender interaction, increasing with age in men but decreasing with age in women. Consequently, sErbB1 concentrations are significantly higher in premenopausal women compared with either postmenopausal women or age-matched men and in age-matched men compared with postmenopausal women. Serum sErbB1 concentrations show significant negative associations with both FSH and LH concentrations in healthy women and a significant positive association with FSH concentrations in healthy men. Univariate linear regression models show that these respective gonadotropic hormones and age are independent predictors of sErbB1 concentrations in men and women. Multivariate models show that when age and FSH and LH concentrations are mutually adjusted for each other, they account for 22% of the variability observed in sErbB1 concentrations in healthy women. These data support the hypothesis that gonadotropic and steroid hormones may modulate ERBB1 expression in vivo and suggest that age- and gonadotropin-adjusted sErbB1 concentrations may be of clinical utility. Furthermore, these data demonstrate that gender, age, menstrual cycle phase, menopausal status, and exogenous hormone use must be considered when using serum p110 sErbB1 concentrations as cancer biomarkers.
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PMID:A preliminary study of serum concentrations of soluble epidermal growth factor receptor (sErbB1), gonadotropins, and steroid hormones in healthy men and women. 1170 Feb 66

The article describes the methods for the correction of hypermetropia, i.e. micro-lamellar keratotomy (MLK) and MLK plus thermokeratocoagulation (MLKTKC). The experiment was made on 6 rabbits (12 eyes). Lamellar corneal incisions were implemented by ALK ACS system (USA) to a depth of 73-75% of the corneal thickness. Simultaneously, thermokeratocoagulation (TKC) to 80% of the corneal thickness was made in a part of animals in meridians 6, 8, 10 and 12 (an 8 mm optic zone and 3 to 4 coagulates in each meridian). Postoperatively, the keratometric data were evaluated in 1, 3 and 6 months. The corneal optic power went up, postoperatively, in the center by around 4.0 diopters in cases, when the common surgical technique was used, and it went up to 5.0-9.0 diopters, when the common technique was combined with TKC. A clinical approbation of the MLK and MLKTKC methods in adults with hypermetropia (44 operations, mean age 29.3 years) showed their efficiency and safety. The corneal refraction improvement ranged from 3.5 diopters to 7.5 diopters (mean 4.49 +/- 0.89 diopters). The developed method of the above surgeries (the diameter of the modeled optic zone is 5 mm, the lamellar depth incision is 73%) prevents the complications, which lead to irreversible changes of the cornea; besides, it makes it possible to preserve a sufficiently wide central optic zone with a present refraction. This study provided a foundation for the clinical use of the method in pediatric practice.
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PMID:[Experimental-clinical substantiation of the use of micro-lamellar keratotomy combined with kerato-thermocoagulation in the correction of hypermetropia]. 1367 7

Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). Since the over-expression of receptors for vascular endothelial growth factor (VEGF) is correlated with tumor angiogenesis and subsequent growth, we conjugated a photosensitizer (5-(4-carboxyphenyl)-10,15,20-triphenyl-chlorin, TPC), via a spacer (6-aminohexanoic acid, Ahx), to a VEGF receptor-specific heptapeptide (ATWLPPR). ATWLPPR and TPC-Ahx-ATWLPPR bound exclusively to neuropilin-1 (NRP-1) recombinant chimeric protein (IC50=19 and 171 microM, respectively) but were devoid of affinity for VEGF receptor type 2 (VEGFR-2, KDR), to which ATWLPPR was initially thought to bind. TPC-Ahx-ATWLPPR was incorporated up to 25-fold more in human umbilical vein endothelial cells (HUVEC) than TPC over a 24-h period, and the addition of 8 mM ATWLPPR induced a significant decrease of this uptake (P<0.05), corroborating a receptor-mediated incorporation. Slightly less cytotoxic in the dark, TPC-Ahx-ATWLPPR exhibited enhanced in vitro photodynamic activity (10.4-fold), compared to TPC. Pharmacokinetic analysis in nude mice xenografted with U87 human malignant glioma cells revealed relevant tumor levels as soon as 1 h after intravenous injection of TPC-Ahx-ATWLPPR, and a rapid elimination from the blood compartment. Moreover, TPC-Ahx-ATWLPPR was not degraded in vivo up to 2 h after intravenous injection. Taken together, our results demonstrate that TPC-Ahx-ATWLPPR is a much more potent photosensitizer in vitro than TPC, in NRP-1-expressing cells. Thus, it may efficiently potentiate the vascular effect of PDT in vivo.
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PMID:A peptide competing with VEGF165 binding on neuropilin-1 mediates targeting of a chlorin-type photosensitizer and potentiates its photodynamic activity in human endothelial cells. 1642 22

The American College of Surgeons Commission on Cancer (ACS-CoC) mandates that pathology reports at ACS-CoC-approved cancer programs include all scientifically validated data elements for each site and tumor specimen. The College of American Pathologists (CAP) has produced cancer checklists in static text formats to assist reporting. To be inclusive, the CAP checklists are pages long, requiring extensive text editing and multiple intermediate steps. We created a set of dynamic tumor-reporting templates, using Microsoft Active Server Page (ASP.NET), with drop-down list and data-compile features, and added a reminder function to indicate missing information. Users can access this system on the Internet, prepare the tumor report by selecting relevant data from drop-down lists with an embedded tumor staging scheme, and directly transfer the final report into a laboratory information system by using the copy-and-paste function. By minimizing extensive text editing and eliminating intermediate steps, this system can reduce reporting errors, improve work efficiency, and increase compliance.
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PMID:Synoptic reporting in tumor pathology: advantages of a web-based system. 1750 81

A 10,000 member peptide nucleic acid (PNA) encoded peptide library was prepared, treated with the Abelson tyrosine kinase (Abl), and decoded using a DNA microarray and a fluorescently labeled secondary antiphosphotyrosine antibody. A dual-color approach ensured internal referencing for each and every member of the library and the generation of robust data sets. Analysis identified 155 peptides (out of 10,000) that were strongly phosphorylated by Abl in full agreement with known Abl specificities. BLAST analysis identified known cellular Abl substrates such as c-Jun amino-terminal kinase as well as new potential target proteins such as the G-protein coupled receptor kinase 6 and diacylglycerol kinase gamma. To illustrate the generalization of this approach, two other tyrosine kinases, human epidermal growth factor 2 (Her2) and vascular endothelial growth factor receptor 2/kinase insert domain protein receptor (VEGFR2/KDR), were profiled allowing characterization of specific peptide sequences known to interact with these kinases; under these conditions Her2 was demonstrated to have a marked preference for D-proline perhaps offering a unique means of targeting and inhibiting this kinase.
ACS Chem Biol 2007 Dec 21
PMID:A 10,000 member PNA-encoded peptide library for profiling tyrosine kinases. 1815 68

Molecules specifically designed to modulate protein-protein interactions have tremendous potential as novel therapeutic agents. One important anticancer target is the chaperone Hsp90, whose activity is essential for the folding of many oncogenic proteins, including HER2, IGFIR, AKT, RAF-1, and FLT-3. Here we report the design and characterization of new tetratricopeptide repeat modules, which bind to the C-terminus of Hsp90 with higher affinity and with greater specificity than natural Hsp90-binding co-chaperones. Thus, when these modules are introduced into the cell, they out-compete endogenous co-chaperones for binding, thereby inhibiting Hsp90 function. The effect of Hsp90 inhibition in this fashion is dramatic; HER2 levels are substantially decreased and BT474 HER2 positive breast cancer cells are killed. Our designs thus provide new tools with which to dissect the mechanism of Hsp90-mediated protein folding and also open the door to the development of an entirely new class of anticancer agents.
ACS Chem Biol 2008 Mar 20
PMID:Designed TPR modules as novel anticancer agents. 1835 5

Unregulated cellular proliferation, caused by mutation or dysregulation of growth-promoting proteins, is an underlying cause of cancer. Many such growth-promoting proteins exhibit an increased dependence on the activity of the chaperone heat-shock protein 90 (Hsp90) for correct folding and maturation in the cell. One can therefore envision that inhibition of Hsp90 would be an effective and broadly applicable strategy for the development of anticancer agents. Hsp90 functions in multichaperone complexes driven by the binding and hydrolysis of ATP. Encouraging results have been obtained by inhibiting Hsp90 with 17-AAG, an active-site binding ATP analog. Here we present the results of a different approach to inhibiting Hsp90 by disrupting its interaction with a cochaperone named Hsp organizing protein (HOP). We have used an AlphaScreen technology based high-throughput in vitro screen to identify compounds that inhibit this interaction. In addition, we demonstrate that these compounds are active in vivo. Treatment of human breast cancer cell lines BT474 and SKBR3 with these compounds decreases the levels of the Hsp90-dependent client protein HER2, with associated cell death.
ACS Chem Biol 2008 Oct 17
PMID:A novel class of small molecule inhibitors of Hsp90. 1878 42

Gold nanocages with an average edge length of 65 +/- 7 nm and a strong absorption peak at 800 nm were conjugated with monoclonal antibodies (anti-HER2) to target breast cancer cells (SK-BR-3) through the epidermal growth factor receptor (in this case, HER2), which is overexpressed on the surfaces of the cells. Both the number of immuno Au nanocages immobilized per cell and the photothermal therapeutic effect were quantified using flow cytometry. The targeted cells were irradiated with a pulsed near-infrared laser, and by varying the power density, the duration of laser exposure, and the time of response after irradiation, we were able to optimize the treatment conditions to achieve effective destruction of the cancer cells. We found that cells targeted with the immuno Au nanocages responded immediately to laser irradiation and that the cellular damage was irreversible at power densities greater than 1.6 W/cm(2). The percentage of dead cells increased with increasing exposure time up to 5 min and then became steady. By quantifying the photothermal effect of immuno Au nanocages, critical information with regards to both the optimal dosage of nanocages and parameters of the laser irradiation has been garnered and will be applied to future in vivo studies.
ACS Nano 2008 Aug
PMID:A quantitative study on the photothermal effect of immuno gold nanocages targeted to breast cancer cells. 1920 68


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