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|Apr 17, 2012
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|Sep 25, 2008
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|Sep 26, 2007
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|Lewis Silverman, James Holland
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|Mount Sinai School Of Medicine
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|Patent Citations (78), Non-Patent Citations (13), Referenced by (7), Classifications (15), Legal Events (3)
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This application claims benefit of U.S. Provisional Patent Application Ser. No. 60/975,437, filed Sep. 26, 2007, which is hereby incorporated by reference in its entirety.
This invention relates to azacytidine analogues and uses thereof.
Nucleoside analogues, the derivatives of the natural nucleosides found as building blocks of DNA and RNA, are effective in the clinical treatment of human cancer or viral diseases, although in the early years such compounds were evaluated as anti-tuberculosis agents. Such compounds have been registered in the market for more than 40 years, and approximately 35 products are currently in daily use. The natural nucleosides illustrated in Table 1 below, are constructed from two classes of nitrogen bases, i.e. the purines (exemplified by adenine and guanine) and the pyrimidines (exemplified by thymine, uracil, and cytosine) and from the monosaccharide ribose or deoxyribose.
The natural nucleosides all exist in the so called β-D configuration as illustrated in the Formula A below. The nitrogen base and the hydroxy-methyl side chain on the sugar ring are both on the same side (cis) of the plane of the sugar ring.
In order to obtain nucleoside derivatives with anticancer or antiviral activity, chemical modifications in either the nitrogen base and/or the monosaccharide have been performed. For instance in the nitrogen base, the addition of halogen atoms or other functional groups, insertion of additional nitrogen atoms or a stereochemical change in the monosaccharide ring from ribose to arabinose or removal of the hydroxyl group to deoxyribose may lead to products with a potential therapeutic benefit. In many products, the monosaccharide ring is conserved, while in others, the sugar ring has been changed into a chain. The nucleoside analogues are small molecules with fair to excellent aqueous solubility.
The extensive research and development effort put into the area of nucleoside analogues due to the worldwide AIDS epidemic bolstered the basic knowledge and understanding of mechanism of action, alterations in activity profile due to chemical modifications etc, are also relevant to the field of cancer treatment.
A general weakness with many drugs, including nucleoside analogues, is low activity and inferior specificity for treatment of the actual disease in question. Some of these problems may be related to the inherent activity of the drug substance itself, some may be related to certain resistance mechanisms (either inherent in the patient or acquired during treatment e.g. multiple drug resistance (MDR) in cancer treatment). Some problems may be related to certain inferior transport or cellular uptake and activation mechanisms. Some problems may be related to rapid inactivation and/or excretion of the drug.
The efficacy of nucleoside analogues depends on a large extent on their ability to mimic natural nucleosides, thus interacting with viral and/or cellular enzymes and interfering with or inhibiting critical processes in the metabolism of nucleic acids. In order to exert their antiviral or anti-cancer activity, the nucleoside analogues have to be transformed, via their mono- and di-phosphates, into their corresponding tri-phosphates through the action of viral and/or cellular kinases. As a general rule, the tri-phosphate is the active agent, but for some products, e.g. gemcitabine, even the di-phosphate may exert a clinically significant effect.
In order to reach the diseased, cancerous or virus infected cells or tissues, following either enteral or parenteral administration, the nucleoside analogues should have favorable pharmacokinetic characteristics. In addition to rapid excretion of the administered drug, many nucleoside analogues may be deactivated both in the blood stream and in tissues. For instance may cytosine derivatives, even at the mono-phosphate level, be rapidly deaminated through the action of a class of enzymes called deaminases, to the inactive uracil analogue. The cellular uptake and thus good therapeutic efficacy of many nucleoside analogues strongly depend on membrane bound nucleoside transport proteins (called concentrative and equilibrative nucleoside transporters). Hence, compounds that do not rely on such specific uptake mechanisms are sought. Yet another activity limiting factor, particularly within the anti-cancer field, are the cellular repair mechanisms. When an anti-cancer nucleoside analogue mono-phosphate is incorporated into the cellular DNA, it should not be removed from the cancer cell DNA due to the exonuclease activity linked to the p53 protein. However, removal of a nucleoside analogue from the DNA of a healthy cell is favorable in order to limit the side effects of the drug.
Over the years, many nucleoside analogues have been developed that to a large extent overcome some or many of the activity limiting features. As an example, acyclovir (ACV) can be given to illustrate a compound with great specificity. The ACV-mono-phosphate can only be formed by viral kinases meaning that ACV cannot be activated in uninfected cells. Despite this fact, ACV is not a particularly active product. In order to circumvent the often rate limiting step in the activation of a nucleoside analogue, the intracellular formation of the nucleoside analogue mono-phosphate, several phosphonates, such as cidofovir or even mono-phosphate products, have been developed. In order to facilitate oral uptake or to secure a favorable drug disposition in the body, particular prodrugs such as Hepsera have been made.
In addition to the structural changes made to nucleoside analogues to facilitate enhanced clinical utility, further modifications have been made to improve the activity. There are several examples of modified nucleoside analogues resulting from the addition of lipid moieties (U.S. Pat. Nos. 6,153,594, 6,548,486, 6,316,425, and 6,384,019; European Patent Application Nos. EP-A-56265 and EP-A-393920; and WO 99/26958). This can be achieved by the linking of fatty acids through, for instance, an ester, amide, carbonate, or carbamate bond. More elaborate products can be made, such as phospholipid derivatives of the nucleoside analogues. See Eur J Pharm Sci 11b Suppl 2: 15-27 (2000); European Patent No. 545966; Canadian Patent No. 2468099; and U.S. Pat. Nos. 6,372,725 and 6,670,341. Such analogues are described to have antiviral activity that is particularly suitable for the therapy and prophylaxis of infections caused by DNA, RNA, or retroviruses. They are also suited for treatment of malignant tumours. The nucleoside analogue lipid derivatives may serve several purposes. They may be regarded as a prodrug that is not a substrate for deaminases, thereby protecting the nucleoside analogues from deactivation during transport in the bloodstream. The lipid derivatives may also be more efficiently transported across the cellular membrane, resulting in enhanced intracellular concentration of the nucleoside analogue. Lipid derivatives may also be more suited for use in dermal preparations, oral products (see U.S. Pat. No. 6,576,636 and WO 01/18013), or particular formulations such as liposomes (see U.S. Pat. No. 5,223,263) designed for tumor targeting.
It has been demonstrated that for nucleoside analogues with a conserved β-D configuration of the monosaccharide ring, or for nucleoside analogues with a non-cyclic side chain, the antiviral or anticancer activity can be most efficiently improved through the formation of lipid derivatives of mono-unsaturated ω-9 C18 and C20 fatty acids. See Antimicrobial Agents and Chemotherapy, Vol., 53-61 (1999); Cancer Research 59: 2944-2949 (1999); Gene Therapy, 5: 419-426 (1998); Antiviral Research, 45: 157-167 (2000); and Biochemical Pharmacology, 67: 503-511 (2004). The preferred mono-unsaturated derivatives are not only more active than the poly-unsaturated counterparts but are more crystalline and chemically stable towards oxidation of the lipid chain. Hence, they are more favorable compounds from a chemical and pharmaceutical manufacturing point of view. It has also demonstrated that the mono-unsaturated ω-9 C18 and C20 fatty acids are suited for improvement of the therapeutic activity of a large number of non-nucleoside biologically active compounds (see European Patent No. 0977725).
A relatively new subgroup of nucleoside analogues are the so called aza-C derivatives. In this class of compounds, the CH group in the 5 position in the pyrimidine base is exchanged with a nitrogen atom as shown in Formula B below.
Tumor suppressor genes that have been silenced by aberrant DNA methylation are potential targets for reactivation by these novel chemotherapeutic agents. The potent inhibitors of DNA methylation and antileukemic agents, aza-cytidine and 5-aza-2′-deoxycytidine derivatives (5-aza-C, 5-aza-CdR, Decitabine), can reactivate silent tumor suppressor genes. At high concentrations, the compounds are cytotoxic, but at lower concentrations the hypomethylation leads to differentiation of cell lines. The compounds require metabolic activation by deoxycytidine kinase, and produces an inhibition of DNA methyltransferase. One hindrance to the curative potential of these derivatives are their rapid in vivo inactivation by cytidine deaminase (CD). The instability in aqueous solutions as well as their side effect profiles have limited their clinical activity.
The present invention is directed to overcoming these and other deficiencies in the art.
One aspect of the present invention is directed toward a compound according to Formula (I)
wherein R is H, R5C(O); R1 is
where the crossing dashed line illustrates the bond formed joining R1 to the molecule of Formula (I), R2 and R3 are independently OH or H, provided that R2 and R3 are not simultaneously OH, R4 is H or R5C(O), provided that R and R4 are not simultaneously H, R5 is a C3-C26 alkenyl, or a pharmaceutical salt thereof.
Another aspect of the present invention is directed toward a pharmaceutical composition comprising the compound of Formula (I) and a pharmaceutical excipient, diluent, and/or carrier.
A further aspect of the present invention is directed toward a method of treating a subject for a neoplastic condition. The method includes selecting a subject with a neoplastic condition and administering to the subject a compound of Formula (I), as described above, or a pharmaceutical salt thereof, under conditions effective to treat the neoplastic condition in the subject.
A further aspect of the present invention is directed toward a method of treating a subject for an inflammatory condition. The method includes selecting a subject with an inflammatory condition and administering to the subject a compound of Formula (I), as described above, or a pharmaceutical salt thereof, under conditions effective to treat the inflammatory condition in the subject.
The instability of Aza-C in buffer and plasma is well known (see Israili et al., Cancer Research 36, 1453-1461 (1976); Rudek et al., J Clin Oncol, 23:17, 3906-3911 (2005); Rustum et al., J Chromat, 421:12, 387-91 (1987); Zhao et al., J Chromat B, 813, 81-88 (2004), which are hereby incorporated by reference in their entirety). An average terminal half-life of 1.50�2.30 hours in clinical plasma samples has been reported for Aza-C (see Rudek et al., J Clin Oncol, 23:17, 3906-3911(2005), which is hereby incorporated by reference in its entirety). In vitro, a 20% loss of Aza-C even at −60� C. is noted after 4.5 days storage and a 10% loss within 0.5 hours when stored at room temperature (see Zhao et al., J Chromat B, 813, 81-88 (2004), which is hereby incorporated by reference in its entirety). The prime instability of Aza-C is thought to be due to a rapid (first step being reversible) ring opening of the 5-Aza-pyrimidine ring with a subsequent elimination of formic acid (see Chan et al., J Pharma Sci, 68; 7, 807-12 (1979), which is hereby incorporated by reference in its entirety). Other degradation pathways are thought to be deamination of the position 4 amino group and hydrolysis of the glycoside bond to give D-ribose and 5-azacytosine. It has been surprisingly found that the preferred Aza-C lipid derivatives have a significantly better plasma stability profile than Aza-C its elf. The compounds are stable (percent remaining of initial ≧94%) in blank human plasma matrix at room temperature for at least 4 hours under the experimental conditions, and no significant degradation products were observed in the post-extract supernatant after precipitation of plasma proteins. The plasma stability of the preferred lipid compounds have been examined further when stored at 37� C. It is shown that the ring-opening of the Aza-moiety or other degradation of the compound is significantly reduced when the lipid side chain is attached to Aza-C.
The rapid degradation of Aza-C is a drawback for clinical use of Aza-C. The enhanced plasma stability of the lipid derivatives over Aza-C itself may give both a high and sustained patient plasma level of the lipid derivative. This may lead to a better tissue/organ/tumor distribution and cellular exposure to and uptake of the drug than for Aza-C itself in the first hand, and subsequently better tumor cell DNA exposure to Aza-C after intracellular hydrolysis of the Aza-C-5′-ester bond.
Embodiments of the present invention create, through the modification of azacytidine and deoxycytidine (e.g., 5-aza-2′-deoxycytidine), novel molecules with surprisingly different properties compared to azacytidine and deoxycytidine (e.g., 5-aza-2′-deoxycytidine). This creates a series of compounds with activity that extends well beyond the anti-cancer activity of azacytidine and deoxycytidine (e.g., 5-aza-2′-deoxycytidine) which is limited to hematologic malignancies. These novel compounds have anti-cancer efficacy against a broad array of solid tumors including breast and cervical cancer. The compounds are also surprisingly active against cancers which are resistant to treatment and thus can offer a therapeutic advantage in solid tumors where current treatment choices are limited. Embodiments of the present invention have therapeutic uses to treat cancers where options and efficacy remain limited and fulfill an unmet need.
These compounds exhibit an earlier onset of activity after limited exposure and, therefore, can be effective after only a short duration of treatment in the clinical setting. This would translate into shorter, less frequent treatment exposure and a reduction in drug-related toxicities compared to the parent drugs. This would provide for an enhanced therapeutic index.
The alteration in the structure with the addition of the lipid (includes both esters and amides) component conserves the azole cytidine ring and thus the effects of the molecule on epigenetic mechanisms. Epigenetic modulation offers an important mechanism for altering gene expression in cancer and inflammation. These novel compounds have activity at lower concentrations than azacytidine and, thus, are more potent. These compounds with an altered spectrum of activity can modulate epigenetic targets in solid tumors and inflammatory diseases.
Epigenetic mechanisms are important in pro-inflammatory states which include, but are not exclusive to, inflammatory states of the lung, connective tissues, gastro-intestinal tract and vasculature. These compounds by targeting epigenetic mechanisms can reduce or reverse the inflammatory processes responsible for these diseases.
One aspect of the present invention is directed toward a compound according to Formula (I)
wherein R is H, R5C(O); R1 is
where the crossing dashed line illustrates the bond formed joining R1 to the molecule of Formula (I), R2 and R3 are independently OH or H, provided that R2 and R3 are not simultaneously OH, R4 is H or R5C(O), provided that R and R4 are not simultaneously H, R5 is a C3-C26 alkenyl, or a pharmaceutical salt thereof.
In certain embodiments, R5 may be a C9-C26 alkenyl.
In a preferred embodiment, R is R5C(O), R1 is
R2 is H, R3 is OH, R4 is H, and R5 is CH3—(CH2)7—CH═CH—(CH2)7—.
A broader aspect of the present invention is directed toward a compound according to Formula (I)′
wherein R is H, R5C(O), R5CH2OC(O), or R5CH2NHC(O), R1 is
where the crossing dashed line illustrates the bond formed joining R1 to the molecule of Formula (I)′, R2 and R3 are independently OH or H, provided that R2 and R3 are not simultaneously OH, R4 is H, R5C(O), R5CH2OC(O), or R5CH2NHC(O), provided that R and R4 are not simultaneously H, and R5 is a C3-C26 alkenyl, or a pharmaceutical salt thereof.
In a preferred embodiment of the compound according to Formula (I)′, k is 7 and n is 7. In certain embodiments, R1 is
where the crossing dashed line illustrates the bond formed joining R1 to the molecule of Formula (I)′. In some embodiments, R4 may be H. In certain embodiments, R is R5C(O), k is 7, m is 0, n is 7, R2 is H, and R3 is OH. In certain embodiments R5 is a C9-C26 alkenyl.
Another aspect of the present invention is directed toward a pharmaceutical composition comprising the compound of Formula (I) and a pharmaceutical excipient, diluent, and/or carrier.
Agents of the present invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, or by application to mucous membranes, such as, that of the nose, throat, and bronchial tubes. They may be administered alone or with suitable pharmaceutical carriers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
The active agents of the present invention may be orally administered, for example, with an inert diluent, or with an assimilable edible carrier, or they may be enclosed in hard or soft shell capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active agents may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, and the like. Such compositions and preparations should contain at least 0.1% of active agent. The percentage of the agent in these compositions may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active agent in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions according to the present invention are prepared so that an oral dosage unit contains between about 1 and 250 mg of active agent.
The tablets, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar, or both. A syrup may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye, and flavoring such as cherry or orange flavor.
These active agents may also be administered parenterally. Solutions or suspensions of these active agents can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, water, saline, aqueous dextrose and related sugar solution, and glycols such as, propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
The agents of the present invention may also be administered directly to the airways in the form of an aerosol. For use as aerosols, the agents of the present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants. The materials of the present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
A further aspect of the present invention is directed toward a method of treating a subject for a neoplastic condition. The method includes selecting a subject with a neoplastic condition and administering to the subject a compound of Formula (I), as described above, or a pharmaceutical salt thereof, under conditions effective to treat the neoplastic condition in the subject.
In certain embodiments, the neoplastic condition is a cancerous disease. The cancerous disease may be a solid tumor or a hematological cancer or malignancy. The cancerous disease may be leukemia, lymphoma, multiple myeloma, or myelodysplastic syndrome.
In certain embodiments, the solid tumor may be a cancer of a tissue such as breast, ovary, prostate, brain, bladder, and lung tissues.
A further aspect of the present invention is directed toward a method of treating a subject for an inflammatory condition. The method includes selecting a subject with a an inflammatory condition and administering to the subject a compound of Formula (I), as described above, or a pharmaceutical salt thereof, under conditions effective to treat the inflammatory condition in the subject.
In certain embodiments the inflammatory condition is an inflammatory state of the lung, connective tissue, gastro-intestinal tract, or vasculature.
Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
5-azacytidine 5′-elaidate (CP or CP-4200) was obtained from Clavis Pharma AS Company, cell proliferation reagent WST-1 was obtained from Roche Applied Science (Manheim, Germany), PI and Annexin V-FITC apoptosis kit were purchased from BD Biosciences, Palo Alto, Calif., 5-azacytidine (5-AzaC), ethidium bromide (EB), acridine orange (AO), nitro blue tetrazolium (NBT), phorbol 12-myristate 13-acetate (TPA) were purchased from Sigma Chemical Co (St. Louis, Mo.).
Human promyelocytic leukemia cell lines HL60, human histiocytic lymphoma U937, human chronic myelogenous leukemia K562, human acute T cell Jurkat, breast adenocarcinoma MCF-7, urinary bladder carcinoma 5637, prostate carcinoma DU-145 were purchased from American Type Culture Collection. All cell lines except Jurkat were maintained in RPMI 1640 medium (Gibco, Glasgow, UK) supplemented with 10% heat-inactivated fetal calf serum (FCS), 100 U/ml of penicillin, and 100 mg/ml streptomycin, in an atmosphere of 5% CO2 at 37� C. Jurkat cells were cultured in RPMI 1640 medium supplemented with 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM sodium pyruvate, and 10% FCS, 100 U/ml of penicillin, and 100 mg/ml streptomycin.
The cytotoxicity of 5-azacytidine lipid was determined by calorimetric assay based on the cleavage of the tetrazolium salt WST-1 (4-[3-(4-Iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate) by mitochondrial dehydrogenases in viable cells. Cells were seeded at an initial concentration of 1�106/ml (HL60 cells) or 1.25�105/ml (U937, K562 and Jurkat) in medium with or without various concentrations of 5-azacytidine lipid in a 96-well flat bottom micro-plates and cultured for 24 to 72 hours. MCF-7, DU-145, and 5637 cells (1�104/ml) were plated and allowed to adhere and spread for 24 hours. The various concentrations of 5-azacytidine lipid were added and cultures were maintained for an additional 24 to 72 hours. Cultures were incubated with WST-1 reagent for 1 hour. The production of formazan was measured by a microplate reader (Bio-Tek Instruments, Elx 800) at 450 nm with a reference wavelength of 650 nm. Growth inhibition was determined as compared to untreated cells (%). IC50 values were calculated using CalcuSyn software (Biosoft).
Apoptotic cells were defined using morphological criteria and fluorescence-activated cell sorting (FACS) after staining with Annexin V-FITC. For morphologic analysis, 1 μl of stock solution containing 100 μg/ml AO and 100 μg/ml EB was added to 25 μl cells suspension. The apoptitic cells and apoptotic bodies were analyzed with the aid of a fluorescence microscopy. The percentage of apoptotic cells was calculated after counting total 300 cells. For FACS analysis, 2�105 to 5�106 cells were washed with PBS and then labeled with Annexin V-FICS and propidium iodide (PI) in medium-binding reagent according to the Annexin V-FITC apoptosis detection kit instruction provided by the manufacturer. Fluorescent signals of FITC and PI were detected, respectively, at 518 nm and at 620 nm on FACSCAN (Becton Dickinson, San Jose, Calif.). The log of Annexin V-FITC fluorescence was displayed on the X-axis and the log of PI fluorescence was displayed on the Y axis. The data was analyzed by the CellQuest program (Becton Dickinson). For each analysis, 10,000 cells events were recorded.
Cells were pelleted by centrifugation, and washed twice with PBS, fixed with 70% (v/v) cold ethanol (−20� C.), and stored at 4� C. for at least 24 hours. The cells were washed in PBS. Cell pellets were stained with PI/RNase staining solution. The cell suspension was incubated in the dark at room temperature for 30 min. DNA content was determined using a FACSCalibur flow cytometry (Becton Dickinson, Mount View, Calif.). Percentages of cells in Sub-G1, G1, S and G2/M stages of the cell cycle were determined with DNA histogram-fitting program (Becton Dickinson). A minimum of 10,000 events per sample was recorded.
Oleic acid (1.77 mmol, 500 mg) was dissolved in toluene (3 ml). DMF (10 μl) was added, followed by oxalyl chloride (3.6 mmol, 457 mg) over 10 min at room temperature. After 3 h, the toluene was removed in vacuo.
Aza-C (1.75 mmol, 427 mg) was suspended in DMA (6 ml), HCl (1 M in Et2O, 2.0 mmol, 2.0 ml) was added, and, after 5 min at room temperature, the Et2O was removed in vacuo. The resulting turbid solution was cooled in an ice-water bath, and the acid chloride, dissolved in DMA (2 ml), was added over 2 h. The reaction mixture was stirred overnight while the temperature slowly reached room temperature, then it was heated at 30 C for 2 h. After cooling to room temperature, the reaction mixture was partitioned between saturated. aq. NaHCO3, and EtOAc (25 ml of each). The aqueous phase was extracted with another 3�25 ml EtOAc. The organic phases were combined, washed with brine, and dried (MgSO4). After removal of the solvents in vacuo, the crude, oily product was purified by flash chromatography (SiO2, CH2Cl2 with 2.5, 5, and 10% MeOH). Yield: 110 mg (13%).
5-azacytidine (4.1 mmol, 1.00 g) was suspended in dry DMA (15 ml), and a solution of HCl in diethyl ether (4.9 mmol, 1 M, 4.9 ml) was slowly added at room temperature to give a clear solution. The ether was then removed in vacuo, resulting in a slightly turbid solution. A solution of elaidoyl chloride (4.8 mmol, 1.44 g) in dry DMA (8 ml) was added over 1 h at room temperature. The reaction mixture was then heated at 30� C. overnight, cooled to room temperature, and quenched with methanol (0.05 ml). After at least 1 h, the reaction mixture was concentrated at ca. 10−2 mbar and the residue was partitioned between saturated aq. NaHCO3 and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The organic phases where then combined, washed (brine), dried (Na2SO4), and concentrated in vacuo. Purification by flash chromatography (SiO2, CH2Cl2 with 0-10% methanol) gave 0.9 g (43%) product.
The cytotoxic activity of 5-azacytidine 5′-elaidate and 5-AzaC on leukemia and solid tumor cell lines was compared. Compared to 5-AzaC, the cytotoxic effect of 5-azacytidine 5′-elaidate was higher in all cell lines studied. Compared to solid tumors, leukemia cell lines were more sensitive to both 5-azacytidine 5′-elaidate (CP) and 5-AzaC See Table 2 (below) and
TABLE 2 Table 2. Comparative cytotoxic activity of 5-azacytidine 5′-elaidate (CP) and 5-AzaC on leukemia and solid tumor cell lines. (IC50 values). 24 hour (μM) 48 hour (μM) 72 hour (μM) U937 CP 0.44 0.60 0.87 5-AzaC 1.63 2.37 4.77 K562 CP 1.26 0.92 0.42 5-AzaC 8.27 15.51 5.83 HL60 CP 3.19 3.60 2.68 5-AzaC 7.28 4.92 4.71 Jurkat CP 1.19 0.88 0.84 5-AzaC 9.5 5.32 4.77 MCF-7 CP 19.10 9.32 9.99 5-AzaC >160 93.7 53.00 DU145 CP 6.79 6.31 5.88 5-AzaC 20.94 7.11 7.20 5637 CP 9.39 5.95 3.52 5-AzaC 24.56 6.72 5.21 The cells were treated for 24, 48, and 72 hours and cytotoxicity was determined in the WST-1 assay. IC50 were calculated using CalcuSyn software.
The early onset of activity for 5-azacytidine 5′-elaidate, which is not observed in azacytidine, is a surprising result.
HL60, K562, and U937 cells were untreated or treated with 5-azacytidine 5′-elaidate (0.5-4 μM) for 24 hours. The percentage of apoptotic cells was determined with the aid of a fluoresence microscope after staining with acridine orange and ethidium bromide (See
Effect of exposure to 5-azacytidine 5′-elaidate on cell cycle was studied. Cells were cultured for the indicated lengths of time before being processed for analyses of DNA contents by flow cytometry. Numerical values in a panel represent gated cell population with sub-G1 DNA contents. The most significant changes were observed after 24 hours of treatment. Compared to control (8.3%), the percentage in Sub-G1 phase (apoptotic cells) was increased up to 33.6% in the cells treated with 5-azacytidine 5′-elaidate 2 μM, and in G1, S, and G2/M phase were decreased. Results are summarized in
Table 3. Effect of 5-azacytidine 5′-elaidate (CP) exposure on cell cycle.
% cell
dose (μM)
Sub G1
24 hour
48 hour
72 hour
Cells were cultured for the indicated lengths of time before being processed for analyses of DNA contents by flow cytometry. The number shown is the cell percentage in various phases.
Cell differentiation was studied in terms of morphology. Since single exposure (96 hours) had no effect, cells were exposed to 5-azacytidine 5′-elaidate or 5-AzaC for 11 (HL60 cells) or 14 (U937 and K562 cells) days. After initial treatment on day 0, cells were exposed to the new portions of drugs on day 4, 7, and 10. The differentiation was evaluated by NBT reduction assay (U937 and HL60) or by benzidine staining (K562). Although 5-azacytidine 5′-elaidate was slightly more effective, both agents did not induce significant differentiation. See
5-Aza-C-5′-elaidic acid ester was spiked into pooled human plasma at five concentration levels (0.1, 1, 3, 10, and 30 μM, respectively). The mixture was incubated in a shaking water batch at 37� C. Aliquots (100 μl) of the incubation solutions were withdrawn in triplicate (n=3) at the designed incubation period (0, 15, 30, 60 and 120 minutes), and plasma protein was immediately precipitated using acetonitrile containing 0.1% formic acid (300 μl). Negative controls were prepared with the test compound and Aza-C in the assay buffer (PBS, pH 7.4) at one concentration of incubation (1 μM). After centrifugation, the supernatant was directly introduced for LC-MS-MS analysis. See Table 4.
Metabolic stability of 5-Aza-5′-elaidic acid ester in pooled human plasma
% Remaining of initial (mean � SD, n = 3)
0 min
15 min
30 min
60 min
120 min
95.8 � 3.0
95.0 � 2.0
92.1 � 3.4
59.0 � 1.6
93.3 � 1.1
88.9 � 1.1
79.8 � 2.6
52.5 � 3.1
99.0 � 3.5
96.0 � 3.0
85.4 � 3.4
56.6 � 1.6
96.0 � 2.0
93.1 � 0.0
77.1 � 3.1
39.1 � 1.7
97.7 � 3.5
90.4 � 2.6
78.5 � 1.7
47.4 � 1.1
The cytotoxicity of Aza-C and 5-Aza-C-5′-elaidic acid was determined in a breast cancer cell line MT-3 and the adriablastin resistant cell line MT-3/ADR. The MT-3/ADR overexpress the MDR-1/p-glycoprotein. The cells were seeded in 96-well plates with 5�103 cells per well, in RPMI 1640 medium with 2 mM glutamine and 10% FBS. The cells were incubated for 24 hours. The test compounds were dissolved in DMSO and further diluted in medium just prior to use. Six wells were used per test concentration. The cells were incubated with test compound for 24 hours. 20 μl of freshly prepared MTT solution was added to each well and incubated for 4 hours. IC50 values were determined from growth curves presented graphically based on 8 different concentrations ranging from 0.01 μM to 100 μM. The results are presented in Table 5. Similar activity was obtained for Aza-C and 5-Aza-C-5′-elaidic acid in the MT-3 breast carcinoma cell line, but in the MT-3/ADR resistant cell line the activity of Aza-C was lost. No activity was observed in the concentration range tested up to 100 μM, whilst 5-Aza-C-5′-elaidic acid was active with a similar IC50 value in the resistant cell line and the non-resistant MT-3 line. This may be of importance in the treatment of resistant cancer. See Table 5.
Cytotoxic activity of and 5-Aza-C-5′-elaidic acid in the breast
carcinoma cell line MT-3 with or without multi drug resistance.
IC50 (μM)
acid IC50(μM)
MT-3 breast carcinoma
12.62 � 2.35
17.03 � 15.75
MT-3/ADR resistant
14.82 � 12.76
breast carcinoma
The impact of nucleoside transporter inhibition on cytotoxic activity has been evaluated in Hela mutant cervix carcinoma cells for Aza-C and 5-Aza-C-5′-elaidic acid. Dipyridamole was used as an inhibitor of the equilibrative nucleoside transporters hENT1 and hENT2. The cells were seeded in 96-well plates with 5�103 cells per well, in RPMI 1640 medium with 2 mM glutamine and 10% FBS. The cells were pre-incubated for 24 hours. Dipyridamole (10 μM) was added to the cells 30 minutes prior to the addition of the test compounds. The test compounds were dissolved in DMSO and further diluted in medium just prior to use. Six wells were used per test concentration. The cells were incubated with test compound for 72 hours. 20 μl of freshly prepared MTT solution was added to each well and incubated for 4 hours. IC50 values were determined from growth curves presented graphically based on 8 different concentrations ranging from 0.01 μM to 100 μM. The results are presented in Table 6. The activity of Aza-C was reduced 3 fold by the addition of the nucleoside transport inhibitor dipyridamole, indicating that the influx and efflux of Aza-C are partly dependent on the nucleoside transporters hENT1 and hENT2. The cytotoxic activity of 5-Aza-C-5′-elaidic acid was not only maintained but increased 50-fold when the hENT1 and hENT2 nucleoside transporters were blocked by the use of dipyridamole. The increased activity in cells where the nucleoside transporters are blocked by dipyridamole is surprising, and may indicate even higher activity in patients with resistance to treatment caused by lack of nucleoside transporters. See Table 6.
Cytotoxic activity of Aza-C and 5-Aza-C-5′-elaidic
acid in Hela cervix carcinoma cells with or without
addition of nucleoside transport inhibitor.
5-Aza-C-5′-elaidic acid
IC50 (μM)
IC50 (μM)
Hela with
The activation of the nuclear transcription factor-κB (NFκB) was evaluated in order to estimate the impact on inflammation. NFκB is involved in the control of a large number of both immune and inflammatory responses, developmental processes, cellular growth and apoptosis.
NFκB-luciferase reporter genes were used to determine the influence of Aza-C and 5-Aza-C-5′-elaidic acid on NFκB-induced luciferase activity in a human monocytic cell line U937, stably transfected with a luciferase reporter containing three NFκB-binding sites. The induction of NFκB was performed using lipopolysaccharide (LPS) at 1 μg/ml for 30 minutes prior to the addition of Aza-C or 5-Aza-C-5′-elaidic acid in the concentrations 10 nM to the medium. The cells were cultured in RPMI-1640 medium including 10% fetal bovine serum. Before stimulation with LPS the cells were transferred to medium containing only 2% fetal bovine serum. Luciferase activity was measured by imaging in an IVIS imaging System 100 (Xenogen Corp., USA) after 1, 3 or 6 hours. The LPS stimulation increased with time over the 6 hours followed in the DMSO treated control cells. Exposure to 10 nM Aza-C further increased the LPS induced NFκB activation compared to the DMSO treated control. 5-azacytidine-5′-eladiate did not differ from the DMSO control in LPS stimulated NFκB activity. Generally, a positive stimulation of NFκB as observed for azacytidine is not positive, and it is positive that the LPS stimulation is not further increased by 5′Aza-C-5′-elaidic acid. See
The gene expression (determined on RNA level) of estrogen receptor beta was determined by quantitative real-time PCR. (TaqMan). MCF-7 mammary carcinoma cells were grown in estrogen deficient media (Phenol-Red-free RPMI with 2% glutamine and 10% charcoal-dextran treated fetal calf serum). The cells were seeded into 25 cm2 flasks and attached for 24 hours prior to treatment with 1 μM of azacytidine or 5-azacytidine 5′-elaidate. One untreated control was included as control. The cells were harvested after 5 days of exposure to the compounds; they were harvested by trypsination, washed and shock frozen in liquid nitrogen.
The total RNA was extracted from approximately 106 shock frozen MCF-7 cells. The RNA concentration and purity was measured, and RNA was transcribed into cDNA using TaqMan Reverse Trancription reagents (N808-0234). Real-time quantification was performed using standard protocols and premixed PCR reagents. The primer-probe mixes were ordered from Applied Biosystems, ER β (ID Hs00230957_ml) and housekeeping gene hydrocylmethyl-bilane synthase HMBS (ID Hs00609297_ml). Gene expression was calculated using the comparative delta-delta Ct method. The induction of expression of ER β was 5.26 fold after exposure to 5-azacytidine 5′-elaidate compared to only 2.51 fold after exposure to azacytidine. See Table 7. This may be of high relevance in hormone refractory tumors where hormone sensitivity can be restored. See Table 7.
induction of
Ct ER β
Ct HMBS
Delta delta
the ERβ gene
1 μM
elaidic acid
1 μM aza-C
Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.
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text:
the 19 stages of taper
BodyGlide Giveaway post! Comment below or on our Facebook page for a chance to win a sweet For Her BodyGlide Pack with the must-have glide and sweet running hat! Winner picked April 24th. This post is dedicated to all my buddies running the Eugene Marathon races this weekend. I hold you in my hearts as I do those involved in … [continue]

subset: commoncrawl


text:
The Knights of Columbus are the world's largest Catholic fraternal service organization, founded on the principle of charity. Knights the world over combine to give more that 50 million hours of volunteer service and over $100 million to a wide range of Church, community and charitable activities and programs. Our members are very active in St. Therese. Some of the local and state charities supported by the St. Therese council include: Right-to-Life, Catholic Charities, Birth Haven, Eyes for the Needy, Hope House, Dover Soup Kitchen, Social Services of Roxbury, Global Catholic Network (EWTN), Department for Persons with Disabilities and Calabrese House, Lyons Campus of the VA New Jersey Health Care System, Project WARMTH, Seminarians, Project Graduation, and Local Boy Scouts of America and Girl Scouts of the USA.
They help in set up of Luncheons, Fashion Shows, Carnival, Parking lot attendants, and Ushers. They also provide High School and College Scholarships.
All men in the parish who are good practicing Catholics and are 18 or older are eligible to join. All that is required is to fill out an application and attend a First Degree, which is the official induction into the Knights. There is an initiation fee of $10 with annual membership dues of $24.
Contact: Dave Reinknecht, Grand Knight
Phone: 201-960-9727
Website: www.kofc6320.org
This Society is an organization of Catholic women whose primary purpose is to show praise and honor to the Blessed Virgin Mary and to recite the Rosary. We are dedicated to supporting the parish and our community. We meet once a month from September to June, usually on the second Monday of the month. After celebrating Mass and reciting the Most Holy Rosary, there is a short meeting where we discuss and plan upcoming events or listen to guest speakers. Light refreshments are served.
Some of the activities include sponsoring an annual Tricky Tray, hosting a fashion show/ luncheon, organizing blood drives, organizing food drives for the Carmelite Sisters, assisting with the Senior Luncheon at Christmas, providing Rosaries to all First Communicants (including RCIA candidates), and serving as the hostesses for most liturgical events and religious anniversaries within the parish community.
Our donations support all church related fundraisers especially the Capital Improvement and Liturgical Renovation Project including the Baptistry, Signs, Vestments, plus: CYO, Rightto- Life, local Boy and Girl Scouting, Birth Haven, Home School Association and the Knights of Columbus.
Contact: Eileen Redfern
In the Book of Proverbs it states, "Train up a child in the way they should go and when they are old they will not depart from it." Learning to share with those in need begins at an early age. The Social Justice Committee organizes the Baskets of Hope program which is designed to motivate the children of the parish to provide for others less fortunate. Six Sundays a year, the children of the parish are encouraged to bring specific items to church and personally place them in the collection box in the atrium. Items are collected, sorted, boxed and delivered to one of several locations. We have provided to shelters for homeless and runaways, as well as missions with extensive outreaches in Roxbury, Paterson, Appalachia, Mississippi and Haiti. Volunteers are needed on a month-by-month basis to contact centers, make announcements from the pulpit, sort and box items, and deliver items to centers. We can use individuals and groups, adults and children. The purpose of this committee is to act as an outreach, bringing the love of God to others by providing for their fundamental needs. This program also acts as an evangelization tool for the children of our parish by helping them see their potential to make a difference in the life of one less fortunate.
*Volunteers working with children must fulfull "Protecting God's Children" requirements
Contact: Alexandria Ortiz
Phone: 908-310-4121
The Bereavement group assists those undergoing the bereavement process. Sessions are held periodically and are open to all whether the loss is recent or in the distant past.
Contact: Robin Porter
Phone: 973-584-8271 x 733
This committee organizes, collects and distributes turkeys, dinner and gifts to 40 - 50 families in need in Roxbury and St. Agnes Church for Thanksgiving and Christmas. We also provide ham dinners and Easter Baskets for Roxbury families for Easter. The committee meets in the middle of October to begin to organize. Volunteers help sign up fellow parishioners at church to donate turkeys and dinners and make phone calls to remind parishioners to return meal items to the church on a certain date, and then organize and distribute dinners. Volunteers also make Angel gift tags for the Giving Tree and help organize and distribute gifts to the families.
Contact: Anita Galan, 973-584-9211
contact: Donna Kobza, 973-989-6906
For those confined, the elderly and/or shut-in, whether they be at home or in the hospital, please inform the Rectory. Holy Communion will be brought to the home of any person permanently or temporarily homebound. Homebound visits include a smile, a listening ear, and time for them to talk and pray with someone. This giving heals a person's spirit, gives them strength and hope, and often a helping hand. Also, please inform the Rectory immediately for the seriously sick or dying.
Contact: St. Therese Rectory
Phone: 973-584-8271
On a rotating basis, teams of two bring Holy Communion to the Catholics at Merry Heart every Sunday after the 7:45 am Mass is completed. Training as an Extraordinary Minister of Holy Communion is required.
Contact: Jim Salerno
Phone: 973-479-9301
The Respect-Life group educates members and parishioners about pro-life teachings and issues focusing on protecting the sanctity of life in all of its stages, from fertilization until natural death. Activities include coordinating the spiritual adoption program, the pro-life baby shower, and the annual March for Life trip to Washington, DC, providing financial support to pro-life groups, lobbying on prolife issues, and much more. New members are always welcome.
Contact: Linda Wallace
Phone: 973-584-5531
Parishioners help those in need of assistance by providing needed items to families and individuals living in our town. Our Parish Pantry collects non-perishable food, detergents, diapers, soap, shampoo, etc. on the fourth Sunday of each month and delivers them to Roxbury Social Services for distribution to those in need. Donations are voluntary. Social Services depends on our generosity to help fill shelves that are often lacking in supplies. There is a notice in the church bulletin the week before collection, sometimes suggesting things they are particularly low on. You can help by donating needed items or by volunteering your time to deliver the items to Social Services. You may not realize that there are over 170 neighboring families who need our help.
Contact: Joanne Heyert
Phone: 973-927-2586
Faith Kitchen is located on Blackwell Street in Dover and serves a hearty meal to between 75 and 100 people Monday through Saturday. St. Therese participates in the program on Saturdays. Each Saturday, three or four cooks prepare a hot meal consisting of a meat, starch and vegetable and bring the food to the Rectory around 10:00 am. Servers for that week transport the food to the Faith Kitchen by 10:30 am, make coffee, juice and sandwiches, set the tables and set out fruit and pastries. The kitchen opens at 11:30 for serving the meal. Any left over food is distributed in takeout containers. The kitchen is cleaned up and servers are usually able to depart by 12:30. The schedule for cooking or serving is prepared on a six-month basis and people are usually scheduled twice in that timeframe.
Contact: Carolyn Steinhauer
Phone: 908-850-4527
Altar Servers are young people who volunteer their time and talent to serving God at each Mass. Girls and boys in grades 4 and up are invited to participate and be trained in this wonderful ministry.
Contact: Dominick Calabrese
Phone: 973-252-6563
The Liturgy of the Word for Children offers kindergarten to 3rd graders the opportunity to hear God's Word and take part in a homily adapted for children. The children are escorted from the main worship area and divided into groups. The scripture and gospel readings are read to them by an adult volunteer, then explained to them on their level by a Priest or Deacon.
No registration required
Time: Sunday 10:30am Mass
The Confirmation program is a two-year program beginning in September of 9th grade and concluding in May of 10th grade with the receiving of the Sacrament of Confirmation. The program consists of Faith Theme Sessions (candidates meet in small groups at the Church or school with Sponsor Catechists who lead discussion on various topics regarding the Catholic faith), retreats, liturgical events and community service. Approximately 90 students are confirmed each year. Adults are needed to serve as Sponsor Catechists. High school juniors and seniors already confirmed pair up to coach candidates.
Contact: Michael Harding
Phone: 973-584-8271 x 734
Email: firstname.lastname@example.com
All parish boys and girls in grades 4 through 8 are eligible to participate. The program serves the entire parish - it is not limited to St. Therese School attendees. Registration is held in late summer and there is a $65 fee to participate. Adults may also assist as coaches at all levels. Parents help at the snack stand, collect fees, and support fundraisers.
Contact: Mike Elko
Email: firstname.lastname@example.com
Contact: Michael Harding
Phone: 973-584-8271 ex 734
Email: email@example.com
Contact: Deacon Bruce
Phone: 973-584-8271 x 732
Email: email@example.com
*Volunteers working with children must fulfull "Protecting God's Children" requirements


text:
Tag Archives: U.S.-Mexico border
The 10 Best Observer Stories of 2016: 'I Have a Name/Yo Tengo Nombre'
'I Have a Name' is an online visual database to help identify migrants who died crossing the Texas-Mexico border.
Editor's Note: This is not a story per se. It's a labor of love that took Multimedia Editor Jen Reel a year to complete. It's also a blend of journali...Read More
Introducing 'I Have a Name/Yo Tengo Nombre'
'I Have a Name' is an online visual database to help identify migrants who died crossing the Texas-Mexico border.
Today, the Texas Observer is launching a project a year in the making. "I Have a Name/Yo Tengo Nombre" is an unusual undertaking for the Observer: Most of t...Read More
Renaissance Tejana: 'Rant. Chant. Chisme.'
Amalia Ortiz transforms her rants, chants and poetry slams for the printed page.
Like the matadora, Ortiz practices her craft while a stampede rages around her. This is what she will be known for....Read More
Beyond 'Beyond the Border'
Help us build an online tool to identify migrants who died in South Texas.
Today, we're launching a crowdfunding campaign with Beacon to build an online tool that we think can help. Working with forensic anthropologists at Baylor Uni...Read More
Femicide in Juárez is Not a Myth
A vocal group of American critics claims that Juarez is not a place of disproportionate violence against women. Here's why they're wrong.
While Molloy, Powell and other critics may not consider femicide to be real or important compared to their preferred research on drug violence and global capita...Read More
New Hope for Identifying Migrant Bodies in South Texas
In the past seven years, the bodies of hundreds of migrants have been recovered in the Texas borderlands, but only a fraction of the remains have been identifie...Read More
A Q&A With Todd Miller, Author of Border Patrol Nation
Miller talks about the growing global border security industry and the changing role of the U.S. Border Patrol...Read More
Federal Investigation Does Little to Explain Killings by Border Patrol Agents
A new Investigation by the Department of Homeland Security Does Little to Explain Spate of Fatal Shootings and Beatings by Border Patrol Agents....Read More


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Warrior Songs to Hold Veteran Songwriters Retreat at Wallingford, PA, June 19-23rd
WarriorSongs, a non-profit organization to help veterans recover from combat experiences, military sexual trauma or other military-related mental health challenges, will be holding a workshop from June 19th to the 23rd at Wallingford, Pennsylvania. Structured as a poetry and songwriting retreat, director and songwriter Jason Moon, himself an Iraq war veteran, will guide participants through a weekend of creativity, music, poetry, reflection, healing and bonding.
The event will take place at Pendle Hill, a Quaker study center founded in 1930. Lodging is available on site. Full scholarships are available from Warriorsongs.
Jason Moon, the founder and director of Warriorsongs, returned from a deployment to Iraq with a combat engineer company in 2004. Struggling with PTSD, Moon abandoned his pre-war passion for songwriting and instead turned increasingly to alcohol and risky behavior, in an attempt to recreate the kind of adrenaline rush he experienced in Iraq.
"Before the war, songwriting was my greatest joy, and suddenly, I couldn't write about anything," he says. "Even writing about something happy just reminded me of how sad I was." Moon took a five year hiatus from songwriting – ending shortly after he was hospitalized for depression and suicidal ideation culminating in an attempt to take his own life by overdosing on prescription drugs and alcohol.
While recuperating, he participated in the filming of On the Bridge, a film by Oliver Morel on the struggle to overcome PTSD. Morel asked Moon to contribute some original songs – and the floodgates opened.
Since beginning his workshops, Jason and Warriorsongs have been featured prominently by the Associated Press and the Huffington Post, and have had favorable mentions in many local papers where Warriorsongs has held workshops and events across the country.
You can purchase a copy of Jason Moon's CD, Trying to Find My Way Home, here. His ReverbNation page allows you to listen some of his material as well.
The Wallingford retreat is limited to 17-18 participants. Scholarships are available. Contact Warriorsongs for more information at firstname.lastname@example.com.


text:
Panel discussion by members of PBCBA on honey bees. General beekeeping questions and answers on how to get started, what to do, and how to do it.
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Join Palm Beach County Beekeepers Association
Welcome toPalm Beach County Beekeepers Association
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Help Build the Bee Lab for research and education. It will be located in Gainesville, FL. Save The Bees! Every dollar counts.
December 1, 2017 from 6pm to 10pm – President's Kevin and Carol Residence
December 1, 2017 from 6pm to 10pm – President Kevin Easton's and Carol's Residence
To join the group "Swarm Catchers" go to Groups
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You are here
McLaren teases new track-ready racer
Good news! At next week's Goodwood Festival of Speed, McLaren will host the global unveil of a brand new racing car.
Bad news! We have no idea what it is.
Well, we kind of have an idea of what it is. It's the moodily shot car in the picture above; most likely a racing version of the newly revealed 650S - the car that effectively replaces the old 12C (if you can call that car old) - to be built and race ready in time for next year's season.
McLaren tells us it's part of the brand's 'addiction to winning' demonstration, and as such, we'll also be treated to static displays of the 'standard' 650S, 650S Spider and the not-too-shabby McLaren P1. Jeremy kind of likes that car.
Not only that, but the company will also showcase the M7C; the car driven by McLaren founder Bruce to three podium finishes during the 1969 Formula One season.
We're also hearing that someone called 'Jenson Button' will pilot something fast and McLaren shaped up the Goodwood hill too, so that'd be worth watching if you're about. And we suggest you go this year, because it promises to be a good one.
The full reveal will take place at 11am on 27 June. We'll have more details for you then…
What do you think?
This service is provided by Disqus and is subject to their privacy policy and terms of use. Please read Top Gear's code of conduct (link below) before posting.


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There are two kinds of kings, the oppressor and the liberator.
The oppressor oppresses. His first act of oppression is conquest. He acquires lands and peoples and declares them his possessions. Once he acquires the documents to prove that they have become his properties, such properties become subjects at his disposal. To him, people are not citizens but subjects. In reality, they are not only subjects, but oppressed. To him, the oppressed are filthy. Most of the time, he distances himself from them. The oppressed are ignorant, too. He sends his wise men to educate them. The oppressed are poor and miserable. He presents himself as their charitable king.
The National Elections is six months away. We will once again be subjected to an election of no choice. Our election is always a story of the oppressed choosing from among the different types of oppressors. We cannot distinguish the oppressors from behaviors. They are all the same. The only distinguishing marks are their family names.
They are the pseudo-leaders whom we see and hear during elections. For a scrap of pork, we lend them our eyes and ears for an hour or two during campaign. We know that what they say are lies. We go anyway. After they win the elections, they have to distance themselves from us. That keeps them healthy. We are a dirty people. We are like lepers. Distance from us means health for them.
They are the pseudo-teachers who lecture us on constitution and state policies, about 'deals and no deals,' about taxation, reproduction and progress, about security and tanim bala. For a scrap of pork, we ought to listen to them, but we ought not argue. Oppressors are not comfortable with questions. They are insecure of their power and claim as the learned in the society. We, the oppressed, are ignorant. Even our questions are reflection of our ignorance. In exchange for their wisdom, we ought to repay them with unquestioning loyalty.
They are the pseudo-kings who possess all the treasures of the state. They are rich because they are learned and industrious. We are ignorant and lazy. For a scrap of pork, we have to fall in line and beg from them. We are but beggars, and thieves. Our sacred duty is to beg for money and mercy from them. We ought to make them feel generous. They become suspicious of us when we no longer beg from them.
The liberator liberates. His first act of liberation is to go to the periphery and seek out the oppressed. While the oppressor is blind to his act of oppression, the liberator is able to see oppression and find the oppressed. Then he listens to their untold stories.
Today's gospel and solemnity gives us a glimpse of hope for our country. A genuine leader exists. An authentic teacher lives. A true mighty king remains. He is Jesus. For our story of dirt and illness, He grants us forgiveness and compassion. For a scrap of bread, he gives us nourishment and health. For our confession of ignorance, He grants us light and understanding. For opening up our empty hearts, He fills us up with hope and love.


text:
Bi-directional Electric Clutches Datasheets
from GEEPLUS Inc.
Wrap spring clutches are used in applications where several axis need to be engaged/disengaged and synchronised to a rotating main drive axis. By using gears other speeds can also be realised. Typical examples for applications are paper transportation in printers, copiers or money handling and money... [See More]
- Features: Bidirectional (optional feature)
- Power: 0.0034
- Torque: 1.3
- Voltage: 12 to 24
from Hilliard Corporation (The)
This easy-to-install, self-contained package includes a solenoid-operated, single revolution clutch with anti-rollback and anti-overrun features. Designed to provide greater life than wrap-spring assemblies, the Hilliard IDA is built to last through millions of cycles. [See More]
- Features: Other (optional feature); Bidirectional (optional feature); Anti-Overrun Mechanism
- Speed: 325 to 500
- Torque: 22.0 to 106.0
- Voltage: 24 to 230
from Ogura Industrial Corp.
CUSTOM MOLDED GEAR. The MIC assembly includes a custom-molded gear or timing pulley designed to your specifications. ONE PIECE ASSEMBLY. The entire assembly is delivered pre-assembled, so it simply slides onto the shaft. There are no adjustments to make or gaps to set. BI-DIRECTIONAL OPERATION. The... [See More]
- Features: Zero-Backlash; Bidirectional
- Power: 0.0046
- Torque: 0.2
- Speed: 300
from Tiny-Clutch | Helander Products, Inc.
A-Series Tiny-Clutches are miniature roller and cam type single revolution clutches. They also function as a general purpose, rapid action clutch for selectively coupling a continuously rotating input and a driven shaft. The clutch features fast response, high torque capacity for a given size and... [See More]
- Features: Adjustable Torque; Zero-Backlash; Bidirectional
- Speed: 4000
- Torque: 4.2
- Magnetic Type: Electromagnetic (optional feature)


text:
Whenever we hear of a domestic violence situation we ask why she puts up with it. By far the most common question asked about violence in relationships is: 'why doesn't she just leave?'.
We respond this way out of a gut feeling, a revulsion and hope all twisted up into one emotion: we want the woman to just walk away. We want, on that gut level, for that to be possible. Unfortunately, it isn't that easy. And when 'why do you stay?' is the first thing we ask, we end up putting the blame on her. We don't ask 'how does he get away with it?' or even 'what can I do to help?', though that might be what we mean. Culturally, defensively, out of sheer denial of how complicated the issue is, we ask the wrong questions.
"Why doesn't she leave?" implies that the victim is stupid, defective, damaged, or weak. It puts the responsibility for change solely on her shoulders. It shames her for choosing an abusive man. It minimizes the very real threats and fears a woman faces in an abusive situation. And it makes a myth: we think of abused women as broken, cowed, slump shouldered victims who slink back to their partners again and again. The truth is, most women DO leave.
In truth, 75% of emergency room visits related to partner violence occur during or after separation: violence escalates when she leaves. She is probably very aware of this, and aware of the danger. She is probably aware that – in many situations – it is safer for her to stay for the time being.
We need to trust the woman's own judgement and sense of timing. Notice that I said 'for the time being'. Again, most women DO leave their abusive partners. One out of three women experience violence in an intimate relationship. This does not mean that one out of three men are abusive. It does mean that a very small minority of men are abusive, and they are able to hurt one woman after another. It means that abused women leave the relationship, and he moves on to another victim.
Women face a number of barriers to leaving, and we should never minimize the danger she faces. Women die when they try to leave. Other women lose their children, or have to relocate and lose a job, their friendships and community, or face significant pressure to stay from family and friends. Choosing to leave a relationship always carries loss, loneliness, and grief. In an abusive situation, it can also mean physical danger, loss of social status, financial security, employment, and other significant or important relationships (to church, family, neighborhood, mutual friends).
Although each woman has a unique situation, abuse often takes on similar tactics and the barriers to leaving are therefore often commonplace. However, the abuse itself isolates the victim and she often feels she is alone in her experience. Abusers also blame the victim and/or tell her she is exaggerating, imagining, or distorting the truth. She is chronically denied the truth of her experience, and after time she may doubt herself. Learning how common some of these experiences are might be helpful in breaking out of the cycle and isolation.
Learning some of the common barriers can also show people outside the relationship how complex and threatening the situation really is. It's never as simple as 'why doesn't she just leave?' Once we understand some of the barriers, we can start to appreciate her intuition and support her choices; we can ask her what she most needs from us at any given time, rather than assuming we already know. It is vital to remember that
Fear is an important factor
women want the violence to end, not the relationship
most abused women have been told they will be hurt or killed if they leave, that he will hurt himself if she leaves, and/or that no one will believe her or the abuse is her fault: she may have come to believe this on some level.
Counteracting these messages is important. Family and friends can help a victim with the messages:
Abuse is never ok
nothing you do or don't do causes his behavior
his behavior is a choice
no one, including you, deserves abuse
abuse is wrong, all the time
you are not alone
I believe you
I support your decisions
Women in abusive relationships may fear reprisals or punishment if they seek help. They have probably experienced an escalation in the abuse when they try to change, confront, or leave the abuser: it's usually safest to try to please, de-escalate, or placate the abuser. She may have been threatened, and she has no reason not to believe those threats (I'll kill you/myself/the kids/the pet. I'll find you. You'll be sorry. Do you know what I'd do? You don't dare…)
She may fear being found. Most women do have to attempt to leave a partner FIVE times. This may have less to do with her will power or self-respect than it has to do with his co-erciveness and the resources available to her. Most women will first try to leave to friends and/or family: abusers usually know where this is. Abusers are commonly known to make things difficult for a woman with her friends and family by telling lies, withholding her access, expressing jealousy of time spent away, demeaning friends and family, blaming friends and family, or causing scenes to embarrass or humiliate her. Women have also been found by their social security numbers, through the children's school, by following friends, waiting at work, or placing warrants out for their arrest. Many women have had to leave their homes, communities, employers, and support systems behind without a trace in order to successfully evade stalking.
She may fear destruction to her belongings or home.
She may fear harm to her reputation, career, or studies.
She may fear for the safety of children, family, or pets.
She may fear for his safety. Abusers often threaten suicide, explicitly or implicitly (I can't live without you). Abusers also put the responsibility for their own well being in their partners hands: if he feels depressed, gets drunk, loses a job, gets angry, it's 'her fault'.
She may fear court or police involvement. No one wants to deal with these issues. If the abuser is seen as a powerful person (ie wealthy, influential, popular, well known, smarter or more powerful than her) this can be exacerbated. Women often fear his resentment and community opinion – as well as the reflection such an involvement might have on her future. If a woman has any immigration issues, fear of authorities is legitimate and has often been manipulated by the abuser. Women of color or lower socio-economic status have valid reasons to believe the courts and/or social services and/or police will bring harm or discrimination or unfairness to the situation. Women (often correctly) feel that police, courts, or others "won't understand" and may make matters worse.
Women are often encouraged by social messages, community, and the abuser, to believe:
His violence is temporary. Not that his abuse is a chosen behavior, but that it's a result of stress, an argument, intoxication, difficult life situations, etc. Abusers usually promise to change. Abusers are not abusive all the time; most women will wonder if the abuse might not become a thing of the past.
With loyalty and love, she can make him change.
His promise to 'never let it happen again'.
It's her responsibility to keep the family together.
There will be more good times.
If she can help her partner through his pain, difficulties, or past experiences, he will change.
He's had a hard life.
He needs me.
Many men are violent. It's to be expected. I'd never find any better.
She may deny or minimize the abuse. She may believe him when he blames her, denies, minimizes, or excuses the abuse.
Abusers often control or limit a woman's financial resources. She may also have been dissuaded from working outside the home, pressured to drop her career advancement or education, and encouraged to let him control finances even if she is the breadwinner. Women are isolated in abuse – even if she has outside employment or opportunities, she faces issues of communication, understanding, discrimination, more frequent absenteeism and poor job performance; depression, stress and fatigue are common results of abuse and impair a woman's earning capacity.
Fear of poverty keeps many women in abusive situations.
Women often have few sources of income and or assets within safe control: he can follow credit cards, bank reports, etc.
Women with children face the stigma and added financial risk of raising children alone.
Women often face returning to the workforce after long periods of unemployment.
Religion often focuses on mutual responsibility and will encourage women to 'forgive' or look for her 'part' in violence.
Religion often looks down on divorce.
Religion often sends messages of enduring suffering as a virtue, and marriage as a sacred duty.
Family may disapprove of divorce or offer little support. Conversely, they may have tried to help and grown frustrated, resulting in isolation, judgement, or criticism of the victim.
Family may contribute to messages of blame, enduring suffering, and the need to 'stand by your man'
Women face stigma as single mothers, divorcees, and abuse victims
Unaware of services available to battered women.
Lack of adequate child care.
Few jobs.
Negative experiences with service providers.
Lack of affordable housing.
Isolated from community services.
No support from family and friends.
Abuser may charge her with 'kidnapping' or sue for custody.
Abuser may abduct or abuse the children.
Questions whether she can care for and support children on her own.
Fears losing custody of her children.
Believes children need a father.
When we say 'why doesn't she leave?' we imply that we know what another needs: that the best solution is for her to leave, immediately. However, the reality of the situation (and our culture) often means that a woman CAN'T 'just leave'. The danger is real. The threats are frightening. And the hope for what comes after (where will I go? What will I do? What will happen?) are often stacked against her. Remember, most women will leave. Remember: it might be safest for her to stay for the time being. Until a woman can come up with a safety plan that addresses all of her barriers, attempting to leave or change the relationship may increase the danger.


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About Us
Michele Jones has been with Horn of Plenty, which designs specialty gift baskets unlike you've ever seen before, for nineteen years. Ten years ago Jones became president and owner and does she ever have an interesting job! Part of her role is to be constantly searching for new ideas to fill her clients' individual needs.
Her clients include corporations and individuals who want to give something special to someone, these individuals want to set themselves apart by the gift baskets they send.
Baskets from the Horn of Plenty are designed to meet any of your gift giving needs: Thank You, Congratulations On A New Baby, New Home, New Project, New Job, Project or Meeting a Sales Goal, Prizes for Golf Outings, Get well, Sympathy or any occasion and Holidays.
"We pride ourselves on individually hand-picked, handpacked baskets with care to meet anyone's price range. We love to make the senders and recipients smile" Jones said. We even make our bows by hand.


text:
|21 Jul 2011
Cannot right/left click in topbar in Windows 7
Hi guys,
If somebody can help me, I don't know if anyone has had this issue, but sometimes I cannot click the "back" button or "file" or any other topbar icons either in IE9, chrome, also with office 2010. It is strange as when I restore to a smaller window then it works immediately, but as soon as I maximize it, it doesn't work.
I have asus c90s laptop with win 7 32bit with aero on, I have some customized settings but I still don't know where is this coming from, it happens many times, and sometimes it just restores back to normal, also happens with my itunes, etc... basically any program maximized doesn't left/right click on any part of the topbar only if I restore the window to smaller size. Also it shows that when i try to click on the bar, it just goes transparent like I have chosen something from the back of the window, any help will be greatly appreciated.
I have tried to disable Aero and still the problem persists, the only way to work is with Windows classic theme, but it is too basic for me
|My System Specs
|23 Jul 2011
I have searched but I don't seem to find this type of problem, if somebody can help me, it would be great
|My System Specs
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Laptop keyboard mouse:right click and left click functions reversal
Hi, I am after some help. My laptop has decided to reverse the right click and left click functions, ie: if I left click it now does not select but instead brings up a menu (which the right click button should and used to do!) I've tried holding down both buttons (as suggested by a friend) by this...
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For the last few weeks whenever I left click on the desktop it brings the right click menu. This dosen't happen in the browser (firefox), but only in the windows desktop and start menu. However i the browser if I am on a web player like youtube, the portion that displays the video fails to display...
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This modern, very representative villa is located in Roses, Almadrava, only a few steps from the beach. Already from the street, one can see the remarkably spectacular length of the property, which is an absolute eye-catcher especially with its spectacular night lighting. The interior offers three bedrooms and two bathrooms. The stunning and very spacious living area and the large terraces offer a unique luxurious ambience. From here one has a breathtaking view to the bay of Almadrava. In the lower outside area there is another sun terrace with swimming pool. The property is also equipped with air conditioning warn /cold and a garage. A really representative house of dreams with exclusive ambiance!
The popular bay of "Almadrava" with its numerous water sports, is about 4 km from the center of the coastal town of Roses. The natural park of Cap de Creus is adjacent to the residential areas. Restaurants and shops are available during summer months. Because of the very beautiful beach and its surroundings, the area in general has luxury homes and small apartment buildings.
Availability upon agreement.
Engel & Völkers does not accept responsibility as the information provided in this brochure is for information only and it is subject to errors, omissions, change of price or withdrawal without notice. Taxes, notary and registry fees must be paid by purchaser, the commission to E&V paid by the seller as stipulated by Spanish regulations.


text:
I did dog rescue for many years with a private breed rescue. Ark Valley is held in high esteem in the rescue community. My group considered them one of the two best shelters in the state (the other is Boulder Humane - much larger and with a lot more funds at their disposal). Now that my family is ready to adopt a cat, I plan to adopt from Ark Vallry, even though we live in a town over 2 hours away.
The first day I walked into Ark-Valley I sensed the compassion everyone had for the animals in its care. Every staff member and most volunteers know the personal history and needs of each dog and cat and other pets that come to it. I love working with older or special needs dogs to help them become more adoptable. The team spirit among staff and volunteers can't be beat!


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Tuesday 24 October 2006
It was Tuesday, under the sign of Scorpio. The US president was George W. Bush (Republican).
In that special week of October people in US were listening to Money Maker by Ludacris.
In UK America by Razorlight was in the top 5 hits.
Perfume: The Story of a Murderer, directed by Tom Tykwer, was one of the most viewed movies released in 2006
while A Series of Unfortunate Events #13: The End by Lemony Snicket was one of the best selling books.
On TV people were watching Pride Fighting Championships.
If you liked videogames you were probably playing Dead Rising or Lost Planet (series).
But much more happened that day: find out below..
You can also have a look at the whole 2006 or at October 24 across the years.
Old Newspapers
Have a look at the old newspapers from 24 October 2006 and get them!
TV Series
Which were the most popular TV series released in the last 30 days ?
Which were the most popular movies released in the last 30 days ?
Find out your future
Get a FREE Numerology report based on the digits of 24 October 2006!
Wish him/her..
Historical Events
Which were the important events of 24 October 2006 ?
- Also see October 24 (Eastern Orthodox liturgics)
- In The Fellowship of the Ring, by J.R.R. Tolkien, the date is mentioned to Frodo Baggins by Gandalf upon his waking in Rivendell.
- Discordianism - Maladay
- Zambia - Independence Day (1964)
- R.C. Saints - optional memorial of Antonio Maria Claret
- United Nations Day (charter 1945)
Famous Birthdays:See famous people born on 24 October
Famous Deaths:
- William Montgomery Watt: Scottish historian and Islamic scholar (Born 1909).
- Justice Rutherford of the Ontario Superior Court of Justice struck down the ''motive clause'', an important part of the Canadian Anti-Terrorism Act.
- Ethiopian Prime Minister Meles Zenawi accuses the Government of Eritrea of jeopardizing regional stability by engaging in a proxy war through its assistance to the Islamic Courts Union in Somalia. Zenawi warns the Ethiopian Parliament that ampquotJihadists are amassing their forces near our borders.ampquot (allAfrica)
- The Dow Jones Industrial Average closes at another record high. (News Limited)
- Solomon Islands Prime Minister Manasseh Sogavare formally proposes reducing the role of Australia in the Regional Assistance Mission to the Solomon Islands (RAMSI) in his country at a Pacific leaders forum in Fiji. (ABC News Australia)
- The European Union announces it plans to assist Kazakhstan in developing nuclear power for ampquotpeaceful purposes.ampquot (NASDAQ)
- Iranian President Mahmoud Ahmadinejad opposes a bill in Iranian parliament that would require the fingerprinting of any citizens of the United States that are visiting Iran, stating, ampquotWe do not have a problem with American people. We oppose only the U.S. government.ampquot (AP via ABC)
- An Associated Press photographer is released after a day in the hands of Palestinian gunmen. (AP via WCBS)
- Speaker of the United States House of Representatives Dennis Hastert sits down with ethics investigators trying to determine when he and his staff learned about ex-Rep. Mark Foley's come-ons to former male pages and what they did to stop it. (AP via San Francisco Chronicle)
- Firefox 2.0 is released. (CNET)
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What news were making the headlines those days in October 2006?
- SportsIllustrated: Sports Illustrated: no.10516
- Time: Photo of Barack Obama
- SportsIllustrated: Sports Illustrated: no.10515
Which were the most popular books released in the last weeks ?
Remember when
What videogames would you be playing back in the days ?


text:
Using Technology to Support Early Learning STEM - by Michal Sered-Schoenberg
In late April the White House, U.S. Department of Education, U.S. Department of Health and Human Services, and Invest in US, held an event at the White House on the importance of early STEM education. Approximately three months later, the U.S. Department of Education hosted "Early Learning in STEM", a Google+ Hangout used to follow up on the White House symposium. Invest In US commitment makers such as The … Read More


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1 Wild Slide Link Menu
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Easily create a wild drop menu that "slides in" the text links next to the options selected on the menu. This lets the user to see where the link will take them, which you can't get with the average drop menu. It also gives them control of whether or not to click on the link(s) that "slide" in.Visit publisher site: 1 Wild Slide Link Menu
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I was there with some friends. We booked the hotel through airasiago (or you can book it from booking.com) 2 weeks before the trip and got a pretty good deal. One chalet only costed us RM80 per night which is considered super cheap. We were served with a welcome drink upon arrival and were given keys to the rooms. The rooms are very spacious and clean with free wifi. We had some problems with one of the safes in the cupboard and the friendly staff came over straight away and fixed it for us.
Transportation is fairly convenient. They provide free tuk tuk rides(big ones which can fit more ppl unlike the 2 seater ones in bangkok) to the Ao Nang street which is less than 5 mins away. Call the hotel any time before 10pm and they will send you back to the hotel.
They have different prices for rooms facing the garden and the swimming pool. Of course those facing the pools are more expensive but the pools are just a small walk away from our chalets so that didn't really bother us.
The good thing and also bad thing about this hotel is, its further off from the street. Compared to other hotels which are just walking distance from the Ao Nang street, you will definitely need a ride to the hotel and the road to the hotel is extremely dark and deserted, which is also a good thing because you can have a good night's sleep without noises from the night life on the streets.
Overall, RM80 a night for a stay like this is really a steal. We really enjoyed our stay there!
- Official Description (provided by the hotel):
- A 3-star-boutique resort in the villa or bungalow style. The property is provided 48 guest rooms and classified to 3 room types; The Canal Side, The Pool side, and the Garden View. ... more less
- Reservation Options:
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- Also Known As:
- Sunda Hotel Ao Nang
- Sunda Hotel Krabi
- Sunda Resort Krabi/Ao Nang