1. A method of screening for an inhibitor of an active KIT tyrosine kinase receptor in a cell comprising:
(a) contacting a cell comprising an active KIT tyrosine kinase receptor with a candidate inhibitor; and
(b) detecting KIT activity by using a phosphotyrosine-specific antibody to determine the amount of KIT tyrosine phosphorylation in the presence and in the absence of said inhibitor,
wherein a decrease in KIT tyrosine phosphorylation in the presence of said candidate inhibitor in comparison to the KIT tyrosine phosphorylation in its absence identifies the candidate inhibitor as a KIT inhibitor.
2. The method according to claim 1 wherein said KIT tyrosine kinase receptor is constitutively active.
3. The method according to claim 2 wherein the constitutively active KIT tyrosine kinase receptor has a mutation in the phosphotransferase tyrosine kinase domain.
4. The method according to claim 3 wherein the mutation is in the activation loop of the KIT tyrosine kinase domain.
5. The method according to claim 2 wherein the constitutively active KIT tyrosine kinase receptor has a mutation in the juxtamembrane domain.
6. The method according to claim 5 wherein the mutation is a deletion of amino acids 550-558 of SEQ ID NO:2.
7. The method according to claim 2 wherein the constitutively active KIT tyrosine kinase receptor has a mutation in the extracellular domain.
8. The method according to claim 7 wherein the mutation is a substitution mutation of AY502-503 in SEQ ID NO: 2.
9. The method according to claim 1 wherein the KIT tyrosine kinase receptor comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:2, 4, and 6
10. The method according to claim 9 wherein the KIT tyrosine kinase receptor comprises the amino acid sequence set forth in SEQ ID NO:2.
11. The method according to claim 4 wherein the KIT tyrosine kinase receptor comprises a substituted amino acid at position 816 of SEQ ID NO:2.
12. The method according to claim 11 wherein the substituted amino acid is selected from the group consisting of Valine, Histidine, Phenylalanine, Tyrosine, or Glycine.
13. The method according to claim 12 wherein the substituted amino acid is Valine.
14. The method according to claim 1 wherein the cell comprising the active KIT tyrosine kinase receptor is bound to a solid support.
15. The method according to claim 14 further comprising detecting cellular morphology, cytoskeletal rearrangement, or nuclear staining of said cell in the presence and in the absence of the candidate inhibitor.
16. The method according to claim 1 wherein the phosphotyrosine-specific antibody is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, a chimeric antibody, a humanized antibody, a single-chain antibody, and an antibody fragment.
17. The method according to claim 16 wherein the phosphotyrosine-specific antibody is pY823.
18. The method according to claim 16 wherein the phosphotyrosine-specific antibody binds to an auto-phosphorylation site of said KIT tyrosine kinase receptor.
19. The method according to claim 16 wherein the phosphotyrosine-specific antibody is detectably labeled.
20. The method according to claim 19 wherein the detectable label is a fluorophore or a radiolabel.
21. The method according to claim 1 wherein the detecting step comprises flow cytometry.
22. The method according to claim 1 wherein the active KIT tyrosine kinase receptor is expressed from a heterologous vector.
23. The method according to claim 1 wherein the active KIT tyrosine kinase receptor is endogenous to the cell.
24. The method according to claim 23 wherein the cell is isolated from a tumor.
25. The method according to claim 24 wherein the tumor is selected from the group consisting of a mast cell leukemia, mast cell sarcoma, a germ cell tumor, a gastrointestinal stromal tumor, an acute myeloid leukemia (AML), a chronic myeloid leukemia (CML), a chronic myelomonocytic leukemia (CMML), a sinonasal lymphoma, an ovarian tumor, a breast tumor, a small lung cell carcinoma, a neuroblastoma, and a melanoma.
26. A kit for screening for an inhibitor of active KIT tyrosine kinase receptor comprising a phosphotyrosine antibody and instruction for performing a screen according to claim 1 for said inhibitor.
27. A method of treating a condition selected from the group consisting of mastocytosis, mast cell leukemia, mast cell sarcoma, a germ cell tumor, a gastrointestinal stromal tumor, an acute myeloid leukemia (AML), a chronic myeloid leukemia (CML), a chronic myelomonocytic leukemia (CMML), a sinonasal lymphoma, an ovarian tumor, a breast tumor, a small lung cell carcinoma, a neuroblastoma, and a melanoma, comprising administering an inhibitor identified according to the method of claim 1.
28. A method for designing a treatment regimen for a patient with a mast cell disorder comprising:
(a) isolating a cell from said patient, wherein said cell comprises an active KIT tyrosine kinase receptor;
(b) contacting said cell with a KIT inhibitor identified by the method of claim 1;
(c) detecting KIT activity in said cell using a phosphotyrosine-specific antibody to determine the amount of KIT tyrosine phosphorylation in the presence and in the absence of said inhibitor; and
(d) designing a treatment regimen for said patient which includes administration of the KIT inhibitor that specifically inhibits KIT activity in said patient.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A stent comprising:
a body portion having an exterior surface defined thereon, said body portion being expandable from a first position, wherein said body portion is sized for insertion into said lumen, to a second position, wherein at least a portion of said stent is in contact with said lumen wall, wherein the body portion is formed of an alloy including about 11 to about 18 wt. % chromium, about 5 to about 12 wt. % nickel, at least about 15 wt. % iron, and about 5 to about 50 wt. % platinum.
2. The stent as recited in claim 1, wherein the alloy further comprises up to about 3.0 wt. % molybdenum.
3. The stent as recited in claim 1, wherein the alloy further comprises carbon in a concentration of less than about 0.030 wt. %.
4. The stent as recited in claim 1, wherein the stent is an intravascular stent adapted for treating a vessel wall, the body portion being
a generally tubular structure having an exterior surface defined by a plurality of interconnected struts having interstitial spaces therebetween, said generally tubular structure expandable from a first position, wherein said stent is sized for intravascular insertion, to a second position, wherein at least a portion of said stent contacts said vessel wall, said expanding of said generally tubular structure accommodated by flexing and bending of said interconnected struts, wherein the generally tubular structure is formed from the alloy.
5. The stent as recited in claim 4, wherein the alloy further comprises up to about 3.0 wt. % molybdenum.
6. The stent as recited in claim 4, wherein the alloy further comprises carbon in a concentration of less than about 0.030 wt. %.
7. The stent as recited in claim 1, wherein the stent has a proximal end and a distal end, wherein the stent comprises:
a first undulating band comprising a series of alternating first peaks and first troughs, the first peaks oriented in a distal direction, the first troughs oriented in a proximal direction, the first undulating band having a first wavelength and a first amplitude; and
a second undulating band comprising a series of alternating second peaks and second troughs, the second peaks oriented in a distal direction, the second troughs oriented in a proximal direction, the second undulating band having a second wavelength and a second amplitude, the second amplitude different from the first amplitude, the second wavelength different from the first wavelength.
8. The stent as recited in claim 7, wherein the stent has a thickness that is less than about 0.005 inches.
9. The stent as recited in claim 7, wherein the alloy further comprises up to about 3.0 wt. % molybdenum.
10. The stent as recited in claim 7, wherein the alloy further comprises carbon in a concentration of less than about 0.030 wt. %.
11. A biocompatible composition having a greater absorption of X-ray radiation than type 316 stainless, said biocompatible composition comprising:
between about 11.0 weight percent and about 18.0 weight percent Chromium;
between about 5.0 weight percent and about 12.0 weight percent Nickel;
at least about 15 weight percent Iron; and
between about 2.0 weight percent and about 50.0 weight percent Platinum.
12. A composition as recited in claim 11, wherein said composition further comprises Molybdenum and the weight percent of said Molybdenum is between about 2.0 and about 3.0.
13. A composition as recited in claim 11, wherein said composition further comprises Carbon and said Carbon is less than about 0.030 weight percent.
14. A composition as recited in claim 11, further comprising Manganese in an amount that is greater than zero and less than about 2.0 weight percent.
15. A composition as recited in claim 11, wherein said composition further comprises Phosphorus and said Phosphorus is less than about 0.008 weight percent.
16. A composition as recited in claim 11, wherein said composition further comprises Sulfur and said Sulfur is less than about 0.004 weight percent.
17. A composition as recited in claim 11, further comprising Silicon in an amount that is greater than zero and less than about 0.75 weight percent.
18. An intravascular biocompatible composition having a greater absorption of X-ray radiation than type 316 stainless, said intravascular biocompatible composition comprising:
between about 11.0 weight percent and about 18.0 weight percent Chromium;
between about 5.0 weight percent and about 12.0 weight percent Nickel;
at least about 15 weight percent Iron;
between about 2.0 weight percent and about 3.0 weight percent Molybdenum; and
between about 2.0 weight percent and about 50.0 weight percent Platinum.