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A method of formulating a particle composition having a pre-selected cell internalization mode involves selecting a target cell having surface receptors and obtaining particles that have i) surface moieties, that have an affinity for or are capable of binding to the surface receptors of the cell and ii) a preselected shape, where a surface distribution of the surface moieties on the particles and the shape of the particles are effective for the pre-selected cell internalization mode.
1. A method of formulating a particle composition having a preselected cell internalization mode, comprising:
a) selecting a cell having surface receptors; and
b) fabricating ellipsoidal particles that have i) surface moieties that have an affinity for or are capable of binding to the receptors, and ii) an aspect ratio that is effective for the preselected cell internalization mode for the selected cell, wherein the pre-selected internalization mode is selected from a full endocytosis, a frustrated endocytosis and no endocytosis.
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This invention was made with government support under Grant No. W31P4Q-07-1-0008, awarded by Defense Advanced Research Projects Agency (DARPA); and under Grant No. NNJ06HE06A, awarded by NASA. The U.S. government has certain rights in the invention.
The inventions relate generally to micro and nanosized particle compositions and their applications and, more particularly, to micro and nanosized particle compositions having a particular pre-selected cell internalization mode.
Endocytosis is a general term defining processes, by which a cell can import and/or export selected extracellular species, such as molecules, viruses, particles and microorganisms and target them to specific organelles within a cytoplasm. Endocytosis can occur through a variety of pathways including clathrin-mediated and caveole-mediated endocytosis; phagocytosis; clathrin- and caveole-independent endocytosis. A particular endocytosis pathway may depend on the size and nature of the extracellular cargo, see e.g. Conner S. D. and S. L. Schmid. 2003. Nature 422: 37-44. For instance, caveole-mediated endocytosis is assisted by the activation of caveole, plasma membrane invaginations, with a characteristic size of 50-60 nm; clathrin-mediated endocytosis requires the concentration of transmembrane receptors and their bound ligands on the plasma membrane leading to the formation of vesicular cages with a characteristic size up to few hundreds microns (100-500 nm); phagocytosis involves specific cell-surface receptors and signaling cascades with the formation of cell membrane protrusions that eventually envelope the external micrometer cargo (>1 μm). Clathrin- and caveole-independent endocytosis can be associated with the formation of invaginating vesicles smaller than 100 nm.
Particle endocytosis can be of fundamental importance in several fields, such as virology, drug and gene delivery and in nanotoxicology, see e.g. Marsh M. and A. Helenius. 2006. Cell 124:729-40; Vasir J. K., and V. Labhasetwar. 2006. Expert Opin. Drug Deliv. 3:325-344; Oberdorster G., E. Oberdorster, J. Oberdorster. 2005. 113:823-39.
For nanosized particles, both natural, such as enveloped viruses, or artificial, such as biomimetic particulates, the most effective internalization mechanism can be a receptor-mediated endocytosis, in which molecules (ligands) distributed over the particle surface bind to countermolecules (receptors) expressed over the cell membrane, which can eventually bend to invaginate the foreign cargo, see e.g. Marsh M. and A. Helenius. 2006. Cell 124:729-40; Smith A. E., A. Helenius. 2004. Science 304:237-42. These receptors can be collected at the site of invagination by surface diffusion, without which endocytosis would not occur or would occur over a much longer time scale.
One embodiment provides a method of formulating a particle composition having a pre-selected cell internalization mode, which comprises a) selecting a cell having surface receptors; and b) obtaining particles that have i) surface moieties, that have an affinity for or are capable of binding to the receptors, and ii) a shape, wherein a surface distribution of the surface moieties and the shape are effective for the pre-selected cell internalization mode for the selected cell.
Another embodiment is a method of treating or monitoring a physiological condition comprising administering to a subject in need thereof an effective amount of a particle composition having a pre-selected cell internalization mode.
Yet another embodiment is a particle composition having a pre-selected cell internalization mode.
The following research articles and patent documents, which are all incorporated herein by reference in their entirety, may be useful for understanding the present inventions:
Unless otherwise specified "a" or "an" means one or more.
Unless otherwise specified the terms "endocytosis" and "endocytotic" mean receptor mediated endocytosis and receptor mediated endocytotic respectively.
"Microparticle" refers to a particle having a maximum dimension from 1 micrometer to 1000 micrometers, or, in some embodiments from 1 micron to 100 microns as specified.
"Nanoparticle" refers to a particle having a maximum dimension of less than 1 micron.
"Phagocytosis" refers to an uptake of large (characteristic size of more than 2 microns) particles by specialized phagocyte cells, which include macrophages, monocytes and neutrophils. Phagocytosis involves the formation of protrusions in the cell membrane that eventually envelope the external particle.
"Receptor mediated endocytosis" or RME refers to an internalization by a cell of a particle, which has moieties, such as ligands, distributed over its surface, which can bind to countermoieties (receptors) expressed over the cell's membrane. RME involves bending of the cell's membrane, which results in a full wrapping of the particle by the membrane and eventual internalization of the particle by the cell. Particles that are internalized via RME can have smaller characteristic size than particles that undergo internalization via phagocytosis. RME is not limited to phagocyte cells.
"Biodegradable" refers to a material that can dissolve or degrade in a physiological medium or a biocompatible polymeric material that can be degraded under physiological conditions by physiological enzymes and/or chemical conditions.
The present inventors recognized an importance of a particle shape for a receptor mediated endocytosis. Accordingly, the present invention provides a method of formulating a particle composition with a pre-selected cell internalization mode, which can involve selecting a target cell and obtaining particles that have on their surfaces surface moieties, that have affinity for or are capable of binding to surface receptors of the surface of the target cell. The surface distribution of the surface moieties on the particles and a shape of the particles are such that they are effective for the pre-selected cell internalization mode for the selected cell.
The pre-selected cell internalization mode may be selected from an "endocytosis" or "no-endocytosis" mode. "Endocytosis" refers to a mode, when a particle can be fully wrapped by the cell's membrane via a receptor mediated endocytosis and eventually internalized, "no-endocytosis" refers to a mode, when the particle can be at most partially wrapped by the cell's membrane.
In some embodiments, the pre-selected cell internalization mode may a frustrated or partial endocytosis. "Frustrated endocytosis" refers to a mode, when the particle gets only partially wrapped by the cell's membrane and does not get internalized by the cell.
The particles with a pre-selected cell internalization mode may be used for treating and/or monitoring a physiological condition. In such a case, one can select a target site, which is affected with the physiological condition and has cells of which have surface receptors on its surface, in a body of a subject, such as a mammal, preferably a human, and administering to the subject an effective amount of a composition that comprises particles with a pre-selected internalization mode for the cells of the target site. The physiological condition can be for example a disease, such as cancer or an inflammation.
In general, the selected cell may be any type of cell that has surface receptors on its surface. In many embodiments, the selected cells can be a mammal cell, such as a human cell.
A particular selected internalization mode may depend on the application intended for the particles. For example, the endocytosis mode may be preferred when the particle contains a cargo, such as an imaging or a therapeutic agent, which is desired to be delivered inside the cell. On the other hand, no endocytosis or frustrated endocytosis modes may be preferred when the particle contains a cargo, which is not intended for delivery inside the cell. One example of such situation can be a multistage delivery vehicle disclosed in PCT publication WO 2008/021908, where a first stage particle of the vehicle, which contains inside second stage particles, is intended to recognize and adhere to a target site in endothelium, without being internalized by the endothelial cells. After adherence, the first stage particle can release the second stage particles.
In many embodiments, the selected cell can be a non-phagocyte cell, i.e. a cell that cannot perform phagocytosis. Examples of phagocyte cells, i.e. cells that perform phagocytosis include neutrophills, monocytes and macrophages.
In some embodiments, the selected cell may be an endothelial cell, such as an endothelial vasculature cell, and the target site may be a vasculature site, such as a coopted vasculature, an angiotensic vasculature or a renormalized vasculature. For cells of coopted vasculature, the surface receptors may be angiopoietin 2 receptors; for cells of angiogenic vasculature, the surface receptors may be vascular endothelial growth factors (VEGF), basic fibroblast growth factors or endothelial markers such as αvβ3 integrins; for cells of renormalized vasculature, the surface receptors may be carcinoembionic-related cell adhesion molecules 1 (CEACAM1), endothelin-B receptor (ET-B), vascular endothelial growth factor inhibitors gravin/AKAP12, scaffolding proteins for protein kinase A and protein kinase C.
The surface moieties of the particle's surface can be complimentary to the receptors on the selected cell's surface. The surface moieties may be, for example, antibodies, aptamers or ligands with affinity for or capable of binding to the receptors on the selected cell's membrane surface. In some embodiments, the surface moieties may include specific moieties to the receptors on the selected cell's membrane surface. In some embodiments, the surface moieties may include non-specific moieties to the receptors on the selected cell's membrane surface. Yet in other embodiments, the surface moieties may include both specific and non-specific moieties.
Particles with a pre-selected internalization mode may be a part of a composition that can also include particles without the pre-selected internalization mode. The particles with the pre-selected internalization mode may constitute at least 10% or at least 25% or at least 50% or at least 75% or at least 90% by number of the total number of particles in the composition.
In many embodiments, the particle can be a non-spherical particle. In some embodiments, the particle can be a particle with a circular cross section. In some embodiments, the particle can be an ellipsoidal particle. Yet in other embodiments, the particle can be a cylindrical particle with an elliptical cross section in a direction perpendicular to the axis of the cylinder.
In some embodiments, the particle's largest characteristic size, such as a length of its major axis for a particle with an elliptical cross section, can be less than 2 microns, or less than 1 micron or less than 800 nm or from 5 nm to 500 nm or from 5 nm to 800 nm from 5 nm to 1 micron or from 10 nm to 1 micron or from 10 nm to 800 nm or from 10 nm to 500 nm or from 20 nm to 1 micron or from 20 nm to 800 nm or from 20 nm to 500 nm or from 50 nm to 1 micron or from 50 nm to 800 nm or from 50 nm to 500 nm.
Preferably, the particle's largest characteristic size is substantially smaller than a characteristic size of the selected cell. The particle's largest characteristic size can be at least 3 times smaller or at least 5 times smaller or at least 10 times smaller or at least 20 times smaller or at least 30 times smaller or at least 50 times smaller or at least 100 times smaller or at least 200 times smaller or at least 300 times smaller or at least 500 times smaller or at least 100 times smaller than the characteristic size of the selected cell. A characteristic size of the selected cell may vary from about 5 microns to about 40 microns or from about 10 microns to about 30 microns.
In some embodiments, the obtained particles may be particles that have a convex subsurface with a local curvature and a local surface density of the moieties, such as ligands, that are effective for internalization of the particles via a receptor mediated endocytosis, which means that the local curvature κ is smaller than a maximum endocytosis curvature κmax for the local surface density of the moieties. Maximum endocytosis curvature can depend on a binding energy between moieties on the surface of the particle and receptors on the surface of the selected cell's membrane, a bending energy factor of the selected cell's membrane and surface densities of the moieties of the particle and of the receptors on the selected cell's membrane. Methods of evaluating maximum endocytosis curvature are disclosed below.
In some embodiments, the local surface density of the moieties at the convex surface may be greater than a surface density of the moieties at other parts of the surface of the particle, thus, making a surface distribution of the surface moieties on the surface of the particle non-uniform.
For particles with an elliptical cross section, obtaining particles with a pre-selected cell internalization mode may involve obtaining particles that have an aspect ratio corresponding to the selected mode.
For example,
The elliptical cross section can be characterized R1 and R2, which are semi-lengths of the axes of the ellipse. An aspect ratio of the ellipse, which can be defined as Γ=R1/R2. The cross sectional area of the particle is A=πR1R2=πΓR2 2=πRs 2, where Rs is a radius of a particle with a circular cross-section that has the same are as the elliptical particle.
The geometry of the particle can be fully defined by a number of pairs of parameters such R1 and R2; Γ and R1; Γ and R2, Γ and Rs or Γ and V, where V is the volume of the particle.
In a case, when the geometry of the particle is defined through Γ and R2, a shape parameter determining a pre-selected internalization mode can be an aspect ratio Γ for a particular R2.
The particle with an elliptical cross section can be in a "no-endocytosis" mode if the aspect ratio of the particle for a particular semilength of a minor axis is less than a first critical value Γ′=(R2κmax)−1/2, where κmax is a maximum endocytosis curvature, which is defined below.
The particle can be in a frustrated endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is no greater than a second critical value, Γ″=R2κmax.
The particle can be in an endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is greater than the first critical value, Γ′, and less than the second critical value, Γ″.
The maximum endocytosis curvature κmax can be defined as an inverse minimum endocytotic radius calculated for the selected cell for a spherical particle or a particle with a circular cross section that has the same ligands on its surface as the non-spherical particle.
The minimum endocytotic radius and thus the maximum endocytotic curvature can be evaluated using the formula (1)
In the equation above, C is the ligand-receptor binding energy relative to kBT, where kB is the Bolzmann's constant and T is a temperature of the cell or the target site expressed in Kelvins (absolute temperature). C depends on a particular ligand-receptor pair. In particular, C=log[Kd 2D], Kd 2D is an equilibrium dissociation constant for the ligand-receptor interacting at the cell/particle interface. Kd 2D can be estimated from the following relation Kd 2D=Kd/h, where Kd is an equilibrium dissociation constant for the same ligand-receptor pair determined, for example, experimentally in solution and h is a thickness of a confinement region, to which the ligand-receptor sites are restricted. In many cases, h can be equal approximately to 10 nm.
B is a bending energy factor of the cell's membrane, which can be determined as detailed in Hochmuth, R. M., J. Biomech., 33:15-22, 2000.
mr, which is an average surface density on the receptors, when the particle is not interacting with the cell, can be determined using methods known to those of ordinary skill in the art. For example, one can determine mr in vivo by using radiolabeled monoclonal antibodies complimentary to the receptors as detailed for intercellular adhesion molecule 1 receptors in Panes J., et al. Am. J. Physiol. 1995; 269(6Pt2):H1955-64. Alternatively, mr can be determined using fluorescently labeled monoclonal antibodies complementary to the receptors. Such fluorescently labeled monoclonal antibodies can be antibodies labeled with phycoerythrin disclosed in U.S. Pat. No. 4,520,110.
ml is a local surface density of ligands ml, which can be varied by controlling surface functionalization conditions for the particle and/or by varying a size of the ligand molecule. The actual surface density of ligands on the particle can be verified experimentally using citofluometry or radiolabeled countermolecules in radioassays.
For a particle with a uniform surface distribution of ligands, the local surface density and the average surface density can be the same.
In certain embodiments, the minimum endocytotic radius and thus the maximum endocytotic curvature can be evaluated as disclosed in U.S. patent application Ser. No. 12/034,259 "Endocytotic particles" filed Feb. 20, 2008, which is incorporated herein by reference in its entirety.
As the particle size R2 grows, the aspect ratio Γmin, for which the internalization time is the smallest, reduces from 1 (R2=Rmin) to 0.3 (R2=500 nm).
In some cases, the two parameters describing the geometry of the elliptical cylindrical particle may be Γ and Rs.
In such a case, a shape parameter determining a pre-selected cell internalization mode can be an aspect ratio Γ for a particular value of Rs.
The particle with an elliptical cross section can be in a "no-endocytosis" mode if the aspect ratio of the particle for a particular semilength of a minor axis is less than a first critical value Γ′1=(Rsκmax)−2/3, where κmax is a maximum endocytosis curvature, which is defined below.
The particle can be in a frustrated endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is no greater than a second critical value, Γ″1=(Rsκmax)2/3.
The particle can be in an endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is greater than the first critical value, Γ′1, and less than the second critical value, γ″1.
A type of a particle with a pre-selected internalization mode is not particularly limiting. For example, the particle may be a liposome, a polymer-based particle, a silicon-and silica based particle, a quantum dot, a gold nanoshell, a dendrimer or a viral particle.
In some embodiments, particles may be fabricated with a shape effective for a pre-selected internalization mode. Yet in some embodiments, particles having a shape effective for a pre-selected internalization mode may be selected from a pool of particles, which may have a broad distribution of shapes and/or sizes. The selection from the pool of particles may be performed, for example, using Zetasizer™ Nano series instrument from Malvern Instruments, Worcestershire, United Kingdom, which allows measuring geometrical dimensions of the particles.
Particles may be fabricated using a number of methods. In general, fabrication methods that provide a control of the size and shape of the particles may be preferred.
In some embodiments, the particles may be fabricated by top-down microfabrication or nanofabrication methods, such as photolithography, electron beam lithography, X-ray lithography, deep UV lithography or nanoprint lithography. The advantage of using the top-down fabrication methods can be that such methods may provide for a scaled up production of particles that are uniform in dimensions.
The particles may have on their surfaces targeting moieties, such as ligands, aptamers or antibodies. For example, ligands may be chemically linked to appropriate reactive groups on the surface of the particles. Protein ligands may be linked to amino- and thiol-reactive groups under conditions effective to form thioether or amide bonds respectively. Methods for attaching antibody or other polymer binding agents to an inorganic or polymeric support are detailed, for example, in Taylor, R., Ed., Protein Immobilization Fundamentals and Applications, pp. 109110 (1991).
Non-uniform surface distribution of surface moieties can be achieved, for example, when making particles by top-down microfabrication or nanofabrication methods. For example, a substrate, from which the particles are made, may be patterned using a coating that resists ligands deposition, so that the particle has at least two different surface areas: one that is resistant to ligand deposition and one that is not. Subsequent exposure of the substrate to a solution containing a ligand may result in particles having non-uniform distribution of ligands upon their release from the substrate.
In some embodiments, the particle may have one or more channels connecting a reservoir with the surface. In some embodiments, the reservoir and the channels may be pores in the body of the particle. In such case, the particle may comprise a porous or nanoporous material. The pores of the porous or nanoporous material may be controlled to achieve a desired load of the active agent and/or a desired release rate. The nanoporous material with controllable pore size may be an oxide material, such as SiO2, Al2O3, or TiO2. Fabrication of nanoporous oxide particles, also known as sol gel particles, is detailed, for example, in Paik J. A. et. al. J. Mater. Res., Vol. 17, August 2002. The nanoporous material with controllable pore size may be also nanoporous silicon. For details of fabrication of nanoporous silicon particles, see, for instance, Cohen M. H. et. al. Biomedical Microdevices 5:3, 253-259, 2003.
In some other embodiments, the particle may have no channels at all. Such particle may comprise, for example, a biodegradable material. For example, the particle may be formed of metals, such as iron, titanium, gold, silver, platinum, copper, and alloys and oxides thereof. The biodegradable material may be also a biodegradable polymer such as polyorthoesters, polyanhydrides, polyamides, polyalkylcyanoacrylates, polyphosphazenes, and polyesters. Exemplary biodegradable polymers are described, for example, in U.S. Pat. Nos. 4,933,185, 4,888,176, and 5,010,167. Specific examples of such biodegradable polymer materials include poly(lactic acid), polyglycolic acid, polycaprolactone, polyhydroxybutyrate, poly(N-palmitoyl-trans-4-hydroxy-L-proline ester) and poly(DTH carbonate).
In certain embodiments, the particle may be an active agent per se.
The active agent may be a therapeutic compound and/or an imaging agent. The selection of a particular active agent depends on the desired application.
The therapeutic agent may be a physiologically or pharmacologically active substance that can produce a desired biological effect in fenestrated vasculature of the subject, such as a mammal or a human. The therapeutic agent may be an inorganic or organic compound, including peptides, proteins, nucleic acids, and small molecules. The therapeutic agent may be in various forms, such as an unchanged molecule, molecular complex, pharmacologically acceptable salt, such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, salicylate, and the like. For an acidic therapeutic agent, salts of metals, amines or organic cations, for example, quaternary ammonium, may be used. Derivatives of drugs, such as bases, esters and amides also may be used as a therapeutic agent. A therapeutic agent that is water insoluble may be used in a form that is a water soluble derivative thereof, or as a base derivative thereof, which in either instance, or by its delivery, is converted by enzymes, hydrolyzed by the body pH, or by other metabolic processes to the original therapeutically active form.
The therapeutic agent may be a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic compound, a radioactive isotope, a receptor, and a pro-drug activating enzyme, which may be naturally occurring or produced by synthetic or recombinant methods, or any combination thereof.
Drugs that are affected by classical multidrug resistance, such as vinca alkaloids (e.g., vinblastine and vincristine), the anthracyclines (e.g., doxorubicin and daunorubicin), RNA transcription inhibitors (e.g., actinomycin-D) and microtubule stabilizing drugs (e.g., paclitaxel) may have a particular utility as the therapeutic agent.
A cancer chemotherapy agent can be also a preferred therapeutic agent. Useful cancer chemotherapy drugs include nitrogen mustards, nitrosorueas, ethyleneimine, alkane sulfonates, tetrazine, platinum compounds, pyrimidine analogs, purine analogs, antimetabolites, folate analogs, anthracyclines, taxanes, vinca alkaloids, topoisomerase inhibitors and hormonal agents. Exemplary chemotherapy drugs are Actinomycin-D, Alkeran, Ara-C, Anastrozole, Asparaginase, BiCNU, Bicalutamide, Bleomycin, Busulfan, Capecitabine, Carboplatin, Carboplatinum, Carmustine, CCNU, Chlorambucil, Cisplatin, Cladribine, CPT-11, Cyclophosphamide, Cytarabine, Cytosine arabinoside, Cytoxan, Dacarbazine, Dactinomycin, Daunorubicin, Dexrazoxane, Docetaxel, Doxorubicin, DTIC, Epirubicin, Ethyleneimine, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Fotemustine, Gemcitabine, Herceptin, Hexamethylamine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Mechlorethamine, Melphalan, Mercaptopurine, Methotrexate, Mitomycin, Mitotane, Mitoxantrone, Oxaliplatin, Paclitaxel, Pamidronate, Pentostatin, Plicamycin, Procarbazine, Rituximab, Steroids, Streptozocin, STI-571, Streptozocin, Tamoxifen, Temozolomide, Teniposide, Tetrazine, Thioguanine, Thiotepa, Tomudex, Topotecan, Treosulphan, Trimetrexate, Vinblastine, Vincristine, Vindesine, Vinorelbine, VP-16, and Xeloda.
Useful cancer chemotherapy drugs also include alkylating agents, such as Thiotepa and cyclosphosphamide; alkyl sulfonates, such as Busulfan, Improsulfan and Piposulfan; aziridines, such as Benzodopa, Carboquone, Meturedopa, and Uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards, such as Chlorambucil, Chlornaphazine, Cholophosphamide, Estramustine, Ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, Melphalan, Novembiehin, Phenesterine, Prednimustine, Trofosfamide, uracil mustard; nitroureas, such as Cannustine, Chlorozotocin, Fotemustine, Lomustine, Nimustine, and Ranimustine; antibiotics, such as Aclacinomysins, Actinomycin, Authramycin, Azaserine, Bleomycins, Cactinomycin, Calicheamicin, Carabicin, Carminomycin, Carzinophilin, Chromoinycins, Dactinomycin, Daunorubicin, Detorubicin, 6-diazo-5-oxo-L-norleucine, Doxorubicin, Epirubicin, Esorubicin, Idambicin, Marcellomycin, Mitomycins, mycophenolic acid, Nogalamycin, Olivomycins, Peplomycin, Potfiromycin, Puromycin, Quelamycin, Rodorubicin, Streptonigrin, Streptozocin, Tubercidin, Ubenimex, Zinostatin, and Zorubicin; anti-metabolites such as Methotrexate and 5-fluorouracil (5-FU); folic acid analogues, such as Denopterin, Methotrexate, Pteropterin, and Trimetrexate; purine analogs, such as Fludarabine, 6-mercaptopurine, Thiamiprine, and Thioguanine; pyrimidine analogs, such as Ancitabine, Azacitidine, 6-azauridine, Carmofur, Cytarabine, Dideoxyuridine, Doxifluridine, Enocitabine, Floxuridine, and 5-FU; androgens, such as Calusterone, Dromostanolone Propionate, Epitiostanol, Rnepitiostane, and Testolactone; anti-adrenals, such as aminoglutethimide, Mitotane, and Trilostane; folic acid replenisher, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; Amsacrine; Bestrabucil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diaziquone; Elfornithine; elliptinium acetate; Etoglucid; gallium nitrate; hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Phenamet; Pirarubicin; podophyllinic acid; 2-ethylhydrazide; Procarbazine; PSK®; Razoxane; Sizofrran; Spirogermanium; tenuazonic acid; triaziquone; 2,2′,2″-trichlorotriethylamine; Urethan; Vindesine; Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacytosine; Arabinoside ("Ara-C"); cyclophosphamide; thiotEPa; taxoids, e.g., Paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.J.) and Doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); Chlorambucil; Gemcitabine; 6-thioguanine; Mercaptopurine; Methotrexate; platinum analogs, such as Cisplatin and Carboplatin; Vinblastine; platinum; etoposide (VP-16); Ifosfamide; Mitomycin C; Mitoxantrone; Vincristine; Vinorelbine; Navelbine; Novantrone; Teniposide; Daunomycin; Aminopterin; Xeloda; Ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; Esperamicins; Capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Also included are anti-hormonal agents that act to regulate or inhibit hormone action on tumors, such as anti-estrogens including for example Tamoxifen, Raloxifene, aromatase inhibiting 4(5)-imidazoles, 4 Hydroxytamoxifen, Trioxifene, Keoxifene, Onapristone, And Toremifene (Fareston); and anti-androgens such as Flutamide, Nilutamide, Bicalutamide, Leuprolide, and Goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
Cytokines may be also used as the therapeutic agent. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones, such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones, such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor-α and -β; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors, such as NGF-β; platelet growth factor; transforming growth factors (TGFs), such as TGF-α and TGF-β; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-α, -β and -γ; colony stimulating factors (CSFs), such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); and granulocyte-CSF (GCSF); interleukins (ILs), such as IL-1, IL-1a, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-11, IL-12, IL-15; a tumor necrosis factor, such as TNF-α or TNF-β; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the tern cytokine includes proteins from natural sources or from recombinant cell culture and biologically active equivalents of the native sequence cytokines.
The imaging agent may be a substance, that can provide imaging information about a targeted site in a body of an animal, such as a mammal or a human being. The imaging agent can comprise magnetic material, such as iron oxide, for magnetic resonance imaging. For optical imaging, the active agent can be, for example, a semiconductor nanocrystal or quantum dot. For optical coherence tomography imaging, the imaging agent can be a metal, e.g. gold or silver, nanocage particle. The imaging agent can be also an ultrasound contrast agent, such as a micro or nanobubble or iron oxide micro or nanoparticle.
The particles having a pre-selected internalization cell mode for particular type of cells can be part of a composition, such as a pharmaceutical composition. Such a composition may be a suspension comprising the particles described above for use in administering a therapeutic or imaging agent. To form the suspension, the particles may be suspended in an aqueous medium at a selected concentration. The optimal concentration can depend on the characteristics (e.g., solubilization properties) of the particle, type of therapeutic application and mode of administration. For example, compositions for oral administration can be relatively viscous, and may therefore contain a higher concentration (e.g., >50%) of the particle. Solutions for bolus injections preferably contain a relatively concentrated suspension of the particles (e.g., 10-50%), but not so concentrated that it has an appreciably higher viscosity than saline (to minimize need for large-bore needles). The solution used for continuous intravenous infusion typically can contain a relatively low concentration (e.g., 2-10% suspension) of the particles, due to the relatively large volumes of fluid that are administered.
The particles may be suspended in a number of suitable aqueous carrier vehicles. A suitable pharmaceutical carrier can be a carrier that is non-toxic to the recipient at the dosages and concentrations employed and is compatible with other ingredients in the formulation. Examples of suitable carrier vehicles include but are not limited to water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin. Suspensions for use in injectable formulations are preferably isotonic with the subject's blood. Generally, the carrier can contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives, as well as low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose or dextrans, chelating agents such as EDTA, or other excipients.
Prior to administration to the subject, the suspension of particles may be sterilized by a suitable sterilization method. Particles fabricated from a heat-stable material may be heat-sterilized, e.g., using an autoclave. Particles fabricated from a not heat-stable material may be sterilized by passage through a commercially-available sterilization filter. Of course, filtration may be used only in cases where the particles is smaller than the pores of the sterilizing filter.
The particles may be administered to a subject in need of therapeutic intervention via a number of suitable administration methods. The particular method employed for a specific application can be determined by the attending physician. For example, the particles may be administered by one of the following routes: topical, parenteral, inhalation, oral, vaginal and anal. Intravascular administration, which includes intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection, may be particularly preferred.
Intravascular administration may be either local or systemic. Local intravascular delivery may be used to bring the particles in the vicinity of a body site having a known tumor or inflammation by use of guided catheter system, such as a CAT-scan guided catheter. General injection, such as a bolus i.v. injection or continuous/trickle-feed i.v. infusion are typically systemic.
The particles may be injected into the blood stream and allowed to circulate and localize to their target site. Preferably, the particles are injected to a vasculature of the target site.
Although the foregoing refers to particular preferred embodiments, it will be understood that the present invention is not so limited. It will occur to those of ordinary skill in the art that various modifications may be made to the disclosed embodiments and that such modifications are intended to be within the scope of the present invention.
All of the publications, patent applications and patents cited in this specification are incorporated herein by reference in their entirety.
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text:
Lost Odyssey
Treasure Trove: What the Primaguide is missing
- Back To:
- Board List
- Topic List
- Topic Archived
- Page 1 of 2
- Last
I used the Prima Guide and got Treasure Trove inside the Great Staff. From my experience, the Prima Guide has every treasure EXCEPT:
.) 24 Treasures under the sea
.) Tablet fragment in sorcerer´s shrine (roll boulder on elevator)
.) the 19th crystal fragment in sorcerer´s shrine
.) Exchanging all three tablet fragment in numara artist house
.) A Mana Potion in Burning Caves (Boss room, return after boss fight)
.) A sidequest in numara AFTER obtaining the white boa (talk to the children, the cat girl should be standing with them)
.) Treasures in Gongora´s lab: 2 Chests (one is barely visible, at the back of the room) and 1 item on the table
And do not forget to get every treasure hunt, every invisible treasure and every royal seal.
Born to play RPGs - Forced to work
Now playing: Lost Odyssey
Can you miss items for the TT achievement or is any missable item available at the auction house at the end of disc 4?
I was under the impression the Achievement only related to chests, not hidden items.
Since i never needed the auction house i do not know for sure.
According to a sticky, two spells are permanently missable (there are only two opportunities to buy them).
Born to play RPGs - Forced to work
Now playing: Lost Odyssey
Okay, I haven't started this game yet, but I do have the strategy guide, and I was hoping to get through it with the guide and info from GameFaqs that the guide is missing. So my question is, as far as everyone knows, are these all that is missing from the guide?
Also, will I be able to understand these treasures like "24 treasures from the sea" when I get to them, or is it a bit more descriptive than that, sorry, some of the treasures listed I just don't understand. And also, are those in sequential order. Thanks a lot for any help. Sorry if I come across as naggy, just wanna have a descriptive guide about items missing from the guide so i can get 1000/1000, haha.
Anyone for Doomsday?
soulrend1 posted...
Yeah, what Berny wrote is everything that is missing. But I have the guide and I still missed 3 things out of the guide. The under water thing is basically hug the coastline underwater; there is a map of the underwater somewhere in the forums, but for some reason the mods are/were? removing it when ppl were posting a link to it. and the Achievment is for every item wheter it be in a pot, on a vine or sparkling on the ground.
This looks to be about it. The two permanently-missable spells are Shieldus and Barricadus, available first on the boatride over to the Experimental Staff at the shop, and then in Gohtza. After that, they aren't available anymore (as far as I know. They may be available at the Gohtza shop on disc 4).
History really does repeat itself. I'm learning the same things now that I did in 3rd grade!
what and where are these tablets? I have done everything in the game but get treasure trove and fought gongora yet.
Bump for those who need it, someone should make this a sticky or compile all the info into one post and make it a sticky, i'm curious about the tablets too, thx.
Anyone for Doomsday?
where's the 19th Crystal Fragment specifically located in the Sorceress's Shrine?

subset: commoncrawl


text:
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Worldwide Campaign to stop the Abuse and Torture of Mind Control/DEWs
Peacepink is the name of a kind of Pink Color Rose. It means: Peace and Love. We share Peace, Love and Care.
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energyweaponsatme Online
One of the twenty-first century's greatest violations of human rights is the proliferation of mind control technologies and their accompanying abuse and torture.
Despite of disagreements of religions, I indeed believe that everyone should fight against torture and abuse of mind control technologies and Directed Energy Weapons.
No matter what religions you believe, I wish that you can stand up for justice - To expose…Continue
Created by Soleilmavis Aug 21, 2009 at 7:30am. Last updated by Soleilmavis Jan 7, 2014.
Created by Soleilmavis Oct 10, 2008 at 7:05am. Last updated by Soleilmavis Dec 17, 2013.
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Created by Soleilmavis Sep 29, 2008 at 10:33am. Last updated by Soleilmavis Sep 29, 2008.
I have collected many reported articles which introduce 'mind control technologies'. The listing of these articles will not mislead readers; it is a short cut for readers to learn what mind control technologies are.
Soleilmavis Liu, Author of the book: "Twelve Years in the Grave – Mind Control with Electromagnetic Spectrums, the Invisible Modern Concentration Camp", is helping the public understand voice-to-skull, and remote electromagnetic mind control technologies. Her book provides the sound facts and evidence about the secret abuse and torture with such technologies.
Started by energyweaponsatme in Advanced technologies. Last reply by deca 54 minutes ago. 79 Replies 0 Likes
Started by fin27uk in Victims Stories. Last reply by thenewmind 5 hours ago. 719 Replies 0 Likes
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Posted by Agathawu on May 29, 2015 at 2:46pm 0 Comments 0 Likes
One of Buy Fifa Coins the complications is that you can buy bogus cash which will be a spend of cash. This normally happens when you buy the coinage without doing your evaluation.
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Nick says he hears voices in his head, almost every day, that demean him and threaten him and his family. "[They say] 'We're going to beat you,'" he says. "The voices have told me I should kill myself, which is not going to happen ... They say, 'We put poison in your food,' and that they have a predictor machine that's capable of…Continue
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2Timothy2:3Thou therefore endure hardness, as a good soldier of Jesus Christ.
God gave mankind freedom and liberty. God never controlled mankind's minds. Only Satan and his supporters wanted to control mankind's minds. Nazis were the first to develop the mind control weapons. With the help of Satan, they even wanted to conquer the whole world. Even though the world had destroyed Nazis, People had not been able to prevent the proliferation of mind control weapons, and prevent such weapons from falling into the hands of followers of Dragon and Beasts. More followers of Dragon and Beast started to research and develop mind control weapons. The Dragon, Beasts and their followers wanted to control their followers and also used their mind control weapons to abuse and torture God's people secretly.
2 Samuel 12:12 You did it in secret, but I will do this thing in broad daylight before all Israel.'
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Shippers still seeking seasonal workers
Mitchell Hartman
Nov 30, 2012 Online retailers and shippers say that despite high unemployment, they have unfilled temporary positions.
Strike at Los Angeles ports starts to back up commerce
David Weinberg
Dec 6, 2012 Already the strike has idled thousands of trucks and trains that take containers from the Ports of Los Angeles and Long Beach to factories and distribution centers.
Prolonged California port strike could affect retailers
Krissy Clark
Nov 30, 2012 Unionized clerical workers who staff the ports of Los Angeles and Long Beach have entered the fourth day of their strike. If the dispute continues, the ripple effects could soon be felt across the country.
FedEx to restructure to cut costs
Kai Ryssdal
Oct 10, 2012 The shipping company said it could boost its bottom line by nearly $2 billion.
Summer ice melt in the Arctic sets yet another record
Scott Tong
Sep 20, 2012 Shipping across the ice-free Arctic appears closer than ever. The new route will save fuel, but bring emissions and soot directly to the Arctic -- possibly accelerating the ice melt.
What's good for iPhones is good for FedEx
Jeremy Hobson
Interview by
Sep 18, 2012 Apple says it received two million orders for the iPhone 5 in the first 24 hours of availability. That is good news of course for Apple. It's also good news for shipping companies like Fed Ex.
FedEx earnings down, global economy to blame
Mitchell Hartman
Sep 5, 2012 FedEx has downgraded -- again -- its quarterly earnings estimate for the period ending in August.
The next Panama Canal could be on its way
Jeremy Hobson
Interview by
Aug 1, 2012 The government of Nicaragua is paying two Dutch companies about $750,000 to study the feasability of building a canal -- a canal that would rival the Panama Canal and create another link from the Pacific Ocean to the Caribbean Sea.
FedEx to acquire Brazilian shipper
David Brancaccio
Interview by
May 30, 2012 Despite global economic woes and nervous markets, FedEx announced today that it will purchase the Brazilian shipper Rapidao Cometa Logistica e Transportes for $6.8 billion.
UPS buys Dutch shipping rival for $6.8 billion
Scott Tong
Mar 19, 2012 The U.S. shipping giant said Monday it will acquire Europe's No. 2 delivery company, TNT Express, in effort to expand its global reach.


text:
Director Ayan Mukerji, who is currently busy with the post-production of "Yeh Jawani Hai Deewani" (YJHD), is said to have dubbed Deepika Padukone's voice in superstar Shah Rukh Khan's vanity van.
Mukerji recently landed at Wai, 250 km from Mumbai, on the sets of Shah Rukh and Deepika starrer "Chennai Express" to dub a few lines for the trailer of YJHD. But to his dismay, he found there was no suitable infrastructure around.
Shah Rukh immediately offered for their dub his luxury makeup trailer that has one of the best sound systems that a mobile van can have, said a statement.
"SRK not only allowed Mukerji and his team to use his van for dubbing, he also ensured that the YJHD team was treated to a sumptuous lunch and also offered them recreational facilities as they had driven seven hours at a stretch to reach the sets," said a source.
Releasing May 31, YJHD also stars Kalki Koechlin and Aditya Roy Kapur.
Do you like this article?
|Posted by:
|India-Forums.com Staff
|User Rating
|(25 Votes)
|eshita123, Frozy, jewel47, desiserialfan, sheenalipkknd, nida.swaron, virgo24, Nikhi., ..PriyaB.., BlueOrchids, gowri1712, nj_SRKholic, -SanzAngel-, shruthiR, christiandior., shonasandy, sonu-monu, MS-meghasharma, Baki, -MamuKiBhanji-, whiterose29, Abhinaya08, -LetItGo-, -INFINITE-, aftermath..
SRK u r rocks.luv uuu
srk rocks.he is a sweetheart.luv srk!!!
How sweet! Love you SRK, your the best <3
thats way u called KING KHAN , KING of bollywood ... love you Shahrukh Khan :) good luck Deeps and YJHJ Team ;) loveee youu SRK
Love uShah Rukh Khan!!!!!!!!!!!!!!!
u Rocks!!!!!!!!!!!!!!!!
Dats SRK...!!! D person who v luk it as idol..
very nice of u shah rukh khan
waiting for YJHD n chennai express
What can I say??SRK just has a heart of gold!!!!!
He is just too amazing <3 love him <3
wow so these days we hear news such like these. media has surely run out of their lives.
Shah Rukh Khan was seen watching Rab Ne Bana Di Jodi during his break time. 5
Yami Gautam, who ventured into Bollywood with Shoojit Sircar's "Vicky ...
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Confections have never been so cute or so crafty! Hisako Ogita returns to the US with her latest book that should tempt tastebuds and tickle funny bones as she combines candy-making with simple crafting and modern decorative design in Gummi Fun.
Hisako Ogita's Gummi Fun includes more than 40 gummi recipes and 8 different packaging and presentation techniques.
Written by Hisako Ogita.
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Baltimore County Now
Keith Dorsey
Director, Office of Budget and Finance
Yesterday, the Baltimore County Council unanimously passed County Executive Kamenetz's budget for Fiscal Year 15 with only minor changes. The County's General Fund Operating Budget, subject to spending affordability, for FY 2015 is $1.75 billion, an increase of only 3.85% above the previous year. When including special funds, the total operating budget is $2.9 billion.
The budget holds the line on taxes and maintains our top bond rating.
No increase in property tax rate – 26th year in a row
No increase in income tax rate – 22nd year in a row
Maintains Triple AAA bond rating – one of only 38 counties in the nation
You may view details of the budget on the County web site. Here's a quick overview of the total operating budget:
by Keith Dorsey
Director, Baltimore County Budget & Finance
In Baltimore County, when we talk about AAA, we're not talking minor league baseball. We're talking about the three AAA bond ratings Baltimore County just received (again) from the major rating agencies. Moody's, Standard & Poor's and Fitch have each given the County their highest credit ratings.
Why should you care? Think of a bond rating as the County's credit score. The higher your score/rating, the lower your interest rate when you borrow money. The County's AAA ratings save us millions of dollars in interest payments when we borrow money for major capital expenses such as new and expanding schools and heavy equipment for public works and the fire department.
Fewer than 1% of the counties in the nation earn a Triple/Triple A bond rating, placing Baltimore County in elite company. We work hard to be sure the County manages taxpayer dollars wisely. Three AAA ratings are a sign that we're doing a good job.
If you want to find out more about our AAA bond ratings, click here.


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Author(s): Shiller, Robert J.
ISBN 10: 0691123357. See all ISBN's
Edition: 2
Publisher: Princeton University Press
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This first edition of this book was a broad study, drawing on a wide range of published research and historical evidence, of the enormous stock market boom that started around 1982 and picked up incredible speed after 1995. Although it took as its specific starting point this ongoing boom, it placed it in the context of stock market booms generally, and it also made concrete suggestions regarding policy changes that should be initiated in response to this and other such booms. The book argued that the boom represents a speculative bubble, not grounded in sensible economic fundamentals. Part one of the book considered structural factors behind the boom. A list of twelve precipitating factors that appear to be its ultimate causes was given. Amplification mechanisms, naturally-occurring Ponzi processes, that enlarge the effects of these precipitating factors, were described. Part Two discussed cultural factors, the effects of the news media, and of "new era" economic thinking. Part Three discussed psychological factors, psychological anchors for the market and herd behavior. Part Four discussed attempts to rationalize exuberance: efficient markets theory and theories that investors are learning. Part Five presented policy options and actions that should be taken.
The second edition, 2005, added an analysis of the real estate bubble as similar to the stock market bubble that preceded it, and warned that "Significant further rises in these markets could lead, eventually, to even more significant declines. The bad outcome could be that eventual declines would result in a substantial increase in the rate of personal bankruptcies, which could lead to a secondary string of bankruptcies of financial institutions as well. Another long-run consequence could be a decline in consumer and business confidence, and another, possibly worldwide, recession." Thus, the second edition of this book was among the first to warn of the global financial crisis that began with the subprime mortgage debacle in 2007
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Tennessee sent SEC letter in 2006 alleging UConn violations
Updated: April 25, 2008, 9:24 PM ETBy Shelley Smith | ESPN.com
The University of Tennessee alleges the Connecticut women's basketball program had a pattern of violating NCAA rules, including allowing former players to practice with the team on a regular basis, arranging a tour of ESPN for a highly touted recruit and permitting former players to serve as recruiters, according to a complaint Tennessee filed nearly two years ago but was released for the first time Friday.
Tennessee officials asked the Southeastern Conference ...
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A simple open source programming game that allows editing of scripts while the game is still being run. The scripts control the AI of some combatants in a Quake III-style game.
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|Yankees Favored to Win World Series
|Written by TheSpread
|Thursday, 05 October 2006 04:37
Yankees Overwhelming Favorite to Win World Series
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The Guardian newspaper says the insider who blew the whistle on the NSA's probing of major U.S. Internet and telecom companies is a 29-year-old analyst who's been working for the agency under a government contract. His name is Edward Snowden.
Source: NPR
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Staff Reporter
Panel discussion held to promote awareness of Indian art
CHENNAI: Orissa art and crafts have hit the town with a stunning variety of Patta paintings, appliques and silver filigree.
The exhibition was organised by Karma, a society of Sambalpur sponsored by the Government of Orissa. It will be open at C.P. Art Centre from 10.30 a.m. to 8.30 p.m. till March 12.
Orissa's Ikat tradition unfolds in finely woven, blurry-edged, gem coloured tie-and-dye designs. The products include quilts, furnishings, dress materials and tapestry.
UP handicrafts
The Uttar Pradesh Handicrafts and Handlooms too is showcasing timeless craftsmanship as a major draw at Sri Sankara Hall. Actress Vindhya inaugurated the show.
The exhibits include a heritage collection of black metal, white metal and brass items, stone paintings, gagra cholis and churidars from Rajasthan, and Lucknowi chikan work. Visitors have plenty to choose: from bangles to bedspreads. The exhibition is open from 10 a.m. to 9 p.m. till March 20.
At Lalit Kala Akademi
The Paramparik Karigar has assembled craftsmen from 12 States at Lalit Kala Akademi to display palm leaf etchings, Mithila paintings, Sholapith work, Bagru prints and lacquered wooden toys. Many of the participants are master craftsmen, who are national award winners.
As part of the event, a panel discussion was held on Friday to promote an awareness of the tradition of Indian art. Asrafi Bhagat, Department of Fine Arts, Stella Maris; V.R. Devika, Craft Promoter; and Aarti Kawlra, design expert; participated in the discussion. Deborah Thyagarajan, founder of DakshinaChitra and Madras Craft Foundation, acted as the moderator.
The exhibition also featured a book release. The book was authored by five master craftsmen on the art of kalamkari, mittikaam, mithila, gadwakam and tana bana. Apoorva Verma, General Manager, Handicrafts and Handloom Exports Corporation of India, received the first copy. Special rebates are offered at all the exhibitions.


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Home > Products > DJ Equipment > Mixer > DJM-2000NXS
DJM-2000 nexus - Flagship 4-channel DJ mixer
Sync Master / Beat Slice / Quantise / Beat Effects / Studio-quality Instant FX / PRO DJ Link via LAN connection / Live Sampler / Three performance modes / 5.8-inch LCD multi-touch screen / Peak Limiter / High performance channel faders / Built-in USB soundcard / Talk-over function / 3-band isolator EQ
NEW Beat Slice
To sample and slice tracks on the fly for spontaneous creativity.
Frequency Remix
Seven-band touch cross fader so DJs can choose which frequencies are in the mix.
ProDJ Link via LAN
Enables a smooth link with up to four CDJ players/turntables and two laptops.
Quantise Beat Effects
Rekordbox BPM and beat grid information is retreived to automatically sync all beat effects in perfect time with the mix.
Side Chain Remix
Borrowing technology from the groundbreaking RMX-1000 remix station, to deliver louder side chain oscillators and multiple effect chaining.
MIDI mode
to control PCs or laptops running almost every DJ software on the market.
Watch and enjoy the demo video
Overall score: 9.8/10
- Overall performance
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Sheepskin Padded Leather Harness
We make this harness from latigo leather and use the finest hardware. It is stitched and riveted. It has a padded breast plate that is first felt lined then sheepskin over that for your dogs comfort. The straps have 5 points of adjustment with 5 roller buckles.
You can choose from sizes small to Xlarge and is in the color of black & brown.
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Rural Call Completion
Many of you have found it difficult to contact us. We are in a rural area and have found out that we are experiencing problems with the Rural Call Completion. Please email us at email@example.com with any problems.
There is an Indian legend which says, "When a human dies there is a bridge they must cross to enter into heaven. At the head of that bridge waits every animal that human encountered during their lifetime. The animals, based upon what they know of this person, decide which humans may cross the bridge.... and which are turned away..." -- Unknown
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|By Marketwired .
Article Rating:
|February 10, 2014 12:01 AM EST
HARTFORD, CT -- (Marketwired) -- 02/10/14 -- The Reality Crowd TV show (http://www.RealityCrowdTV.com) announced today that it has added two important marketing tools to help extend the program's ability to reach the growing worldwide audience that wants to learn about the benefits of equity crowdfunding and how to use the process effectively to raise money to start or expand small businesses.
The first business development tool launched was a http://www.Meetup.com/RealityCrowdTV Meetup Group, which is a social media networking site that allows the program to reach millions of members worldwide who are searching for weekly activities to attend based on their personal interests. Meetups feature an activity calendar, discussion groups, email blasts and other communication tools that make it easy to schedule crowdfunding events and invite a wide range of members to attend.
The second enhancement includes creating one of Google's recently released Google+ Hangouts. The Hangouts allow the Reality Crowd TV program to host a fully interactive video news broadcast, which allows viewers to ask pre-newscast questions to be answered during interviews; to share PowerPoint presentations and conduct polls during the broadcast; as well as access cool new social media marketing tools that allow the show to target the very hard to reach target audience of 18 to 34 year-old millennials.
Reality Crowd TV's next Google+ Hangout, entitled "Introduction of Title II Equity Crowdfunding to Entrepreneurs," will be held Thursday, February 13th at 6:00 pm Eastern Time.
Panelists can sign up for future shows at: http://www.linkedin.com/groups/Reality-Crowd-TV-Crowdfunding-Hangout-7455927?home=&gid=7455927&trk=anet_ug_hm.
After the news cast concludes the video will be archived on both Google+ and Youtube.com.
Guest Speakers include:
1. Manolis Sfinarolakis, Host, Reality Crowd TV 2. Kelly Peterson, CEO, OTT Communications Inc. 3. Joseph Barisonzi, CEO, CommunityLeader 4. Jeremy Andrews, CEO, Smart Money Entrepreneurs 5. Brian Korn, Attorney, Pepper Hamilton LLP
If your business would like to be featured on Reality Crowd TV, simply line up a panel of crowdfunding speakers that provide a good story and send us a media pitch at: http://www.realitycrowdtv.com/contact-us-crowdfunding/
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Manolis Sfinarolakis
Reality Crowd TV
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If cloud computing benefits are so clear, why have so few enterprises migrated their mission-critical apps? The answer is often inertia and FUD. No one ever got fired for not moving to the cloud - not yet. In his session at 15th Cloud Expo, Michael Hoch, SVP, Cloud Advisory Service at Virtustream, discussed the six key steps to justify and execute your MCA cloud migration.
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Container technology is sending shock waves through the world of cloud computing. Heralded as the 'next big thing,' containers provide software owners a consistent way to package their software and dependencies while infrastructure operators benefit from a standard way to deploy and run them. Containers present new challenges for tracking usage due to their dynamic nature. They can also be deployed to bare metal, virtual machines and various cloud platforms. How do software owners track the usag...
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SYS-CON Events announced today that BMC will exhibit at SYS-CON's 16th International Cloud Expo®, which will take place on June 9-11, 2015, at the Javits Center in New York City, NY. BMC delivers software solutions that help IT transform digital enterprises for the ultimate competitive business advantage. BMC has worked with thousands of leading companies to create and deliver powerful IT management services. From mainframe to cloud to mobile, BMC pairs high-speed digital innovation with robust...
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Containers Expo Blog covers the world of containers, as this lightweight alternative to virtual machines enables developers to work with identical dev environments and stacks. Containers Expo Blog offers top articles, news stories, and blog posts from the world's well-known experts and guarantees better exposure for its authors than any other publication. Bookmark Containers Expo Blog ▸ Here Follow new article posts on Twitter at @ContainersExpo
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Compute virtualization has been transformational, yet security policy implementation and enforcement has lagged behind in agility and automation. There are a number of key considerations when implementing policy in private and hybrid clouds. In his session at 15th Cloud Expo, Malcolm Rieke, the Director of Product Management at Catbird, discussed the impact of this new paradigm and what organizations can do today to safely move to software-defined network and compute architectures, including: ...
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We're entering a new era of computing technology that many are calling the Internet of Things (IoT). Machine to machine, machine to infrastructure, machine to environment, the Internet of Everything, the Internet of Intelligent Things, intelligent systems – call it what you want, but it's happening, and its potential is huge. IoT is comprised of smart machines interacting and communicating with other machines, objects, environments and infrastructures. As a result, huge volumes of data are bein...
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Can the spatial component of your Big Data be harnessed and visualized, adding another dimension of power and analytics to your data? In his session at Big Data Expo®, John Meza, Product Engineer and Performance Engineering Team Lead at Esri, discussed the spatial queries that can be used within the Hadoop ecosystem and their integration with GeoSpatial applications. The GIS Tools for Hadoop project was also discussed and its implementation to discover location-based patterns and relationships...
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Cloud and Big Data present unique dilemmas: embracing the benefits of these new technologies while maintaining the security of your organization's assets. When an outside party owns, controls and manages your infrastructure and computational resources, how can you be assured that sensitive data remains private and secure? How do you best protect data in mixed use cloud and big data infrastructure sets? Can you still satisfy the full range of reporting, compliance and regulatory requirements? In...
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In this scenarios approach Joe Thykattil, Technology Architect & Sales at TimeWarner / Navisite, presented examples that will allow business-savvy professionals to make informed decisions based on a sound business model. This model covered the technology options in detail as well as a financial analysis. The TCO (Total Cost of Ownership) and ROI (Return on Investment) demonstrated how to start, develop and formulate a business case that will allow both small and large scale projects to achieve...
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The move to the cloud brings a number of new security challenges, but the application remains your last line of defense. In his session at 15th Cloud Expo, Arthur Hicken, Evangelist at Parasoft, discussed how developers are extremely well-poised to perform tasks critical for securing the application – provided that certain key obstacles are overcome. Arthur Hicken has been involved in automating various practices at Parasoft for almost 20 years. He has worked on projects including database dev...
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Building low-cost wearable devices can enhance the quality of our lives. In his session at Internet of @ThingsExpo, Sai Yamanoor, Embedded Software Engineer at Altschool, provided an example of putting together a small keychain within a $50 budget that educates the user about the air quality in their surroundings. He also provided examples such as building a wearable device that provides transit or recreational information. He then reviewed the resources available to build wearable devices at ...
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There has been a lot of discussion recently in the DevOps space over whether there is a unique form of DevOps for large enterprises or is it just vendors looking to sell services and tools. In his session at DevOps Summit, Chris Riley, a technologist, discussed whether Enterprise DevOps is a unique species or not. What makes DevOps adoption in the enterprise unique or what doesn't? Unique or not, what does this mean for adopting DevOps in enterprise size organizations? He also explored differe...
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Cloud Foundry open Platform as a Service makes it easy to operate, scale and deploy application for your dedicated cloud environments. It enables developers and operators to be significantly more agile, writing great applications and deliver them in days instead of months. Cloud Foundry takes care of all the infrastructure and network plumbing that you need to build, run and operate your applications and can do this while patching and updating systems and services without any downtime.
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The CCCB is always interested in new venues and publics, and collaboration with other organizations with a view to coproducing, sharing or exchanging projects.
As a result of these relations, some of our exhibitions, audiovisual cycles, lectures and debates are presented at museums and arts centres all over the world.
Head of Touring Activities: Carlota Broggi
Casa del Lector
From 2.10.15 to 7.20.15
Museum of Finnish Architecture
La Casa Encendida (Madrid)
Martin Gropius Bau (Berlin)


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Bryans Win Third Beijing Title In Four Years; Mike Breaks Woodbridge Record
Beijing, China
by ATP Staff|
Bob Bryan and Mike Bryan did not drop a set en route to winning their third China Open title in four years on Sunday.
The top seeds lost just eight points on serve to beat Carlos Berlocq and Denis Istomin 6-3, 6-2 in 57 minutes and add to their 2009-'10 crowns. It was their seventh title of the year (7-3 overall).
It was Mike Bryan's 84th career doubles title (84-45), an all-time record, over-taking Australian Todd Woodbridge's mark of 83 trophies. Bob Bryan is now 82-44 in tour-level finals.
"It's obviously an honour to hold this prestigious record," said Mike Bryan. "There are some incredible names towards the top of this list and it's humbling to be in such elite company. Huge props must go out to Todd Woodbridge, who epitomised class and excellence on and off the court."
The American twins improved to a 59-9 record on the season, earning $156,740 in prize money and 500 ATP Doubles Rankings points.
"It feels great to win again in Beijing," said Bob Bryan. "We love playing here and have created some really fond memories in this city. The facility is impressive, the hospitality is first class, and we always receive tremendous support from the fans."
Carlos Berlocq and Denis Istomin, who beat second seeds Max Mirnyi and Daniel Nestor in the first round, split $70,720 and 300 points. The duo was an alternate pair, replacing Frenchmen Julien Benneteau and Richard Gasquet in the doubles draw.
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Docker announces enterprise expansion amid news of CoreOS competition
After his opening keynote at the European Docker conference, CEO Ben Golub talked to JAXenter about Docker's new enterprise solution and the news of competition from CoreOS.
After his opening keynote at the European Docker conference, CEO Ben Golub talked to JAXenter about Docker's new enterprise solution and the news of competition from CoreOS.
Oracle recently announced a new version of the JavaScript platform Avatar. It's time to take a deeper look at the changes that await us.
When it comes to successful software, does it pay to have fast coders? Or does slow and steady always win the race?
Basho's new head of EMEA operations discusses the changing field of Big Data and the challenges that face databases in the near future.
MongoDB is making claims that it's a "schemaless database" because it's a JSON-style data store. But does that really make it schemaless? And what does "schemaless" even mean anyway?
If you've ever wanted to get started with Web Components and find out what they're useful for, here's your chance.
Why a new cloud-based development tool called Terminal is about to change how we develop, teach, QA and collaborate.
Elasticsearch founder shares his experiences with Lucene and tells us how Elasticsearch all started with a simple cooking app for his wife.
The next major release of Angular is bringing a unified method for injecting dependencies into a directive.
Microservices are in – Amazon, Ebay and Netflix are changing the game by breaking up the monolithic approach. Should we allow follow suit?
Alex Zhitnitsky takes a look at Takipi's survey of the most requested Java 9 features in the community.
Many commentators have taken insult at the new developer Barbie doll – but let's take a look at her programming skills before we go judging her.


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Music - Page 16
A Very Nervous Christopher Maloney Amazes X-Factor Judges
Flashing back to this episode of X Factor gives us chills. Leading up to Christopher Maloney's X-Factor performance, you would of never seen his incredible performance coming. Christopher had a bad case of stage fright and was shaking as he took the stage.
16-Year-Old David Thibault Sounds Exactly Like Elvis [Watch]
Could this be Elvis Presley reincarnated? Watch David Thibault perform 'Blue Christmas' on Quebec radio station CKOI.
Britney Spears Las Vegas Tour Rider? Cheetos + Cheeseburgers
We can hear her arteries hardening! The rider for Britney Spears' Las Vegas residency is loaded with junk food and empty calories. Thankfully, the singer is dancing harder than she ever has in her life, since she'll need to work off these eats.
Who the Hell is "Bastille" and Why is Everyone Requesting "Pompeii?" [VIDEO]
Our studio line has been blowing up for the song "Pompeii" for the past several weeks. We did our research and found that the band "Bastille" is from the U.K. and got their name from an event celebrated on July 14th called Bastille Day (which also happens to be singer-songwriter Dan Smith's birthday).
Watch The Lone Bellow's Dream Show + Hear the Band Live in Minneapolis Sunday, Dec. 15 at 8 PM
Over the summer, the Lone Bellow brought a little Southern country rock to Minneapolis (via their home base in Brooklyn). Miss the epic show? We think the video above captures the spirit pretty well
American Authors Dish on Success, Slobs and Stress [VIDEO] [EXCLUSIVE]
I caught up with the guys from American Authors last Sunday afternoon when their tour stopped at the Triple Rock Social Club in Minneapolis.
What Does Caroline Pennell from The Voice Have in Common with my Daughter [AUDIO]
We had the pleasure of chatting with Caroline Pennell (Team Cee Lo) from The Voice this morning on the Get Up & Go show. She was extremely sweet and excited for what the new year holds. Caroline made the Top 8 on The Voice before being eliminated last week.
HELP! Are We Playing Enough Holiday Music This Month [POLL]
Please help me out with this holiday music poll. I've gotten feedback from people who absolutely love holiday music and those that can't stand to hear it at all. Right now, were playing one holiday song per hour 6:00-6:00PM.
Former Voice Contestant 'Kat Robichaud' Tells Us Who She Thinks Will Win this Season [AUDIO] [VIDEO]
We caught up with Kat Robichaud (Team Cee Lo) this morning on the Get Up & Go Show. She was open to discussing her song choices on The Voice and of course whats next for her, but when it came to the million dollar question; "Who's going to win this season?", she wasn't so chatty.
American Authors Coming to Minneapolis December 1st [VIDEO]
Catch the guys on tour this winter at the Triple Rock Social Club in Minneapolis on December 1st and win a download of their debut E.P by commenting below.
Selena Gomez Performs 'Slow Down' While Leather-Clad on 'X Factor' [VIDEO]
The ratings of U.S. 'X Factor' may be in the toilet, but the producers are still wrangling A-list talent, like Selena Gomez, to perform on the live shows. The singer and actress performed 'Slow Down' while leather-clad on the program last night (Nov. 14).


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Learning To Code and Losing My Mind (Reprise)
Wednesday, August 20, 2014
Coding is not for everybody. We admit it. But we should all take at least a peek under the hood of the computers and devices that power our lives. It's empowering.
Starting at a screen full of cryptic code is daunting, confusing, and might just well up some latent math anxiety. That's how New Tech City host Manoush Zomorodi felt, which is exactly why she decided to dive in head first. She signed up for a one-day computer programming intensive. This episode chronicle's how it went.
In short: It began a jumble of doubt and worry with baggage from high school math holding her back. "I am going to have to commit an act of coding to bring my anxiety level down a notch," she decided by late morning during the theory portion of the day. Yet within hours, Manoush had made a mostly functioning web app for her kids. "The mere act of making it myself made it less scary," she concludes.
Along the way she gains a greater reverence for the language of our machines and for the people fluent in them. Manoush wrote about this wild ride in more detail here, when a previous version of this show first aired.
Also in this episode:
- Keith Devlin, author of "Introduction to Mathematical Thinking" and many other books, describes the kind of thinker that tech firms are desperately looking for. The new tech economy needs mathematicians, but he says, of the kind of math that is not so much about numbers, as problem solving and pattern recognition. These skills can be learned!
If you liked this story, please click here to subscribe to our podcast on iTunes / RSS to find our other episodes. We're on Twitter too: @NewTechCity
Now watch Manoush learn to code, despite her 10th grade math teacher!
(This episode is a longer version, with additional information, of our show that aired on January 8.)
Comments [1]
At around 1:49 when it says "Javascript" on the screen, Manoush refers to "Java". Those are two different things. This is not really Manoush's fault. Java is a programming language. It's pretty powerful and is what a lot of stuff runs on, notably every Android phone and tablet. Javascript is a totally different thing and is used to do tons of stuff, primarily on the web. When it was released, Javascript's creators decided it would be a good marketing idea to make it seem related to Java, which was very hot at the time. In reality, Javascript has very little in common with Java. This confused me lots when I was learning to code and is really the fault of some marketing guys trying to make a buck.
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Age of Conan Feedback thread
View Single Post
Registered User
Join Date: Jan 2007
Posts: 468
Re: Age of Conan Feedback thread
Well first off I did not play the Beta a whole lot, I wanted to be able to experience as much of the game new when it went live as I could.
But from the classes that I did try out in Beta, Demo & Necro, I did find that there were a few small changes, for the better imo. Things like DPS, how pets work, I could not find a pet control bar besides that little tiny one on the UI, now we have an actual tool bar for it.
Mob spawn points are different. When you came out of the main city gate and head up the volcano to right where you crossed that first bridge there was a spawn point there and past. That seems to be gone so you can continue to quests.
But the general feeling I have about the game is very good. But it's nothing like starting areas in WoW with mobs you just go out and kill and simple quests. Because of the nature of the game you are mostly alone in the beginning lvl's, with instanced quest areas. I like this so far as it allows me to play the game at my own pace.
This is not typical of other MMO where there is a mad rush at spawn areas to kill quest mobs.
I like it so far
FPS is 30-50 for my system (not my new rig, but my older QX7600, 8800GTX rig. I will install it on my new rig today or tomorrow), no stuttering or lag that I have felt anywhere. Game is very smooth, nice graphics etc.
I have 1 of each of the 3 casters, all lvl 10 so far and moving along at a nice pace.
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Kimi Harris
Kimi Harris
Kimi is a food writer who loves the intersection of food and family and frugality. She creates recipes with that intersection in mind, hoping to help other busy moms who want to keep their families well-fed and food-curious. In addition to writing for MNN.com, she writes the Nourishing Gourmet blog, where you can find more of her simple but delicious recipes.
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Ayala Corp. invests in infrastructure, water firms in Vietnam
popular .
MANILA, Philippines — The Ayala group has strengthened its foothold in Vietnam, one of Southeast Asia's rising stars, with the acquisition of a significant minority interest in a leading infrastructure company and a bulk water supply company both based in Ho Chi Minh City.
In a press statement late Wednesday, Ayala Corp. and its subsidiary Manila Water Co. announced that they had won the right to buy a 10-percent stake in Ho Chi Minh City Infrastructure Investment Joint Stock Co. (CII) and a 49 percent stake in Kenh Dong Water Supply Joint Stock Co. (Kenh Dong).
"This investment primarily supports and complements the expansion of Manila Water Co. as it gradually builds its presence in Vietnam. At the same time, this also provides strategic access to other related infrastructure opportunities which may be of value to the group," Ayala president and Manila Water chair Fernando Zobel de Ayala said.
"We recognize Vietnam is a high growth area in the region and there is strong demand for infrastructure investments. This may potentially present opportunities for the Ayala group to establish presence across several sectors."
Ayala had offered to purchase a 10 percent stake in CII, which is listed on the Ho Chi Minh Stock Exchange, concurrent with MWC's offer to acquire a 49 percent stake in Kenh Dong.
Established in 2001, CII is a leading player in the infrastructure sector in Vietnam with a solid track record in sourcing, implementing and operating infrastructure assets.
The company has a portfolio of strategic infrastructure assets, including water treatment plants and toll roads serving Ho Chi Minh City and surrounding areas. This water company also holds a stake in Thu Duc Water BOO Corp., a water treatment company which is now 49-percent-owned by Manila Water.
In addition to water infrastructure, CII holds toll road concession agreements such as the 15.7-kilometer expansion of the existing Ha Noi Highway which connects the northeastern part of Ho Chi Minh City to Bien Hoa, an industrial center located in the southern part of Vietnam. CII wants to invest further in new water infrastructure initiatives and is considering expansion into other types of infrastructure projects such as public transportation terminals.
Kenh Dong was established in 2003 to build, own, and operate major water infrastructure in Ho Chi Minh City. Its water treatment plant is expected to start commercial operations by the second semester of 2012 with a capacity of 200 million liters per day (mld).
This is expected to benefit the suburban districts of District 12, Tan Phu and Binh Tan, where water coverage is very low, averaging at about 50 percent of the population.
Currently, Kenh Dong has a bulk water supply contract with Saigon Water Corp. (SAWACO) for a guaranteed volume of 150 mld. SAWACO is the state-owned enterprise managing the water supply system in Ho Chi Minh City.
Meanwhile, Ayala has obtained an approval from the Securities and Exchange Commission to offer up to P10 billion in 15-year bonds building up fresh funds for expansion particularly in its new growth areas of power generation and infrastructure-building. The offer will run from April 30 to May 7. The indicative rate is about 6 percent per annum, based on documents from the SEC.
These proposed fixed rate bonds of due in 2027 obtained the highest local issue credit rating of triple-A from Philippine Rating Services Corp.
The bonds will be redeemable (in full but not in parts) by the Ayala via call options starting on the 10th year and every year thereafter until the 14th year.
The bonds are rated "PRS Aaa" by Philippine Ratings Corp., which means these are deemed of the "highest quality with minimal credit risk" and that the obligor's capacity to meet its financial commitment is "extremely strong."
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