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Patent application title: Use of Cymipristone Type Compounds in Aids Treatment
Mingwei Wang (San Diego, CA, US)
Lin Zuo (Shanghai, CN)
Minghua Ying (Zhejiang Province, CN)
IPC8 Class: AA61K31575FI
USPC Class:
Class name: Designated organic active ingredient containing (doai) cyclopentanohydrophenanthrene ring system doai with additional active ingredient
Publication date: 2009-04-30
Patent application number: 20090111781
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This invention refers to use of cymipristone type compounds of formula
(I), salt or solvate thereof in preparation of medicament for treating
AIDS. Cymipristone type compounds are a new type glucocorticoid receptor
antagonist. Pharmacological test shows that cymipristone has
anti-glucocorticoid activity and very strong affinity with glucocorticoid
receptor. Test indicates that cymipristone is a glucocorticoid antagonist
on receptor level and can block the function of glucocorticoid receptor.
The inventor uses cymipristone to test the inhibition on the growth of
AIDS virus in vitro and finds that cymipristone has significant growth
inhibition action on AIDS pathogen HIV-1.
1. A method of treating AIDS, comprising administering to a patient in
need thereof an amount of compound of formula (I) or salt or solvate
thereof ##STR00004## wherein, R1 is cyclopentyl, cyclohexyl or
cycloheptyl; R2 is H or C1-C6 alkyl; R3 is selected
from the group consisting of --C≡C--R5 and
--CH═CH--R6, wherein R5 is H, C1-C6 alkyl or
hydroxymethyl, R6 is H, C1-C6 alkyl or hydroxymethyl; and
R4 is H or hydroxymethylene.
2. The method of claim 1, wherein, R2 is H or methyl, R3 is --C≡C--CH3 or --C≡C--CH2OH, and R4 is H.
3. The method of claim 2, wherein the compound of formula (I) is 11.beta.-[4-(N-methyl-N-cyclohexylamino)phenyl]-17.alpha.-(1-propynyl)-17- β-hydroxyl-4,9-estradiene-3-one.
4. The method of any one of claims 1-3 further comprising administering one or more reverse transcriptase inhibitor and/or proteolytic enzyme inhibitor.
5. The method of claim 4, wherein, the reverse transcriptase inhibitor is selected from the group consisting of zidovudine (AZT), didanosine (DDI), zalcitabine (DDC), stavudine (D4T), lamivudine (3TC), abacavir (ABC), nevirapine, delavirdine, and efavirenz (EFV).
6. The method of claim 4, wherein, the proteolytic enzyme inhibitor is selected from the group consisting of saquinavir, itonavir, indinavir, nelfinavir and amprenavir.
[0001]This invention refers to pharmaceutical chemistry, in particular, use of cymipristone type compounds in AIDS treatment.
[0002]Acquired immunodeficiency syndrome (AIDS) is one of cosmopolitan important infectious diseases threatening human health and life. Human immunodeficiency virus (HIV), namely the pathogen of AIDS, is divided into two subgroups HIV-1 and HIV-2. HIV-1 is highly pathogenic and the main pathogen causing global epidemic of AIDS. And that HIV-2 has a lower transmission and pathogenicity, a longer latency and course of disease and a mild symptom, even, does not develop into AIDS in some infected patients. The most of AIDS patients are infected by HIV-1. HIV-2 infection is only localized in West Africa. So the current studies about AIDS virus mainly aim at HIV-1.
[0003]At the initial stage of HIV infection, viremia appears and there mild fever and lymphadenectasis. Afterwards, viremia reduces to a level difficult to be detected, antinuclear protein and antienvelope protein antibodies appear successively, and disease course enters into a symptomless carrier stage or latent infection period, which can be several years or even over 10 years, but up to now the mechanism of this long latency is not clear. Under the action of some factors, the virus can replicate in large quantities, and viremia appears again with AIDS symptoms, large quantity of helper T lymphocyte are destroyed by virus, immunological function of cell and body fluid decreases and becomes unable to resist invasion from outside pathogenic microorganisms, and finally the disease develops into AIDS.
[0004]The course of HIV proliferation can be divided generally into 9 steps, namely, adsorption, penetration, exuviation, initial stage protein synthesis, virus genome nucleic acid replication, late stage protein synthesis, nucleocapsid assembly, virus maturity, release, etc. Theoretically, each step in above course can be taken as the target for screening HIV medicaments. Through several years of efforts, corresponding inhibitors have been found for each phase involved in HIV proliferation and the different types of compounds have entered into preclinical or clinical study stage or have been approved by medicament administration department to market and to use in AIDS treatment. Now anti-AIDS medicaments that have been developed successfully include mainly: (1) reverse transcriptase inhibitor (as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, nevirapine, delavirdine, efavirenz, etc.) and (2) proteolytic enzyme inhibitor (as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, etc.). As HIV has high antigen variation characteristic and very easily produces medicament resistance, the single use of above medicaments will often fail in treatment on account of rapid production of medicament resistance. Although using reverse transcriptase inhibitor and proteolytic enzyme inhibitor simultaneously (cocktail therapy) can delay the appearance of medicament resistance and prolong the life of AIDS patient, the problem of medicament resistance cannot be radically solved and AIDS cannot be completely cured. Cocktail therapy may produce serious toxic side effect (as bone marrow inhibition, amnesia, etc.) and appearance of medicament resistant virus strain. Therefore, a new anti-HIV medicament of different chemical structure and action mechanism is urgently need clinically. Finding action target of new anti-HIV medicament is the key to realize this purpose.
[0005]The genome of HIV is mainly consists of genes Gag, Pol and Env. Besides, there are 6 supplementary genes (Tat, Vpr, Vpu, Nef, Rev and Vif), in which Vpr codes is a protein. Its molecular weight is about 14 kDa containing 96 amino acids.
[0006]Researches indicate that, after HIV infects host cell, Vpr interacts with several proteins in cell, and produces a series of influence on replication of virus, cycle and differentiation of host cell, for example, Vpr protein plays an important role in cell death caused by HIV. As the pathogenic mechanism of MV virus is in some respects abnormal regulation of cell induced by Vpr (Wei Qiang et al., "China Bioengineering Journal", 2003, vol. 23, 6), so Vpr protein has the potential of becoming a new target of anti-AIDS medicaments.
[0007]In studies on Vpr protein, scientists find that Vpr protein and glucocorticoid (as dexamethasone, hydrocortisone, etc.) can block cell proliferation in similar degree. So they conjecture that the inhibitory effect of Vpr on cell proliferation is at least partly similar to the action route of glucocorticoid (Ayyavoo et al., "Nature Medicine", 1997, vol. 3, 1117).
[0008]In the course of adjusting the immunological reaction of cell to different pathogens, several cellular factors mediate many important signal conduction function and play a key role in immunological reaction of cell. The glucocorticoid realizes its anti-inflammatory and immunological inhibition effect via interference on TCGF (interleukin 2) and synthesis or function of other cellular factors. Studies show that Vpr has also the action of interfering cellular factors. So it is conjectured that the anti-cell proliferation function of Vpr may depend partly on its inhibitory effect on cellular factors (including interleukin 2 and 12). As the initial reaction of cellular factors is very important for inhibiting the replication of HIV in infected cell, the negative effect of Vpr on cellular factors can destroy the immunological reaction of host, especially the immunological reaction of cell not yet infected by HIV-1 (Ayyavoo, V. et al., "Nature Medicine", 1997, vol. 3, 1117).
[0009]Experimental results indicate that glucocorticoid mediated by NF-kB reaction element inhibits the production of cellular factors by inhibiting cellular factor promoter. Glucocorticoid induces the gene transcription of IkB, the translation formed IkB inhibits the activity of NF-kB by producing inactive NF-kB--IkB compound. Besides, all Vpr, either expressed by the cell itself or introduced by exogenous protein, can inhibit partly the gene activation mediated by NF-kB via inducting transcription of IkB. Since NF-kB is the key factor in activating cellular factor gene, blocking its function can effectively avoid or reduce the production of cellular factor, and this explains partly the action mechanism of Vpr.
[0010]Vpr protein, as analog of glucocorticoid, can adjust proliferation and death of cell and help replication of HIV in cell. Glucocorticoid receptor antagonist can reverse the action of Vpr, inhibit the replication of HIV in cell, and protect the cell to avoid entering into the cell death process mediated by Vpr (Ayyavoo, V. et al., "Nature Medicine" 1997, vol. 3, 1117). The inventor uses cymipristone, glucocorticoid receptor antagonist, to test the inhibition on growth of MV virus in vitro and finds that cymipristone has significant growth inhibition action on HIV-1.
[0011]The Chinese patent (ZL 99 1 16829.1, Application No. CN 1287123A) granted for the inventor discloses the cymipristone type compounds of this invention, its preparation method and its use in preparation of medicament for treating diseases related to progestogen dependence, antifertility, abortion or contraception and antineoplasm, etc. The patent is cited as reference in this application.
[0012]The cymipristone type compounds involved in this invention are the steroid of following formula:
in which, R1 is cyclopentyl, cyclohexyl or cycloheptyl; R2 is H or C1-C6 alkyl; R3 is selected from the group consisting of --C≡C--R5 and --CH═CH--R6, in which R5 is H, C1-C6 alkyl or hydroxymethyl, R6 is H, C1-C6 alkyl or hydroxymethyl; R4 is H or hydroxymethylene (═CHOH).
[0013]The inventor has found that cymipristone type compounds are a new type glucocorticoid receptor antagonist. Pharmacological test shows that cymipristone has anti-glucocorticoid activity and cymipristone type compounds have very high affinity with glucocorticoid receptor. Above test proves that cymipristone is a glucocorticoid antagonist on receptor level and can block the function of glucocorticoid receptor.
[0014]The inventor uses cymipristone to test its inhibition on HIV growth in vitro. In MT-4 cell culture medium, the 50% inhibitory dose (IC50) of cymipristone on HIV-1 IIIB P24 antigen is 1.30 μg/ml (2.62 μM). In PBMC cell culture medium, the 50% effective concentration (EC50) of cymipristone on P24 antigen of HIV-1 AZT sensitive strain 018a is 12.36 μg/ml and that for P24 antigen of HIV-1 AZT resistant strain 018c is 7.90 μg/ml. This indicates that cymipristone has significant growth inhibition action on AIDS pathogen HIV-1. Thus, this invention is completed.
[0015]This invention provides the use of cymipristone type compounds, salt or solvate thereof in preparation of a medicament for treating AIDS.
[0016]The inventor has found that cymipristone type compounds can be used to treat AIDS. The cymipristone type compounds, salt or solvate thereof involved in this invention is a known steroid of following general formula (I):
in which, R1 is cyclopentyl, cyclohexyl or cycloheptyl; R2 is H or C1-C6 alkyl; R3 is selected from the group consisting of --C≡C--R5 and --CH═CH--R6, in which R5 is H, C1-C6 alkyl or hydroxymethyl, R6 is H, C1-C6 alkyl or hydroxymethyl; and R4 is H or hydroxymethylene (═CHOH).
[0017]The compounds in this invention can be prepared according to the method disclosed in Chinese patent CN1287123A.
[0018]The compounds in this invention can exist in the form of salt or solvate. As it has several asymmetric carbon atoms, it has several isomers. All these salts and isomers belong to the use scope protected by this patent.
[0019]Among the compounds of formula (I) in this invention, the compound, in which R2 is H or methyl, R3 is --C≡C--CH3 or --C≡C--CH2OH, and R4 is H, is preferable.
[0020]The more preferable compound is: 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propynyl)-17- β-hydroxyl-4,9-estradiene-3-one, namely cymipristone.
[0021]The inventor finds that cymipristone type compounds are a glucocorticoid receptor antagonist, has significant growth inhibition action on HIV-1 and can be used to treat AIDS.
[0022]HIV has produced serious medicament-resistance against existing medicaments (including reverse transcriptase inhibitor and proteolytic enzyme inhibitor), but cymipristone type compounds have a mechanism of inhibiting HIV growth completely different from that of above medicaments. Therefore it can be used to treat not only diseases caused by non-resistant HIV infection, but also AIDS patients resistant to existing anti-HIV medicaments (including reverse transcriptase inhibitor and proteolytic enzyme inhibitor).
[0023]HIV is a complex reverse transcription virus and simultaneously using medicaments of different action mechanisms is an effective means for treating AIDS. In this invention, a more preferable implementation method is to use cymipristone type compound together with one or several of other medicaments that can treat HIV infection effectively, this medicament is preferable but not limited to reverse transcriptase inhibitor and/or proteolytic enzyme inhibitor. In which, the reverse transcriptase inhibitor is selected from zidovudine (AZT), didanosine (DDI), zalcitabine (DDC), stavudine (D4T), lamivudine (3TC), abacavir (ABC), nevirapine, delavirdine and efavirenz (EFV) and atc, one or several; the proteolytic enzyme inhibitor is selected from saquinavir, ritonavir, indinavir, nelfinavir, amprenavir and atc, one or several.
[0024]The therapeutic use of this invention can be implemented by the form of medicament combination. Therefore, this invention provides a medicament combination for treating AIDS, which can be prepared with conventional pharmaceutical technology. The medicament combination can be in the form of solid preparation as tablet, capsule, pill, granule, etc., and that of liquid preparation as injection, suspension, emulsion, solution, etc., or that of percutaneous preparation, including the preparation with special actions as sustained release, controlled release, target, pulse, etc.
[0025]The following examples further explain this invention. It should be understood that examples of this invention are used to explain and not to limit this invention and that all modifications based on essential of this invention are belong to the protection scope of this invention. Unless otherwise stated, all percentages in this invention are weight percentages.
Example 1
Preparation of Cymipristone
Synthesis of Cymipristone
[0026](1) Preparation of 4-(N-methyl-N-cyclohexylamino)Phenyl Magnesium Bromide
[0027]1.4 g of magnesium tablet (Mg) and 10 ml of anhydrous tetrahydrofuran (THF) are put into a four-neck flask, no adding iodine or adding a little quantity of iodine, 10.86 g of 4-bromo-N-methyl-N-cyclohexylaniline (dissolved in 24 ml of anhydrous tetrahydrofuran) are added dropwise into the flask at about 50° C. When the adding is completed, maintaining temperature and agitation are continued for 1 hour, and a solution of 4-N-methyl-N-cyclohexylamino)phenyl magnesium bromide is obtained (for next step addition reaction) in tetrahydrofuran.(2) Preparation of 3,3-ethylenedioxy-5α, 17β-dihydroxy-11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17.alp- ha.-(1-propynyl)-9(10)-estrene (Adduct)Put 5 g of 3,3-ethylenedioxy-5,10-epoxy-17α-(1-propynyl)-17β-hydroxy-9(11- )-estrene (epoxide), 29.1 ml of anhydrous tetrahydrofuran (THF) and 0.1 g of cuprous chloride (Cu2Cl2) into a four-neck flask, control temperature to below 5° C., the solution of 4-(N-methyl-N-cyclohexylamino)phenyl magnesium bromide in tetrahydrofuran is added dropwise into the flask. When the adding is completed, maintaining the temperature and reaction are continued for 5 hours. When the reaction is complete, the reaction liquid is poured into saturated aqueous solution of ammonium chloride, the water layer is separated. The organic layer is washed with saturated ammonium chloride solution and the water layer is extracted with ethyl acetate for several times. The organic layers are combined, and washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure, separated with silica gel column, eluting agent is cyclohexane:acetone=(5:1), and 6 g of 3,3-ethylenedioxy-5α, 17β-dihydroxy-11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17.alp- ha.-(1-propynyl)-9(10)-estrene (Adduct) solid are obtained.
[0028]IR: (KBr) cm-1: 3515 (C5--oH, C17--OH), 1612, 1515 (benzene ring), 819 (aromatic hydrogen).
[0029]1H NMR: (CDCl3) δ ppm: 0.47 (3H, S, C13--CH3), 1.88 (3H, S, C≡C--CH3), 2.72 (3H, S, N--CH3), 6.65-7.03 (4K ArH).
(3) Preparation of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propynyl) -17β-hydroxyl-4,9-estradiene-3-one (cymipristone)2.5 g of p-toluene sulfonic acid (PTS) and 5 g of 3,3-ethylenedioxy-5α, 17β-dihydroxy-11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17.alp- ha.-(1-propynyl)-9(10)-estrene (Adduct) are dissolved in 50 ml of 90% ethyl alcohol (V/V) and reacted by agitation for 3 hours under 5-40° C. The reaction liquid is poured into diluted aqueous solution of sodium hydroxide, separate out solids, filter by suction and wash with water to neutral. The filter cake is dissolved in 50 ml of ethyl acetate and washed with saturated aqueous solution of sodium chloride. The water layer is separated and a part of solvent is removed by distillation, separate out solid, filter by suction and dry, 3 g of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propynyl)-17- β-hydroxyl-4,9-estradiene-3-one (cymipristone), light yellow solids, are obtained.
[0030]IR: (KBr) cm-1: 3447 (C17--OH), 1655 (unsaturated ketone), 1607, 1513 (benzene ring), 865, 819 (aromatic hydrogen).
[0031]1H NMR: (CDCl3) δ ppm: 0.56 (3H, S, C13--CH3), 1.89 (3H, S, --C≡C--CH3), 2.74 (3H, S, N--CH3), 4.34 (1H, S, C11--H), 5.75 (1H, S, C4--H), 6.68-6.99 (4H, ArH).
Example 2
Determination of Binding Activity of Cymipristone on Human Glucocorticoid Receptor
[0032]Purpose: To determine the binding power of cymipristone on human glucocorticoid receptor and compare with mifepristone of similar chemical structure.
(1) Method
[0033]Buffer solution is composed of 25 mM NaPO4, 20 mM NaMoO4, 10 mM KF and 10% glycerol (pH=7.3) and stored under 4° C. Stock solution is prepared with CHAPS and DTT and stored under -20° C. The solutions of positive drug (dexamethasone) and tested compound are prepared according to certain concentration gradient. Add 2.5 μl/hole into 96-pore plate. Take out appropriate amount of buffer solution reserve into solution to make the final concentration of CHAPS and DDT to become 0.25 mM and 2 mM respectively. Add protease inhibitors (aprotinin and leupeptin) to make its final concentration to become 1 μg/μl, and place in an ice bath. After adding human nuclear receptor GR (1:8), PR (1:100), ER (1:2000), AR (1:200) and MR (1:40) into the reaction system respectively, adequately mix suitable quantity of [3H]-dexamethasone, [3H]-progesterone, [3H]-estradiol and [3H]-DHT (from Amersham), rapidly add into 96-pore plate (100 μl/pore) and incubate overnight under 4° C. On the next day, add 25 μl of hydroxyapatite suspension into each pore and mix with shaking. After incubating for 10 min, separate by centrifuge for 3 min at 2500 rpm. The precipitate is washed with 100 μl of buffer solution and separated by centrifuge twice. Add 150 μl of scintillation solution (from Perkin Elmer) into each pore, mix with shaking and count by MicroBeta counter.
(2) Result
[0034]As shown in Table 1, the binding activity of cymipristone on glucocorticoid receptor (GR) is greatly higher than that of progestogen receptor (PR), estrogen receptor (ER), androgen receptor (AR) and mineralocorticoid receptor (MR), and the binding activity of cymipristone on human glucocorticoid receptor is more than that of mifepristone.
TABLE-US-00001 TABLE 1 Binding activity of cymipristone on different nuclear receptors (mean ± SD, n = 4) Receptor Cymipristone (IC50, nM) Mifepristone (IC50, nM) GR 0.45 ± 0.069 0.63 ± 0.056 PRa 5.2 ± 0.26 ERα 516.3 ± 62.8 ERβ 278.7 ± 0.63 AR 69.64 ± 15.37 MR >2000
Example 3
Detection of Binding Activity of Cymipristone on Glucocorticoid Receptor of Rat Hepatic Cytoplasm
[0035]Purpose: To detect the binding power of cymipristone on animal glucocorticoid receptor and compare with mifepristone of similar chemical structure.
(1) Method
[0036]Clean female SD rats, body weight 200-250 g, are fed with certain quantity of food and freely drink water. The temperature is controlled at about 24° C. and an illumination cycle are for 11 hours by day and 13 hours at night. All animals are observed for 1 week before experiment.Incisions are made on two sides below arch of ribs on dorsal position of rats to extirpate adrenal glands. After operation, the rats are fed with physiological saline to maintain water-electrolyte balance.On the third day after operation, animals are acutely executed. The liver is taken out immediately and placed in ice cold buffer solution; the blood should be washed off as much as possible. Take certain quantity of tissue, add buffer solution (1:4), cut the tissue with scissors, intermittently homogenize the tissue under low temperature, centrifuge at 175000 g for 1 hour, and take out the supernatant liquid as reserve. Determine the concentration of protein in supernatant liquid and adjust the concentration of protein to 2 mg/ml. evaporate to dry the labeled and non-labeled dexamethasone, cymipristone and mifepristone dissolved in ethyl alcohol at 37° C. Then carry out the competition inhibition experiment.Competition analysis; Take 0.2 ml of cytoplasm, add [3H]-dexamethasone of certain concentration as tracer. Add tested compounds (cymipristone, mifepristone and dexamethasone) of different concentrations, and incubate at 4° C. for 24 hours. Use DCC to separate free and bound [3H]-dexamethasone and determine the radioactivity of supernatant liquid and precipitate with liquid scintillation counter.
(2) Data Processing
[0037]Relative binding affinity (RBA): calculate based on the standard of RBA of dexamethasone as 100%,
R B A = IC 50 of dexamethosone IC 50 of corresponding compound ##EQU00001##
(3) Result
[0038]Competition inhibition experiment: each compounds can inhibit the binding of [3H]-dexamethasone (7.87 nml/L) with glucocorticoid receptor of rat hepatic cytoplasm within the concentration range of 16×10-10˜5×10-7 mol/L. The inhibition rates are listed in Table 2.
TABLE-US-00002 TABLE 2 Inhibition rate of cymipristone on binding of [3H]-dexamethasone with glucocorticoid receptor of rat hepatic cytoplasm and comparison with mifepristone (mean ± SD, %, n = 4) Concentration of tested compounds (mol/L) Dexamethasone Cymipristone Mifepristone 5 × 10-7 89.23 ± 8.56 95.36 ± 5.34 93.84 ± 3.78 1 × 10-7 60.37 ± 5.67 88.94 ± 9.01 88.95 ± 5.69 2 × 10-8 39.42 ± 4.83 75.60 ± 3.56 70.24 ± 4.13 4 × 10-9 24.83 ± 5.92 54.54 ± 4.24 46.84 ± 7.25 .sup. 8 × 10-10 14.72 ± 7.34 31.25 ± 3.87 24.43 ± 3.97 16 × 10-10 10.37 ± 6.11 17.25 ± 6.76 16.74 ± 8.07 Based on above calculation method, calculate the receptor pharmacological characteristic index of each compounds, see Table 3.
TABLE-US-00003 TABLE 3 Relative binding activity (RBA) of cymipristone with glucocorticoid receptor of rat hepatic cytoplasm (mean ± SD, n = 4) Compound IC50 (nmol/L) RBA (%) Dexamethasone 14.50 ± 1.89 100.00 Cymipristone 2.60 ± 0.53 557.69 ± 65.23 Mifepristone 4.21 ± 1.02 344.41 ± 57.41 Note: Calculated based on the binding activity of dexamethasone as 100.
RBA ratio of dexamethasone, cymipristone and mifepristone is 1:5.6:3.4. IC50 are 14.50, 2.60 and 4.21 nmol/L respectively. IC50 ratio of cymipristone and mifepristone is 1.00:1.62, indicating that cymipristone has very high binding power on glucocorticoid receptor and its binding power is stronger than that of mifepristone. The results from example 2 and 3 show that cymipristone is a stronger glucocorticoid receptor antagonist than mifepristone and has a greater potential in treating AIDS.
Example 4
Antagonism of Cymipristone on Human Glucocorticoid Receptor
[0039]Purpose: To detect the antagonism of cymipristone on human glucocorticoid receptor.
(1) Method
[0040]Inoculate (6×105) of CV-1 cells into cell culture dish of 60 mm diameter using phenol red-free low-sugar DMEM containing 10% FBS as culture medium and incubate overnight under 37° C. and 5% CO2. Suction according to 1:5 ratio pipet 2 μg of plasmid carried GR genes and luciferase reporting genes, cotransfect CV-1 cells with FuGene 6 transfection reagent (from Roche), and incubate for 8 hours under above conditions, Inoculate the transfected cells into 96-pore micro culture plate, 8000 cells/100 μl/pore, and incubate cells to adhibit on the wall of dish. Dilute the positive compound (Dexamethasone, final concentration 10 nM) and tested compound with culture medium according to certain concentration and add into above culture plate according to 10 μl/pore, incubate for 24 hours. Discard the culture liquid, wash the cells twice with PBS, and pipet off all residual PBS. fragment the cells by CCLR Assay Kit (from Progema) for 15 min. Add 20 μl of fragmentation solution into 96 pore cell culture plate with white edge and white bottom, add CCLR substrate (from Progema), 100 μl/pore, and immediately detect the chemical luminescence count value caused by activated luciferase on Wallac 1420 Multilabel Counter.
(2) Result
[0041]As shown in Table 4, cymipristone has a significant antagonistic activity on human glucocorticoid receptor function caused by dexamethasone in gene cotransfected live cells.
TABLE-US-00004 TABLE 4 Antagonism of cymipristone on dexamethasone at cell level (mean ± SD, n = 4) Receptor Cymipristone (IC50, nM) GR 0.26 ± 0.02
Example 5
Anti-Glucocorticoid Activity Test for Cymipristone
[0042]Purpose: To detect the anti-glucocorticoid activity of cymipristone.
(1) Method
[0043]Clean female SD rats, body weight 200-250 g, are fed with certain quantity of food and freely drink water. The temperature is controlled at about 24° C. and an illumination cycle are for 11 hours by day and 13 hours at night. All animals are observed for 1 week before experiment.Rats are anesthetized with ethyl ether. Incisions are made on two sides below costal arch of ribs on dorsal position of rats to extirpate adrenal glands. The rats are fed with physiological saline after operation. On the seventh day, animals are acutely executed. Take out thymus gland to place in to HBSS buffer solution, wash twice, remove connective tissue, cut the tissue with scissors, lightly grind with homogenizer, filter with three layers of gauze, and centrifuge the filtrate for 5 min (500 rpm). Wash the precipitated cells twice with HBSS, re-suspend the cells in RPMI1640 culture medium for cell count and cell survival rate determination, and adjust cell concentration to 1×107/ml.Determination of anti-glucocorticoid activity: Add tested compound into culture medium, reaction concentration 6×10-8˜2×106 mol/L, and place in 37° C. incubator for 3 hours. Add thymus gland cells to make cell concentration to become 107/ml and incubate at 37° C. for 3 hours. Add 1 μCi of label substance, mix, and incubate for 1 hour. Add 100 μl of ice cold 5% trichloroacetic acid to end the reaction. Place the test tube on ice and wash twice with 2 ml of ice cold 5% trichloroacetic acid and centrifuge twice, 500 rpm×5 min, Add 0.5 ml of 1N NaOH to dissolve the precipitated cells, pipet out the liquid, dry the residue with cotton stick, place into same scintillation bottle, and determine the radioactivity by liquid scintillation counter. In this test, dexamethasone of 6×10-8 mol/L concentration is selected to detect the anti-glucocorticoid activity, the concentration of tested compound is 6×10-8˜2×10-6 mol/L
(2) Data Processing
[0044]Calculate the incorporation rate of [3H]-TdR:
Incorporation rate = Td - N S B T - N S B × 100 % ##EQU00002##
In which: T=[3H]-TdR count without presence of compound, Td=count with presence of compound, and NSB=non-specific adsorption.
[0045]The anti-glucocorticoid activity of cymipristone calculated according to the formula, includes the incorporation rate of [3H]-TdR and residual inhibition rate, in which, residual inhibition rate is calculated as 100% when the concentration of dexamethasone is 6×10-8 mol/L.
Inhibition rate=100%-incorporation rate
Residual inhibition rate = Inhibition rate of tested compound combined with dexamethosone Inhibition rate of dexamethosone ##EQU00003##
(3) Result
[0046]When dexamethasone of 6×10-8 mol/L concentration is used singly, incorporation rate of [3H]-TdR is 43.2%±3.7%. When dexamethasone is combined with tested compound to use, its action receives different degrees of antagonism (Table 5). Residual inhibition rate shows the capability of cymipristone in the action of anti-glucocorticoid (Table 6).
TABLE-US-00005 TABLE 5 Antagonism of cymipristone against dexamethasone (Mean ± SD, %, n = 4) Concentration (mol/L) Cymipristone 6 × 10-8 80.0 ± 4.3 2 × 10-7 67.2 ± 2.9 6 × 10-7 76.0 ± 3.8 2 × 10-6 63.6 ± 5.1
TABLE-US-00006 TABLE 6 Effect of cymipristone on residual inhibition rate of dexamethasone (Mean ± SD, %, n = 4) Concentration (mol/L) Cymipristone 6 × 10-8 35.2 ± 2.4 2 × 10-7 57.7 ± 3.5 6 × 10-7 42.2 ± 1.9 2 × 10-6 64.1 ± 5.6 Result shows that cymipristone has anti-glucocorticoid activity.
Example 6
Growth Inhibition Action of Cymipristone on HIV-1 in MT-4 Cell Culture
[0047]Purpose; To detect the anti-HIV-1 action of cymipristone.
I. Method
1. Toxicity on Cell and Inhibition Action on HIV-1 P24 Antigen Formation of Cymipristone in MT-4 Cell Culture
[0048](1) Inoculate MT4 cells into 96-pore cell culture plate, 1×105 cells/ml, infect with HIV-1-IIIB virus strain of about 100TCID50, and add cymipristone solution at the same time, its concentration is below 100 μg/ml, triply diluted to 8 concentrations. Set virus TCID50 determination group and cell control group. Each concentration is duplicated in two pore. Incubate under 37° C., 5% CO2 and saturated humidity in an incubator.
(2) Determination of Cytotoxicity of Cymipristone by Cytopathic Method (TC50 and TC0)
[0049]Daily observe the cytopathy in above culture plate by microscope, record the degree of cytopathy with routine method, and calculate the 50% toxic concentration (TC50) and maximum nontoxic concentration (TC0) of drug according to Reed & Muench method.(3) Determination on HIV-1 P24 Antigen with Supernatant Liquid Pipetted from Cell Culture Plate Added DrugAfter 4 days (96 hours), pipette out the supernatant liquid from cell culture added drug and freeze HIV-1 P24 antigen used for determination.
(4) Determination of Cytotoxicity of Cymipristone by MTT Staining Method
[0050]Add MTT into each pore of cell culture plate pipetted supernatant liquid to stain, continue to incubate for 4 hours, add decolorizing liquid, determine OD value at 570 nm wavelength by enzyme-linked apparatus, and calculate TC50 and TC0 as above.
(5) Determination of HIV-1 P24 Antigen and Inhibitory Action of Cymipristone on HIV-1 P24 Antigen
[0051]Take the supernatant liquid on the fourth day, combine the liquid from two pore, and dilute by 1:100, Determine the HIV-1 P24 antigen titer (OD value) by ELISA method according to the instruction of HIV-1 P24 antigen reagent kit. Compare the OD value of tested drug group with that of virus control group, and calculate the inhibition %, 50% effective concentration (IC50) and selection index (SI) of drug. At the same time, determine the 50% infection concentration of HIV-1/IIIB virus strain in MT-4 cells and virus infection quantity (TCID50).
2. Calculation of 50% Toxic Concentration (TC50), 50% Effective Concentration (IC50) and Selection Index (SI)
(1) Calculation of TC50, IC50 and SI of Drug in Cell Culture According to Reed & Muench Method
[0052] TC 50 or IC 50 = antilog ( log < 50 % drug concentration + 50 - < 50 % cumulative inhibition % > 50 % cumulative inhibition % - < 50 % cumulative inhibition % × log dilution multiple ) ##EQU00004##
II. Result
1. Cytotoxicity of Cymipristone in MT-4 Cell Culture Liquid (Table 7)
[0053](1) Cytotoxicity TC50 from Cytopathic Method (CPE):TC50 of cymipristone is 7.704 μg/ml (15.50 μM).(2) Cytotoxicity TC50 from MTT Staining Method:TC50 of cymipristone is 30.26 μg/ml (60.89 μM).
TABLE-US-00007 TABLE 7 Cytotoxicity of cymipristone in MT-4 cell culture Determination method Cymipristone (TC50) CPE 7.704 μg/ml (15.50 μM) MTT 30.26 μg/ml (60.89 μM)
2. Inhibition Action of Cymipristone on HIV-1 IIIB P24 Antigen in MT-4 Cell Culture (Table 8)
[0054]In MT-4 cell culture, the inhibition activity (TC50) of cymipristone on HIV-1 IIIB P24 antigen formation is 1.30 μg/ml (2.62 μM).
TABLE-US-00008 TABLE 8 Inhibition action of cymipristone on HIV-1 P24 antigen in MT-4 cell culture Concentration of cymipristone (μg/ml) Inhibition rate (%) 3.70 93 1.23 29 0.41 13 0.14 17 0.05 14 IC50 1.30 μg/ml (2.62 μM)
3. Selection Index (SI; Table 9)
[0055]Calculate SI by CPE cytotoxicity, cymipristone is 5.93; calculate SI by MTT cytotoxicity: cymipristone is 23.28.
TABLE-US-00009 TABLE 9 selection index (SI) of cymipristone inhibiting HIV-1 in MT-4 cell culture Cytotoxicity determination method Selection index (SI) CPE 5.93 MTT 23.28
III. Conclusion
[0056]1. Cymipristone has no significant toxicity on cultured human T-lymphocyte MT-4. [0057]2. Cymipristone has significant inhibitory action on infection of HIV-1 virus IIIB experimental strain in passage MT-4 cell culture. [0058]3. Cymipristone has significant inhibitory effect on HIV-1 P24 antigen formation in MT-4 cell culture.
Example 7
Inhibitory Action of Cymipristone on HIV-1 in PBMC Cell Culture
[0059]Purpose: To detect the inhibitory action of cymipristone on clinically separated AZT (zidovudine-sensitive HIV-1 018a and AZT-resistant HIV-1 018c virus strains in human peripheral blood mononuclear cell (PBMC) culture, and to compare with mifepristone of similar chemical structure.I. Determination Method of Cytotoxicity and Drug Effect by Adding Drug after 2 Hours of HIV Virus InfectionTake healthy human fresh venous blood, separate human peripheral blood mononuclear cells (PBMC) by FiColl separating liquid, prepare 1.5×105 cells/ml suspension with culture solution containing PHA, inoculate in culture flask, and incubate under 37° C. and 5% CO2 for 72 hours in an incubator. Collect cells with curette, infect cells with 10-2 AZT sensitive (018a) or AZT resistant (018c) virus strain liquid, and adsorb for 2 hours, Wash off unabsorbed virus with 1640 culture medium without serum, prepare cells infected by virus to 1×106/ml with culture solution, and inoculate on 96-pore culture plate, 100 μl/pore. At the same time, respectively add 100 μl of 1:2 diluted cymipristone and mifepristone, and 1:5 diluted positive control drug AZT. Set cell control group and virus infected cell control group. Incubate under 37° C. and 5% CO2. On the fourth day (96 hours), pipette out the supernatant liquid and store under -20° C. for determination of HIV-1 P24 antigen titer and calculation of drug inhibitory action. Add MTT staining to cells for determination of cytotoxicity.Determination of cytotoxicity by MTT staining: Add 10 μl of 5 mg/ml MTT stain into each pore, continue to incubate under 37° C., 5% CO2 and saturated humidity for 4 hours. Add 100 μl of 50% DMF-17% Triton X-100 decolorizing solution into each pore, set overnight under 37° C., determine OD570nm value by enzyme-linked apparatus at 570 nm wavelength, and calculate the 50% toxic concentration (CC50) of drug.Determination of HIV-1 P24 antigen by ELISA method: thaw and dilute the supernatant liquid infected and drug-added PBMC cells and adjust dilution ratio according to pretest results. Determine the HIV-1 P24 antigen titer according to the operation procedure provided by the HIV-1 P24 antigen reagent kit. Compare the drug-added group with virus control group. Calculate the 50% effective concentration (EC50) of cymipristone, mifepristone or positive control drug AZT.Calculation method of 50% toxic concentration (CC50), 50% effective concentration (EC50) and selection index (SI):
(1) Calculation Method of Inhibition Rate of Drug on Cell or HIV-1 P24 Antigen in Cell Culture
[0060] Inhibition rate ( % ) = Experemental group O D - Virus control group O D Normal control group O D - Virus control group O D × 100 ##EQU00005##
(2) Calculation Method of CC50 and EC50 of Drug in Cell Culture According to Reed & Muench Method
[0061] CC 50 or EC 50 - antilog ( log < 50 % drug concentration + 50 - < 50 % cumulative inhibition % > 50 % cumulative inhibition % - < 50 % cumulative inhibition % × log dilution multiple ) ##EQU00006##
(3) Calculation Method of Selection Index (SI) on HIV-1 P24 Antigen in Cell Culture SI=CC50/EC50
II. Result
[0062]1. Cytotoxicity and Inhibition Action on P24 Antigen of Cymipristone Etc. in PBMC Cell Culture after Infection by AZT-Sensitive Strain HIV-1 018a for 2 Hours.
(1) Cytotoxicity (Table 10)
TABLE-US-00010 [0063]TABLE 10 Toxicity of cymipristone and mifepristone on PBMC cell culture infected by HIV-1 AZT-sensitive strain 018a 50% toxic concentration on PBMC infected by AZT-sensitive strain 018a (CC50, μg/ml) Drug Experiment 1 Experiment 2 Average SD Cymipristone 103.62 156.05 129.84 37.07 Mifepristone 69.42 97.82 83.62 20.08 AZT 58.84 72.69 65.77 9.79
(2) Inhibition Action on HIV-1 018a P24 Antigen (Table 11)
TABLE-US-00011 [0064]TABLE 11 Anti-HIV-1 018a action of cymipristone and mifepristone in PBMC cells (administration after adsorbing for 2 hous) EC50 (μg/ml) SI Drug Experiment 1 Experiment 2 Average SD Experiment 1 Experiment 2 Average SD Cymipristone 12.48 12.23 12.36 0.18 8.30 12.76 10.53 3.15 Mifepristone 12.40 12.37 12.38 0.02 5.60 7.91 6.76 1.63 AZT <0.0061 <0.0064 <0.0064 0 9193.75 11357.81 10275.78 1530.22
2. Cytotoxicity and Inhibition Action of on P24 Antigen Cymipristone etc. in PBMC Cell Culture after Infection by AZT Resistant Strain HIV-1 018c for 2 Hours.
(1) Cytotoxicity (Table 12)
TABLE-US-00012 [0065]TABLE 12 Toxicity of cymipristone and mifepristone on PBMC cell culture infected by HIV-1 AZT-resistant strain 018c 50% toxic concentration on PBMC infected by AZT-resistant strain 018c(CC50, μg/ml) Drug Experiment 1 Experiment 2 Average SD Cymipristone 102.83 104.42 103.63 1.12 Mifepristone 105.02 74.69 89.86 21.45 AZT 70.72 77.90 74.31 5.08
(2) Inhibition Action on AZT-Resistant Virus Strain HIV-1 018c P24 Antigen (Table 13)
TABLE-US-00013 [0066]TABLE 13 Anti-HIV-1 018c (AZT resistant strain) action of cymipristone and mifepristone in PBMC cells (administration after adsorbing for 2 hous) EC50 (μg/ml) SI Drug Experiment 1 Experiment 2 Average SD Experiment 1 Experiment 2 Average SD Cymipristone 8.42 7.38 7.90 0.74 12.21 14.15 13.18 1.37 Mifepristone 10.38 9.84 10.11 0.38 10.12 7.59 8.86 1.79 AZT 0.047 0.061 0.054 0.01 1504.68 1277.05 1390.87 160.96
III. Conclusion:
[0067]1. Cymipristone has inhibition action on P24 antigen caused by AZT sensitive and resistant HIV-1 virus in PBMC cell culture,2. Selection index of cymipristone inhibiting HIV-1 018a and HIV-018c in PBMC cell culture is higher than that of mifepristone, suggesting that cymipristone has a better application prospect than mifepristone in treating AIDS.3. Cymipristone has no cross resistance with currently clinically widely used zidovudine (AZT).
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text: 01 May 2015 UK walking holidays: 10 best British hikes Previous slide Next slide 1 of 10 View All Skip Ad From the Peak District to little trodden Welsh mountain massifs, the most spectacular hiking routes in the UK. Ben Nevis via Carn Mor Dearg, Scottish Highlands Distance: 10¼ miles Details: The finest route to the top of Ben Nevis. This is for experienced mountain climbers who don't fear the odd scramble, mountain paths cover the majority of the route. Edale skyline, Peak District Distance: 22 miles. Details: A Peaks must-do, highlights of the route include Win Hill, Brown Knoll and Rushup Edge. Visit Peak District Credit: AP Images Blencathra via Sharp Edge, Lake District Distance: five miles Details: A British alpine classic is an ascent of this blunt mountain via the scythe-like ridge of Sharp Edge. •The best hotels in the Lake District Bochlwyd Horseshoe, Snowdonia Distance: four miles. Details: Involves a Grade-1 scramble that brings you to the summit of Glyder Fach. Credit: FLPA/REX The Calf & Cautley Spout, Howgill Fells, Cumbria Distance: 11½ miles Details: Climb approximately 562 metres to visit the highest waterfall in the UK, views are spectacular and the area is peaceful and quite wild. Credit: AP/ Fotolia Pumlumon, Mid-Wales, Cambrian Mountains Distance: 19 miles Details: One of Britain's least-trodden mountain massifs, it's also the highest point in mid-Wales and is the source of the river Severn and the river Wye. Credit: Alamy Ben Lui, Scottish Highlands Distance: 11 miles Details: One of the shapeliest and most underrated mountains in Scotland. Credit: WestEnd61/REX Weymouth to Swanage, Dorset Distance: 27 miles Details: A superb section of coastline that throws up some stunning geological oddities, such as Durdle Door. •The best hotels in Dorset Credit: F1 Online/REX The Saddle via Forcan Ridge, Northwest Highlands Distance: Eight miles Details: Great views into Knoydart, to the Five Sisters of Kintail and over the sea to Skye as you scramble over the the Highlands. The Coniston Round, Lake District Distance: 14 miles Deatils: Head in a clockwise direction to catch the morning light. Routes selected in 2010 by Matt Swaine, then editor of 'Trail' magazine •The best hotels in the Lake District Back to image Back to image Back to image Back to image Back to image Back to image Back to image Back to image Back to image Back to image Back to image

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text: Free DownloadsFebruary 20, 2013 FREE MIXTAPE: Heath McNease – Jesus Shuttlesworth...The Mixtape Jesus Shuttlesworth…The Mixtape by Heath McNease Tweet SHARE ON Facebook Twitter Google + Email You may also like Buck Barnabas – The Lazarus Effect Truth & TeK – The World vs Your Soul Domingo Guyton – We In Need Joey The Jerk – Catch Me If You Can (Free Album Download) Cory Cifax signs to CTZN Music and gives away new music Deacon D.A.S. – Give It Over (ft. Steven Seay) Bio Latest Posts Zema Promos I'm a follower of Jesus, a music-lover, and the Founder & CEO of Zema Promotions — a company that seeks to promote God's glory through the arts. I expose you to over one hundred thousand people. I also provide a service to build your social media presence, so if you're on Twitter, Google+, or Facebook, contact me about my good rates. Twitter Facebook Google+ Latest Posts By Zema Promos Jordan Miller – Legends Never Die feat. Fresh Will and Jordan Miller – Separate from Separation Jordan Miller – 1773 Collection Previous articleFREE ALBUM: Fro W.U.N.D.A.S. – UltraSound Next articleFREE EP: A. Sims (of Commoners and Kings) – What Dreams May Come Vol. 1


text:
Meals are served at Wesley Community Senior Center, 1615 S. Roberts St. Breakfast is served from 8 to 8:30 a.m. Lunch is served at noon. Milk is served at all lunches. There is a $3 charge. Meals are for seniors, 55 and older.
Seniors and visitors planning to have lunch at Wesley Community Senior Center are asked to call 806-372-7960 by
9 a.m. daily.
Wednesday — Breakfast: milk, cereal, bananas. Lunch: milk, taco salad, rice, beans and pears. Snack: grape juice, Goldfish crackers, fruit cocktail.
Thursday — Breakfast: milk, pancakes, syrup, strawberries. Lunch: milk, hamburgers, lettuce and tomato, tater tots and pineapple. Snack: crisped tortilla chips, bean dip and apple slices.
Friday — Breakfast: milk, sausage and biscuit, seasonal fresh fruit. Lunch: milk, corn dogs, french fries, peaches. Snack: milk, Go-gurt yogurt, graham crackers.
Monday — Breakfast: milk, honey buns, applesauce. Lunch: milk, meat loaf, mashed potatoes, bread, green beans and pears. Snack: orange juice, celery, carrots, ranch dressing and cheese crackers.
Tuesday — Breakfast: milk, eggs and toast, oranges. Lunch: milk, fish sticks, broccoli and cheese, bread and peaches. Snack: milk, sugar cookies, pineapple.
Lunch is served at the Amarillo Senior Citizens Association, 1200 S. Polk St., from 11 a.m. to 1 p.m. Sunday through Friday for $5.50 for members and $6.50 for nonmembers. All meals include choice of entree, two sides, a salad, dessert and beverage.
Wednesday — Fried Chicken
Thursday — Hamburger Steak
Friday — Fried Cod
Monday — Pork Roast
Tuesday — Lasagna


text:
figleaves.com - Designer Lingerie, Bras, Briefs, Underwear, Swimwear
£10 off* when you spend £40 - Enter code SUMMER40
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Here at figleaves' we know that nursing lingerie is important to new mums, which is why our range has a great choice to guarantee that you feel great when it comes to nursing your new arrival. Our nursing bra range features co-ordinating sets of bras and knickers, as well as pretty fabrics and bright colours. You'll find a great selection of cup and back sizes in styles including full cups, padded bras and sporty shapes.


text:
For the second year in a row, Trinity Fellowship Church has won best in show at the annual Addy Awards, which recognize the best in creative marketing and advertising efforts.
Patrick Kemp, associate pastor of creative ministries at Trinity, said the church entered the contest each year to laud the efforts of its staff and to foster relationships with other designers and printers in the area.
He said it was vital for churches to craft relevant messages in a way the public could relate to.
"Usually what you see is that churches are behind the mark of what the world and other businesses in town are doing. We are doing our best to reach people just as much as Coca-Cola is. Marketing and advertising is the modern language we all speak. It's our outlet to speak the hope of Jesus Christ through a language that everyone understands."
Kemp oversees a staff of six, including two full-time graphic designers, who create materials for the megachurch's roster of activities and outreach.
He says the first step in devising any marketing campaign was to identify the target audience.
"Right now, there are 67,000 people in the Amarillo metro area that claim no religion. Our sole purpose is making sure people know about Jesus, not about Trinity."
Tyler Merrick, president of Merrick Pet Care, said the event was a nice opportunity to display the company's products as artistic creations, rather than simply as products on a store shelf.
"We really want to give our guys a chance to showcase their talent. It's a really nice opportunity to let them compete," said Merrick, who has a creative staff of five, including himself. "It's really neat as a morale booster for our entire team. We've got some of the most talented people on staff. I'd put ours up against anyone in the country."
Tony Freeman, sales manager for Cenveo-Trafton who was the Addy chairman in 1974, said Amarillo has a strong advertising community.
"I've been involved in the advertising club for 36 years," Freeman said. "First Addy awards I went to was in 1971. Judges come from all over and spend two days judging. They're always very complimentary of Amarillo. We have some strong competitors."
2006 Addy Awards
Best of Show
Trinity Fellowship Missions Brochure
Judges Awards
Excellence in Visual Presentation: Cenveo-Trafton, Hideaway brochure; Outstanding Creative & Coordinated Program: Cenveo-Trafton, Marriage Today's Marriage on the Rock Curriculum Kit;
Outstanding Talent: Northwest Texas Healthcare System, "Where Do Babies Come From" television campaign; Outstanding Body of Work: Merrick Pet Care Ltd.
Student Best of Show
Alicia Flake, Amarillo College, Love Life
Student Judges Awards
Award for Strong Graphic Execution: Bradley Cloud, West Texas A&M University, Muddy Waters (Blues) Postage Stamp
Special Judges Award for Best Coordinated Concept: Wheeler Preddy, Amarillo College, wedding invitation
Gold Trophies
Trinity Fellowship, Missions brochure; Cenveo-Trafton, Hideaway brochure; Cenveo-Trafton, Marriage Today's Marriage on the Rock Curriculum Kit; Northwest Texas Healthcare System, "Where Do Babies Come From" television campaign; Trinity Fellowship, Camp Blu animation;
Trinity Fellowship, Belong Banquet animation; Trinity Fellowship Generations Building Campaign video; Merrick Pet Care, Merrick Product Catalog; Merrick Pet Care, Merrick Web animations; Cenveo-Trafton Marriage Today's Prepare to Last Wedding Kit; McCormick Co., Neely Craig & Walton Shoot-out invitation; American Quarter Horse Association, Promo DVD (Part 1); Design SBD, Armstrong County Musuem/Charles Goodnight Historical Center - Goodnight Gathering; Merrick Pet Care, gourmet sausage ad campaign; Johansson & Associates Advertising, Sprouse Shrader Smith "We Know Law" magazine ad; Johansson & Associates Advertising, Church Loans & Investments Trust - Refined by Fire; lone star film & video, Impact Futures, AISD Take a Stand campaign; Graphic Design, David Palmer - Quartz Mountain poster; CFX Studios, Danny Benites Motor Cars - Who's Your Danny? interactive media; Johansson & Associates Advertising, Cardiology Center of Amarillo, Knowledge Television; Trinity Fellowship, Generations mixed media campaign
Silver awards
Cenveo-Trafton PCCA Texas Jubilee Invitation; Trinity Fellowship, Blu video; Trinity Fellowship, Camp Blu Video; Trinity Fellowship, men's retreat videos; Ralph Duke Photographer, self-promotion campaign; Merrick Pet Care, gourmet sausage box display; Merrick Pet Care, Merrick Product Catalog Covers; lone star film and video, Bouchard for U.S. Senate "Date"; McCormick Co., Allergy A.R.T.S. Opera ad; McCormick Co., Nolan Ryan's beef merchandising kit; McCormick Co., Nolan Ryan's beef merchandising kit; Randy Christian & Partners, 2006 Lone Star Ballet Season Brochure; Johansson & Associates Advertising, Cardiology Center of Amarillo - Knowledge**Experience**Compassion; Coffee Memorial Blood Center, Because of You Luncheon Invitation; American Quarter Horse Association, Junior Master Horseman mixed media campaign; McCormick Co., Timmerman Corn Fed Beef direct mail campaign; American Quarter Horse Association, cover photo - AQHA Handbook; McCormick Co., Jr. Travel Study Club - Derby Day Luncheon Hat invitation; McCormick Co., Marian Carpenter - Stanley Studer Tribute; McCormick Co., Center City & Amarillo Historical Preservation Foundation Paramount Sign Re-Lighting Reception Postcard; Design SDB, Reese Beddingfield - Gemini Birthday Invitation; Design SDB, Bates/Mitchell Wedding; Merrick Pet Care, gourmet lunch box ad campaign; Merrick Pet Care, organic chicken ad campaign; Johansson & Associates Advertising, Church Loans & Investments Trust - Refined by Fire Annual Report; Joppa Design, Amarillo Little Theatre Web Site; Johansson & Associates Advertising, The Donut Stop - Yum Yum Sip Sip; lone star film & video, Impact Futures/AISD - Take a Stand/Don't Give Up; Active Media, Designworks Group - Investment Casting Institute, Interactive CD; Merrick Pet Care, O, Christmas Tree; Johansson & Associates Advertising, Premier Vision TV Campaign; Johansson & Associates Advertising, Sprouse Shrader Smith "You Do the Head Count"; Admarc Southwest, Amarillo Town Club "Fitness = Power" television campaign; Admarc Southwest, Brown & Fortunato - fine arts ad campaign; McCormick Co., Robert Parks Tribute; Amarillo Globe-News, Globe News Center for the Performing Arts Web site and Special Section
Student Gold
Alicia Flake, Amarillo College, Love Life poster; Wheeler Preddy, Amarillo College, wedding invitation; Bradley Cloud, West Texas A&M University, Muddy Waters (Blues) Postage Stamp; Rosa Gutierrez, Amarillo College, Memorial; Fareidoon Hemmat, Amarillo College, Outsider Art Auction mixed media campaign; Jarred Elrod, West Texas A&M University, Fontman Ad Campaign; Wheeler Preddy, Amarillo College, Silent Conversations annual report; Steve Bargas, West Texas A&M University, editorial design
Student Silver
Rosa Gutierrez, Amarillo College, Salmo 119:105; Rosa Gutierrez, Amarillo College, Pasaporte; Ronica Farrar, Amarillo College, Poison Control Center mixed media campaign; Jarred Elrod, West Texas A&M University, The Gule Shirt POP & Merchandising Tag; Brad Cloud, West Texas A&M University, MUFON/Mutual U.F.O. Network International Symposium Announcement; Cassadie Lock, Amanda Howell, Casey Carruth, West Texas A&M University, The Eternal Flame 05-06 annual report; James Barrett, Kathryn Barnes, West Texas A&M University, "Filling in the Blanks" magazine AdAddy Awards
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text:
Re: Never co-sign a loan. Never, ever ever.
It appears that the credit union ignored my first GW letter, so I have to try again this week. This credit union is very hard to deal with because they are very large and they like to pretend that they are one of those "too big to fail" commercial banks. They are being really unreasonable.
I guess the next step is to contact the CEO and see if they can do anything about the mess. I'm still really upset about getting this late on my report after all my hard work.
My score rebounded by 25 points because some old baddies fell off my report, but unfortunately I'm still down by 10 points right now and the score simulator on this site says I can't get my score above 700 within the next year due to my ex's late car payment. This is so infuriating!
Starting Score: TU: 566
Current Score: TU: 741 (Discover FICO); EQ: 755 (MyFico) EX: 774 (FAKO)
Goal Score: 800
Take the FICO Fitness Challenge


text:
I am upgrading from a hard drive to an SSD and looking at Carbon Copy Cloner 3.4.5. However I am uncertain what settings I should use as far as handling data already on the destination. Essentially I am expecting the destination to be completely empty after I just partitioned it, but I am a little bit confused about all the options available.
What I want is essentially everything the same on my mac running snow leopard as it was before except residing on an SSD, so what settings should I use? There are customizable settings and advanced settings.


text:
Lafourche Parish Sheriff's office has new website
Published: Tuesday, October 1, 2013 at 8:46 a.m.
Last Modified: Tuesday, October 1, 2013 at 8:46 a.m.
The Lafourche Parish Sheriff's office launched their new website today.
The website features new functionality as well as a new look. Users now have online access to forms that formerly had to be printed out and mailed in, said the Lafourche Parish Sheriff's office.
Also, users now have quicker access to the latest news from the Sheriff's office such as press releases, active warrants, and the database of local registered sex offenders, said the Sheriff's office.
The Sheriff's office will be rolling out new functionality in the coming months. Features will include a new, interactive crime map and online registration for P.O.S.T. academy, the Sheriff's office said.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.


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Kathryn Finney
|Kathryn Finney
|Milwaukee, Wisconsin
|Author, entrepreneur, blogger
|Years active
|Known for
|Founder of The Budget Fashionista, digitalundivided
|www.digitalundivided.comwww.thebudgetfashionista.com www.kathrynfinney.com
Kathryn A. Finney is an author,[1] tech entrepreneur[2] television correspondent.[3][4][5][6]
In 2013, Finney received a Champion of Change Award from the White House for her work in making tech more inclusive.[7][8] She was also named to the 2013 Ebony100 list of the most influential African Americans in the United States,[9] as one of the Top Ten Women in Money by AOL in 2010 along with Maria Shriver, Elizabeth Warren, and Suze Orman,[10] and an Essence Magazine Woman of Style. In 2015, Kathryn was honored by Manhattan Borough President Gale Brewer with the "Kathryn Finney Appreciation Day".[11] Finney is a 2016 Eisenhower fellow, a fellowship given to exceptional young global leaders.[12]
In late 2012, Finney founded digitalundivided,[13] a social enterprise that develops programs that increase the active participation of urban communities, especially women, in the digital space. For three years, DID hosted the FOCUS100 Conference, considered to be the "most diverse tech conference" the first weekend of Oct in New York City.[14] She also spearheaded the FOCUS Fellows program, a tech inculator and fellowship program that provides diverse women founders with training and access to various startup resources, including support, mentorship, and seed funding.[15]
Finney's work in the area of tech entrepreneurship has been recognized by several press outlets including the Wall Street Journal, Pando Daily, and New York Times.,[16][17][18][19][20]
She is also known as one of the first lifestyle bloggers for her blog, The Budget Fashionista,[21] which was named by MSN as one of the 100 most useful sites on the web.[22]
Early life[edit]
Born in Milwaukee, Wisconsin, Finney was introduced to technology through her father, Robert Finney, who was introduced to technology via courses at the local OIC, and rose to become a Senior Systems Engineer at Microsoft and later EMC. He led the development of one of the first high school based computer based technology academies at St Louis Park High School in St Louis Park, MN.[23]
She graduated from Washburn High School in Minneapolis, MN, where she was her class president, member of National Honor Society, delegate to Girls State and Girls Nation, and received the Washburn High School Service Award.
Finney has an undergraduate degree from Rutgers University in Women's Studies and Politics, where she was a member of the Rutgers College Student Government, a James Dickson Carr Scholar, Rutgers College Honors Program, The USA Today All Academic team, and was voted by her graduating class to receive the class of 1998 Alumni Award for Outstanding Scholarship and Community Service. During her junior year, Finney was a Washington Center Washington Fellow and interned at the White House as well as with the late Senator Paul Wellstone.
She also earned a Master of Public Health degree from the Yale University, where she was a Courtland Van Creed Scholar. She received the Weinerman Fellowship for her work as an international epidemiologist in the South African region.
Prior to starting her media company, Finney worked for USAID and other non-profits in Ghana, West Africa and South Africa.
The Budget Fashionista years[edit]
Finney started her blog in April 2003 as a hobby, and started blogging full-time in June 2004. Her blog, The Budget Fashionista, which was one of the first fashion blogs,[24] is one of the top fashion blogs on the net.[25][26]
Finney is considered an icon and pioneer in the style blogging community,[27] having earned the monikers of "Master of Cheap Chic" [28] and "Scheherazade of the Sales Rack".[29] She is considered to be one of America's best bargain shoppers (Style Network, 2004) and has appeared on several national TV shows such as NBC's Today Show, Fox Network News, CNN, etc. She has also appeared in over 1000 articles including Essence, USA Today, The New York Times, LA Times [30] and Redbook, as a style expert on looking fabulous for less. She's also the former fashion editor of Real Magazine. Finney's popular Twitter feed has been listed by numerous publications including the New York Post, Clutch Magazine,[31] and The Grio.[32]
In May 2006, her first book was published entitled, How to be a Budget Fashionista: The Ultimate Guide to Looking Fabulous for Less by Ballantine Books, an imprint of Random House. It became an Amazon bestselling book in the Art and Photography category and is now on its 11th printing.
From 2012-2014, Finney was the Editor-at-Large at BlogHer, a global media group representing over 40 million women.[33][34]
Building digitalundivided (DID)[edit]
In late 2012, Finney utilized personal funds [35] and founded digitalundivided (DID), a social enterprise which finds, trains, and supports innovative leaders and entrepreneurs.[36] She also launched the FOCUS Fellows, a rigorous fellowship program for black women founders of developed, but early staged, technology-enabled companies. To date, more than 50% of the FOCUS fellows have raised Angel and venture funding, while 10% have raised at least $1MM. Many had gone on to work in leadership positions at leading start-up companies like Uber and Facebook.[37]
DID held its first FOCUS100 conference in October 2012 in New York City. It initially received support from venture firm Andreessen Horowitz, marketing agency Ogilvy, and other top firms. The following year, the event received support from Google, American Express, as well as Andreessen Horowitz and Ogilvy.[38] On its third year (2014), the event received support once more from American Express, as well as from Facebook, Mobile Future, and the Portland Development Commission. During the event closing, Finney announced 2014 as the last year of the FOCUS100 conference. She also announced the expansion of its FOCUS Fellows program to a residency "inculator" for black women-led startups.[39]
DID continues to bring its ensemble of programs like START and Innovation Thursday, to various cities in the U.S in partnership with various organizations and companies such as UNCF[40] and Etsy.[41]
Finney has received numerous recognition for her work in building tech eco-systems in urban communities, including the Champion of Change Award from the White House in 2013 [42] and the "Kathryn Finney Appreciation Day" from Manhattan Borough President Gale Brewer[43] in 2015. She has also received the New York Business Journal's Women of Influence Award,[44] UPSTART 100 List of Top Innovators,[45] SXSW Black Innovator Award, The Grio 100,[46] Ebony Power 100 List of the Most Influential African Americans, Black Enterprise "40 under 40" list,[47] and induction into Spelman College's "Game Changers Academy".[48]
Finney has been a keynote speaker at top conferences. She has keynoted at the White House,[49] as well as for Omidyar Network,[50] SXSW Interactive,[51] and more.
Finney serves as an adviser to black women-led startups and organizations, including MentorMe, Inc and All-Star Code.[52] She is also a trustee of The Robert Finney Foundation,[53] a foundation she started with her mother and brother to honor her late father. The foundation provides scholarships to African-American students pursuing studies in the field of technology. Finney has also served on the boards of the Hudson Guild
In Modern Culture[edit]
Finney is credited with coining several major shopping and internet marketing terms, including "The Budget Fashionista" [54] (which she owns the trademark), the term "Love what you buy and buy what you love", meaning shoppers should focus on purchasing items that make them feel and look great and "blogroots", which is a term meaning to aggressively market a product, book, idea, through networking with blogs.[55]
- Kathryn Finney (2006-05-30). How to Be a Budget Fashionista: The Ultimate Guide to Looking Fabulous for Less. Ballantine Books. ISBN 978-0-8129-7516-1.
- ^ Kathryn Finney Author Bookshelf - Random House - Books - Audiobooks - Ebooks Random House Author Page- Kathryn Finney
- ^ Minorities Entering Tech Wall Street Journal
- ^ Kathryn Finney on Dallas Fox TV Video Fox Dallas, June 2006
- ^ Kathryn Finney on Geraldo Rivera's Fox Show Video Fox News Network- Geraldo Rivera Show
- ^ Kathryn Finney/The Budget Fashionista CNN Clips Video CNN
- ^ Kathryn Finney on CNBC's On the Money Video CNBC, September, 2009
- ^ WhiteHouse.Gov WhiteHouse.gov
- ^ Black Enterprise: White House Recognizes Tech Leaders As 'Champions of Change for Tech Inclusion' Black Enterprise
- ^ Ebony Power100 2013: Emerging Leaders Ebony
- ^ The Top 10 Women in Money | The Top 10 Women in Money | Comcast.net AOL Top Ten Women in Money
- ^ [1] Manhattan Borough President's Black History Month Reception
- ^ [2] Kathryn Finney: Eisenhower Fellow 2016
- ^ digitalundivided digitalundivided
- ^ Silicon Forrest, Notes from the Most Diverse Tech Conference on the Planet Silicon Forrest
- ^ [3] Inside the Campaign to Disrupt Tech's Huge Diversity Problem.
- ^ Wall Street Journal, Kathryn Finney Wall Street Journal
- ^ digitalundivided OZY.com Integrating an Industry
- ^ Silicon Forrest, Notes from the Most Diverse Tech Conference on the Planet Silicon Forrest
- ^ Venture Beat, Black Female and Smart Venture Beat
- ^ Pando Daily, digitalundivided wants to Start a Dialogue About More Black People in Tech Pando Daily
- ^ Gothamist: Kathryn Finney, Blogger, Thebudgetfashionista.com, Author, How To Be a Budget Fashionista
- ^ Liz Pulliam Weston: Best Web sites for saving money and time - MSN Money
- ^ Robert Finney, Computer Guru at St Louis Park High School Highbeam
- ^ "Shoppers flock to designer deals" Deseret News (Salt Lake City)
- ^ Chicago Sun-Times: jump local: Fashion's best blogs Archived July 30, 2007, at the Wayback Machine.
- ^ mode femme vetement fashion verbaudet at fashionnewssite.com Archived June 30, 2007, at the Wayback Machine.
- ^ Life, Love, and the Pursuit of Fabulousness: The Budget Fashionista 5th Anniversary « Clutch Magazine
- ^ Book Review: How To Be A Budget Fashionista
- ^ Express: A Publication of The Washington Post
- ^ http://www.look-look.com/look/abus.news.html?sectionName=online&id=1 Archived copy at WebCite (January 24, 2006).
- ^ Tweeting Fashion: The Top 15 to Follow « Clutch Magazine
- ^ Fashion to follow: 15 top twitter feeds
- ^ [4] BlogHer Names Kathryn Finney, Editor at Large
- ^ [5] BlogHer Names 'The Budget Fashionista', It's new Editor at Large
- ^ Tackling the Lack of Women in Tech Black Enterprise
- ^ [6] digitalundivided
- ^ [7] digitalundivided: About FOCUS Fellows
- ^ Venture Beat, Black Female and Smart Venture Beat
- ^ [8] #FOCUS100 NYC Conference Saturday Session Recap
- ^ [9] UNCF & HBCU Partners Launch Tech-empowerment Week At The Atlanta University Center
- ^ [10] digitalundivided Presents Innovation Thursdays At Etsy Hq
- ^ [11] Kathryn Finney | White House Champion of Change
- ^ [12] Manhattan Borough President's Black History Month Reception
- ^ [13] Meet Kathryn Finney, Women of Influence honoree, and learn how her father's work ethic influenced her career
- ^ [14] Kathryn Finney Profile on Upstart100
- ^ [15] theGrio's 100: Kathryn Finney
- ^ [16] 40 Rising Stars 40 & Under
- ^ [17] Spelman College Announces Honorees and Speakers for 2015 Women of Color Conference
- ^ [18] Kathryn Finney | White House Champion of Change
- ^ [19] Social impact drives Omidyar Network's civil tech investments
- ^ [20] Kathryn Finney's Lanyrd profile
- ^ [21] Kathryn Finney's LinkedIn Profile
- ^ http://www.wfmn.org/PDFs/EqualityReport_Spring2007.pdf
- ^ I Am Not A Fashionista: Why We're Over All Words Ending in '-ista' Coco & Creme
- ^ "6 Brilliant Advice On Starting A Blog Help To Solve Biggest Problems". Blog Marketing Sea. Retrieved 2015-06-14.


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Orange Date And Almond Medley
13 Feb 2011
|5 , peeled and sliced
|1 Cup (16 tbs), coarsely diced
|Orange juice
|2⁄3 Cup (10.67 tbs)
|Grand marnier liqueur
|2 Tablespoon
|Toasted slivered almonds
|1⁄2 Cup (8 tbs)
Cut the orange slices in half and mix them with the dates, orange juice, and Grand Marnier, if you use it.
Chill at least 2 hours and stir in the nuts.
Recipe Summary
Difficulty Level:Easy
Course:Dessert, Fruit Dessert
Rate It
Nutrition Rank
Nutrition Facts
Serving size: Complete recipe
Calories 1358 Calories from Fat 303
% Daily Value*
Total Fat 33 g50.3%
Saturated Fat 2.3 g11.5%
Trans Fat 0 g
Cholesterol 0 mg
Sodium 25.2 mg1.1%
Total Carbohydrates 261 g87%
Dietary Fiber 39.6 g158.6%
Sugars 201.3 g
Protein 23 g46.2%
Vitamin A 42.7% Vitamin C 735.2%
Calcium 55% Iron 27%
*Based on a 2000 Calorie diet
0 Comments
Orange Date And Almond Medley Recipe


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WWE Announces NXT "Takeover" Live Special For WWE Network On May 29th
WWE issued the following press release today …
WWE NXT Takeover to air LIVE on WWE Network on Thursday, May 29 at 8 p.m. ET
STAMFORD, Conn. — WWE announced today that NXT Takeover, a live, two-hour action-packed special, will air exclusively on WWE Network on Thursday, May 29 at 8 p.m. ET. Following the success of NXT ArRIVAL, the special will once again showcase the best and brightest from the WWE Performance Center and include appearances by WWE Superstars and Legends.
30 minutes prior to the event, the NXT Takeover pre-show will air at 7:30 p.m. ET and include exclusive interviews and appearances by NXT Superstars, WWE Superstars and Legends.
"As NXT continues to grow in popularity and our fans demand to see more of the next generation of WWE Superstars, we are going to deliver live, in-ring programs featuring up-and-coming talent on WWE Network," said Paul "Triple H" Levesque, Executive Vice President, Talent, Live Events & Creative. "Our live NXT specials on WWE Network bring out the very best in our performers and make for must-see TV for the WWE Universe."
On February 27, NXT ArRIVAL on WWE Network had 21 worldwide Twitter trends and was No. 3 in overall social mentions for primetime programs on both cable and broadcast. The event had more social mentions than American Idol, the Vikings premiere on History Channel, college basketball on ESPN and Vampire Diaries on CW.
For a detailed spoiler report of the next four weeks of WWE NXT television, which contain the storylines leading up to three matches being announced for NXT Takeover, check out the following 24Wrestling.com article: (Spoilers) WWE NXT Taping Results For May 1st Through May 22nd


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More Than 500,000 Hoverboards Recalled After FiresMore than 500,000 hoverboards are being recalled after some of the motorized scooters overheated, burned riders and damaged property. There have been 99 reports of hoverboard battery packs that exploded or caught fire.
I-Team: How To Stop Your Shower Door From Spontaneously ExplodingImagine being inside the shower when your glass door suddenly explodes.
Top 5 Dangerous Recalled Child ProductsEvery year thousands of kids are injured and hundreds killed from unsafe child products.
Vans Recalls Boy's Hoodies Due To Strangulation HazardVans is recalling about 2,400 of its 'AV Edict' hooded jackets for boys because the drawstrings in the hood around the neck area pose a strangulation hazard to young children.
Wire Brushes Present Hidden Grilling DangerBefore you begin your backyard grilling, CBS 11 News has uncovered a danger that you may be cooking up. It's not about the meat, and it's not about any food-borne illness.
Thousands Of Kids' Tabletop Chairs RecalledTens of thousands of tabletop feeding chairs for babies and toddlers were recalled Wednesday after reports that they can come loose and send children plummeting to the floor.
Government Recalls Stadium Light Poles


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User/Comment Login
"Wedding Belles," is "the quintessential sweet, Southern dramedy," said director Mandi Tucker.
"While 'Wedding Belles' is set in a small Texas town in 1942, it could just as easily be set in 1942 Palatka," Tucker said. "There is a rhythm to a small town where everyone knows everybody (and their business). The play also does a wonderful job exploring lifetime friendships (and problems) among the four women who constitute the cast. The fear of being themselves has long drifted away. They have no problem saying exactly what's on their mind."
I confess, up front, to knowing virtually nothing about Lionel Bart's musical "Oliver!" before seeing it performed this past weekend on the Limelight main stage. Sure, I knew it was based on Charles Dickens' "Oliver Twist," the maltreated orphan boy in 1850s England, but that was essentially all.
Who could have foretold this production under the executive direction of Beth Lambert.
Director Tom Fallon, who also designed the set, music director Shelli Long and choreographer Roxanna Lewis... every aspect of the production is at professional levels.
Jon Robin Baitz's "Other Desert Cities" 2011 initial Broadway run — starring Stockard Channing and Stacy Keach — was a huge critical success, garnering five Tony nominations, and a Pulitzer consideration. Originally (and more appropriately) titled "Love and Mercy," (motivations behind the name change defy explanation).
This intense, often brutal, inter-generational adult drama, directed by Gary Cadwallader, is anything but a carefree travelogue romp.
It continues on the Limelight's mainstage through May 11.
St. Augustine Record ©2016. All Rights Reserved.


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Maintain a sanitary environment in your commercial kitchen by providing employees with these disposable gloves! Use them for a variety of tasks, including food prep, serving, and operating the cash register. These disposable gloves for cooking are designed to fit comfortably on the users' hands, encouraging them to wear them whenever handling food.These disposable gloves are available in a range of durable materials and are meant for one-time use. Simply throw them away after handling a certain food product to eliminate cross-contamination. Whether you operate a cafeteria, bake shop, concession stand, or restaurant, these gloves are necessary items for your staff!


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??!! David Mamet Directs Car Commercials
posted by April 17 at 14:52 PMon
Pulitzer Prizewinning David Mamet?
Yes, Pulitzer Prizewinning David Mamet has directed TWO commercials for Ford.
Car commercials?
Car commercials.
Mamet only directed the commercials. The "dialogue" was apparently written in Mamet's trademark style by an ad agency.
Watch them at your own peril:


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Product Reviews
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Men's jockstrap wrestling singlet Men's bodysuit made from polyamide/spandex Machine wash Imported Good Devil style 9011 Innovation at its best! This new wrestling singlet from Good Devil features a supportive jockstrap bottom and a super soft and stretchy body. The Good Devil Jockstrap Singlet fits beautifully like a second skin so you can be comfortable wrestling or playing. Slip on this sexy, sporty men's bodysuit and get ready to rumble!
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Blood Music by cococream45Watch
©2012-2016 cococream45
Grell and his music!! The head phones are from (c) skull candy brands which are the good ones. I just thought putting those on a reaper is a good combination!!
This is really amazing!
I really like this! Nice job!
oh im so jealouse! great work!
Awesome. Wish I could do something like that!
SO COOL! Was this made with marker? I could never do something like this... XD
Perfect! *_*
I'd so like to make music...I mean listen to music with Grell Sempai. lol
Sure just remember who drew it!!
very nice!
omfg this is AWESOME. His headphones and hair are spectacular. alskflakfghjlsjd
OH HE IS SO BEAUTIFUL!!!! Love his headphone dewsign - they look so sttylish. Love the background - it looks so cool and dark and I just generally love the colours black and re together d, specially here as the red looks like vblood. I love Grell´s pose and look that looks bit flirty and fun and his hair makes it look moving as well - just like his dancing after his favorite tune after killing someone.*adds to favorites*
Grell is sweet AMAZING work
oh wow *o* good job!!!
I love this! <3
I love this! <3


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National "Stand Your Ground" debate hits home
Last Thanksgiving, Byron Smith got more than turkey, cranberry, and mashed potatoes on his plate. The 64-year-old retired State Department employee shot and killed two wayward local teenagers when they allegedly tried to burglarize his home on Elm Street in Little Falls, a town of 8,000 residents approximately 100 miles northwest of Minneapolis.
Nicholas Brady, 17, and his cousin Haile Kifer, 18, had robbed an unoccupied home outside of Little Falls just days before, making off with prescription medication. Likely they were looking for more pills when they broke into Smith's house.
Smith, who told authorities that his home had been broken into eight times in recent years, was in his basement when he heard an upstairs window break. He saw Brady on the stairwell descending toward the basement and shot the unarmed teenager with a Ruger Mini-14 semi-automatic rifle. Then he methodically finished off Brady with a gunshot to the face at point-blank range. An audio surveillance recording at the house captured Smith saying the words, "You're dead."
Within 18 seconds, Smith produced a tarp, rolled up Brady's body, and dragged it into his workshop. Ten minutes later, according to the audio recording, Kifer called out for Brady, then crept down the stairs. Smith shot her once before his gun jammed, about which he sardonically quipped, "Oh, sorry about that."
"Oh my God! Oh my God!" Kifer reportedly moaned in pain.
Smith fired several more shots with a .22-caliber revolver, telling Kifer, "You're dying, you're dying," as she crumpled to the basement floor. He dragged her body next to Brady's, then noticed the teenage girl still gasping for air. That's when he fired what he later called a "good clean finishing shot" up into her cranium.
Upon seeing Kifer's body offer a death twitch, Smith commented, "It works the same in a beaver or a deer."
Byron Smith didn't call the police to tell them about the two dead bodies in his basement, instead phoning his brother in California. The next day he told a neighbor what he had done and, likely at their encouragement, hired a lawyer. Only then were the authorities alerted.
"He didn't want to trouble us on the holiday," Morrison County Sheriff Michel Wetzel says Smith told investigators.
Smith has been charged with murder and was released on bail December 18. Pretrial hearings will resume on May 6 as the court awaits toxicology and DNA results. In the meantime, a firestorm of public opinion has engulfed Little Falls. On one side are those who view Smith as a cold-blooded killer of unarmed kids. On the other are those who believe Smith had a right to defend his home from burglary.
William Anderson, Smith's neighbor and friend, says that if law enforcement had done its job in October — the last time Smith's home was burglarized — there wouldn't be two dead kids today.
"If they hadn't been breaking into homes, they would be alive today," adds Anderson. "That's what we're going to write in granite at the local school."
Byron Smith's defense in court will undoubtedly rest on his legal right to protect himself against intruders inside his home. Adam Johnson, an associate at Meshbesher & Associates, which will represent Smith, couldn't comment on the specifics of the case, but told City Pages, "We're preparing our defense based on both a person's right to self-defense and to defend their home."
Smith's lawyers will appeal to the "castle doctrine" or "defense of habitation law," which derives from the 17th-century British jurist Sir Edward Coke, who articulated in his The Institutes of the Laws of England that "an Englishman's home is his castle," and he has the right to exclude anyone from his home. The dictum followed colonists to the New World, where over the next 377 years it merged with America's frontier individualism and gun culture to metastasize into today's "Stand Your Ground" laws, versions of which exist in 26 states.
The doctrine designates a person's home — and in some states, car or place of business — as a place where that person has certain protections and immunities and may, under certain circumstances, use deadly force to defend against an intruder without threat of prosecution. Prior to the passage of these shoot-first-ask-questions-later laws, the homeowner had a duty to try to retreat and call authorities for help.
Morrison County Sheriff Wetzel alluded to the "castle doctrine" in a statement after Smith was arrested, but insinuated that the Little Falls man had gone too far.
"A person has every right to defend themselves and their homes, even employing deadly force if necessary," Wetzel began, but added that investigators believe Smith's actions went beyond self-defense. "The law doesn't permit you to execute somebody after the threat is gone."
Pete Orput, the veteran Minneapolis homicide prosecutor who will help Morrison County authorities put Smith on trial, says that this case isn't about gun rights, it's about murder.
"This case is big," Orput says. "This is Minnesota's Trayvon Martin case."
The fatal shooting of Trayvon Martin by George Zimmerman in Sanford, Florida, last February commanded national headlines and set off angry protests far beyond the Sunshine State.
The story had an explosive racial element, since Martin was an unarmed 17-year-old African-American and his killer was a 28-year-old white Hispanic. Even President Barack Obama commented on the issue, saying, "If I had a son, he'd look like Trayvon."
The national handwringing over guns in Florida was in some ways fitting. Seven years earlier, Florida Gov. Jeb Bush signed the nation's first "Stand Your Ground" bill into law. Prompted in large part by the Trayvon Martin case, the Tampa Bay Times published a comprehensive study of nearly 200 Florida Stand Your Ground cases and their outcomes: Among them were cases of drug dealers avoiding murder charges, but also exonerated defendants legitimately acting in self-defense, including a woman who stood her ground after being choked and beaten by an irate tenant.
Among the Tampa Bay Times' findings: that 70 percent of those who invoke Stand Your Ground to avoid prosecution have gone free; defendants claiming Stand Your Ground are more likely to prevail if the victim is black; and that the number of cases is increasing as defense attorneys use Stand Your Ground in ways that state legislators never envisioned. Stand Your Ground claims have arisen following incidents outside an ice cream parlor, on a racquetball court, and at a school bus stop. Two-thirds of the defendants used guns, but other weapons have included an ice pick, a shovel, and a chair leg.
In November, another grisly tale emerged in Florida of an older armed man initiating an argument with a black teenager that ended in a fatal gunshot. This time 17-year-old Jordan Davis was shot by gun collector Michael Dunn following an argument over loud music outside a Jacksonville convenience store. The reaction to Davis's death didn't reach the fever pitch of Trayvon Martin's case because local police quickly charged Dunn with murder.
Since it was born in 2005, Stand Your Ground has spread like wildfire. Seven years later, more than half of the states in the union have adopted some version of it — not by organic political means, but after they were pushed as "model legislation" by the National Rifle Association and the Koch brothers-funded American Legislative Exchange Council (ALEC), a corporate-sponsored neo-conservative consortium of lawmakers.
According to Mother Jones magazine, the year after Florida adopted Stand Your Ground, the stepchild of England's castle doctrine spread to 12 other states across the Deep South as well as Kansas, Michigan, and Indiana.
In Miami that year, a man shot 14 bullets at a car full of gang members and avoided prosecution by citing the law. In 2007, justifiable homicides more than tripled in Florida, while four more states adopted "Stand Your Ground."
In 2008, a 15-year-old boy in Tallahassee died after getting caught in a shoot-out between rival gangs — two of the gang members successfully hid behind "Stand Your Ground."
Meanwhile, Ohio and West Virginia joined the list of states to adopt the statute. Four months after the law took effect in Montana in 2009, a Walmart employee in Billings was released from custody after claiming he shot a co-worker in the face in self-defense.
Has the introduction of Stand Your Ground laws by state legislatures emboldened gun owners to shoot and kill without fear of prosecutorial reprisal? Has Stand Your Ground, as Florida state Sen. Steve Geller warned, encouraged people to think that "you ought to be able to kill people that are walking toward you on the street because of this subjective belief that you're worried that they may get in a fight with you?"
It apparently did for Joe Horn.
In the Houston suburb of Pasadena on November 14, 2007 — two months after Texas passed Stand Your Ground — the 61-year-old retiree saw two burglars breaking into the house next door. He called 911, but also grabbed his shotgun.
Horn told the operator, "I've got a shotgun; do you want me to stop them?"
The Pasadena emergency operator responded: "Nope. Don't do that. Ain't no property worth shooting somebody over, okay?"
A back-and-forth ensued, and the operator told Horn that officers would arrive soon.
"Okay," Horn countered. "But I have a right to protect myself too, sir," adding, "The laws have been changed in this country since September the first, and you know it."
"You're going to get yourself shot," countered the operator.
To which Horn replied: "You want to make a bet? I'm going to kill them."
When the authorities arrived, they found Hernando Torres and David Ortiz dead from bullet wounds fired from behind them. Eight months later, a Harris County grand jury declined to indict Horn on any criminal charges.
"Stand Your Ground serves to enable paranoid crazies to commit murder without fear of any consequences," said Elliot Fineman, CEO of the National Gun Victims Action Council. "The most cursory look into basic psychology shows the certain potential of Stand Your Ground for stimulating aggression, and all for the fantasy of self-protection by way of a carried gun in public."
Examples abound of Stand Your Ground promoting vigilantism around the country in 2012. Last March in Wisconsin, Bo Morrison was shot and killed by a homeowner who found the unarmed 20-year-old on his porch early one morning. Morrison had tried to evade police responding to a noise complaint at a neighboring underage drinking party. The homeowner was not charged by the local district attorney.
Wisconsin doesn't officially have Stand Your Ground, but Gov. Scott Walker signed an "intruders bill" in 2011 that presumes somebody who uses deadly force against a trespasser in their home, business, or vehicle acted reasonably, whether or not the intruder was armed.
In April, 22-year-old Cordell Jude shot and killed Daniel Adkins Jr., a mentally disabled pedestrian who walked in front of Jude's car as he was pulling up to the window of a Taco Bell drive-thru in Arizona, which passed Stand Your Ground in 2010. Jude thought he saw Adkins wield a metal pipe in the air, but it was actually a dog leash. No arrest was made.
In June, a judge in Miami dismissed a second-degree murder charge against Greyston Garcia after he chased a suspected burglar and stabbed him to death. The judge decided the stabbing was justified because the burglar had swung a bag of stolen car radios at Garcia. The judge found Garcia was "well within his rights to pursue the victim and demand the return of his property."
In October, citing the state's newly strengthened castle doctrine law, Montana prosecutor Ed Corrigan declined to indict Brice Harper, who had shot and killed Dan Fredenberg, the husband of the woman with whom Harper was having an affair. Harper killed an unarmed Fredenberg when he walked into Harper's garage.
"I told him I had a gun," Harper told the police, "but he just kept coming at me."
And on December 10 in Rochester, Minnesota, a 61-year-old man shot and critically wounded his 16-year-old granddaughter when he mistook her for an intruder entering his house just before 11 p.m. The grandfather, who reportedly had a recent burglary at the nearby Rochester Recreation Center on his mind, responded to a noise outside by arming himself with a handgun and firing two rounds at the figure he saw standing on his patio. The girl was in critical condition but is expected to survive.
Minnesota has a law on the books that stipulates that shooting an intruder is legal if the shooter has a reasonable belief that doing so would prevent a felony from occurring inside the home. Nevertheless, Gov. Mark Dayton early last year vetoed a "Stand Your Ground" bill that the Republican-controlled Legislature had passed with the support of some Democratic lawmakers from rural districts.
Minnesota's Stand Your Ground bill, H.F. 1467, was sponsored by Republican state Rep. Tony Cornish and state Sen. Gretchen Hoffman, and would have been among the "craziest gun laws in America," according to Salon. Had Dayton not vetoed it, the Minnesota version would have exempted homeowners from any duty to retreat if an intruder enters illegally; allowed the use of deadly force if someone is threatened with substantial, albeit temporary, bodily harm (including a punch to the face); granted total immunity from criminal prosecution; and disallowed the arrest of the suspect until police had fully considered any claim of self-defense.
Tom Weyandt, a former assistant city attorney in St. Paul, published a detailed critique of H.F. 1467 last year in which he did a line-by-line reading of Minnesota's vetoed Stand Your Ground bill in comparison to Florida's law, coming to the conclusion that Minnesota's version was far worse.
"The law currently says you can use deadly force if you're subjected to the risk of great bodily harm or death," explains Weyandt. "They [proposed changing] it to lower the standard to substantial bodily harm, which could mean as little as a bruise — a temporary visible injury. If you feared that I was gonna punch you in the eye, under their proposal you could kill me. Every doofus on the street who says 'self-defense' would get a much greater chance of a walk than he has now."
The deluge of Stand Your Ground killings hasn't deterred gun-rights advocates like Representative Cornish — nor did the December school massacre in Newtown, Connecticut. Cornish said in November that, with his party now in the legislative minority, there was "zero" chance he'd propose the "deadly force" bill again this session. But the Sandy Hook tragedy, and a push by the White House for stronger gun laws, apparently changed his mind.
Cornish recently reloaded, insinuating that he'll make another effort to allow teachers and staff to carry concealed weapons even if a school's principal or administrators don't approve. Current law requires permission from administrators before a teacher can bring a weapon to school. Cornish will also try to require public colleges to let students carry handguns on campus if they have the applicable permits.
Had it passed Governor Dayton's desk last year, would Minnesota's shoot-first bill have given Byron Smith a get-out-of-jail-free card? Cornish doesn't think so.
"You could feasibly see [Smith] mounting a defense for the first shot," Cornish says. "But after that initial one shot, then he went completely out of the realm of reality and executed two helpless people."
But if Minnesota had Stand Your Ground, would Little Falls authorities even have had the power to question Smith, listen to the audio recordings, and learn how he killed the two teens?
"They would not have been able to arrest him until they could come up with enough evidence that his claim of self-defense was unreasonable," says Weyandt. "In Florida, everybody gave the chief of police [in the Travyon Martin case] a ton of crap. But [under a Stand Your Ground law] you can't arrest a guy until you can prove his claim of defense was invalid."
Morrison County Sheriff Wetzel, who was part of the team that arrested Smith at his house the day after Thanksgiving, agrees that Cornish's bill would have proved problematic.
"How would you ever again convict someone of homicide in their own home?" asks Wetzel. "One could just say, 'I was afraid and I feared for my life.' But there needs to be an objective standard. Was it reasonable for you to be afraid?"
Law enforcement around the state took a strong stand against the shoot-first bill. The Minnesota County Attorneys Association, the Minnesota Chiefs of Police, the Minnesota Sheriffs Association, and the Minnesota Police and Peace Officers Association all lobbied lawmakers and Governor Dayton to shoot down Stand Your Ground.
"Our concern was that, had that legislation been signed into law, it would have made a Byron Smith-type situation more difficult to prosecute," says John Kingrey, executive director of the Minnesota County Attorneys Association. "Most people would agree that you have the right to use force with force, but once an intruder is incapacitated, your duty to continue using force ceases."
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Three returning champions will look to defend titles as the District 3-4A tennis tournament starts today at the Dumas High courts.
The tournament includes girls singles, girls doubles and boys doubles championships. Competition will start at 9 a.m. today. The finals, third-place and playback matches will start at 9 a.m. Tuesday, also at the Dumas High courts. The poor weather that passed through the Panhandle area during the weekend might force some changes with the schedule but those will not be determined until today.
Frank Granado from Hereford is the defending boys singles champion. The Dumas girls doubles tandem of Jessie Lucero and Abbi Moore and Randall's boys doubles team of Brad McKenzie and Stephen Davis are back to play for a second straight title.
The top two finishers qualify for regionals, which will be held April 23-24 at San Angelo.
- Globe-News Staff
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