text:
|Publication number||US4880918 A|
|Application number||US 06/397,897|
|Publication date||Nov 14, 1989|
|Filing date||Jul 13, 1982|
|Priority date||Jul 13, 1982|
|Also published as||DE3376295D1, EP0100022A1, EP0100022B1|
|Publication number||06397897, 397897, US 4880918 A, US 4880918A, US-A-4880918, US4880918 A, US4880918A|
|Original Assignee||Eliezer Rapaport|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (2), Non-Patent Citations (8), Referenced by (24), Classifications (13), Legal Events (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
This invention relates to the use of adenosine 5'-diphosphate (ADP) and/or adenosine 5'-triphosphate (ATP) for selective inhibition of growth and subsequent killing of malignant cells, e.g., human malignant cells, thereby utilizing a normal metabolite for inhibiting, e.g., human tumor cell growth.
It is known to use antimetabolites (e.g., cytotoxic nucleosides or bases) such as purines and pyrimidines as antineoplastic drugs. However, such antimetabolites are taken up by both normal and tumor cells, and therefore not only can inhibit the growth of tumor cells, but also growth of normal cells.
U.S. Pat. No. 4,291,024 to Turcotte discloses a process for the preparation of liponucleotide analogs of nucleosides or bases having known cytotoxic activity (e.g., 1-β-D-arabinofuranosyl-cytosine, known as Ara-C). This patent discloses that these liponucleotide analogs of nucleosides provide a means for delivering cytotoxic nucleosides into the tumor cells. Once inside the cells, the cytotoxic nucleoside can be released in a phosphorylated form, thus circumventing the dependency upon kinase activity on the nucleoside itself. This is beneficial since the cytotoxic nucleosides or bases exert their anti-proliferative activities via the nucleoside triphosphate form. The objects stated in U.S. Pat. No. 4,291,024 do not mention delivery of normal cellular metabolites (e.g., ADP or ATP) into tumor cells via the liponucleotide analog; however, the liponucleotide analog of ADP falls within the broad disclosure of this U.S. patent. In any event, the liponucleotide analog disclosed by Turcotte enter the cancer cell via the process of lysosomo-tropism or related membrane phenomena; as such, these analogs can also enter normal non-cancerous cells (e.g., bone marrow, lymph node or intestinal epithelium cells), resulting in disruption of the normal cycling cell metabolism.
ATP is a known vasodilator that may cause circulatory changes in humans and experimental animals. See, e.g., Davies, et al., "Circulatory and Respiratory Effects of Adenosine Triphosphate in Man", in Circulation 3:543-550 (April 1951); Duff, et al., "A Quantitative Study of the Response to Adenosine Triphosphate of the Blood Vessels of the Human Hand and Forearm, in J. Physiol. 125:581-589 (1954); Rowe, et al., "The Systemic and Coronary Hemodynamic Effects of Adenosine Triphosphate and Adenosine", in American Heart J. 64:228-234 (1962). Moreover, cellular pools of acid-soluble nucleotides, especially ADP and ATP, have been previously shown by Rapaport and collaborators to act in the regulation of DNA replication and growth of mammalian cells. See, e.g., Rapaport, et al., "Incorporation of Adenosine into ATP:Formation of Compartmentalized ATP", in Proc. Natl. Acad. Sci. USA, Vol. 73, No. 9:3122-3125 (September 1976); Rapaport, et al., "Increased Incorporation of Adenosine into Adenine Nucleotide Pools in Serum-Deprived Mammalian Cells", in Proc. Natl. Acad. Sci. USA, Vol. 75, No. 3:1145-1147 (March 1978); Rapaport, et al., "Elevated Nuclear ATP Pools and ATP/ADP Ratios Mediate Adenosine Toxicity in Fibroblasts", In Regulation of Macromolecular Synthesis by Low Molecular Weight Mediators, Acadamic Press, 1979, pp. 223-231; Rapaport, et al., "Regulation of DNA Replication in S Phase Nuclei by ATP and ADP Pools", in Proc. Natl. Acad. Sci. USA, Vol. 76, No. 4:1643-1647 (April 1979); Rapaport, et al., "Selective High Metabolic Lability of Uridine, Guanosine and Cytosine Triphosphate in Response to Glucose Deprivation and Refeeding of Untransformed and Polyoma Virus-transformed Hamster Fibroblasts", in J. Cell. Physiol., Vol. 101, No. 2:229-236 (November 1979); Rapaport, et al., "Selective High Metabolic Liability of Uridine Triphosphate in Response to Glucosamine Feeding of Untransformed and Polyoma Virus-transformed Hamster Fibroblasts", in J. Cell. Physiol., 104:253-259 (1980); Rapaport, "Compartmentalized ATP Pools Produced from Adenosine Are Nuclear Pools", in J. Cell. Physiol., 105:267-274 (1980); and Rapaport, et al., "Retinoic Acid-Promoted Expansion of Tofal Cellular ATP Pools in 3T3 Cells Can Mediate its Stimulatory and Growth Inhibitory Effects" in J. Cell. Physiol., 110:318-322 (1982).
However, these references showing use of ADP and ATP as regulators of DNA replication and growth of mammalian cells do not disclose that the materials, or a process of using such materials, selectively attack malignant cells, e.g., human malignant cells, and not attack normal cells, leading to the arrest of growth and killing of said malignant cells while causing sustantially no arrest of growth or killing of normal cells.
Accordingly, it is an object of this invention to provide a process for selectively arresting and killing malignant cells, e.g., human malignant cells, while causing substantially no arrest or killing of normal cells.
It is a further object of this invention to provide a process for inhibiting tumor cell growth utilizing normal metabolites having selective penetration exclusively into tumor cells to disrupt cellular metabolism.
In order to accomplish the foregoing objects, applicant has found that exposure of a variety of malignant cells, e.g., a variety of types of human malignant cells, to low doses of ADP and/or ATP will result in marked inhibition of DNA synthesis and arrest of significant populations of cells in the S phase of their cycle, and continued exposure to such low doses of ADP and/or ATP will result in death of such malignant cells, with such effect on malignant cells occurring with substantially no effect on normal cells.
FIGS. 1A-1D are quantitative showings of the total cellular acid-soluble nucleotide pools for cell line designations HT29 and HS294T each treated with adenosine 5'-monophosphate (AMP) and ATP;
FIG. 2 shows the DNA distribution of human tumor cells (CAPAN-1, HT29, and HS584T) and normal human intestine cells (HS586INT) after 48 hours treatment with 40 μM of adenosine, AMP, ADP or ATP, comparisons being made with non-treated cells;
FIG. 3 shows the growth curves of several types of human tumor cells, either untreated or treated with 40 μM of ADP;
FIGS. 4A-4C are photomicrographs (x50) of HT29 cells----human colon adenocarcinoma----without treatment, with 4 days treatment according to the invention with 40 μM ADP, and with 4 days treatment according to the invention with 40 μM ATP, respectively; and
FIGS. 5A-5C are photomicrographs (x50) of CAPAN-1 cells----human pancreatic adenocarcinoma----without treatment, with 4 days treatment according to the invention with 40 μM ADP, and with 4 days treatment according to the invention with 40 μM ATP, respectively.
Applicant has found that ADP and ATP can permeate through the plasma membrane of tumor cells, e.g., human tumor cells, without prior degradation to adenosine -5'-monophosphate (AMP) or adenosine, with incorporation into cellular acid-soluble nucleotide pools followed by the disruption of cellular functions. Tumor cells from a variety of sources allow the direct incorporation of externally added ADP and/or ATP into their cellular acid-soluble nucleotide pools.
Such permeation by ADP or ATP through the plasma membrane of tumor cells without prior degradation to AMP or adenosine does not occur in normal animal cells; it is widely known that acid-soluble nucleotides are incapable of entering normal animal cells in intact form due to their negative charge, but must first be degraded to AMP and adenosine. The ability of ADP and/or ATP to permeate the plasma membrane of a variety of tumor cells, and not normal cells, is related to lesions in the plasma membrane found exclusively in many types of tumor cells.
By having the ADP and/or ATP incorporated into the cellular acid-soluble nucleotide pools of the tumor cells, such pools are altered, leading to the arrest of growth in the S phase of the cell cycle and eventual cell death. These effects are specific to ADP and ATP and cannot be achieved by treatment with other adenine nucleotides or adenosine. Thus, exposure of a variety of human tumor cells to, e.g., 40 μM of ADP and/or ATP for 48 hours results in marked inhibition of DNA synthesis and arrest of significant populations of cells in the S phase of their cycle. Continued treatment of such tumor cells with, e.g., 40 μM of ADP or ATP beyond 48 hours results in significant amounts of cell death. The exposure of human tumor cells to ADP or ATP for the purpose of arresting these cells in the S phase of their cycle need not be continuous. Cellular death however, is directly related to the magnitude of S phase arrest that has been achieved during the 48 hours after the onset of treatment. Thus, the criterion for obtaining human tumor cell death by this procedure is the initial production of S phase arrest in these cells.
Since ADP and/or ATP in a pharmaceutically acceptable salt form are very soluble in aqueous solutions, they provide very suitable means for administration as anticancer agents in humans. Sustaining sufficient blood levels of ADP and/or ATP can thus be achieved by injections or infusions. Phosphomonoesterase activity which is especially high in the kidney would tend to metabolize ADP and/or ATP and lower their blood plasma levels. It has, however, been reported that phosphomonoesterase activities of human tissues are low in comparison with mice and other experimental animals with especially low phosphomonoesterase levels reported for human kidneys. Whereas the use of derivatives of anticancer nucleotides, nucleosides or bases do not differentiate between, and are cytotoxic to tumor cells as well as to normally proliferating cells in the host (e.g., bone marrow, lymph node and intestinal epithelium cells), the use of low doses (25-100 μM) of ADP and/or ATP affords a desired antineoplastic selectivity. A more preferable range for the
ADP or ATP dosage is 40-80 μM . Only much higher doses of ATP (above 250 μM) were reported to affect cellular components of the immune system and it is demonstrated in this disclosure that human intestinal cells are not affected by low doses of either ADP or ATP.
The ADP and/or ATP can be employed in a pharmaceutically acceptable salt form and can be employed in a variety of conventional pharmaceutical preparations. These preparations can contain organic or inorganic material suitable for internal administration. The high solubility of ADP and/or ATP salts in isotonic aqueous solutions of sodium chloride, etc., enable administration of these agents in the form of injection or infusion of single or multiple doses. The injection or infusion can be intravenous or intra-arterial. ADP and/or ATP are also suitable for oral, enteral or topical application when employed with conventional organic or inorganic carrier substances. The effective doses should be in the range of 1-100 mg/kg of body weight for oral or topical administration and 0.05-20 mg/kg of body weight for injections. Intravenous or intra-arterial infusions of ADP and/or ATP, in a suitable salt form, is preferably administered at a rate of 0.01-1.5 mg/kg of body weight per minute.
For solid tumors, infusion of ADP or ATP is the preferable administration method, since it can deliver greater amounts of ADP or ATP into the vicinity of the tumor with minimal physiological effects on the blood flow.
With regard to the rate of infusion of the ADP and/or ATP, the various references, cited previously, disclosing that ATP is a known vasodilator, are noted. From these references, it can be appreciated that single rapid injections of 40 mg of the sodium salt of ATP, either intravenously or intra-arterially, produced small subjective and physiological changes in human subjects. Slow injections or infusions of the same dose of ATP produced much lesser or no response at all (see Davies, et al., supra.)
Experiments on dogs have shown that the threshhold dose which would elicit any kind of an effect on the coronary circulation is 2 micromole (1.2 mg) of ATP per kg weight per minute (see Rowe, et al., supra.) Infusions in these experiments lasted for 30 minutes. It has also been established that vasodilation by ATP was more profound if the magnesium salt of ATP was used instead of its sodium salt. No subjective sensation or any physiological effects were observed upon infusions of 1 mg/minute of sodium salt of ATP into the brachial artery of healthy subjects (see Duff, et al., supra.)
A variety of human tumor cell lines and a cell line derived from human intestine cells (i.e., normal cells) are utilized (summarized in Table 1) for demonstration of the invention in a nonlimiting fashion.
TABLE 1__________________________________________________________________________Cells of Human Origin Used to Demonstratethe InventionCell Line Tissue of Cell GrowthDesignation Origin Source of the Cells Morphology Medium__________________________________________________________________________CAPAN-1 Pancreatic tumor Sloan-Kettering Inst. Epitheloid RPMI 1640BxPc Pancreatic tumor Boston University Epitheloid RPMI 1640 School of MedicineHT29 Cancer of the Naval Bioscience Epitheloid MEM colon LabsHS294T Melanoma Naval Bioscience Epitheloid MEM metastatic to Labs lymph nodeHS584T Mammary gland Naval Bioscience Fibroblastic RPMI 1640 tumor LabsHS586INT Normal intestine Naval Bioscience Fibroblastic RPMI 1640 Labs__________________________________________________________________________ Media: RPMI 1640 RPMI medium 1640, Grand Island Biological Co., Cat. No. H18. MEM Eagle's minimal essential medium with nonessential amino acids, Grand Island Biological Co., Cat. No. F15.
Cells are cultured in 100-mm or 35-mm plastic petri dishes, as discussed below, at 37° C. in a humidified atmosphere of 90% air, 10% CO2 and in media supplemented with 10% fetal calf serum. The use of heat inactivated (20 hours at 58° C.) fetal calf serum is important since untreated serum contains high phosphomonoesterase and phosphodiesterase activities which lead to rapid degradation of adenine nucleotides. Cells are passaged every 4-5 days. All cells have been demonstrated to be free of Mycoplasma contamination.
Actively proliferating cells (logarithmic phase) in 35-mm petri dishes are exposed to a variety of nucleotides in 2 ml of the corresponding media supplemented with 10% heat inactivated fetal calf serum (20 hours at 58° C.). After 48 hours the medium is removed and the cells are exposed to [3 H] thymidine in 1 ml of the corresponding media without serum (1 μCi/ml of medium) for 1 hour; the medium is removed and the cells treated immediately with 1 ml of ice-cold 15% trichloroacetic acid (TCA) containing 3.4 nmol of xanthosine diphosphate (XDP, quantitative marker for determination of acid soluble nucleotide pools by high pressure liquid chromatography). Extraction of acid-soluble nucleotides is performed on ice for 30 minutes. The TCA extract is neutralized by vigorous extraction with 0.5 M tri-n-octylamine in Freon-113. The neutralized extract is used for HPLC analysis (on a Waters Associates ALC 204 instrument) of acid-soluble nucleotides on strong ion exchange columns (Whatman's Partisil-10 SAX). Chromatographic separation of total cellular acid-soluble nucleotides is demonstrated for HT29 and HS294T cells after 48 hours treatment with either AMP or ATP in FIGS. 1A-1D. In FIGS. 1A-1D, the HT29 cells treated for 48 hours with AMP and ATP are shown in A and B, respectively, and the HS294T cells treated for 48 hours with AMP and ATP are shown in FIGS. 1C and 1D, respectively. The extracts used in producing FIGS. 1A-1D were prepared from FIG. 1A:1.4×106 ; FIG. 1B:0.8×106 ; FIG. 1C:0.3×106 ; and FIG. 1D:0.2×106 cells, and treatment was with 40 μM of the nucleotide. Peaks are integrated electronically with a Hewlett-Packard HP3380A integrator. Specific radioactivity of the [3 H]dTTP peak is determined by collection of all the dTTP peak. The TCA insoluble material after incorporation of [3 H]thymidine is washed twice with ice-cold 5% TCA and twice with 95% ethanol. The acid-insoluble material is then lysed in 1 ml of 0.3 M NaOH and counted. Tables 2 through 6 demonstrate the effects on DNA synthesis and total cellular acid-soluble nucleotide pools of 48 hours treatment of a variety of human tumor cells with low doses of adenosine, AMP, ADP and ATP.
Demonstration of the effects of 40 μm of adenosine, AMP, ADP or ATP treatment for 48 hours on DNA synthesis and acid-soluble nucleotide pools of human tumor cells. In each table, the initial cell numbers are identical in control cells (no treatment) and cells treated with a variety of adenine nucleotides. The corresponding cell growth curves are illustrated in FIG. 3.
TABLE 2__________________________________________________________________________CAPAN-1 Cells Acid- DNA Synthesis/Final Cell ADP ATP UTP GTP [3 H]dTTP Insoluble %Nucleotide Number nmols/106 cells cpm cpm of Control__________________________________________________________________________None 7.0 × 105 1.3 ± 0.1 9.5 ± 0.4 3.1 ± 0.1 2.4 ± 0.2 4556 407252 100Adenosine 7.1 × 105 1.3 ± 0.1 11.7 ± 0.3 2.6 ± 0.1 2.3 ± 0.1 4967 411156 93AMP 7.0 × 105 1.1 ± 0.1 10.5 ± 0.1 2.7 ± 0.1 2.3 ± 0.2 5049 410276 90ADP 5.5 × 105 0.9 ± 0.1 10.9 ± 0.3 0.9 ± 0.1 1.5 ± 0.1 7702 408509 59ATP 5.2 × 105 1.0 ± 0.1 10.3 ± 0.2 0.8 ± 0.1 1.4 ± 0.1 8619 453678 59__________________________________________________________________________
TABLE 3.__________________________________________________________________________BxPc Cells Acid- DNA SynthesisFinal Cell ADP ATP UTP GTP [3 H]dTTP Insoluble %Nucleotide Number nmols/106 cells cpm cpm of Control__________________________________________________________________________None 2.6 × 105 2.1 ± 0.1 16.0 ± 0.2 5.3 ± 0.2 4.9 ± 0.1 696 20247 100Adenosine 2.6 × 105 2.0 ± 0.1 15.7 ± 0.2 5.1 ± 0.3 4.5 ± 0.3 793 21657 94AMP 2.6 × 105 1.9 ± 0.1 16.4 ± 0.4 4.4 ± 0.2 4.1 ± 0.1 920 24391 91ADP 2.5 × 105 1.8 ± 0.1 15.7 ± 0.3 2.3 ± 0.1 3.2 ± 0.1 1727 34176 68ATP 2.4 × 105 2.0 ± 0.2 15.6 ± 0.3 2.3 ± 0.1 3.3 ± 0.2 1803 42241 80__________________________________________________________________________
TABLE 4__________________________________________________________________________HS584T Acid- DNA SynthesisFinal Cell ADP ATP UTP GTP [3 H]dTTP Insoluble %Nucleotide Number nmols/106 cells cpm cpm of Control__________________________________________________________________________None 1.3 × 105 3.9 ± 0.2 17.4 ± 0.2 6.2 ± 0.2 4.3 ± 0.2 7435 12189 100Adenosine 1.3 × 105 4.0 ± 0.2 18.7 ± 0.4 5.7 ± 0.2 3.5 ± 0.2 3019 5355 108AMP 1.2 × 105 3.2 ± 0.1 19.5 ± 0.9 5.9 ± 0.2 3.7 ± 0.3 2905 4817 101ADP 1.1 × 105 4.5 ± 0.2 18.7 ± 0.5 4.4 ± 0.1 3.1 ± 0.2 2761 2213 49ATP 1.1 × 105 3.9 ± 0.1 19.2 ± 0.5 4.5 ± 0.2 3.0 ± 0.2 2369 2302 59__________________________________________________________________________
TABLE 5__________________________________________________________________________HT29 Acid- DNA SynthesisFinal Cell ADP ATP UTP GTP [3 H]dTTP Insoluble %Nucleotide Number nmols/106 cells cpm cpm of Control__________________________________________________________________________None 1.4 × 106 0.4 ± 0.1 5.1 ± 0.1 1.5 ± 0.1 1.0 ± 0.1 5746 158626 100Adenosine 1.3 × 106 0.5 ± 0.1 5.9 ± 0.1 1.2 ± 0.1 1.1 ± 0.2 6198 189502 110AMP 1.3 × 106 0.6 ± 0.1 6.1 ± 0.1 1.2 ± 0.1 1.1 ± 0.1 7087 201566 103ADP 0.8 × 106 1.0 ± 0.1 9.9 ± 0.2 0.9 ± 0.1 1.1 ± 0.1 12724 231614 65ATP 0.9 × 106 1.0 ± 0.1 9.7 ± 0.3 0.9 ± 0.1 1.3 ± 0.1 11646 274377 85__________________________________________________________________________
TABLE 6__________________________________________________________________________HS294T Acid- DNA SynthesisFinal Cell ADP ATP UTP GTP [3 H]dTTP Insoluble %Nucleotide Number nmols/106 cells cpm cpm of Control__________________________________________________________________________None 0.33 × 105 1.5 ± 0.1 9.9 ± 0.3 3.7 ± 0.1 3.1 ± 0.2 8079 57429 100Adenosine 0.32 × 105 1.6 ± 0.1 11.2 ± 0.3 3.1 ± 0.2 2.9 ± 0.2 9437 67177 100AMP 0.30 × 105 1.7 ± 0.1 11.1 ± 0.2 2.8 ± 0.2 2.7 ± 0.1 9388 72275 108ADP 0.21 × 105 2.2 ± 0.2 10.8 ± 0.2 1.5 ± 0.2 1.9 ± 0.1 6478 36419 79ATP 0.21 × 105 2.2 ± 0.1 11.3 ± 0.3 1.6 ± 0.2 2.1 ± 0.2 6755 33770 70__________________________________________________________________________ All determinations represent the mean of three experiments (± standard error). Determination of cellular acidsoluble nucleotides is illustrated in FIG. 1.
The data outlined in Tables 2-6 yield the following conclusions:
1. Treatment of a variety of human tumor cells with low doses of ADP or ATP for as short a time as 48 hours produces inhibition of both DNA synthesis and cellular growth.
2. The effects on cellular growth is unique to ADP and ATP and cannot be duplicated by any of their degradation products, namely, adenosine and AMP.
3. The activity of ADP and ATP in inhibiting cellular growth is due to their direct incorporation into cellular acid-soluble nucleotide pools by penetrating the plasma membrane of a variety of human tumor cells. The incorporation of external ADP or ATP into cellular acid-soluble nucleotide pools causes a severe reduction in total cellular UTP pools and to a lesser extent a depletion of GTP pools. Only in one case (HT29) is there a substantial increase in cellular ATP pools after exposure of the cells to ADP or ATP.
Similar treatment of normal human intestine cells (HS586INT) does not produce any inhibition of DNA synthesis or cellular growth with minor differences in cellular acid-soluble nucleotide pools. The effects on cellular acid-soluble nucleotide pools of HS586INT produced by ADP or ATP treatment are similar to the effects produced by either AMP or adenosine treatment. It is thus concluded that in the case of HS586INT there is prior breakdown of ADP and ATP to AMP or adenosine, before incorporation into cellular acid-soluble nucleotide pools, without any effect on DNA synthesis or cellular growth.
Cells are cultured in 100-mm petri dishes. Asynchronous cultures are treated with nucleotides in 10 ml of the corresponding media supplemented with heat inactivated fetal calf serum for 48 hours. The cells are then removed from the dish by trypsin/EDTA treatment. DNA fluorescent staining is achieved by treating 106 cells with 0.3 ml of staining solution composed of 0.05 mg/ml propidium iodide in 0.1% sodium citrate and 0.1% Nonidet P-40. Stained cells are subjected to flow microfluorimetric analysis utilizing Ortho Diagnostic Systems Cytofluorograph System 50H with a 500 mWatts excitation at 488 nm. Total fluorescence was measured in the 590+ nm range. FIG. 2 illustrates the results for three of the human tumor cell lines and one normal human intestine cell line. Relative DNA content of cells indicate cell populations in G1 phase (left peak), S phase (trough), and G2 +M phase (right peak). Treatment of human tumor cells with low doses of ADP or ATP for 48 hours leads to substantial increases in S phase cells in all the cases of human tumor cells tested. Normal cell populations HS586INT do not show any change in their DNA distribution after similar treatment.
The conclusion based on the data presented in FIG. 2 is that human tumor cells are arrested by ADP and ATP treatment specifically in the S phase of their cycle. The arrest of growth is attributed directly to ADP or ATP treatment and not to their degradation products since neither AMP nor adenosine produce any noticeable effects on the DNA distribution of human tumor cells.
Human tumor cells were cultured in 35- mm petri dishes and treated with 2 ml of the corresponding media supplemented with 10% heat inactivated fetal calf serum and containing adenosine, AMP, ADP and ATP. Cell numbers were determined at different time periods after the start of treatment by removing the cells with trypsin/EDTA and counting them in an electronic particle counter (Coulter Electronics). Growth curves of human tumor cells with and without exposure to low doses of ADP are illustrated in FIG. 3. FIG. 3 demonstrates in a nonlimiting fashion that treatment of human tumor cells with ADP for periods of time longer than 48 hours results in cell death. In FIG. 3, ( ) denotes untreated cells and ( ) denotes cells treated with 40 μM ADP. As for the specific types of cells, (O) denotes HT29 cells, (□) denotes HS294T cells, (Δ) denotes CAPAN-1 cells and () denotes BxPc cells. Similar results are obtained for ATP treatment but not for treatment with adenosine or AMP. It can thus be seen that treatment of human tumor cells with ADP or ATP is lethal to these cells after the initial arrest of growth discussed in the previous section of this application. The killing of human tumor cells by ADP or ATP is not attributed to their degradation products adenosine or AMP, since these agents fail to produce similar results.
The lethal effects of low doses of ADP and ATP on two representative human tumors are demonstrated in the photomicrographs of FIGS. 4 and 5. As can be appreciated, the extent of the tumors after 4 days of treatment with either ADP (see FIGS. 4B and 5B) or ATP (see FIGS. 4C and 5C), according to this invention, is decreased as compared with the untreated tumors (see FIGS. 4A and 5A).
While I have shown and described several embodiments in accordance with the present invention, it is understood that the same is not limited thereto but is susceptible of numerous changes and modifications as known to one having ordinary skill in the art and I therefore do not wish to be limited to the details shown and described herein, but intend to cover all such modifications as are encompassed by the scope of the appended claims.
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|U.S. Classification||514/46, 536/26.21, 536/26.26|
|International Classification||A61P35/00, C07H19/20, A61K31/7052, A61K31/70, A61K31/7076, A61K31/7042|
|Cooperative Classification||A61K31/70, C07H19/20|
|European Classification||C07H19/20, A61K31/70|
|May 12, 1993||FPAY||Fee payment|
Year of fee payment: 4
|Jun 24, 1997||REMI||Maintenance fee reminder mailed|
|Nov 14, 1997||SULP||Surcharge for late payment|
|Nov 14, 1997||FPAY||Fee payment|
Year of fee payment: 8
|May 14, 2001||FPAY||Fee payment|
Year of fee payment: 12

domain: literature


text:
Re-reading The Namesake
I’m teaching this novel again and the more I read Ashima’s character, the more of my mother I see in her. If my mother were Indian, she’d be the exact image of Ashima. Her and her “perpetual fear of disaster, ” yes, that’s my mother.
Life would be infinitely happier if we could only be born at the age of eighty...– Mark Twain This quote is what inspired F. Scott Fitzgerald to write The Curious Case of Benjamin Button
A former student of mine just started his own bootcamp and asked me if I’d be interested in joining. Be the all-time supporter of my kids I was all gung-ho. Today was my first day. Everything hurts. Forever. Goodnight, Tumblr.
The work day is over
Talk about a lack of enthusiasm. Damn you, rainy Mondays. Not only are you a Monday, you’re rainy too.
A lovely reminder
The girls bathroom at our school has no mirrors in front of the bathroom sinks. There is only one mirror inside the handicap stall. Today, I went in there to rinse out my coffee mug. As I looked up at the white tiles that line the walls I noticed something, a phrase scrawled faintly in pencil. I leaned in for a closer look and read this: I’m sure you look wonderful :) I never go into this...
Nothing in his memory anywhere of anything so good.– The Road
Babycakes Goes Shopping
I went to the book store yesterday and bought the following books. The Whale by Philip Hoare Everything is Illuminated Jonathan Safran Foer Franny and Zooey by J.D. Salinger Unaccustomed Earth by Jhumpa Lahiri The Amazing Adventures of Kavalier and Clay by Michael Chabon White Oleander by Janet Fitch Lady Chatterley’s Lover by D.H. Lawrence
What my yia yia could never understand about America was why everyone pretended...– The Virgin Suicides. Jeffrey Eugenides
If you break little promises, you’ll break big ones. That’s what you...– The boy, The Road by Cormac McCarthy
This was the perfect day of his childhood. This the day to shape the days upon.– The Road by Cormac McCarthy
I am currently experiencing another low. I look at all the people I encounter on a daily basis and I listen to what they like to do, what they’re obsessed with, etc and I realize that there is really nothing that I want more than anything in this world but to be a writer. Yet, I’m doing nothing about it. I see Laz and I am envious that he immerses himself so fully and completely in his...
How do you...
Reclaim enthusiasm? Recapture youth? Revisit old memories? Retain your innoncence? Relive special moments? Remember old friends? Regret the past? Restore your faith. -AH
Modest Mouse Announce Summer Tour
7/02 Royal Oak, MI - Royal Oak Theater 7/03 Milwaukee, WI - Summerfest 7/06 Kansas City, MO - Crossroads KC @ Grinders 7/09 Santa Fe, NM - Paolo Soleri Amphitheatre 7/10 Broomfield, CO - 1STBANK Center 7/12 Sioux Falls, SD - Ramkota Exhibit Hall 7/13 Fargo, ND - Hub at the Venue 7/14 Minneapolis, MN - The Orpheum Theatre 7/16 Chicago, IL - Pitchfork Festival 7/17 St. Louis, MO -...


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Tucked away in the peaceful northern end of Clearwater Beach and just 2 blocks from the Gulf of Mexico, this charming home is on a large lot located in the lovely & quiet Mandalay neighborhood. 5 bathrooms plus a bonus room that could be used as a...
Visit this property in CLEARWATER BEACH:
956 BRUCE AVE, CLEARWATER BEACH
The Harbor is the first developed residence in the newly approved and under construction Madeira Beach Town Center. Ride your elevator down and walk around town center will includes 2 world class resorts, a 43 slip world class marina, 45,000 sq....
Visit this property in MADEIRA BEACH:
300 150TH #200, MADEIRA BEACH
A prep sink sits in the expansive kitchen island with gorgeous granite & seating for 5+. 4 spacious guest bedrooms & bathrooms are perfect for family & guests. An expansive lawn leads down to the 152’ composite dock with boatlift. A 2 car garage,...
Visit this property in CLEARWATER:
608 N OSCEOLA AVE, CLEARWATER
Welcome to Encore by David Weekley Homes. Can you imagine living in a gated community with a 5000 sq. just to name a few. The Shower in lieu of a tub features a seamless shower glass enclosure and is large enough for two grown adults.
Visit this property in LITHIA:
6008 SPARROWHEAD WAY, LITHIA
10904 CARNELIAN LN,
This property's status is "Pending" or "Removed". You can use
our detailed search to look for similar properties.

domain: geography


Boeing and Lufthansa employees joined leaders from both companies, media and suppliers for a delivery ceremony at the Future of Flight Aviation Center beside Paine Field airport in Everett, Washington.
At the conclusion of the ceremony, Carsten Spohr, chairman of the executive board and CEO of Deutsche Lufthansa; Nico Buchholz, executive vice president, Group Fleet Management, Lufthansa; and Elizabeth Lund, Boeing vice president and general manager, 747 Program, boarded the airplane with about 30 passengers and crew for the flight taking the airplane from Everett to Lufthansa’s home base at Frankfurt, Germany.
When the 747-8 lands today (2nd May) at Frankfurt Lufthansa will host a special celebration. The aircraft will begin regular revenue service on the 1st June with a flight from Frankfurt to Washington, D.C.
The 747-8 Intercontinental will bring double-digit improvements in fuel burn and emissions over its predecessor, the 747-400, while generating 30 percent less noise. The 747-8 Intercontinental’s Dreamliner-inspired interior includes a new curved, upswept architecture giving passengers a greater feeling of space and comfort, while adding more room for personal belongings. It is powered by GE Aviation‘s GEnx-2B engines.


It is accurate to say that ONESIDE is successfully carving out its own niche though. “Progressive rock-grass” and “Americana fusion” are among the more satisfying terms being thrown around. As deBary explains, “I think our sound comes from our diverse musical backgrounds, combined with our respect for one another, and of course our love of playing music together.” This respect leads to a musical open mindedness that is the breeding ground for ONESIDE’s unique, organic sound. The individual members of ONESIDE combine to form a band steeped in classic rock, traditional bluegrass, folk, pop, funk, and jazz.
Before ONESIDE’S Chris Hersh ever picked up a banjo and fell in love with the instrument, he was a star jazz guitar student at the prestigious New England Conservatory of Music. DeBary is a deft, prolific songwriter who can draw song structures from traditional folk and blues, as well as from more modern and abstract influences such as Radiohead. Whatever the structure, the melodies always benefit from deBary’s tasteful pop sensibility, and are full of catchy lines and hooks. Bass player Grafton Pease is a disciple of melodic bass players like Paul McCartney and John Paul Jones.
Much like his idols, he can lay down a deceivingly simple, rock solid groove when the song calls for it, but also has the chops to amaze audiences when more overtly adventurous playing is appropriate. As drummers often are, Jake Brooks is ONESIDE’s secret weapon. He can change the feel from laid back country shuffles to head-nodding funk, and then over to an odd meter, while always propelling the music forward and making sure the underlying theme remains rooted in “Rock”. Where others have tried and failed, ONESIDE somehow manages to make all this ambitious diversity coherent.
Debary adds, “Another unifying aspect to our band is that we all love the banjo, and think it deserves a prominent place in modern American music”. Hence Oneside works, and the band has been simultaneously mystifying and delighting audiences all over the country. Read more on Last.fm. User-contributed text is available under the Creative Commons By-SA License; additional terms may apply..
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Listeners lock on to melodies, first – that means it's our job to make sure our melodies blow them away!
These seven tips are a distillation of melodic techniques learned in formal music training.
You won't need to go through all of that, because I'm giving them all to you in simple and easy-to-read language.
I've helped over 1,000 people make their melodies better with just these seven tips. Apply them to any melody, in any genre.
Best part: they're repeatable until you've refined your melody to where you want it.
Don't write another melody without watching this video training, first.
It’s completely free, just tell me where to send it...


We Gladly Deliver A High Quality, Premium Heating Oil At An Affordable Cost Across Suffolk County.
Emissions from today’s diesel trucks and buses are near zero thanks to more efficient engines, more effective emissions control technology and the nationwide availability of ultra-low sulfur diesel fuel.
Diesel is a petroleum-based fuel with a high energy content - helping diesel go further per gallon than most other alternatives.
- Refiners reduced the sulfur content in diesel fuel by 97 percent. This ultra-clean fuel is important because sulfur tends to hamper exhaust-control devices in diesel engines, like lead once impeded the catalytic converters on gasoline cars. Just as taking the lead out of gasoline in the 1970s enabled a new generation of emissions control technologies that have made gasoline vehicles over 95 percent cleaner, so will removing the sulfur from diesel help usher in a new generation of clean diesel technology.
- Ultra-low sulfur fuel (ULSD) is now available nationwide.
Read DTF's Diesel Fuel StudyDiesel: Fueling the Future in a Green Economy.
Source: U.S. Energy Information Administration, based on the National Defense University.
Diesel is the world's most efficient internal combustion engine. It provides more power and more fuel efficiency than alternatives such as gasoline, compressed natural gas or liquefied natural gas.
- Fuel combustion is the primary difference between gasoline and diesel engines. Gasoline engines ignite fuel with spark plugs, whereas diesels ignite fuel with compression. The piston stroke in a diesel engine results in a compression of the fuel air mixture so intense that it combusts spontaneously.
- Advanced new technologies such as electronic controls, common rail fuel injection, variable injection timing, improved combustion chamber configuration and turbocharging have made diesel engines cleaner, quieter and more powerful than past vehicles.
The Emissions Control System
With the introduction of lower sulfur diesel fuel, a number of exhaust treatment systems can further reduce emissions from diesel engines.
- Particulate Traps - collect particulate matter as the exhaust gases pass through and can reduce particulate emissions by 80-90 percent using a catalytic reaction or an auxiliary heating element.
- Catalytic Converters - use a chemical reaction to convert emissions into harmless substances. Some catalysts such as selective catalytic reduction (SCR) devices and NOx absorbers - focus on nitrogen oxides and can reduce these emissions by 25-50 percent.
Hometown Fuel Premium Diesel
As of Fall 2013 Hometown Fuel is delivering a premium detergent enriched diesel fuel. In addition our diesel has the following features and benefits:
- Meets industry requirements for diesel injector cleanliness
- Maintains injector spray pattern
- Keeps injectors clean
- Helps maintain peak engine performance
COLD FLOW (LTFT)
- Lowers LTFT Cold Flow Results
- Lowers fuel pour point and CFPP
- Increases fuel flow through filters
- Reduces waxing and gelling
- Can increase service life of sensitive fuel system components
- Improves performance
- Minimizes fuel contamination with corrosion by-products
- Protects fuel system components
- Reduces maintenance costs
- Inhibits the formation of filter plugging gums and residue
- Reduces maintenance costs
- Helps maintain injector cleanliness
- Prevents water related problems that can occur in diesel fuel
Hometown fuel has fueling solutions you need to efficiently and cost effectively fuel your fleet. If you own a trucking company, bus company or have a diesel generator and would like to start receiving diesel deliveries give us a call 631-878-8700 or use our contact us page and someone will be happy to assist you.


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This Time It's Different in 1982. It was released through the WEA label as catalogue number: 6002121
This Time It's Different first charted on June 14th, 1982, peaked at 22nd position and stayed in the charts for 26 weeks
Advertise your album here for less than a dollar per week!
Find out how here
Australian Music History Facebook Page
@AusMusicHistory on Twitter

domain: entertainment


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TWG Tea Loose Tea Party Loose Tea (100g)
£25.00 Product Code 4773091
Infused with sweet vanilla and floral marigold, this light Tea Party blend features a delicious base of black tea, creating a drink which pairs perfectly with cakes and sandwiches at afternoon tea. Expertly blending luxurious ingredients from all over the world, TWG Tea’s fine loose leaf tea is presented in a decorative tin and makes a gorgeous gift or perfect indulgence.
- Loose leaf black tea
- Presented in a decorative tin
Regrettably, this product is non-returnable.
Ingredients: camellia sinensis, vanilla, marigold
- Delivery & Returns
International Delivery Charges
If paying in another currency your delivery charge will be calculated at checkout.
Delivery Option Duration Price Standard Delivery 3-5 days, Monday-Friday only. £5.95 Next Day Delivery Next working day on all orders placed before 3pm, Mon-Sat only. £12 Saturday Delivery Saturday only on orders placed before Friday 3pm £15.95 Delivery to Europe £20 Outside of Europe Click here for International Delivery Terms for overseas shipping. £25
Find out more information on our International Deliveries.

domain: food


Several projects, including more than $1 million for restoration of the Grange City Covered Bridge in Fleming County, were among those included in the final 2018-2020 biennial highway construction plan.
The plan was approved by the General Assembly on Monday and sent to Gov. Matt Bevin for his signature.
The road plan was approved unanimously in the Senate and then the House agreed to the changes made in the Senate by a 74-15 vote, according to information from the Kentucky Press Association.
“Overall, I wish we could have done more for Mason, Bracken, Fleming and Robertson counties, but since Kentucky has more needs than revenue, I’m not the only legislator feeling this way,” State Rep. John Sims said Tuesday. “I’ve gotten to know this issue well over the past year as co-chair of the bipartisan House Working Group on Kentucky’s Transportation Infrastructure, which is why I co-sponsored House Bill 609 this year. That legislation would restore some of the revenues we’ve lost due to the volatile nature of the gas-tax law before we modernized it a few years ago. “
“To be competitive economically, a well-maintained highway system is critical, and historically, we’ve gotten high marks in this area,” Sim said. “I want to make sure it stays that way.”
Among the projects which made the cut for Mason County is a pavement project to deal with asphalt over concrete surfaces on U.S. 68 at a total cost of $9 million in 2020 and addressing deficiencies on the William Harsha Bridge also in 2020 for a total cost of $2.8 million.
Several bridge projects were on the list, Mason County Judge-Executive Joe Pfeffer said, and those include repairs to the bridge on U.S. 68 over Lawrence Creek at a cost of $468,000; address deficiencies to the bridge on Kentucky 3056 over the south fork of Lawrence Creek at $1.1 million; addressing deficiencies over a bridge on Davis Lane at a cost of $875,000; addressing deficiencies on the bridge Kennedy Creek Road at a costs of $560,000; and repair a bridge on Dixie Pike at a cost of $60,000.
Mason County’s total funding over the period is about $16 million.
In Fleming County, several bridge projects were also earmarked, including addressing deficiencies on a bridge over Allison Creek on Kentucky 111 at a costs of $2.1 million; addressing deficiencies on a bridge over Fleming Creek on McIntire Road for a total of $725,000; addressing deficiencies on a bridge over Mud Lick Creek on Kentucky 32 for $560,000; and addressing deficiencies on a bridge over a branch of Hillsboro Creek on Kentucky 111 at cost of $1.5 million.
Other Fleming projects include the restoration work on the Grange City Covered Bridge set for 2019 at a cost of $1.2 million.
Funds set aside for Fleming County projects over the biennial total $25.2 million.
Work in the plan for other area counties includes:
Bracken County — $190,000 each in 2019 and 2020 for operation of the Augusta Ferry’ about $4 million over the same period to address deficiencies on a bridge over Holts Creek on Kentucky 8 at Foster. Total for the county in the plan is $4.2 million.
Lewis County — Construct a new bridge crossing the North Fork of the Licking River at the Fleming County-Lewis County line at a costs of $3.6 million; address deficiencies on a bridge over Laurel Fork on Kentucky 1068 for $1 million; address deficiencies on a bridge over Grassy Branch in Kentucky 344 at a cost of $1.9 million; address deficiencies on a bridge over Brierly Creek on Kentucky 1021 at a cost of $1,2 million, Total funds set aside for Lewis County are $7.8 million.
Robertson County — $460,00 for improvements to the curve on Kentucky 616 for a total of $460,000.


Massachusetts Institute of Technology
School of Engineering
Exhibit Design: Proun Design, LLC
Content Development: Sarah Morris
Fabrication: Mystic Scenic Studios, Inc
Founded on the eve of the Civil War, MIT began as a school focusing on mechanical, civil, and geological engineering.
150 years later, MIT is pioneering in fields as diverse as aeronautics, bioengineering, and nuclear science.
Proun designed an exhibit for the corridor outside of the Dean’s office that celebrates this rich history. A map of the campus printed on a slate chalk board, a common denominator throughout the history of the school, introduces the exhibit and asks the question: What are YOU working on now?
Sumptuously designed panels highlight the achievements of each of the nine engineering departments: from Doc Edgerton’s strobe photography, to the human-powered flight of the Daedalus, to the latest advances in nano technology. A timeline rail pulls the exhibit together with a comprehensive accounting of some of MIT’s most notable moments.


TOPEKA, Kan. (AP) The U.S. Army Corps of Engineers is taking steps in Kansas to prevent the spread of a beetle that is killing ash trees in the Northeast and Midwest.
Starting Friday, campers at Perry Lake in northeastern Kansas will be barred from bringing in firewood that did not originate in surrounding Jefferson County. The Corps is also banning all firewood from ash trees, no matter where it comes from.
The goal is to protect Perry Lake’s trees from the emerald ash borer beetle, which was recently detected in northwestern Missouri’s Platte County. The Corps says that’s the beetle’s western-most confirmed presence.
Visitors who bring non-native firewood to Perry Lake will be able to exchange it for native wood to use during their stay.


Monthly Archives: December 2010
There is no doubt about it, farm and ranch families perform a lot of dirty, tough jobs in the process of providing food and fiber for their fellow Americans. But, the big question is—Can they compete with the Discovery Channel’s Dirty Jobs show host and narrator Mike Rowe. Video contest being hosted by the American Farm Bureau Federation.
Jan D’Atri, local media celebrity, had fallen in love with Arizona agriculture. Follow her on her latest adventure on an Arizona cotton farm.
Winter Arizona Wine Festival at the Tempe Festival of the Arts
Move over ordinary rice casseroles. I may have brought you a new favorite.
Superstition Farm is hosting its 3rd Annual Moo-ey Christmas event again this year; bigger and better than ever.


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Set of two jewelled geometric bangles.
This unique set of two geometric bangles would make a great gift for any quirky individual. The set includes one bangle with gold tone geometric shapes and one bangle with jewelled geometric shapes - one diamonte and one iridescent jewel. The bangles are made in an antique gold tone and are available in one size only.
Stack it high with a selection of our other bangles or wear alone for an understated look.
Your order will arrive wrapped in an organza gift bag as shown in the final product image. Alongside a 'Hello beautiful' card, the packaging ensures that your order is ready to gift your chosen one.
Antiqued gold tone alloy and acrylic.
Bangle width measures approx 0.4 cm. Diameter measures approx 6.2 cm.

domain: design


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Japan’s government is offering a new incentive for families to move out of the overcrowded capital of Tokyo in an effort to revitalize countryside towns and boost the falling birth rate.
Starting in April, families in the Tokyo metropolitan area, including single-parent households, will be eligible to receive 1 million yen (10,000 CAD) per child if they move to less-populated areas across the country.
This is not the first time the government has attempted to address the issue of overcrowding in Tokyo and a shrinking population in the rest of Japan.
Past incentives, however, have been ineffective. In an effort to increase the incentive’s effectiveness, the government is now offering 1 million yen per child to families who move from the Tokyo region to almost anywhere else in Japan for at least five years.
The incentives apply to children aged under 18 or dependents aged 18 and over if they are still attending high school.
Additionally, the new subsidy will come on top of the approximately $30,000 in relocation support payments already available to those who start a business, get a local job, or work remotely from a new community.
For decades, people across Japan have migrated to urban centers such as Tokyo in search of job opportunities.
As a result, Tokyo has become the country’s most populous city with roughly 37 million residents.
However, with the country’s overall population, one of the world’s oldest, recording its biggest-ever natural decline in 2021 and a record low birth rate, something needs to be done to address the issue.
Cities and towns in Japan’s countryside are aging and shrinking the fastest, which is depleting their tax base, shuttering schools and leaving many municipalities on the brink of extinction.
With the new incentives, the government hopes to attract families to move to these areas and help revitalize them.


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Posted on March 7 2013
Here are Gunday Images from Gunday movie Shooting - Hot Priyanka Chopra in Saari with Young Boy Arjun Kapoor and "Hot Boy" Ranveer Singh.
Priyanka Chopra is busy in kolkata for shooting of her upcoming movie "Gunday" with young male actors "Ranveer Singh" and "Arjun Kapoor".
In this movie all character has special and different looks from their past movies.
In this movie Priyanka looks charming and sexy in Saari with a role of Desi Girl and Ranveer Singh and Arjun Kapoor also looks hot with their different look and new hair style.
After a long time PC looks in Saari in whole movie in sari.


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Small and compact, the Bridget Floor Lamp is perfect to place beside sofas or chairs to shine just the right amount of light. Its playful design and matte finish adds a retro-chic element to any modern living room. Pair it with the Bridget Table Lamp to create the ultimate set that meets your lighting needs.
Highlights:• Bulb: E27/6W included
• Screw cap: E27
• Location of switch: On cable
• Voltage: 220V
• Max. wattage: 40W
• 3-pin plug
• Simple self-assembly required
Overall:H160 Ø30 cm
Other:Base: Ø28 T1 cm
Materials & Care
Notes:Product may vary slightly from images due to the use of natural materials (e.g. wood, marble and leather grains), or due to photoshoot lighting conditions and screen settings.


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Hungry-Man Double Meat Bowls Smothered Salisbury Steak 15 oz
2 Salisbury steak patties + chunky mashed potatoes and onion & mushroom gravy. 28 g protein per serving. Per 1 Bowl: 630 calories; 17 g sat fat (85% DV); 1920 mg sodium (83% DV); 4 g total sugars. New! Double meat. Double hearty. Savory Salisbury steak. Rich onion & mushroom gravy. Creamy mashed potatoes. U.S. inspected and passed by Department of Agriculture. www.hungry-man.com. how2recycle.info. SmartLabel: Scan or call 1-800-719-5859 for more food information. Questions or comments, visit us at www.hungry-man.com or call 1-800-719-5859.


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It's no surprise that as Sandy reached the East Coast, interest grew among Chicago Tribune readers. Here's what getting that information to you has involved:
Chicagotribune.com producers Laura Moran and Kurt Gessler worked late Monday and started early Tuesday to find the latest information on Sandy’s impact from Tribune wire reports and correspondents and place it prominently on our web site. Tribune senior photo editor Meg Theno has been assembling photo galleries of Sandy’s devastation from the East Coast.
Meanwhile, Sandy's long reach touches Chicago, as well. Tribune reporters have been pulling together local reports. And starting Monday morning, Tribune photographers Chris Walker, Zbigniew Bzdak, Armando Sanchez, and Alex Garcia cruised the lakefront from the north shore to the Indiana state line -- paying special attention in areas where lakefront paths or Lake Shore Drive is closest to the water, says photo director Todd Panagopoulos.
While on the lookout for crashing waves, "we found wave watchers, surfers, and sailboarders. Monitoring the police scanner around 4 p.m. [Monday], we learned the Chicago Police Department was concerned with runners and bikers between Oak Street and North Avenue Beaches as the wave activity building. Terrace James was dispatched to that stretch of the path as police put up barricades. Photographer Nuccio DiNuzzo kept up the watch until about 11 p.m. when he filed our last photo and video clip for the day."
Planning for Tuesday, photo editor Mario Petitti arranged for photographers Heather Charles and Chris Walker to be on early wave watch at first light for stills and video.
Additionally, photographer Mike Tercha headed to Northwest Indiana where some of the biggest waves were expected as the winds pushed the lake south into the beaches.
Watch for more reporting from the Tribune's resources throughout Tuesday and Wednesday as the storm's physical, geographical -- and political -- impact become more fully known.
Join Trib Nation on Facebook for more of the how and why of Tribune journalism.


These dynamic bookshelf speakers really live up to their name and deliver stunning sound.
Designed for high-resolution playback, the Clarity HD and produce the type of sound staging usually associated with much larger speakers.
Inside are a 6.5-inch bass driver, concave 1-inch Tweeter and a digital power amp.
There is a built-in iPhone/iPod dock in the right speaker along with an auxiliary mini-jack input to connect other smartphones, MP3 players, tablets and computers.
The Monster Clarity HD speakers include a volume control, a high frequency filter and can also be connected to a TV to add some audio punch to your viewing.
There is also a Monster StreamCast Wireless Port which can fit Monster’s new Wireless module, which is sold separately, to allow music to be streamed wirelessly from an iPhone or iPad.
The Monster Clarity HD is available now and come in red or yellow. They are priced at $999 a pair.
They are available from Harvey Norman stores Australia-wide.


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Books and Articles
Found 5 results
Filters: Keyword is San Miguel County (N.M.) [Clear All Filters]
Abstract of title to the Antonio Ortiz grant, situated in San Miguel County, New Mexico. Las Vegas, NM: Las Vegas Title Guaranty Co., 1919.,
Comprehensive plan, Las Vegas, San Miguel County. Albuquerque, NM: Jose Luis Yguado & Associates, 1963.
Report of San Miguel County. Santa Fe, NM: New Mexican Print. Co., 1882.

domain: library


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Settlers, Palestinians and the Israeli military each released different versions of events on Sunday regarding Saturday's clashes between settlers from the outpost of Adei Ad and Palestinians from the village of Al-Mughayyir, in which Hamdy Taleb Na'asan was shot and killed.
The army believes that settlers shot Na’asan during the clashes. According to the army, the settlers used live fire, while the army only used means of riot control.
The settlers do not deny that they fired live bullets, but contrary to their statements on Saturday, on Sunday morning they said that the army also used live fire. The Palestinians affirmed the settlers' claim, but the army has denied it.
The commander of the West Bank district police ordered an investigation, which was launched Sunday. However, residents of Adei Ad said that their civilian emergency responders had yet to be summoned for questioning. The nature of the suspicions against them is still unclear.
- Palestinian shot dead by settler in West Bank clashes, IDF officials believe
- In land of illegal outposts and hate crimes, another Palestinian life claimed
- The sadists who destroyed a decades-old Palestinian olive grove can rest easy
While the settlers place sole blame for the incident on residents of Al-Mughayyir, the latter said that they were attacked by people from Adei Ad.
There are unanswered questions in all three versions of events.
The settlers’ version
The settlers gave conflicting accounts on Saturday. According to the first version, a group of hikers from Adei Ad was attacked near Al-Mughayyir and one of them called civilian emergency responders from the outpost, fearing that the Palestinians would abduct one of the settlers.
According to the second version, which has since become the official version, a settler teen who does not live in Adei Ad went to the outskirts of the Al-Mughayyir, where he was attacked by Palestinians.
The teen says that he was a few meters from the southernmost house in the outpost when he was stabbed by three Palestinians. He sustained minor injuries, he said, presenting a wound on his hand. He said that the Palestinians tried to drag him toward Al-Mughayyir, but he managed to get away and call the emergency responders for help.
The settlers said that the emergency responders identified the three Palestinians who had attacked the boy and followed them towards the village. At that point, a few dozen Palestinians had gathered at the edge of the village and threw stones.
The settlers conceded that they had used live fire. At first, they said the emergency responders fired into the air and then one of them fired “in self-defense.” They said their lives were in danger, yet they are not sure if they were the ones who shot and killed Na’asan.
The settlers said on Sunday morning that IDF soldiers and Border Police personnel arrived at the scene after the initial fire. According to the settlers, the forces used riot control measures and also fired live rounds.
The unanswered questions: It is unclear why the emergency response team left Adei Ad, because their mandate does not entitle them to operate outside the outpost. It is also unclear why civilian responders were summoned instead of the soldiers who were on duty at a guard post near the outpost.
The army’s version
The army doubts that the teen was stabbed. In an IDF spokesperson’s statement on Saturday night, the army said that there was a confrontation between the army and the Palestinians.
The statement also said that “a conflict erupted between Israeli civilians and Palestinians in the area, in which live rounds were fired by the civilians." As far as the army knows that was when the Na’asan was shot and killed, before the army arrived. The army said "several" Palestinians were injured in the incident.
The army rejected claims by the settlers and the Palestinians that it fired live rounds and said that it only used riot control measures to disperse the disturbance that developed in the village.
The unanswered questions: Did the IDF and the Border Police respond using only riot control or did they use live fire?
The Palestinian version
Al-Mughayyir’s mayor, Faraj Na’asan, told Haaretz that a group of settlers tried to attack some of the houses in the northern part of the village. “They opened fire toward the houses and the village, and dozens of young men came out who were hit by settler fire.” After the settlers attacked them, the Palestinians called for help by phone.
In Al-Mughayyir people deny that the settlers were attacked by Palestinians, and said that the settlers instigated the aggression. According to the Palestinians, both the army and the settlers fired live bullets. “We don’t know exactly who was struck by the soldiers’ bullets and who from the settlers’ bullets, but no doubt some people were wounded by bullets from the settlers, who attacked the houses without reason,” the mayor said.
According to the Palestinians, the soldiers and the settlers shot at them as they fled, explaining why Na’asan was shot in the back.
The Palestinian Health Ministry in Ramallah confirmed that Na’asan had been shot in the back. Ten Palestinians were wounded by live fire; three are in serious but stable condition.
The unanswered questions: How do the Palestinians explain the story of the stabbing, considering that the teen did have a stab wound on his hand? It is also still unclear what Na'asan's role was in the incident.

domain: sociology


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Uber Technologies saw its stock rise at the start of Friday's trading session after Needham analyst Bernie McTernan dubbed the business a top pick for 2022.
McTernan added Uber to Needham's conviction list, lowering the price target to $75 from $77 while maintaining a buy rating on the stock.
"Because of the emphasis on EV/Sales multiples, calling the floor in UBER has been challenging. "UBER appeared cheap to us from 6x sales all the way up to 3.5x now," the analyst wrote in a research note.
The projection for adjusted profits before interest, taxes, depreciation, and amortization, which they predict "improving from -$800M in '21E to $1.3B in '22E to $3.3B in '23E." McTernan added, makes him believe this year will be different.
"UBER is on the brink of investors being able to put a multiple on a fairly close annual metric, which should provide a studier floor for valuation,” McTernan said in a client letter," McTernan wrote in a client note.
In other news, Jefferies analyst Brent Thill downgraded LYFT to hold from buy, claiming that Lyft will fall behind Uber owing to "the re-opening focus widening beyond the U.S. to global markets where UBER stands to benefit." in a research note.

domain: finance


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Woodlands is a timber framed house built in 1993, well
maintained and decorated with recently refurbished and stylish kitchen and bathrooms. The accommodation is very spacious and flexible, suitable for both families and couples.
Woodlands is positioned centrally in a 0.4 acre plot at the end of a private driveway, well set back from the road. The plot is peaceful and secluded and just a short walk from the village centre. There is a separate double garage and additional driveway parking for 3-4 cars. The house is surrounded by attractive gardens and has both front and rear terraces, providing sun-facing seating throughout the day.
Henley-on-Thames 7 miles • Wallingford 7.5 miles
Oxford 21 miles • Central London 44 miles
Reading Station 8 miles (25 minutes to London Paddington) Goring & Streatley station 6 miles (50 mins to London Paddington • Henley-on-Thames station 7 miles (40 minutes to London Paddington) Heathrow airport 30 miles • M4 (Junction 11) 11.5 miles
M40 (Junction 5) 11 miles (All distances are approximate)

domain: travel


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how to sove the key master error 1 and error 7 problem(firstname.lastname@example.org)
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Police identify man killed in collapse at Lincoln home
LINCOLN, Neb. (KLKN) – Police have identified the man who was killed after a tree fell onto the chimney, which collapsed into the home near 27th Street and Sheridan Boulevard.
Police say that the branch and chimney hit 59-year-old Kevin Clements, who had been inside the sunroom at the time.
He was pronounced dead at the scene.
Lincoln Fire & Rescue Assistant Chief Michael Smith said the limb falling was “an act of nature.”

domain: news


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IN Lifestyle ON
"There is nothing more uncommon than common sense"- Frank Lloyd Wright
Is common sense that uncommon. It can be I guess because when I came across these riddles, I too pondered over the same thing. Our lifestyle has become so complicated and the problems so complex that we struggle to put our brains into even the most simplest things. Get ready to lose your mind with these mind-boggling riddles.
Well, if this turns out to be a piece of cake for you, smile because you belong to the category of people who are still humans.

domain: psychology


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Thursday 15 October 2009 by Keiko Tamura.
The Australia-Japan Research Project website has been updated with new contents. 1. Japanese Midget Submarine attack on Sydney Harbour and its aftermath The AJRP has conducted a study on the aftermath of the Japanese midget submarine attack in Sydney Harbour in 1942 and the research outcome has been added to our website. Dr Tamura, the AJRP project manager, carried out archival and field research in Australia and Japan to collect …


Christmas drink-drive rise on Surrey roads
The number of people caught drink-driving in Surrey over the Christmas period has risen, say police.
Surrey Police said the proportion of people who were breathalysed and were over the limit rose from 3% in 2011 to 4.5% in 2012.
The number of under 25s who failed the test doubled from the previous year, figures showed.
A total of 1,564 tests were carried out between 1 December 2012 and 1 January 2013.
Duncan Brown, head of road safety and traffic management at Surrey Police, said he was disappointed to see a rise in the "selfish small minority" of people who drink and drive.
He added: "It seems young people are still prepared to risk drinking and driving, worryingly although 12% less under 25s were breath-tested, the number of those who failed was double the previous year - 16 in 2012 compared with eight in 2011."


AG Mednet Delivers Clinical Trial Imaging Platform to Qynapse
AG Mednet is delivering its Judi // Imaging services to Qynapse to ensure accurate deployment of medical images within Qynapse’s quantitative imaging services for clinical trials.
Qynapse provides a cloud-based solution for pharmaceutical companies and healthcare providers to support the accurate diagnosis, prognosis and drug efficacy measurement for central nervous system diseases, enabling improved clinical trial performance and personalized patient care.
Judi // Imaging, part of AG Mednet’s technology platform that includes medical imaging and endpoint adjudication services, provides the functionality and support needed to collect image data, de-identify it to ensure regulatory compliance, apply advanced, automated quality-assurance processes to insure the data is protocol-compliant and readily usable, and deliver it reliably and securely to trial repositories.
“AG Mednet helps us deliver valuable information on time for the delivery of targeted and successful clinical trials,” said Olivier Courrèges, CEO, Qynapse. “We receive imaging data from multiple sites in multiple countries, and it must be compliant, anonymized and secure. Judi Imaging checks all those needs and more.”
Qynapse is using Judi // Imaging to:
- Manage medical images and ensure accurate deployment globally
- Set compliant workflows
- Store and manage imaging data securely
“Qynapse is doing remarkable work with image analysis and machine learning technology in a quest to transform the diagnosis, prognosis and treatment of CNS diseases, and delivering standardized imaging protocols to its clients is critical to achieving this. That’s music to my ears,” said Abraham Gutman, president and CEO, AG Mednet. “The flexibility of using Judi makes so much sense as Qynapse takes in imaging data from sites around the world to help its clients measure drug efficacy.”


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The Achievable Dream 5-part series - the definitive guide on DVD for planning your motorcycle adventure. Get Ready! covers planning, paperwork, medical and many other topics! "Inspirational and Awesome!" See the trailer here!
Gear Up! is a 2-DVD set, 6 hours! Which bike is right for me? How do I prepare the bike? What stuff do I need - riding gear, clothing, camping gear, first aid kit, tires, maps and GPS? What don't I need? How do I pack it all in? Lots of opinions from over 150 travellers! "This DVD will save you a fortune!"See the trailer here!
So you've done it - got inspired, planned your trip, packed your stuff and you're on the road! This section is about staying healthy, happy and secure on your motorcycle adventure. And crossing borders, war zones or oceans!
On the Road! is 5.5 hours of the tips and advice you need to cross borders, break down language barriers, overcome culture shock, ship the bike and deal with breakdowns and emergencies."Just makes me want to pack up and go!" See the trailer here!
Tire Changing!Grant demystifies the black art of Tire Changing and Repair to help you STAY on the road! "Very informative and practical." See the trailer here!
Ladies on the Loose! For the first time ever, a motorcycle travel DVD made for women, by women! These intrepid women share their tips to help you plan your own motorcycle adventure. They also answer the women-only questions, and entertain you with amazing tales from the road! Presented by Lois Pryce, veteran solo traveller through South America and Africa and author of 'Lois on the Loose', and 'Red Tape and White Knuckles.'
"It has me all fired up to go out on my own adventure!" See the trailer here!
We're not a big multi-national company, just two people who love motorcycle travel and have grown a hobby into a full time job and a labour of love.
When you decide to become a Member, it helps directly support the site. You get additional privileges on the HUBB, access to the Members Private Store, and more to come as we roll out new systems. Of course, you get our sincere thanks, good karma and knowing you're helping to keep the motorcycle travel dream alive. :-)
Travel BooksMotorcycle and travel books to inspire and inform you!
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Horizons Unlimited presents!
Achievable Dream The definitive guide to planning your motorcycle adventure! This insanely ambitious 2-year project has produced an informative and entertaining 5-part, 18 hour DVD series. "The ultimate round the world rider's how-to DVD!" MCN UK.
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We reach a dedicated, worldwide group of real travellers, and are the only website focusing exclusively on long distance motorcycle travellers.
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Europe without a Carnet: Shipping a moto into Amsterdam
I just shipped my bike from Bangkok to Amsterdam and my freight forwarder in Amsterdam is saying that in order for me to clear customs that I need a carnet, I need to permantatly import the bike into Netherlands, or the bike needs to leave Netherlands via the same entry port if I wish to use a temporary import permit.
I do not have a carnet and I prefer to not get one as I understood that I did not need one for any of the countries that I visit.
Do any of you have experience with shipping into Europe without a carnet?
Customs is saying that they need proof that the bike leaves Netherlands and can't get it without a carnet.
were is your bike from ? i shiped my (uk) bike to amsterdam from south america and they just wanted me to convince them that my bike would not be staying in holland . i told them were i would be going and showed them a photo of my pannier with all the stickers on and they were happy with that . all the borders are open in europe so even if you told them that you will ship back out the same port they would never know if you just ride out of holland . you should not be needing a carnet.
If you travel to the Netherlands by car, motorbike or with a trailer with a valid number plate of the country where you live you do not have to report your arrival to Customs. In this case, you may take your car, motorbike and/or trailer/caravan across the border and use it in the Netherlands without having to pay taxes. If you are not a Dutch resident
If you are not a Dutch resident then you may use your car, motorbike, caravan or trailer in the Netherlands for a maximum period of 3 months without having to pay tax."
I think if you send and cite the above official Netherlands Customs website statement to your Amsterdam freight forwarder and NL Customs, that should be enough to clarify your situation.
It's not uncommon for seaport/ freight Customs (and freight forwarders) to assume that anything entering through a seaport or airport is business/ commercial goods, rather than "personally owned" [vehicles]; and, Netherlands Customs website does reference use of a Carnet for import of business goods....unless you are personally present to document that this vehicle is your personally-owned vehicle.
In other words, there may also be some confusion because you are not personally present with the bike in Amsterdam during the Customs import/ clearance process, to show your personal passport ID and vehicle ownership papers, but are having a freight forwarder do the import clearance on your behalf.
Get back to your Amsterdam freight forwarder, show him the NL website language and offer to send the freight forwarder any additional documents to prove the bike is a personally-owned vehicle.
I think I may have it worked out without having to pay anything other than handling fees. I"ll post details later, but the short version is my dutch friend (from the Dutchdangleberries.nl :: Home) made a bunch of phone calls and went back and forth with the main customs office, the airport customs office, and my forwarder.
Details to come once I see what happens here at 1pm!
I'm now in Kleve, Germany.. heading back to amsterdam in a couple of days, then Belguim, the Nürburgring, Frankfurt, Luxembourg, Switzerland, then south towards Spain until Santander when I take the ferry back to the UK and make my way east again towards the 'stans.
good work mate . was that 150 euro including a handling and unloading fee ? i paid 180 to get my bike off the ship ,out of the dock and clear customs about 10 months ago. the ocean freight was only 111 euro
Now that summer is here, get On the Road! Take 30% off the Achievable Dream - On the Road! 2-DVD set until August 31 only.
Our veteran travellers share their tips (and great stories) for staying healthy, happy and secure on your motorcycle adventure.
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Check it out at the HU Store! Remember to use Coupon Code 'ONTHEROAD' on your order when you checkout.
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domain: hobby


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January 24 is National Peanut Butter Day, a time to celebrate the protein-packed staple found in 94 percent of American homes. We’ll venture to say no other staple is as fun to celebrate as peanut butter! But, before you mark the occasion by spooning out some ‘crunchy’ for a simple snack or spreading ‘creamy’ over a slice of bread, Southern Peanut Growers encourages you to go all in on PB Day with delicious ideas from early morning to well into the evening.
For National Peanut Butter Day, we challenge you to reach for your favorite jar of peanut butter and enjoy it in as many forms as you can, all day long.
Here’s some inspiration for your celebration:
- Breakfast: Peanut Butter Donuts. Start the day with this delicious peanut butter and maple-flavored treat topped with candied peanuts.
- Lunch: Grilled PB & J. Rethink the traditional PB & J for lunch by layering in fruit, padding with peanut butter and heating on the griddle.
- Dinner: Beef Kabobs with Peanut Sauce. Add some sizzle to the evening by serving kabobs with peanut dipping sauce.
- Dessert: Peanut Butter Vanilla Bean Cake. Every celebration calls for cake! Enjoy this combination of PB, vanilla and great northern beans – candles optional.
- Kids’ beverage: Peanut Butter, Chocolate & Banana Milkshake. Blend up this delicious shake, and it will soon become a family favorite.
- Adult cocktail: Peanut Butter and Raspberry Delight. Just for the grown-ups, it’s time to mix up a new signature drink and make a toast to PB Day.
Surprise your friends with incredible peanut butter knowledge!
Did you know? About half of all the peanuts grown in the United States are used to make peanut butter. Runner peanuts – the variety mostly grown by farmers in Georgia, Alabama, Florida and Mississippi – are favored for peanut butter because of their strong peanut flavor and uniform size which makes for an even roast.
Other lesser-known peanut butter facts include:
- Peanut butter today is remarkably similar to that produced a century ago. To legally label the spread as peanut butter, it must contain a minimum of 90 percent peanuts with no artificial sweeteners, colors or preservatives.
- Peanut butter contains more than 30 essential nutrients and phytonutrients.
- Peanut butter plays a vital role in overcoming malnutrition and global hunger. Peanut butter is on the basic needs list for local food banks and January is a month of critical need in food banks. Special formulations of peanut-based therapeutic foods are saving lives around the world – visit Peanut Butter for the Hungry for more information.
- Peanuts are not actually nuts at all! They are legumes – in the same plant family as beans, peas and lentils.

domain: agronomy


Tilt and turn window mechanisms are different to standard windows. The movement instead of opening outwards, the tilt and turn will tilt in and swing in. It is unusual for tilt and turns to be installed into normal homes because of the windows opening in. This type of window is mainly used on 3rd floor or above (blocks of high rise flats) for safety of leaning out to close the window, and wind pressures whipping the window away from you.
The mechanism is manufactured using solid mild steel tested to BS1449 part 1, a major part of the window is the mechanism. All of Windows Plus Online mechanics have been tested to 30,000 cycles guarantee, if you open and closed your windows 4 times and day the hinge would last over 20 years.
The hinges have been tested to meet the requirements of BS 5588-1:190. All tilt and turn mechanisms are manufactured to a vent weight of 130kg capacity almost double the weight of a standard piece of glass. An additional feature by ordering with Windows Plus Online is that all side openers are fitted with Document B (see here) fire Safety to meet the 2006 edition. Part of the designer makes this easy to differentiate if you have achieved the relative window appropriate dimension, an F will appear within the digital drawing.
Below you will find the technical documentation which relates to the ProLinea handles.


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ADDIS ABABA, June 21 (Xinhua) -- Sudanese President Omar al-Bashir and Djiboutian President Ismail Omar Guelleh arrived in the Ethiopian capital Addis Ababa on Thursday for the South Sudan peace talks to end the more than four years of civil war.
In a press statement, Ethiopia's Ministry of Foreign Affairs (MoFA) said the two leaders who were received on arrival by Ethiopian Prime Minister Abiy Ahmed are expected to attend the 32nd meeting of the regional bloc IGAD that will focus on ending South Sudan's civil war.
On Wednesday, South Sudanese President Salva Kiir and his ex-deputy and leader of the main rebel group Riek Machar arrived in Ethiopia to attend the IGAD-sponsored peace talks dubbed as "the last big hope for peace" for the world's youngest nation.
IGAD's Council of Ministers summit earlier this month revealed a possibility of punitive measures against violators of the Cessation of Hostilities Agreement (CoHA) that was signed by South Sudan's warring factions in December 2017 in Addis Ababa.
South Sudan descended into a civil war in late 2013, and the conflict has created one of the fastest growing refugee crises in the world.
The UN estimates that about 4 million South Sudanese have been displaced internally and externally.

domain: politics


“We have given marijuana the status of medicine with none of the standards,” said one medical official.
As more and more patients turn to cannabis for pain relief in hopes of avoiding opioids, many doctors remain skeptical about what they see as an unproven and unregulated substance taking the place of a proven medication.
“We have given marijuana the status of medicine with none of the standards,” Stanford University psychiatrist Keith Humphreys told Pew Trusts.
New York, Illinois and Colorado now allow physicians to recommend cannabis instead of opioids for pain relief, while other states allow people with opioid use disorder to access a medical marijuana card.
Proponents of these measures, including Colorado Rep. Edie Hooton, say that there are few risks to cannabis, while opioids can be deadly.
“We’re talking about an alternative to managing symptoms to a narcotic, or to a pharmaceutical with severe side effects,” Hooton said.
Opponents Speak Out
However, medical professionals aren’t convinced. In Colorado, fewer than 2% of doctors have recommended cannabis to patients. Some doctors, like pain specialist Ken Finn, say the policy is foolish.
Finn said that the new bill is “the worst policy I’ve ever seen,” and that the interest in it “tells me what lengths people will go to to try to get some relief.”
Ziva Cooper, research director of the UCLA Cannabis Research Initiative, said that studies have shown that cannabis has promise as a pain reliever. However, most of those studies were done using specific compounds in tightly-regulated circumstances.
In addition, most of the study participants were on other pain medications, too. The results may be less predictable with bud from dispensaries.
Cooper said, “We don’t know yet how effective cannabis and cannabinoids are for pain when they’re administered by themselves. We also don’t know how cannabis and cannabinoids stack up next to opioids for pain relief.”
Cooper added that powerful personal stories can sway lawmakers and public opinion, but they do little to prove the effectiveness of cannabis scientifically.
“It’s more based on anecdotes—people reporting that they can wean themselves off opioids,” Cooper said.
Robert Valuck, executive director of the Colorado Consortium for Prescription Drug Abuse Prevention, said that the benefits of cannabis haven’t been proven to outweigh the risks.
“The science is thin,” he said. “We’re seeing increases in what people call cannabis use disorder.”
Many doctors, including Children’s Hospital Colorado’s Jennifer Hagman, cannabis has not yet been proven as good medicine.
“There’s no condition right now where I feel there’s enough information for me to recommend marijuana to a family for a child or an adolescent,” she said.


Label: Baroque Records
Release date: 2012-10-22
Catalog number: BARQ136
Well, we have a bit of a monster package up next on Baroque.. from the ever amazing Beat Factory, and featuring the deep vocal tones of Kamaka Pahinui.
The original is a classy deep rolling vibe with Kamakas vocals gliding effortlessly through.
Bobby Deeps mixes lift the pace, with rapid percs, and buzzing strings & synths, and he has very kindly provided both vocal & dub versions
Big Al himself has also provided a Vocal & Dub version, which take a more funky US house style route, with classic chords & bassline leading the way
Glender gives the track an injection of tough drums, with a tribal tech take on things
And finally Dj Dextro also gives the track a little extra punchy with his stuttering drums leading the way, before a dark progressive vibe takes over.


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Deep Blue Sound Review: Searching for Orcas and Longing for Community
In Abe Kooglers latest play, melancholy islanders try to band together to investigate where their beloved orcas have gone.
When a group of friends and neighbors on a Pacific Northwest island go caroling, they create an amusing cacophony: Warbling in mismatched tones and keys, they stand next to each other but not together. So goes the community in Abe Kooglers new play, Deep Blue Sound friendly and supportive but made up of individuals who cant quite connect.
Although this is an ensemble show, part of Clubbed Thumbs popular incubator series Summerworks, and one with fairly evenly distributed narratives (though most are sketchily drawn because of the number of characters crammed into a concise 90 minutes), a woman named Ella emerges as the emotional center.
Partly this is because she has the most poignant story: She is dying of cancer and has decided to make use of Washington States Death With Dignity Act. And partly its because sad, scared, angry Ella is played by the brilliant Maryann Plunkett, who can turn the simple act of staring into space into a devastating insight.

domain: artistic


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West Melbourne, Victoria
West Melbourne is a suburb in Melbourne, Victoria, Australia. It is part of the local government area of the City of Melbourne.
West Melbourne is situated on the Melbourne side of the Brisbane Water immediately south of Melbourne’s CBD. According to the 2016 census, there are 11,682 people in West Melbourne. West Melbourne is bounded by Melbourne’s central business district to the north and west, Kingsville to the north-east, Collingwood to the east and Port Melbourne to the south.
West Melbourne has plenty of activities to do. From historical sites to shopping, there’s something for everybody. A popular activity is the observation wheel. The wheel is 42 meters tall and has 42 air-conditioned gondolas. This wheel has 42 viewing decks that face west. The observation wheel is at the West Melbourne station, located on Victoria Drive. It is open from 9am to 11pm daily.
The Activities at West Melbourne (AWM), located in Melbourne, Australia, is a place for people of all ages to develop their skills and interests. The Activities in West Melbourne offers classes for adults and children including yoga, art, dance, cooking, dance, crafts, games, and holiday programs. The Activities in West Melbourne also offers activities for children with special needs and for families who speak English as a second language. The Activities at West Melbourne offers adult classes in cooking, dance, crafts, and games. Children are entertained by the music and art programs. The Activities at West Melbourne offers holiday programs for children in kindergarten through fifth grade.
When visiting Melbourne, there are a variety of places to visit. These places include markets, theme parks, art galleries, and beaches. Some of these places are family- and children-friendly, while others can be too rowdy for younger children.
West Melbourne is a quaint beachside town with high-end boutiques, sprawling waterfront homes, and a bedazzled downtown area. While West Melbourne is a beautiful community, it isn’t always the easiest place to navigate during downtime. So whether you are visiting or a resident, check out these top things to do when you’re in West Melbourne.
Staying in West Melbourne, there are various things to do. For people looking for exciting activities, they can visit the beach. Other exciting activities include going to amusement parks, historic sites, and visiting shopping centers.
Let’s explore West Melbourne!


Forces of Valor 80034 German 88mm Flak 36/37 Anti-Aircraft Gun with Trailer - Unidentified Unit, Stalingrad, 1942 (1:32 Scale)
"We must do everything we can to promote anti-tank defense, and work just as hard to guarantee successful counter-attacks through the instrument of powerful tank forces of our own."
- Major-General Heinz Guderian, "Achtung Panzer!"
Originally developed as an anti-aircraft gun, the 8.8cm FLugzeugAbwehrKanone ("Flak") was first employed in the anti-tank gun role in 1936, when the German Condor Legion was testing out its equipment during the Spanish Civil War. Amazingly, German war planners had designed the gun as an AA weapon with a heavy cruciform platform and central fire control operation, not as a multi-purpose anti-tank gun with proper anti-tank sights. Nevertheless, its capability was seen and quietly noted by commanders operating in the field. While the gun was occasionally used in the anti-tank gun role during the Polish and French campaigns, it wasn't until the Afrika Korps joined battle in Cyrenaica with the British Eighth Army that the "88" really showed its prowess as a tank killer. Here the tactical situation was such that it was possible to deploy the guns in their anti-aircraft role in positions that would allow them to be re-trained as anti-tank guns. Moreover their range and penetrating power enabled their crews to dispose of British tanks long before the enemy was close enough to engage the guns with their own two- or six-pounder guns.
Unimax' 1:32 scale rendition of the flak gun comes with four wheels and a tow hook so that it can be attached to the recently announced Sd. Kfz. 7/1 prime mover with FlaK gun. Both sets of wheels can be removed so that the gun, mounted on a cruciform platform, can be set up in a firing position. Gun elevates and fully traverses. Also comes with five crewmen.
Length: 8 inches
Width: 3 inches
Release Date: July 2006
Historical Account: "Here is Stalingrad" - Under the code name Operation Uranus, the Russians launched their offensive to pinch off the German salient in and around Stalingrad on November 19th, 1942. The attacks fell on weakly held sectors north and south of the city, which were manned mainly by Romanian forces in the north and by a mixture of Romanians and units of the 4th Panzer Army in the south.
Despite the sudden attacks, decisive action by the German leadership could have saved the situation.
If General von Paulus, head of the 6th Armee, had acted boldly, sending some units north and south to hold the Russians at bay while withdrawing the bulk of his force from the ruins of Stalingrad, then much of his army would have been saved.
On the 21st, Paulus recommended to Von Weichs at the Army Group level, that he be allowed to withdraw the endangered Army to an arc on the Don and the Chir Rivers. Having initially supported such an immediate breakout, Von Weichs failed to act and the same evening passed on an instruction from OKH that Paulus was to hold the position on the Volga at all costs and that countermeasures to restore the situation were being implemented by the Fuhrer. In the meantime the Army would be supplied by air.
Senior officers under Paulus doubted if the required scale of an airlift could be achieved during a Russian winter. General Fiebig informed Paulus and his Chief of Staff Schmidt, 'Supplying a whole Army by air? Impossible! I warn you against entertaining such exaggerated expectations!' All of his Corps commanders argued for a breakout before the Red Army was able to consolidate its positions. General Hans Hube told Paulus: 'A breakout is our only chance.' Paulus remarks in his memoirs that 'In this situation, my acting against orders, particularly since I could not responsibly oversee the overall situation, would have pulled the operational foundation from under the supreme command. Such a course of action, against the plans of the overall leadership, leads to anarchy in the command structure.' However, perhaps the uniqueness of the situation required someone to take such a course of action. In addition Paulus was suffering continuing dysentery and a general rundown in health, but despite being urged to take sick leave in Germany, he refused.
On December 17th, Von Manstein gave the order for Paulus to break out towards the forces of LVII Panzer Corps, which had fought its way to within 30 miles of the pocket. Hitler, however, ordered that he was expected to both break out and establish a supply corridor, whilst still holding his positions within the city. Paulus rejected the order, arguing that his men were too weak to make such a move and that his vehicles had insufficient fuel to reach the relieving forces. On the 19th, Von Manstein sent an emissary, Major Eismann, into the pocket by air to urge Paulus to do all he could to attempt a break-out and meet the relieving force. It was the last chance for Paulus, but in the end he refused to move, quoting Hitler's orders that the present positions at Stalingrad should be held. He told Eismann, 'Thunderclap, (the code name for a complete breakout) is a catastrophic solution that should be avoided if at all possible.' From that point onward, their fate was sealed.