,patent_number,decision,title,abstract,claims,background,summary,description,cpc_label,ipc_label,filing_date,patent_issue_date,date_published,examiner_id
0,14908945,ACCEPTED,WNT SIGNALING INHIBITOR,"A Wnt signaling inhibitor which comprises, as an active ingredient, a fused-ring heterocyclic compound represented by the following formula (IA) or a pharmaceutically acceptable salt thereof, and the like are provided: (wherein, n1A represents 0 or 1; n2A and n3A may be the same or different, and each represents 1 or 2; ROA represents optionally substituted aryl or the like; R2A represents a hydrogen atom or the like; R3A represents an optionally substituted aromatic heterocyclic group or the like; X1A, X2A, X3A and X4A each represent CH or the like; Y1A represents CH2 or the like; Y2A represents N or the like; and LA represents CH2 or the like).","1: A method of inhibiting Wnt signaling, comprising administering an effective amount of a fused-ring heterocyclic compound represented by formula (IA) or a pharmaceutically acceptable salt thereof to a subject in need thereof: wherein: n1A represents 0 or 1; n2A and n3A may be the same or different, and each represents 1 or 2; ROA represents a hydrogen atom, an optionally substituted aryl, an optionally substituted aromatic heterocyclic group, or an optionally substituted aliphatic heterocyclic group; R2A represents a hydrogen atom or hydroxy; R3A represents an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; X1A, X2A, X3A, and X4A may be the same or different, and each represents N or CR4A; each R4A independently represents a hydrogen atom, a lower alkyl, cyano, a halogen, hydroxy, a lower alkoxy, a lower alkanoyl, or a lower alkylsulfonyl; Y1A represents CH2 or C(═O); Y2A represents CH or N; and LA represents CH2 or NH. 2: A fused-ring heterocyclic compound represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein: n1 represents 0 or 1; n2 and n3 may be the same or different, and each represents 1 or 2; R1 represents an optionally substituted aryl, an optionally substituted aromatic heterocyclic group, or an optionally substituted aliphatic heterocyclic group; R2 represents a hydrogen atom or hydroxy; R3 represents an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; X1, X2, X3, and X4 may be the same or different, and each represents N or CR4; each R4 independently represents a hydrogen atom, a lower alkyl, cyano, a halogen, hydroxy, a lower alkoxy, a lower alkanoyl, or a lower alkylsulfonyl; Y1 represents CH2 or C(═O); Y2 represents CH or N; and L represents CH2 or NH. 3: The compound or pharmaceutically acceptable salt according to claim 2, wherein n2 and n3 are each 2. 4: The compound or pharmaceutically acceptable salt according to claim 2, wherein Y2 is N, and L is CH2. 5: The compound or pharmaceutically acceptable salt according to claim 2, wherein Y1 is CH2. 6: The compound or pharmaceutically acceptable salt according to claim 2, wherein n1 is 0. 7: The compound or pharmaceutically acceptable salt according to claim 2, wherein R1 is (i) an optionally substituted phenyl, or (ii) an optionally substituted pyridyl, pyridonyl, or pyrimidinyl. 8: The compound or pharmaceutically acceptable salt according to claim 2, wherein R1 is: a group represented by formula (a1): wherein R5 represents a hydrogen atom, a C1-10 alkyl which may be substituted with hydroxy, a C1-10 alkoxycarbonyl, a C2-11 alkanoyl, a C1-10 alkylsulfonyl, a —NR6aR6b wherein R6a and R6b may be the same or different, and each represents a hydrogen atom, a C2-11 alkanoyl, or a C1-10 alkyl, —CONR6cR6d wherein R6c and R6d may be the same or different, and each represents a hydrogen atom or a C1-10 alkyl, —SO2NR6eR6f wherein R6e and R6f may be the same or different, and each represents a hydrogen atom or a C1-10 alkyl, a halogen, cyano, carboxy, or nitro; and Z1, Z2, Z3, and Z4 may be the same or different, and each represents N or CR7 wherein R7 represents a hydrogen atom, carboxy, or a halogen; or a group represented by the following formula (a2): wherein R5, Z1 and Z4 are as defined above. 9: The compound or pharmaceutically acceptable salt according to claim 8, wherein R5 is cyano, —CONH2, or —SO2NH2. 10: The compound or pharmaceutically acceptable salt according to claim 8, wherein R5 is cyano. 11: The compound or pharmaceutically acceptable salt according to claim 8, wherein R7 is a hydrogen atom or a fluorine atom. 12: The compound or pharmaceutically acceptable salt according to claim 2, wherein R3 is an optionally substituted aromatic heterocyclic group. 13: The compound or pharmaceutically acceptable salt according to claim 12, wherein the aromatic heterocyclic group is a bicyclic aromatic heterocyclic group. 14: The compound or pharmaceutically acceptable salt according to claim 12, wherein the aromatic heterocyclic group is quinazolinyl. 15: The compound or pharmaceutically acceptable salt according to claim 2, wherein R3 is an optionally substituted aliphatic heterocyclic group. 16: A pharmaceutical composition, comprising, as an active ingredient, the compound or pharmaceutically acceptable salt according to claim 2. 17-21. (canceled) 22: A method of inhibiting Wnt signaling, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 2 to a subject in need thereof. 23: The method according to claim 22, wherein inhibiting Wnt signaling comprises inhibiting Wnt signaling by tankyrase inhibition. 24: A method of treating a disease associated with Wnt signaling, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 2 to a subject in need thereof. 25: The method according to claim 24, wherein the disease is selected from the group consisting of cancer, pulmonary fibrosis, fibromatosis, and osteoarthritis. 26-35. (canceled) 36: A method of preventing a disease associated with Wnt signaling, comprising administering an effective amount of the compound or pharmaceutically acceptable salt according to claim 2 to a subject in need thereof. 37: The method according to claim 36, wherein the disease is selected from the group consisting of cancer, pulmonary fibrosis, fibromatosis, and osteoarthritis.","<SOH> BACKGROUND ART <EOH>In chemotherapy for cancer, various antitumor agents such as microtubule agonists such as taxanes, Vinca alkaloids and the like; topoisomerase inhibitors; alkylating agents and the like are used. These antitumor agents have various problems, for example, the types of cancer for which these antitumor agents can be used are limited, adverse effects such as myelotoxicity, neuropathy and the like are observed, drug-resistant tumors emerge, and the like (Nature Reviews Cancer 2003, 3, 502). Recently, a molecular targeted antitumor agent showing effectiveness against a specific type of cancer has been reported. Imatinib or gefitinib, which is a tyrosine kinase inhibitor, shows effectiveness also in chronic myeloid leukemia or non-small-cell lung cancer against which existing antitumor agents are ineffective. However, the types of cancer against which the agent shows effectiveness are limited, and also, a case where acquisition of resistance is observed has been reported (Nature Reviews Drug Discovery 2004, 3, 1001). Therefore, a novel antitumor agent in which such problems are improved has been demanded. Wnt/β-catenin signaling is an important pathway associated with development, differentiation, and maintenance of living organisms (Nature Reviews Drug Discovery 2006, 5, 997). On the other hand, it is known that abnormal Wnt/β-catenin signaling is also associated with various diseases such as cancer and the like. In the absence of Wnt signaling, cytoplasmic β-catenin is kept at a low level. Axin and Adenomatous Polyposis Coli (APC) form a scaffold to accelerate the phosphorylation of intracellular β-catenin by casein kinase 1α (CK1α) and glycogen synthase kinase 3β (GSK3β). The phosphorylated β-catenin is ubiquitinated and degraded by proteasome. Due to this, β-catenin is kept at a low level, and therefore cannot play a role as a transcriptional activator. In the presence of a Wnt ligand, when the Wnt ligand binds to a Frizzled (Fzd) receptor and a low-density lipoprotein receptor-related protein (LRP) receptor, an Axin-APC-CK1α-GSK3β complex is inactivated through Deshevelled (Dv1). Dephosphorylated β-catenin is stable and is accumulated in cells and transferred to the nucleus, and then binds to a T-cell factor (Tcf)/lymphoid enhancer factor (Lef) family transcription factor. This transcription factor complex induces the transcriptional activation of various target genes associated with proliferation, survival, and differentiation of cells. Abnormal activation of Wnt/β-catenin signaling has been reported in various tumor tissues. The activation of Wnt/β-catenin signaling in a tumor is associated with a gene mutation of a molecule constituting this signaling or an increase or decrease in the expression level of a gene product thereof (Nature Reviews Drug Discovery 2006, 5, 997, Nature Reviews Cancer 2008, 8, 387). For example, in large bowel cancer and familial adenomatous polyposis coli , an APC gene loss-of-function mutation has been reported. In large bowel cancer, hepatocellular carcinoma, hepatoblastoma, and medulloblastoma, an Axin gene loss-of-function mutation has been reported. In large bowel cancer, stomach cancer, hepatocellular carcinoma, hepatoblastoma, Wilms' tumor, ovarian cancer, and pancreatic cancer, a β-catenin gene gain-of-function mutation has been reported. In large bowel cancer, breast cancer, melanoma, head and neck cancer, non-small-cell lung cancer, stomach cancer, mesothelioma, and pancreatic cancer, an increase in the expression of a Wnt ligand has been reported. In large bowel cancer, breast cancer, head and neck cancer, stomach cancer, synovial sarcoma, and pancreatic cancer, an increase in the expression of a Fzd receptor has been reported. In mesothelioma, non-small-cell lung cancer, and cervical cancer, an increase in the expression of a Dvl family member has been reported. In large bowel cancer, breast cancer, stomach cancer, mesothelioma, non-small-cell lung cancer, prostate cancer, esophageal cancer, and leukemia, a decrease in the expression of a secreted frizzled-related protein (SFRP) family member, which is a Wnt ligand inhibitory factor, has been reported. In large bowel cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, and mesothelioma, a decrease in the expression of a Wnt inhibitory factor (WIF) family member has been reported. The inhibition of Wnt/β-catenin signaling inhibits the proliferation of a cancer cell line in which Wnt/β-catenin signaling is activated in this manner (Cell 2002, 111, 241, Oncogene 2005, 24, 3054, Neoplasia 2004, 6, 7, Clinical Cancer Research 2003, 9, 1291, Cancer Research 2004, 64, 5385, Cancer Cell 2004, 5, 91, Proceedings of the National Academy of Sciences of the U.S. Pat. No. 2,004,101, 12682). Therefore, a molecule that inhibits Wnt/β-catenin pathway is considered to be promising as an antitumor agent. There has been a report that diseases other than cancer including pulmonary fibrosis, fibromatosis, and osteoarthritis are associated with Wnt/β-catenin signaling (The American Journal of Pathology 2003, 162, 1393, Proceedings of the National Academy of Sciences of the United States of America 2002, 99, 6973, Proceedings of the National Academy of Sciences of the U.S. Pat. No. 2,004,101, 9757). Therefore, a molecule that inhibits Wnt/β-catenin pathway is expected to be useful as a therapeutic agent in these fields. As a compound that inhibits Wnt/β-catenin signaling, a tankyrase inhibitor has been reported (Nature 2009, 461, 614). Tankyrase belongs to the family of poly-(ADP-ribose) polymerases (PARP), and is also known as “PARP5” (Nature Reviews Molecular Cell Biology 2006, 7, 517). It has been reported that tankyrase binds to Axin which is associated with the degradation of cytoplasmic 3-catenin to perform poly-ADP ribosylation, thereby accelerating the degradation of Axin (Nature 2009, 461, 614). It has been reported that a tankyrase inhibitor accelerates the degradation of β-catenin by stabilizing Axin and inhibits Wnt/β-catenin pathway, thereby inhibiting the proliferation of a cancer cell line in which Wnt/β-catenin signaling is activated (Nature 2009, 461, 614). Therefore, such a tankyrase inhibitor is expected to be useful as a therapeutic agent for a disease in which Wnt/β-catenin signaling is activated as described above. On the other hand, it is known that a compound represented by the following formula (A) has an adenosine uptake activity (patent document 1). It is also known that a compound represented by the following formula (B) has a cardiotonic activity (non-patent document 1). As a compound having a Wnt pathway inhibitory activity, a compound represented by the following formula (C) (non-patent document 2) is known. As a compound having a tankyrase inhibitory activity, a compound represented by the following formula (D) (non-patent document 3), a compound represented by the following formula (E) (non-patent document 4), and the like are known.",<SOH> SUMMARY OF INVENTION <EOH>,"TECHNICAL FIELD The present invention relates to a fused-ring heterocyclic derivative or a pharmaceutically acceptable salt thereof, which has a Wnt signaling inhibitory activity, and is useful as a therapeutic and/or preventive agent for, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like, and the like. BACKGROUND ART In chemotherapy for cancer, various antitumor agents such as microtubule agonists such as taxanes, Vinca alkaloids and the like; topoisomerase inhibitors; alkylating agents and the like are used. These antitumor agents have various problems, for example, the types of cancer for which these antitumor agents can be used are limited, adverse effects such as myelotoxicity, neuropathy and the like are observed, drug-resistant tumors emerge, and the like (Nature Reviews Cancer 2003, 3, 502). Recently, a molecular targeted antitumor agent showing effectiveness against a specific type of cancer has been reported. Imatinib or gefitinib, which is a tyrosine kinase inhibitor, shows effectiveness also in chronic myeloid leukemia or non-small-cell lung cancer against which existing antitumor agents are ineffective. However, the types of cancer against which the agent shows effectiveness are limited, and also, a case where acquisition of resistance is observed has been reported (Nature Reviews Drug Discovery 2004, 3, 1001). Therefore, a novel antitumor agent in which such problems are improved has been demanded. Wnt/β-catenin signaling is an important pathway associated with development, differentiation, and maintenance of living organisms (Nature Reviews Drug Discovery 2006, 5, 997). On the other hand, it is known that abnormal Wnt/β-catenin signaling is also associated with various diseases such as cancer and the like. In the absence of Wnt signaling, cytoplasmic β-catenin is kept at a low level. Axin and Adenomatous Polyposis Coli (APC) form a scaffold to accelerate the phosphorylation of intracellular β-catenin by casein kinase 1α (CK1α) and glycogen synthase kinase 3β (GSK3β). The phosphorylated β-catenin is ubiquitinated and degraded by proteasome. Due to this, β-catenin is kept at a low level, and therefore cannot play a role as a transcriptional activator. In the presence of a Wnt ligand, when the Wnt ligand binds to a Frizzled (Fzd) receptor and a low-density lipoprotein receptor-related protein (LRP) receptor, an Axin-APC-CK1α-GSK3β complex is inactivated through Deshevelled (Dv1). Dephosphorylated β-catenin is stable and is accumulated in cells and transferred to the nucleus, and then binds to a T-cell factor (Tcf)/lymphoid enhancer factor (Lef) family transcription factor. This transcription factor complex induces the transcriptional activation of various target genes associated with proliferation, survival, and differentiation of cells. Abnormal activation of Wnt/β-catenin signaling has been reported in various tumor tissues. The activation of Wnt/β-catenin signaling in a tumor is associated with a gene mutation of a molecule constituting this signaling or an increase or decrease in the expression level of a gene product thereof (Nature Reviews Drug Discovery 2006, 5, 997, Nature Reviews Cancer 2008, 8, 387). For example, in large bowel cancer and familial adenomatous polyposis coli, an APC gene loss-of-function mutation has been reported. In large bowel cancer, hepatocellular carcinoma, hepatoblastoma, and medulloblastoma, an Axin gene loss-of-function mutation has been reported. In large bowel cancer, stomach cancer, hepatocellular carcinoma, hepatoblastoma, Wilms' tumor, ovarian cancer, and pancreatic cancer, a β-catenin gene gain-of-function mutation has been reported. In large bowel cancer, breast cancer, melanoma, head and neck cancer, non-small-cell lung cancer, stomach cancer, mesothelioma, and pancreatic cancer, an increase in the expression of a Wnt ligand has been reported. In large bowel cancer, breast cancer, head and neck cancer, stomach cancer, synovial sarcoma, and pancreatic cancer, an increase in the expression of a Fzd receptor has been reported. In mesothelioma, non-small-cell lung cancer, and cervical cancer, an increase in the expression of a Dvl family member has been reported. In large bowel cancer, breast cancer, stomach cancer, mesothelioma, non-small-cell lung cancer, prostate cancer, esophageal cancer, and leukemia, a decrease in the expression of a secreted frizzled-related protein (SFRP) family member, which is a Wnt ligand inhibitory factor, has been reported. In large bowel cancer, breast cancer, prostate cancer, lung cancer, bladder cancer, and mesothelioma, a decrease in the expression of a Wnt inhibitory factor (WIF) family member has been reported. The inhibition of Wnt/β-catenin signaling inhibits the proliferation of a cancer cell line in which Wnt/β-catenin signaling is activated in this manner (Cell 2002, 111, 241, Oncogene 2005, 24, 3054, Neoplasia 2004, 6, 7, Clinical Cancer Research 2003, 9, 1291, Cancer Research 2004, 64, 5385, Cancer Cell 2004, 5, 91, Proceedings of the National Academy of Sciences of the U.S. Pat. No. 2,004,101, 12682). Therefore, a molecule that inhibits Wnt/β-catenin pathway is considered to be promising as an antitumor agent. There has been a report that diseases other than cancer including pulmonary fibrosis, fibromatosis, and osteoarthritis are associated with Wnt/β-catenin signaling (The American Journal of Pathology 2003, 162, 1393, Proceedings of the National Academy of Sciences of the United States of America 2002, 99, 6973, Proceedings of the National Academy of Sciences of the U.S. Pat. No. 2,004,101, 9757). Therefore, a molecule that inhibits Wnt/β-catenin pathway is expected to be useful as a therapeutic agent in these fields. As a compound that inhibits Wnt/β-catenin signaling, a tankyrase inhibitor has been reported (Nature 2009, 461, 614). Tankyrase belongs to the family of poly-(ADP-ribose) polymerases (PARP), and is also known as “PARP5” (Nature Reviews Molecular Cell Biology 2006, 7, 517). It has been reported that tankyrase binds to Axin which is associated with the degradation of cytoplasmic 3-catenin to perform poly-ADP ribosylation, thereby accelerating the degradation of Axin (Nature 2009, 461, 614). It has been reported that a tankyrase inhibitor accelerates the degradation of β-catenin by stabilizing Axin and inhibits Wnt/β-catenin pathway, thereby inhibiting the proliferation of a cancer cell line in which Wnt/β-catenin signaling is activated (Nature 2009, 461, 614). Therefore, such a tankyrase inhibitor is expected to be useful as a therapeutic agent for a disease in which Wnt/β-catenin signaling is activated as described above. On the other hand, it is known that a compound represented by the following formula (A) has an adenosine uptake activity (patent document 1). It is also known that a compound represented by the following formula (B) has a cardiotonic activity (non-patent document 1). As a compound having a Wnt pathway inhibitory activity, a compound represented by the following formula (C) (non-patent document 2) is known. As a compound having a tankyrase inhibitory activity, a compound represented by the following formula (D) (non-patent document 3), a compound represented by the following formula (E) (non-patent document 4), and the like are known. PRIOR ART DOCUMENTS Patent Document patent document 1: WO96/06841 Non-Patent Documents non-patent document 1: Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull.), 1990, vol. 38, p. 1591 non-patent document 2: Nature Chemical Biology (Nat. Chem. Biol.), 2009, vol. 5, p. 100 non-patent document 3: Journal of Medicinal Chemistry (J. Med. Chem.), 2012, vol. 55, p. 1127 non-patent document 4: Nature, 2009, vol. 461, p. 61 SUMMARY OF INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a fused-ring heterocyclic compound or a pharmaceutically acceptable salt thereof, which has a Wnt signaling inhibitory activity, and is useful as a therapeutic and/or preventive agent for, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like, and the like. Means of Solving the Problems The present invention relates to the following (1) to (35). (1) A Wnt signaling inhibitor, comprising, as an active ingredient, a fused-ring heterocyclic compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof: [wherein n1A represents 0 or 1; n2A and n3A may be the same or different, and each represents 1 or 2; ROA represents a hydrogen atom, optionally substituted aryl, an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; R2A represents a hydrogen atom or hydroxy; R3A represents an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; X1A, X2A, X3A, and X4A may be the same or different, and each represents N or CR4A (wherein R4A represents a hydrogen atom, lower alkyl, cyano, halogen, hydroxy, lower alkoxy, lower alkanoyl or lower alkylsulfonyl); Y1A represents CH2 or C(═O); Y2A represents CH or N; and LA represents CH2 or NH]. (2) A fused-ring heterocyclic compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof: [wherein n1 represents 0 or 1; n2 and n3 may be the same or different, and each represents 1 or 2; R1 represents optionally substituted aryl, an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; R2 represents a hydrogen atom or hydroxy; R3 represents an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group; X1, X2, X3, and X4 may be the same or different, and each represents N or CR4 (wherein R4 represents a hydrogen atom, lower alkyl, cyano, halogen, hydroxy, lower alkoxy, lower alkanoyl or lower alkylsulfonyl); Y1 represents CH2 or C(═O); Y2 represents CH or N; and L represents CH2 or NH]. (3) The compound or the pharmaceutically acceptable salt thereof according to (2), wherein n2 and n3 are each 2. (4) The compound or the pharmaceutically acceptable salt thereof according to (2) or (3), wherein Y2 is N, and L is CH2. (5) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (4), wherein Y1 is CH2. (6) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (5), wherein n1 is 0. (7) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (6), wherein R1 is (i) optionally substituted aryl, in which the aryl is phenyl, or (ii) an optionally substituted aromatic heterocyclic group, in which the aromatic heterocyclic group is pyridyl, pyridonyl or pyrimidinyl. (8) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (7), wherein R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and the group is a group represented by the following formula (a1): [wherein Rs represents a hydrogen atom, C1-10 alkyl which may be substituted with hydroxy, C1-10 alkoxycarbonyl, C2-11 alkanoyl, C1-10 alkylsulfonyl, —NR6aR6b (wherein R6a and R6b may be the same or different, and each represents a hydrogen atom, C2-11 alkanoyl or C1-10 alkyl), —CONR6cR6d (wherein R6c and R6d may be the same or different, and each represents a hydrogen atom or C1-10 alkyl), —SO2NR6eR6f (wherein R6e and R6f may be the same or different, and each represents a hydrogen atom or C1-10 alkyl), halogen, cyano, carboxy or nitro, and Z1, Z2, Z3 and Z4 may be the same or different, and each represents N or CR7 (wherein R7 represents a hydrogen atom, carboxy or halogen)], or a group represented by the following formula (a2): (wherein R5, Z1 and Z4 have the same definitions as described above, respectively). (9) The compound or the pharmaceutically acceptable salt thereof according to (8), wherein R5 is cyano, —CONH2 or —SO2NH2. (10) The compound or the pharmaceutically acceptable salt thereof according to (8), wherein R5 is cyano. (11) The compound or the pharmaceutically acceptable salt thereof according to any one of (8) to (10), wherein R7 is a hydrogen atom or a fluorine atom. (12) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (11), wherein R3 is an optionally substituted aromatic heterocyclic group. (13) The compound or the pharmaceutically acceptable salt thereof according to (12), wherein the aromatic heterocyclic group is a bicyclic aromatic heterocyclic group. (14) The compound or the pharmaceutically acceptable salt thereof according to (12), wherein the aromatic heterocyclic group is quinazolinyl. (15) The compound or the pharmaceutically acceptable salt thereof according to any one of (2) to (11), wherein R3 is an optionally substituted aliphatic heterocyclic group. (16) A pharmaceutical composition, comprising, as an active ingredient, the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15). (17) A Wnt signaling inhibitor, comprising, as an active ingredient, the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15). (18) The Wnt signaling inhibitor according to (1) or (17), wherein the Wnt signaling inhibition is Wnt signaling inhibition by tankyrase inhibition. (19) A therapeutic and/or preventive agent for a disease associated with Wnt signaling, comprising, as an active ingredient, the compound or the pharmaceutically acceptable salt thereof described in any one of (1) to (15). (20) The agent according to (19), wherein the disease associated with Wnt signaling is cancer, pulmonary fibrosis, fibromatosis or osteoarthritis. (21) A method for inhibiting Wnt signaling, comprising administering an effective amount of a fused-ring heterocyclic compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof: (wherein n1A, n2A, n3A, R0A, R2A, R3A, X1A, X2A, X3A, X4A, Y1A, Y2A, and LA have the same definitions as described above, respectively). (22) A method for inhibiting Wnt signaling, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15). (23) The method according to (21) or (22), wherein the method for inhibiting Wnt signaling is a method for inhibiting Wnt signaling by tankyrase inhibition. (24) A method for treating and/or preventing a disease associated with Wnt signaling, comprising administering an effective amount of the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15) and (21). (25) The method according to (24), wherein the disease associated with Wnt signaling is cancer, pulmonary fibrosis, fibromatosis or osteoarthritis. (26) A fused-ring heterocyclic compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof for use in Wnt signaling inhibition: (wherein n1A, n2A, n3A, R0A, R2A, R3A, X1A, X2A, X3A, X4A, Y1A, Y2A, and LA have the same definitions as described above, respectively). (27) The compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15) for use in Wnt signaling inhibition. (28) The compound or the pharmaceutically acceptable salt thereof according to (26) or (27), wherein the Wnt signaling inhibition is Wnt signaling inhibition by tankyrase inhibition. (29) The compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15) and (26) for use in the treatment and/or prevention of a disease associated with Wnt signaling. (30) The compound or the pharmaceutically acceptable salt thereof according to (29), wherein the disease associated with Wnt signaling is cancer, pulmonary fibrosis, fibromatosis or osteoarthritis. (31) Use of a fused-ring heterocyclic compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof for the manufacture of a Wnt signaling inhibitor: (wherein n1A, n2A, n3A, R0A, R2A, R3A, X1A, X2A, X3A, X4A, Y1A, Y2A, and LA have the same definitions as described above, respectively). (32) Use of the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15) for the manufacture of a Wnt signaling inhibitor. (33) The use of the compound or the pharmaceutically acceptable salt thereof according to (31) or (32), wherein the Wnt signaling inhibition is Wnt signaling inhibition by tankyrase inhibition. (34) Use of the compound or the pharmaceutically acceptable salt thereof described in any one of (2) to (15) and (31) for the manufacture of a therapeutic and/or preventive agent for a disease associated with Wnt signaling. (35) The use according to (34), wherein the disease associated with Wnt signaling is cancer, pulmonary fibrosis, fibromatosis or osteoarthritis. Effects of Invention A fused-ring heterocyclic compound or a pharmaceutically acceptable salt thereof according to the present invention has a Wnt signaling inhibitory activity and is useful as a therapeutic and/or preventive agent for, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like. MODE FOR CARRYING OUT THE INVENTION Hereinafter, a compound represented by the general formula (I) is referred to as Compound (I). The compounds having the other formula numbers are referred to in the same manner. In the definitions of the respective groups in the general formula (I) and the general formula (IA), examples of the lower alkyl; the lower alkyl moieties of the lower alkoxy, the lower alkanoyl and the lower alkylsulfonyl; the C1-10 alkyl; and the C1-10 alkyl moieties of the C1-10 alkoxycarbonyl, the C2-11 alkanoyl and the C1-10 alkylsulfonyl include linear or branched alkyl each having 1 to 10 carbon atoms, and more specifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like. Examples of the aryl include aryl each having 6 to 14 carbon atoms, and more specifically include phenyl, naphthyl, azulenyl, anthryl, and the like. Examples of the aliphatic heterocyclic group include a 5- or 6-membered monocyclic aliphatic heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic or tricyclic fused-ring aliphatic heterocyclic group in which 3- to 8-membered rings are fused and at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is contained, and the like, and more specifically include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, morpholino, morpholinyl, thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzoimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, dihydrobenzodioxanyl, 7,8-dihydro-5H-pyrano[4,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, dioxoloquinazolinyl, 6-oxo-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-yl, and the like. Examples of the aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, a bicyclic or tricyclic fused-ring aromatic heterocyclic group in which 3- to 8-membered rings are fused and at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is contained, and the like, and more specifically include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridonyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, 7-oxidopyrido[4,3-d]pyrimidinyl, benzo [d][1,2,3]triazinyl, [1,2,4]triazolo[4,3-a]pyridin-3(2H)-onyl, 8-oxo-8,9-dihydro-7H-purin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl, 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl, 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl, 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-5-yl, 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-yl, imidazo[1,2-a]pyrazinyl, and the like. Examples of the bicyclic aromatic heterocyclic group include, among the above-mentioned aromatic heterocyclic rings, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, isoindolyl, indolyl, indazolyl, benzoimidazolyl, benzotriazolyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyridopyrimidinyl, 7-oxidopyrido[4,3-d]pyrimidinyl, benzo[d][1,2,3]triazinyl, [1,2,4]triazolo[4,3-a]pyridin-3(2H)-onyl, 8-oxo-8,9-dihydro-7H-purin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl, 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl, 4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-7-yl, 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-5-yl, 4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl, 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-yl, imidazo[1,2-a]pyrazinyl, and the like. The halogen means each atom of fluorine, chlorine, bromine or iodine. Examples of the substituents in the optionally substituted aryl and the optionally substituted aromatic heterocyclic group, which may be the same or different and in number of, for example, 1 to 3, include substituents selected from the group comprising halogen, hydroxy, nitro, cyano, carboxy, sulfamoyl, C1-10 alkyl which may be substituted with hydroxy, trifluoromethyl, C3-8 cycloalkyl, C6-14 aryl, an aliphatic heterocyclic group, an aromatic heterocyclic group, C1-10 alkoxy, C3-8 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylsulfanyl, —NRXaRYa (wherein RXa and RYa may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10alkoxycarbonyl or C7-16 aralkyloxycarbonyl, or RXa and RYa are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, C1-10 alkylsulfonyl, —CONRXbRYb (wherein RXb and RYb may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group or C7-16 aralkyl, or RXb and RYb are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), —SO2NRXcRYc (wherein RXc and RYc may be the same or different, and each represents a hydrogen atom or C1-10 alkyl, or RXc and RYc are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), and the like. Examples of the substituents of the optionally substituted aliphatic heterocyclic group, which may be the same or different and in number of, for example, 1 to 3, include substituents selected from the group comprising oxo, halogen, hydroxy, nitro, cyano, carboxy, sulfamoyl, C1-10 alkyl which may be substituted with hydroxy, trifluoromethyl, C3-8 cycloalkyl, C6-14 aryl, an aliphatic heterocyclic group, an aromatic heterocyclic group, C1-10 alkoxy, C3-8 cycloalkoxy, C6-14 aryloxy, C7-16 aralkyloxy, C2-11 alkanoyloxy, C7-15 aroyloxy, C1-10 alkylsulfanyl, —NRXdRYd (wherein RXd and RYd may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group, C7-16 aralkyl, C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl or C7-16 aralkyloxycarbonyl, or RXd and RYd are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), C2-11 alkanoyl, C7-15 aroyl, C1-10 alkoxycarbonyl, C6-14 aryloxycarbonyl, —CONRXeRYe (wherein RXe and RYe may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group or C7-16 aralkyl, or RXe and RYe are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), C1-10 alkylsulfonyl, —SO2NRXfRYf (wherein RXf and RYf may be the same or different, and each represents a hydrogen atom or C1-10 alkyl, or RXf and RYf are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl), and the like. Examples of the C1-10 alkyl and the C1-10 alkyl moieties of the C1-10 alkoxy, the C2-11 alkanoyloxy, the C1-10 alkylsulfanyl, the C2-11 alkanoyl, the C1-10 alkylsulfonyl and the C1-10 alkoxycarbonyl shown here include the groups exemplified as the lower alkyl described above. Examples of the C3-8 cycloalkyl and the cycloalkyl moiety of the C3-8cycloalkoxy include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Examples of the C6-14 aryl and the aryl moieties of the C6-14 aryloxy, the C7-15 aroyl, the C7-15 aroyloxy and the C6-14 aryloxycarbonyl include the groups exemplified as the aryl described above. Examples of the aryl moieties of the C7-16 aralkyloxy, the C7-16 aralkyl and the C7-16 aralkyloxycarbonyl include the groups exemplified as the aryl described above, and examples of the alkyl moieties thereof include C1-10 alkylene, and more specifically include groups in which one hydrogen atom is removed from the groups exemplified as the lower alkyl described above. The aliphatic heterocyclic group, the aromatic heterocyclic group and the halogen have the same definitions as described above, respectively. Examples of the nitrogen-containing heterocyclic group formed together with the adjacent nitrogen atom include a 5- or 6-membered monocyclic heterocyclic group having at least one nitrogen atom (the monocyclic heterocyclic group may contain another nitrogen atom, an oxygen atom or a sulfur atom), a bicyclic or tricyclic fused-ring heterocyclic group in which 3- to 8-membered rings are fused and at least one nitrogen atom is contained (the fused-ring heterocyclic group may contain another nitrogen atom, an oxygen atom or a sulfur atom), and the like, and more specifically include aziridinyl, azetidinyl, pyrrolidinyl, piperidino, azepanyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, piperazinyl, homopiperazinyl, oxazolidinyl, 2H-oxazolyl, thioxazolidinyl, 2H-thioxazolyl, morpholino, thiomorpholinyl, dihydroindolyl, dihydroisoindolyl, indolyl, isoindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydrobenzooxazolyl, dihydrobenzothioxazolyl, benzoimidazolidinyl, benzoimidazolyl, dihydroindazolyl, indazolyl, benzotriazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, and the like. The pharmaceutically acceptable salts of Compounds (IA) and (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the pharmaceutically acceptable acid addition salts of Compounds (IA) and (I) include inorganic acid salts such as hydrochlorides, hydrobromides, nitrates, sulfates, phosphates and the like, organic acid salts such as acetates, oxalates, maleates, fumarates, citrates, benzoates, methanesulfonates and the like. Examples of the pharmaceutically acceptable metal salts include alkali metal salts such as sodium salts, potassium salts and the like, alkaline earth metal salts such as magnesium salts, calcium salts, aluminum salts, zinc salts, and the like. Examples of the pharmaceutically acceptable ammonium salts include salts of ammonium, tetramethylammonium, and the like. Examples of the pharmaceutically acceptable organic amine addition salts include addition salts of morpholine, piperidine, and the like. Examples of the pharmaceutically acceptable amino acid addition salts include addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, and the like. Next, production processes for Compounds (IA) and (I) will be explained. Incidentally, in the production processes shown below, when a defined group changes under the conditions of the production processes or is inappropriate for performing the production processes, a target compound can be produced by using the methods for introducing and removing a protective group conventionally used in the organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, third edition, written by T. W. Greene, John Wiley & Sons, Inc. (1999), and the like] and the like. Also, if necessary, it is possible to change the order of the reaction steps of introducing a substituent and the like. Compounds (IA) and (I) can be produced according to, for example, the following steps. Production Process 1 Among Compounds (I), Compound (I-a) in which Y1 is CH2, Y2 is N, and L is CH2 can be produced according to, for example, the following steps. (wherein, P1 represents a protective group for a nitrogen atom conventionally used in the organic synthetic chemistry, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, or the like, X5 represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like, and X1, X2, X3, X4, R1, R2, R3, n1, n2 and n3 have the same definitions as described above, respectively) Step 1 Compound (a-1) can be produced by, for example, a modified method of the method for removing a protective group described in Protective Groups in Organic Synthesis, written by T. W. Greene, John Wiley & Sons, Inc. (1981), and the like. For example, in the case where P1 is tert-butoxycarbonyl, Compound (a-1) can be produced by treating Compound (A-0), for example, without solvent or in a solvent with 1 equivalent to a large excess amount of an acid at a temperature between −30° C. and 100° C. for 5 minutes to 72 hours. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and the like. Examples of the solvent include methanol, ethanol, 1-propanol, 2-propanol, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane (DME), toluene, ethyl acetate, dichloromethane, 1,2-dichloroethane, water, and the like, and these are used alone or in admixture. Compound (A-0) can be produced according to the below-mentioned steps. Step 2 Compound (I-a) can be produced by reacting Compound (a-1) with preferably 1 to 10 equivalents of Compound (a-2) without solvent or in a solvent, and if necessary, in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours. Examples of the base include potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU), and the like. Examples of the solvent include methanol, ethanol, 2-propanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), pyridine, water, and the like, and these are used alone or in admixture. Compound (a-2) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza (Encyclopedia of Experimental Chemistry), 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Compound (I-a) can be produced by treating Compound (a-1) with preferably 1 to 10 equivalents of Compound (a-3) in a solvent, in the presence of preferably 1 to 10 equivalents of a condensing agent, and if necessary, in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours. Compound (a-3) is obtained as a commercially available product or can be obtained by a known method (for example, Journal of Medicinal Chemistry, 2010, 53, 8089, or the like) or a modified method thereof. Examples of the condensing agent include benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), bromotris(pyrrolidino)phosphonium hexafluorophosphate (PyBroP), and the like, and preferably include BOP and the like. Examples of the base include triethylamine, N,N-diisopropylethylamine, DBU, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), N-methylpiperidine, N-methylphorpholine, and the like, and preferably include DBU and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water, and the like, and these are used alone or in admixture. Compound (A-0) to be used in the above production process 1 can be produced according to the following steps. Among Compounds (A-0), Compound (A-1), in which n1 is 1, and Compound (A-2), in which n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group, can be produced according to, for example, the following steps. (wherein, R1A represents optionally substituted aryl or an optionally substituted aromatic heterocyclic group in the definition of R1, X5A and each represents a chlorine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like, X6 represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, B(ORB1)(ORB2) (wherein RB1 and RB2 may be the same or different, and each represents a hydrogen atom, C1-6 alkyl, or the like, or RB1 and RB2 are combined to represent C1-6 alkylene or the like), or the like, and X1, X2, X3, X4, R2, P1, n2 and n3 have the same definitions as described above, respectively) Step 3 Compound (a-6) can be produced by reacting Compound (a-4) with preferably 1 to 10 equivalents of Compound (a-5) in a solvent, in the presence of preferably 1 to 10 equivalents of a reducing agent and preferably 1 to 10 equivalents of an acid at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours. Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, titanium tetrachloride, and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water, and the like, and these are used alone or in admixture. Compound (a-5) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 14, p. 351, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Compound (a-4) can be obtained as a commercially available product. Step 4 Compound (a-7) can be produced by treating Compound (a-6) in a solvent in the presence of 1 to 30 equivalents of an additive at a temperature between −20° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours, or by treating Compound (a-6) under a hydrogen atmosphere or in the presence of a hydrogen source in the presence of a catalyst at a temperature between −20° C. and the boiling point of the solvent to be used at normal pressure or under increased pressure for 5 minutes to 72 hours. Examples of the additive include reduced iron, tin(II) chloride, and the like. Examples of the catalyst include palladium on carbon, palladium, palladium hydroxide, palladium acetate, palladium black, and the like, and these are used in an amount of preferably 0.01 to 50 weight % with respect to Compound (a-6). Examples of the hydrogen source include formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine, and the like, and these are used in an amount of preferably 2 equivalents to a large excess amount with respect to Compound (a-6). Examples of the solvent include methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, acetic acid, water, and the like, and these are used alone or in admixture. Step 5 Compound (a-8) can be produced by reacting Compound (a-7) in a solvent in the presence of preferably 1 to 10 equivalents of phosgene or 1,1-carbonyldiimidazole, and if necessary, in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours. Examples of the base include potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium hydride, potassium tert-butoxide, triethylamine, diisopropylethylamine, DBU, and the like. Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DMF, NMP, pyridine, and the like, and these are used alone or in admixture. Step 6 Compound (A-1) can be obtained in the same manner as in the above-mentioned Step 2 using Compound (a-8) and preferably 1 to 10 equivalents of Compound (a-9). Compound (a-9) can be obtained as a commercially available product. Step 7 Compound (A-2) can be produced by reacting Compound (a-8) with 1 to 10 equivalents of Compound (a-10) in a solvent in the presence of a catalytic amount to 10 equivalents of a copper catalyst or a palladium catalyst at a temperature between room temperature and 140° C. for 5 minutes to 72 hours. The reaction can also be performed in the presence of a catalytic amount to 10 equivalents of a base, and can also be performed in the presence of a catalytic amount to 10 equivalents of an organophosphorus compound. Examples of the copper catalyst include copper(0), copper(I) iodide, copper(II) iodide, copper(II) acetate, copper(II) oxide, copper(I) chloride, di-μ-hydroxo-bis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)] chloride, and the like, and preferably include copper(I) iodide, copper(II) acetate, and the like. Examples of the palladium catalyst include palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), [1,2-bis(diphenylphosphino)ethane]palladium(II) chloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, Tris(dibenzylideneacetone)dipalladium(0), and the like, and preferably include palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), and the like. Examples of the base include potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, 1,2-diaminocyclohexane, and the like, and preferably include potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, ethylenediamine, 1,2-diaminocyclohexane, triethylamine, and the like. Examples of the organophosphorus compound include triphenylphosphine, tri(2-furyl)phosphine, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, diphenylphosphinoferrocene, 2-dicyclohexylphosphino-2′4′6′-triisopropylbiphenyl (XPhos), and the like, and preferably include 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, XPhos, and the like. Examples of the solvent include diethyl ether, THF, 1,4-dioxane, DMF, DMA, dimethyl sulfoxide (DMSO), benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, ethyl acetate, methyl acetate, methyl ethyl ketone, methanol, ethanol, propanol, 2-propanol, butanol, hexane, and the like, and preferably include THF, 1,4-dioxane, DMF, and the like. Compound (a-10) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Among Compounds (A-0), Compound (A-3) in which n1 is 0 and R1 is an optionally substituted aliphatic heterocyclic group can be produced according to, for example, the following steps. (wherein, R1B represents an optionally substituted aliphatic heterocyclic group in the definition of R1, and X1, X2, X3, X4, R2, P1, n2 and n3 have the same definitions as described above, respectively) Step 8 Compound (a-12) can be produced in the same manner as in the above-mentioned Step 3 using Compound (a-7) obtained in Step 4 and Compound (a-11). Compound (a-11) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 15, p. 154, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 9 Compound (A-3) can be produced in the same manner as in the above-mentioned Step 5 using Compound (a-12). Production Process 2 Among Compounds (I), Compound (I-b) and Compound (I-c), in which R2 is a hydrogen atom, Y1 is CH2, Y2 is CH, and L is NH, and (i) n1 is 1 (Compound (I-b)) or (ii) n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group (Compound (I-c)), can be produced according to, for example, the following steps. (wherein, P1A represents a protective group which can be removed with an acid among the groups represented by P1, for example, tert-butoxycarbonyl or the like, P2 represents a protective group for a nitrogen atom conventionally used in the organic synthetic chemistry, for example, acyl such as formyl, acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, benzoyl, or the like, and X1, X2, X3, X4, X5, X5A, X6, R1, R1A, R3, n2 and n3 have the same definitions as described above, respectively) Step 10 Compound (a-15) can be produced in the same manner as in the above-mentioned Step 3 using Compound (a-13) and Compound (a-14). Compound (a-13) is obtained as a commercially available product or can be obtained by a known method (for example, WO2004/98589 or the like) or a modified method thereof. Compound (a-14) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 15, p. 153, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 11 Compound (a-16) can be produced by, for example, a modified method of the method for introducing a protective group described in Protective Groups in Organic Synthesis, written by T. W. Greene, John Wiley & Sons, Inc. (1981), or the like using Compound (a-15). For example, in the case where P2 is trifluoroacetyl, Compound (a-16) can be produced by reacting Compound (a-15) with preferably 1 to 10 equivalents of trifluoroacetic anhydride without solvent or in a solvent in the presence of preferably 1 to 10 equivalents of a base at a temperature between −78° C. and 150° C. for 5 minutes to 72 hours. Examples of the base include triethylamine, N,N-diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, and the like. Examples of the solvent include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water, and the like, and these are used alone or in admixture. Step 12 Compound (a-17) can be obtained in the same manner as in the above-mentioned Step 1 using Compound (a-16). Step 13 Compound (a-18) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-17) and Compound (a-2). Step 14 Compound (a-19) can be produced by, for example, a modified method of the method for removing a protective group described in Protective Groups in Organic Synthesis, written by T. W. Greene, John Wiley & Sons, Inc. (1981), or the like. For example, in the case where P2 is trifluoroacetyl, Compound (a-19) can be produced by treating Compound (a-18) in a solvent containing water with preferably 1 equivalent to a large excess amount of a base at a temperature between −30° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, dichloromethane, DMF, water, and the like, and these are used alone or in admixture. Step 15 Compounds (I-b) and (I-c) can be obtained in the same manner as in Step 6 or Step 7 using Compound (a-19), and Compound (a-9) or Compound (a-10). Production Process 3 Among Compounds (I), Compound (I-d) and Compound (I-e), in which Y1 is C(═O), Y2 is N, and L is CH2, and (i) n1 is 1 (Compound (I-d)) or (ii) n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group (Compound (I-e)), can be produced according to, for example, the following steps. (wherein, X7 represents a chlorine atom, a bromine atom, an iodine atom, or the like, RP represents C1-10 alkyl, C7-16 aralkyl, or the like, and X1, X2, X3, X4, X5, X5A, X6, R1, R1A, R2, R3, P1, n2 and n3 have the same definitions as described above, respectively) Step 16 Compound (a-21) can be produced by reacting Compound (a-20) with preferably 1 to 10 equivalents of Compound (a-5) in a solvent in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, ethyl acetate, toluene, dichloromethane, DMF, water, and the like, and these are used alone or in admixture. Compound (a-20) can be obtained as a commercially available product. Step 17 Compound (a-23) can be produced by reacting Compound (a-21) with preferably 1 to 10 equivalents of Compound (a-22) in a solvent in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and 150° C. for 5 minutes to 72 hours. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, DBU, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, ethyl acetate, toluene, dichloromethane, 1,2-dichloroethane, DMF, water, and the like, and these are used alone or in admixture. Compound (a-22) can be obtained as a commercially available product. Step 18 Compound (a-24) can be produced by treating Compound (a-23) in a solvent in the presence of preferably 1 to 10 equivalents of a base at a temperature between −20° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, DBU, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, ethyl acetate, toluene, dichloromethane, 1,2-dichloroethane, DMF, water, and the like, and these are used alone or in admixture. Step 19 Compound (a-25) can be produced in the same manner as in the above-mentioned Step 1 using Compound (a-24). Step 20 Compound (a-26) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-25) and Compound (a-2). Step 21 Compound (I-d) and Compound (I-e) can be produced in the same manner as in the above-mentioned Step 6 or Step 7 using Compound (a-26), and Compound (a-9) or Compound (a-10). Production Process 4 Among Compounds (I), Compound (I-f), in which R3 is an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group, and the group is an aromatic heterocyclic group substituted with —NR8R9 (wherein R8 and R9 may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group or C7-16 aralkyl, or R8 and R9 are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl) (the aromatic heterocyclic group may further has another substituent) or an aliphatic heterocyclic group substituted with —NR8R9 (wherein R8 and R9 have the same definitions as described above, respectively) (the aliphatic heterocyclic group may further has another substituent), can also be produced according to, for example, the following method. (wherein, X5B represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like, the ring A represents an aromatic heterocyclic group moiety of an optionally substituted aromatic heterocyclic group (the aromatic heterocyclic group moiety may further has a substituent) or an aliphatic heterocyclic group moiety of an optionally substituted aliphatic heterocyclic group (the aliphatic heterocyclic group moiety may further has a substituent) in the definition of R3, and X1, X2, X3, X4, X5, R1, R2, R8, R9, n1, n2 and n3 have the same definitions as described above, respectively) Step 22 Compound (a-28) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-1) and Compound (a-27). Compound (a-27) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 23 Compound (I-f) can be produced by reacting Compound (a-28) with 1 to 10 equivalents of Compound (a-29) in a solvent in the presence of a catalytic amount to 10 equivalents of a palladium catalyst at a temperature between room temperature and 140° C. for 5 minutes to 72 hours. The reaction can also be performed in the presence of a catalytic amount to 10 equivalents of a base, and can also be performed in the presence of a catalytic amount to 10 equivalents of an organophosphorus compound. Examples of the palladium catalyst include palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), [1,2-bis(diphenylphosphino)ethane]palladium(II) chloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, Tris(dibenzylideneacetone)dipalladium(0), and the like, and preferably include palladium(II) acetate, bis(triphenylphosphine)palladium(II) chloride, tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), and the like. Examples of the base include potassium carbonate, cesium carbonate, lithium chloride, potassium chloride, potassium tert-butoxide, sodium tert-butoxide, triethylamine, potassium acetate, sodium ethoxide, sodium carbonate, sodium hydroxide, potassium phosphate, ethylenediamine, glycine, N-methylpyrrolidine, pyridine, 1,2-diaminocyclohexane, and the like, and preferably include potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium phosphate, triethylamine, and the like. Examples of the organophosphorus compound include triphenylphosphine, tri(2-furyl)phosphine, 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, diphenylphosphinoferrocene, XPhos, and the like, and preferably include 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, XPhos, and the like. Examples of the solvent include diethyl ether, THF, 1,4-dioxane, DMF, DMA, DMSO, benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, acetonitrile, ethyl acetate, methyl acetate, methyl ethyl ketone, methanol, ethanol, propanol, 2-propanol, butanol, hexane, and the like, and preferably include THF, 1,4-dioxane, DMF, and the like. Compound (a-29) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 14, p. 351, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Production Process 5 Among Compounds (I), Compound (I-g) and Compound (I-h), in which R3 is an optionally substituted aromatic heterocyclic group or an optionally substituted aliphatic heterocyclic group, and the group is an aromatic heterocyclic group substituted with carboxy or —CONR8′R9′ (wherein R8′ and R9′ may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group or C7-16 aralkyl, or R8′ and R9′ are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group which may be substituted with C1-10 alkyl) (the aromatic heterocyclic group may further has another substituent) or an aliphatic heterocyclic group substituted with carboxy or —CONR8′R9′ (wherein R8′ and R9′ have the same definitions as described above, respectively) (the aliphatic heterocyclic group may further has another substituent), can also be produced according to, for example, the following method. (wherein, RP′ represents C1-10 alkyl, C7-16 aralkyl, or the like, and the ring A, X1, X2, X3, X4, R1, R2, R8′, R9′, n1, n2 and n3 have the same definitions as described above, respectively) Step 24 Compound (a-30) can be produced by reacting Compound (a-28) in a solvent under a carbon monoxide atmosphere in the presence of preferably 1 equivalent to a large excess amount of RP′OH (wherein RP′ has the same definition as described above) and preferably 1 to 100 mol % of a palladium catalyst, and if necessary, in the presence of preferably 1 to 100 mol % of an organophosphorus compound and/or preferably 1 to 10 equivalents of a base at a temperature between −20° C. and the boiling point of the solvent to be used at normal pressure or under increased pressure for 5 minutes to 72 hours. Examples of the base include potassium carbonate, potassium phosphate, potassium hydroxide, triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, DBU, potassium acetate, sodium acetate, and the like. Examples of the palladium catalyst include palladium acetate, tetrakis(triphenylphosphine)palladium, and the like. Examples of the organophosphorus compound include triphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene, 1,3-bis(diphenylphosphino)propane, and the like. Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, water, and the like, and these are used alone or in admixture. Step 25 Compound (I-g) can be produced by, for example, a modified method of the method for removing a protective group described in Protective Groups in Organic Synthesis, third edition, written by T. W. Greene, John Wiley & Sons, Inc. (1999), or the like using Compound (a-30). For example, in the case where RP′ is methyl, ethyl or n-propyl, Compound (I-g) can be produced by treating Compound (a-30) in a solvent containing water with preferably 1 equivalent to a large excess amount of a base at a temperature between 0° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, dichloromethane, DMF, water, and the like, and these are used alone or in admixture. Further, for example, in the case where RP′ is tert-butyl, Compound (I-g) can be produced by treating Compound (a-30) without solvent or in a solvent with 1 equivalent to a large excess amount of an acid at a temperature between −30° C. and 100° C. for 5 minutes to 72 hours. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, and the like. Examples of the solvent include methanol, ethanol, propanol, THF, 1,4-dioxane, DME, toluene, ethyl acetate, dichloromethane, DMF, water, and the like, and these are used alone or in admixture. Step 26 Compound (I-h) can be produced by reacting Compound (I-g) with preferably 1 to 30 equivalents of Compound (a-29) without solvent or in a solvent, in the presence of preferably 1 to 30 equivalents of a condensing agent, and if necessary, in the presence of preferably 1 to 30 equivalents of an additive at a temperature between −30° C. and 150° C. for 5 minutes to 72 hours. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC), EDC hydrochloride, O-(7-aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), and the like. Examples of the additive include 1-hydroxybenzotriazole monohydrate (HOBt.H2O), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP), and the like, and these are used alone or in admixture. Examples of the solvent include acetonitrile, dichloromethane, 1,2-dichloroethane, chloroform, DME, DMF, DMA, 1,4-dioxane, THF, diethyl ether, diisopropyl ether, benzene, toluene, xylene, pyridine, NMP, water, and the like, and these are used alone or in admixture. Production Process 6 Among Compounds (I), Compound (I-i) and Compound (I-j), in which R3 is an optionally substituted aromatic heterocyclic group, and the aromatic heterocyclic group is an aromatic heterocyclic group containing a nitrogen atom, and is a group in which oxo is attached to the nitrogen of the aromatic heterocyclic group (the group may further has another substituent), and (i) n1 is 1 (Compound (I-i)) or (ii) n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group (Compound (I-j)), can also be produced according to, for example, the following method. (wherein, the ring B represents an optionally substituted aromatic heterocyclic group, and the aromatic heterocyclic group is an aromatic heterocyclic group containing a nitrogen atom (the aromatic heterocyclic group moiety may further has a substituent) in the definition of R3, and X1, X2, X3, X4, X5, X5A, X6, P1, R1, R1A, R2, n2 and n3 have the same definitions as described above, respectively) Step 27 Compound (a-31) can be produced in the same manner as in the above-mentioned Step 1 using Compound (a-8). Step 28 Compound (a-33) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-31) and Compound (a-32). Compound (a-32) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 29 Compound (a-34) can be produced by treating Compound (a-33) in a solvent with 1 equivalent to a large excess amount, preferably, 1 to 10 equivalents of an oxidizing agent at a temperature between 0° C. and the boiling point of the solvent to be used for 5 minutes to 72 hours. Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, THF, 1,4-dioxane, dimethoxyethane, diethyl ether, diisopropyl ether, methanol, ethanol, isopropyl alcohol, benzene, toluene, xylene, acetonitrile, ethyl acetate, water, and the like, and these are used alone or in admixture. Examples of the oxidizing agent include meta-chloroperoxybenzoic acid, benzoyl peroxide, peracetic acid, hydrogen peroxide, sodium periodate, oxone, and the like. Step 30 Compound (I-i) and Compound (I-j) can be produced in the same manner as in the above-mentioned Step 6 or Step 7 using Compound (a-34), and Compound (a-9) or Compound (a-10). Production Process 7 Among Compounds (I), Compound (I-k) in which R3 is represented by the following formula: can also be produced according to, for example, the following method. (wherein, X5C represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like, and X1, X2, X3, X4, X5, R1, R2, n1, n2 and n3 have the same definitions as described above, respectively) Step 31 Compound (a-36) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-1) and Compound (a-35). Compound (a-35) is obtained as a commercially available product or can be obtained by a known method [for example, Patent Literature (US2009/286816) or the like] or a modified method thereof. Step 32 Compound (I-k) can be produced by treating Compound (a-36) in a solvent under a hydrogen atmosphere or in the presence of a hydrogen source in the presence of a catalyst and a base at a temperature between −20° C. and the boiling point of the solvent to be used at normal pressure or under increased pressure for 5 minutes to 72 hours. Examples of the catalyst include palladium on carbon, palladium, palladium hydroxide, palladium acetate, palladium black, and the like, and these are used in an amount of preferably 0.01 to 50% by weight with respect to Compound (a-36). Examples of the hydrogen source include formic acid, ammonium formate, sodium formate, cyclohexadiene, hydrazine, and the like, and these are used in an amount of preferably 2 equivalents to a large excess amount with respect to Compound (a-36). Examples of the base include triethylamine, diisopropylethylamine, pyridine, N-methylphorpholine, and the like, and these are used in an amount of preferably 1 to 30 equivalents with respect to Compound (a-36). Examples of the solvent include methanol, ethanol, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, 1,4-dioxane, DMF, DMA, NMP, acetic acid, water, and the like, and these are used alone or in admixture. Production Process 8 Among Compounds (I), Compound (I-1) and Compound (I-m), in which n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and the group is aryl substituted with carboxy or —CONR8″R9″ (wherein R8″ and R9″ may be the same or different, and each represents a hydrogen atom, C1-10 alkyl, C3-8 cycloalkyl, C6-14 aryl, an aromatic heterocyclic group or C7-16 aralkyl, or R8″ and R9″ are combined together with the adjacent nitrogen atom thereto to form a nitrogen-containing heterocyclic group) (the aryl may further has another substituent) or an aromatic heterocyclic group substituted with carboxy or —CONR8″R9″ (wherein R8″ and R9″ have the same definitions as described above, respectively) (the aromatic heterocyclic group may further has another substituent), can also be produced according to, for example, the following method. (wherein, X7 represents a chlorine atom, a bromine atom, an iodine atom, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy, or the like, the ring C represents an aryl moiety of optionally substituted aryl (the aryl moiety may further has a substituent) or an aromatic heterocyclic group moiety of an optionally substituted aromatic heterocyclic group (the aromatic heterocyclic group moiety may further has a substituent) in the definition of R1, and X1, X2, X3, X4, X5, X6, R2, R3, R8″, R9″, n2 and n3 have the same definitions as described above, respectively) Step 33 Compound (a-37) can be produced in the same manner as in the above-mentioned Step 2 using Compound (a-31) and Compound (a-2). Step 34 Compound (a-39) can be produced in the same manner as in the above-mentioned Step 7 using Compound (a-37) and Compound (a-38) Compound (a-38) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 35 Compound (a-40) can be produced in the same manner as in the above-mentioned Step 24 using Compound (a-39). Step 36 Compound (I-1) can be produced in the same manner as in the above-mentioned Step 25 using Compound (a-40). Step 37 Compound (I-m) can be produced in the same manner as in the above-mentioned Step 26 using Compound (I-1) and Compound (a-29). Production Process 9 Among Compounds (I), Compound (I-n), in which n1 is 0 and R1 is optionally substituted aryl or an optionally substituted aromatic heterocyclic group, and the group is aryl substituted with —CONH2 (the aryl group may further has another substituent) or an aromatic heterocyclic group substituted with —CONH2 (the aromatic heterocyclic group may further has another substituent), can also be produced according to, for example, the following method. (wherein, the ring C, X1, X2, X3, X4, X6, R2, R3, n2 and n3 have the same definitions as described above, respectively) Step 38 Compound (a-42) can be produced in the same manner as in the above-mentioned Step 7 using Compound (a-37) and Compound (a-41). Compound (a-41) is obtained as a commercially available product or can be obtained by a known method [for example, Jikken Kagaku Koza, 5th Ed., vol. 13, p. 341, Maruzen Co., Ltd. (2003), or the like] or a modified method thereof. Step 39 Compound (I-n) can be produced in the same manner as in the above-mentioned Step 25 using Compound (a-42). Production Process 10 Compound (IA) can be produced according to the above-mentioned production process 1 to 11. Also, among Compounds (IA), a compound in which n1 is 0 and R1 is a hydrogen atom can be produced by the method described in Chemical & Pharmaceutical Bulletin 1990, 38(6), 1591 or a modified method thereof. The conversion of a functional group contained in R1A, R2A or R3A in Compound (IA) and in R1, R2 or R3 in Compound (I) can also be performed by a known method [for example, the method described in Comprehensive Organic Transformations 2nd edition, written by R. C. Larock, Vch Verlagsgesellschaft Mbh (1999), or the like] or a modified method thereof. The intermediates and the target compounds in the above-mentioned respective production processes can be isolated and purified by being subjected to a separation and purification method conventionally used in the organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, or the like. Also, the intermediates can be subjected to the subsequent reaction without being particularly purified. Among Compounds (IA) and (I), some compounds may exist as a stereoisomer such as a geometric isomer or an optical isomer, a tautomer, or the like. The present invention encompasses all possible isomers and mixtures thereof including these isomers. Part or all of the respective atoms in Compounds (IA) and (I) may be replaced by corresponding isotope atom(s), respectively, and the present invention also comprises such compounds replaced by isotope atom(s). For example, part or all of the hydrogen atom(s) in Compounds (IA) and (I) may be hydrogen atom(s) having an atomic weight of 2 (deuterium atom(s)). Compounds in which part or all of the respective atom(s) in Compounds (IA) and (I) is/are replaced by corresponding isotope atom(s), respectively, can be produced in the same manner as in the above-mentioned respective production processes using commercially available building blocks. Also, the compounds in which part or all of the hydrogen atom(s) in Compounds (IA) and (I) is/are replaced by deuterium atom(s) can also be synthesized by, for example, 1) a method of deuterating a carboxylic acid and the like under basic conditions using deuterium peroxide (U.S. Pat. No. 3,849,458), 2) a method of deuterating an alcohol, a carboxylic acid, and the like using an iridium complex as a catalyst and also using heavy water as a deuterium source [Journal of the American Chemical Society 2002, 124(10), 2092], 3) a method of deuterating a fatty acid using palladium on carbon as a catalyst and also using only a deuterium gas as a deuterium source [LIPIDS 1974, 9(11), 913], 4) a method of deuterating acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, and the like using a metal such as platinum, palladium, rhodium, ruthenium, iridium and the like as a catalyst and also using heavy water, or heavy water and a deuterium gas, as a deuterium source (JPH5-19536, JPS61-277648, and JPS61-275241), 5) a method of deuterating acrylic acid, methyl methacrylate, and the like using a catalyst such as palladium, nickel, copper, chromite copper and the like, and also using heavy water as a deuterium source (JPS63-198638), and the like. In the case where a salt of Compound (IA) or (I) is desired to be obtained, when Compound (IA) or (I) is obtained in the form of a salt, the salt may be directly purified. Or, when Compound (IA) or (I) is obtained in a free form, Compound (IA) or (I) is dissolved or suspended in a suitable solvent, and an acid or a base is added thereto to form a salt, and then, the salt may be isolated and purified. Further, Compounds (IA) and (I) and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or any of various solvents, and the present invention also comprises these adducts. Specific examples of Compounds (IA) and (I) obtained according to the present invention are shown in Table 1 to Table 5. However, the compounds of the present invention are not limited thereto. TABLE 1 Com- pound No. R1 R3 R4 1 H 2 H 3 H 4 H 5 6 H 7 H 8 H 9 H 10 H 11 H 12 H 13 H 14 H 15 H 16 H TABLE 2 Com- pound No. 17 18 19 20 21 22 [Table 3] TABLE 3 Com- pound No. R3 Z2 23 N 24 N 25 CH 26 CH 27 N 28 N 29 CH 30 N 31 N 32 N 33 N 34 N 35 N 36 N 37 N 38 N TABLE 4 Compound No. R3 Z2 39 N 40 N 41 N 42 N 43 CH 44 CF 45 CF 46 CF 47 CF TABLE 5 Compound No. 48 49 50 51 52 53 Next, the pharmacological activity of representative Compound (I) will be specifically described by way of Test Examples. Test Example 1 Inhibitory Activity Against T-Cell Factor (TCF)-Luciferase Reporter Using Wnt Pathway as Index The inhibitory activity of test compounds against Wnt pathway was evaluated by the following method. A human colorectal adenocarcinoma cell line DLD-1 (Japanese Collection of Research Bioresources) was cultured in RPMI-1640 medium (Gibco/Life Technologies, Inc.) containing 10% fetal bovine serum (Gibco/Life Technologies, Inc.), 10 mmol/L of a 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer solution (Gibco/Life Technologies, Inc.), 1 mmol/L of a sodium pyruvate solution (Gibco/Life Technologies, Inc.), 4.5 g/L of a D-(+)-glucose solution (Sigma-Aldrich, Inc.), 100 units/mL penicillin (Gibco/Life Technologies, Inc.) and 100 [g/mL of streptomycin (Gibco/Life Technologies, Inc.) under the conditions of 37° C. and 5% carbon dioxide gas. The DLD-1 cells were seeded in a 10 cm dish, and 20 g of a luciferase gene plasmid pGL4.27 having a TCF responsive sequence inserted therein was transfected into the cells using 10 μL of Attractene (Qiagen, Inc.) according to the protocol attached to the product. A stably expressing cell line (DLD-1/TCF-Luc) was selected using 600 μg/L of hygromycin B (Wako Pure Chemical Industries Ltd.). The DLD-1/TCF-Luc cells were detached with trypsin and seeded in a 384-well plate, and a test compound was added at different concentrations. After 18 hours, the luciferase activity was measured using Steady-Glo™ Luciferase Assay System (Promega, Inc.). The inhibition ratio was obtained according to the following formula 1. The inhibition ratio (%) of the compound of the present invention at 1 μmol/L against the TCF-luciferase reporter using the Wnt pathway as an index is shown in Table 6. [Math. 1] Inhibition ratio (%)=100−{(luciferase activity when test compound was added)−(luciferase activity of blank)}/{(luciferase activity of control)−(luciferase activity of blank)}×100 Formula 1 TABLE 6 Inhibition Inhibition Compound ratio (%) at Compound ratio (%) at No. 1 μmol/L No. 1 μmol/L 1 88 2 87 3 77 4 74 5 84 6 76 7 76 8 73 9 74 10 79 11 87 12 80 13 80 14 76 15 84 16 63 17 76 18 80 19 91 20 83 21 76 22 75 23 84 24 86 25 86 26 77 27 88 28 84 29 74 30 69 31 74 32 76 33 82 34 78 35 79 36 79 37 82 38 89 39 89 40 78 41 81 42 81 43 85 44 82 45 86 46 84 47 82 48 84 49 82 50 87 51 90 52 81 From the above results, it was shown that Compounds (IA) and (I) and pharmaceutically acceptable salts thereof inhibit Wnt signaling, and therefore are useful as a therapeutic and/or preventive agent for a disease associated with Wnt signaling, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like. Test Example 2 Tankyrase-2 Enzyme Inhibition Test The enzyme activity of tankyrase-2 was evaluated using Tankyrase-2 Chemiluminescent Assay Kit (BPS Bioscience, Inc., Catalog No. 80566). The Tankyrase-2 Chemiluminescent Assay Kit is a kit for evaluating the enzyme activity of tankyrase-2 using autoribosylation of glutathione-S-transferase (GST)-tankyrase-2 fusion protein as an index. All the experimental materials except for PBS (PBST) buffer containing phosphate-buffered saline (PBS) and 0.05% Tween 20 are all included in the kit. The GST-tankyrase-2 enzyme diluted with 50 μL of 1× tankyrase buffer was added to the wells of a 96-well plate coated with glutathione. After the plate was left to stand overnight at 4° C., the plate was washed 3 times with the PBST buffer. 150 μL of blocking buffer was added thereto, and the plate was left to stand at room temperature for 30 minutes to block the wells. The plate was washed 3 times with the PBST buffer. Before the ribosylation reaction, an assay mixture containing a biotinylated substrate and a test compound diluted with 1× tankyrase buffer were mixed, whereby a reaction mixture was prepared. In order to start the ribosylation reaction, 50 μL of the reaction mixture was added to the wells. In a blank well, 1× tankyrase buffer was added in place of the reaction mixture containing a biotinylated substrate. The plate was left to stand at 30° C. for 1 hour. After the reaction, the plate was washed 3 times with the PBST buffer. Streptavidin-horseradish peroxidase (HRP) was diluted to 50-fold with the blocking buffer. The diluted streptavidin-HRP was added to the wells, and the plate was left to stand at room temperature for 30 minutes. The plate was washed 3 times with the PBST buffer. Immediately before use, 50 μL of the HRP chemiluminescent substrate A and 50 μL of the HRP chemiluminescent substrate B were mixed and 100 μL of the resulting mixture was added to the wells. The chemiluminescence was measured using a chemiluminescence measuring apparatus. The inhibition ratio was obtained according to the following formula 2. The tankyrase-2 enzyme inhibitory activity of the compound of the present invention is shown in Table 7. [Math. 2] Inhibition ratio (%)=100−{(chemiluminescence intensity when test compound was added)−(chemiluminescence intensity of blank)}/{(chemiluminescence intensity of control)−(chemiluminescence intensity of blank)}×100 Formula 2 TABLE 7 Inhibition Inhibition Compound ratio (%) at Compound ratio (%) at No. 1 μmol/L No. 1 μmol/L 1 91 2 91 5 94 7 95 8 90 9 91 12 88 13 89 15 92 16 71 18 79 21 93 22 98 24 92 25 81 29 87 30 92 32 94 34 87 35 88 36 88 37 87 38 94 40 93 41 92 44 93 47 80 48 93 50 82 53 100 From the above results, it was shown that Compounds (IA) and (I) and pharmaceutically acceptable salts thereof inhibit the tankyrase-2 enzyme. That is, it was shown that Compounds (IA) and (I) and pharmaceutically acceptable salts thereof inhibit Wnt signaling by inhibiting tankyrase, and therefore are useful as a therapeutic and/or preventive agent for a disease associated with Wnt signaling, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like. Compounds (IA) and (I) and pharmaceutically acceptable salts thereof can be administered alone as they are, but are generally desirably provided as various pharmaceutical preparations. Also, such pharmaceutical preparations are used for animals and human beings. The pharmaceutical preparation according to the present invention can contain, as an active ingredient, Compound (IA) or (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with an active ingredient for any other treatment. Also, such a pharmaceutical preparation is prepared by mixing the active ingredient with one or more pharmaceutically acceptable carriers (for example, a diluent, a solvent, an excipient, and the like) and then subjecting the mixture to any method well known in the technical field of drug formulation study. As the administration route, it is preferred to use the most effective route of administration in the treatment. Examples of the administration route include oral administration and parenteral administration such as intravenous administration or the like. Examples of the administration form include a tablet, an injection, and the like. A suitable administration form for the oral administration, for example, a tablet or the like can be prepared by using an excipient such as lactose and the like, a disintegrator such as starch and the like, a lubricant such as magnesium stearate and the like, a binder such as hydroxypropyl cellulose and the like, and the like. A suitable administration form for the parenteral administration, for example, an injection or the like can be prepared by using a diluent or a solvent such as a salt solution, a glucose solution, or a mixed solution of a salt solution and a glucose solution, and the like, and the like. The dose and the frequency of administration of Compound (IA) or (I) or a pharmaceutically acceptable salt thereof may vary depending on administration form, age and body weight of a patient, nature or seriousness of the symptom to be treated, and the like. However, in the oral administration, in general, a dose of 0.01 to 1000 mg, preferably, 0.05 to 100 mg, is administered to an adult patient once or several times a day. In the parenteral administration such as intravenous administration, a dose of 0.001 to 1000 mg, preferably, 0.01 to 100 mg, is administered to an adult patient once or several times a day. However, such dose and frequency of administration vary depending on the above-mentioned various conditions. Hereinafter, the present invention will be more specifically described by way of Examples and Reference Examples, however, the scope of the present invention is not limited to these Examples. Incidentally, the proton nuclear magnetic resonance spectrum (1H NMR) used in the Examples and Reference Examples was measured at 270 MHz, 300 MHz or 400 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. Incidentally, the multiplicity of signals is expressed in conventional terms, and the term “br” indicates an apparent broad signal. Also, each synthesized compound was named using ChemBioDraw Ultra ver. 12.0. Reference Example 1 3-(Piperidin-4-ylmethyl)-3,4-dihydroquinazolin-2(1H)-one hydrochloride (Compound R1) Step 1: After 2-nitrobenzaldehyde (5.60 g, 37.1 mmol) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (8.00 g, 37.3 mmol) were stirred in methanol at room temperature for 1 hour, sodium cyanoborohydride (4.70 g, 74.8 mmol) was added thereto, and the resulting mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby tert-butyl 4-[(2-nitrobenzylamino)methyl]-piperidine-1-carboxylate (5.00 g, yield: 40%) was obtained. Step 2: Tert-butyl 4-[(2-nitrobenzylamino)methyl]-piperidine-1-carboxylate (10.0 g, 28.6 mmol) obtained in Step 1 was dissolved in methanol (100 mL), and palladium-carbon (10.0 wt %, 1.00 g) was added thereto, and the resulting mixture was stirred under a hydrogen gas (atmospheric pressure) atmosphere at room temperature for 12 hours. After completion of the reaction, the reaction mixture was treated with diatomaceous earth, and then, the solvent was evaporated under reduced pressure, whereby tert-butyl 4-[(2-aminobenzylamino)methyl]-piperidine-1-carboxylate (8.00 g, yield: 88%) was obtained. Step 3: Tert-butyl 4-[(2-aminobenzylamino)methyl]-piperidine-1-carboxylate (10.6 g, 27.7 mmol) obtained in Step 2, N,N′-carbonyldiimidazole (11.2 g, 69.3 mmol) and triethylamine (8.11 mL, 58.2 mmol) were refluxed in acetonitrile (110 mL) for 2 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the deposited solid was collected by filtration, whereby tert-butyl 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)piperidine-1-carboxylate (8.63 g, yield: 93%) was obtained. ESI-MS m/z: 346 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 7.20-7.15 (m, 1H), 7.05-7.03 (m, 1H), 6.97-6.88 (m, 2H), 6.67 (d, J=7.2 Hz, 1H), 4.46 (s, 2H), 4.09 (brs, 2H), 3.31 (br s, 2H), 2.73-2.64 (m, 2H), 1.97-1.84 (m, 1H), 1.70-1.66 (m, 2H), 1.45 (s, 9H), 1.28-1.12 (m, 2H) Step 4: To tert-butyl 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)piperidine-1-carboxylate (13.0 g, 37.6 mmol) obtained in Step 3, a hydrochloric acid-dioxane solution (4.00 mol/L, 150 mL) was added in an ice bath, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, whereby the title Compound R1 (10.5 g, yield: 99%) was obtained. ESI-MS m/z: 246 (M+H)+ Reference Example 2 2-{[2-Oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]methyl}benzonitrile hydrochloride (Compound R2) Step 1: Tert-butyl 4-{[1-(2-cyanobenzyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (2.27 g, 85%) was obtained in the same manner as in Step 1 of Example 1 using tert-butyl 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)piperidine-1-carboxylate obtained in Step 3 of Reference Example 1 and 2-cyanobenzyl bromide. ESI-MS m/z: 461 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 7.68 (d, J=7.8 Hz, 1H), 7.49 (t, J=7.3 Hz, 1H), 7.33 (t, J=7.3 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.14-7.08 (m, 2H), 6.97 (t, J=7.3 Hz, 1H), 6.55 (d, J=7.8 Hz, 1H), 5.33 (s, 2H), 4.51 (s, 2H), 4.14-4.09 (br m, 2H), 3.43-3.35 (br m, 2H), 2.74-2.67 (br m, 2H), 1.97-1.90 (m, 1H), 1.74-1.67 (m, 2H), 1.45 (s, 9H), 1.26-1.19 (m, 2H) Step 2: The title Compound R2 (1.79 g, 92%) was obtained in the same manner as in Step 4 of Reference Example 1 using tert-butyl 4-{[1-(2-cyanobenzyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1. ESI-MS m/z: 361 (M+H)+ Reference Example 3 5-Iodo-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1,2-dihydropyridine-3-carbonitrile (Compound R3) Step 1: 2-Hydroxynicotinonitrile (1.00 g, 8.33 mmol), iodine (2.54 g, 9.99 mmol) and potassium carbonate (1.38 g, 9.99 mmol) were stirred overnight in DMF (10 mL) at room temperature. To the reaction mixture, water was added, and the resulting mixture was extracted with a chloroform/2-propanol mixed solvent. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. To the resulting residue, (2-chloromethoxyethyl)trimethylsilane (SEM-Cl) (1.67 g, 10.0 mmol) and potassium hydroxide (560 mg, 10.0 mmol) were added, and the resulting mixture was stirred in THF (25.0 mL) at room temperature for 3 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (an ethyl acetate/heptane mixed solvent), whereby the title Compound R3 (372 mg, yield: 12%) was obtained. ESI-MS m/z: 377 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 7.89 (d, J=2.6 Hz, 1H), 7.86 (d, J=2.6 Hz, 1H), 5.31 (s, 2H), 3.64 (t, J=8.3 Hz, 2H), 0.95 (t, J=8.3 Hz, 2H), −0.01 (s, 9H) Reference Example 4 Tert-butyl 3-iodophenylsulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate (Compound R4) Step 1: 3-Iodobenzenesulfonamide (100 mg, 0.353 mmol), di-tert-butyl dicarbonate (Boc2O) (116 mg, 0.530 mmol), DMAP (8.63 mg, 0.071 mmol) and triethylamine (54.0 mg, 0,530 mmol) were stirred in dichloromethane (1.50 mL) at room temperature for 3 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a methanol/chloroform mixed solvent), whereby tert-butyl 3-iodophenylsulfonylcarbamate (100 mg, yield: 74%) was obtained. ESI-MS m/z: 384 (M+H)+ Step 2: The title Compound R4 (120 mg, yield: 90%) was obtained in the same manner as in Step 1 of Example 14 using tert-butyl 3-iodophenylsulfonylcarbamate obtained in Step 1. 1H-NMR (300 MHz, CDCl3, δ): 8.36-8.35 (m, 1H), 8.02-7.98 (m, 1H), 7.95-7.91 (m, 1H), 7.28-7.23 (m, 1H), 5.30 (s, 2H), 3.59-3.54 (m, 2H), 1.37 (s, 9H), 1.03-0.98 (m, 2H), 0.00 (s, 9H) ESI-MS m/z: 514 (M+H)+ Reference Example 5 Tert-butyl 4-oxo-3,4-dihydroquinazoline-7-carboxylate (Compound R5) 4-Tert-butyl-1-methyl-1-aminoterephthalic acid (55 mg, 0.22 mmol) obtained by the method described in Journal of Medicinal Chemistry 1999, 42, 545 and formamidine acetate (46 mg, 0.44 mmol) were refluxed overnight in ethanol (2.0 ml). After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound R5 (28 mg, yield: 51%) was obtained. ESI-MS m/z: 247 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.37 (s, 1H), 8.34 (d, J=8.4 Hz, 1H), 8.11-8.07 (m, 2H), 1.64 (s, 9H) Reference Example 6 4-Chloro-5H-pyrido[4,5-b][1,4]oxazin-6(7H)-one (Compound R6) Step 1: Methyl glycolate (488 mg, 5.4 mmol) was dissolved in DMF (20 mL), and in an ice bath, sodium hydride (about 60 wt %, 268 mg) was added thereto, and the resulting mixture was stirred for 30 minutes. Thereafter, a DMF solution (2.0 mL) of 4,6-dichloro-5-nitropyrimidine (1.0 g, 5.1 mmol) was added dropwise thereto, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, ice water was added, and then, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby methyl 2-(6-chloro-5-nitropyrimidin-4-yloxy)acetate (584 mg, 46%) was obtained. 1H-NMR (400 MHz, CDCl3 δ): 8.62 (s, 1H), 5.08 (s, 2H), 3.80 (s, 3H) Step 2: Methyl 2-(6-chloro-5-nitropyrimidin-4-yloxy)acetate (0.58 g, 2.3 mmol) obtained in Step 1 and reduced iron (654 mg, 12 mmol) were heated in acetic acid (15 mL) at 80° C. for 6 hours. The reaction mixture was treated with diatomaceous earth, and a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby the title Compound R6 (270 mg, yield: 62%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 11.0 (br s, 1H), 8.28 (s, 1H), 4.95 (s, 2H) Reference Example 7 8-Chloro-[1,2,4]triazolo[4,3-a]pyrazin-3(2H)-one (Compound R7) 2-Chloro-3-hydrazinylpyrazine (710 mg, 0.49 mmol) obtained by the method described in WO2008/130951 was dissolved in acetonitrile (12 mL), and 1,1′-carbonyldiimidazole (1.6 g, 9.8 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 4 hours. To the reaction mixture, water was added, and the deposited solid was collected by filtration, whereby the title Compound R7 (117 mg, yield: 14%) was obtained. 1H-NMR (400 MHz, DMSO-d6, δ): 13.2 (br s, 1H), 7.93 (d, J=4.0 Hz, 1H), 7.34 (d, J=4.0 Hz, 1H) Reference Example 8 2,3-Difluoroisonicotinamide (Compound R8) 2,3-Difluoroisonicotinic acid (330 mg, 2.1 mmol), an ammonia-methanol solution (about 7.0 mol/L, 5.9 mL), O-(7-aza-1H-benzotriazol-1-yl)-N,N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.6 g, 4.2 mmol) and diisopropylethylamine (1.4 mL) were stirred in DMF (3.0 mL) at room temperature for 5 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. A residue obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound R8 (239 mg, yield: 73%) was obtained. 1H-NMR (400 MHz, CDCl3, δ): 8.11 (d, J=6.8 Hz, 1H), 7.82-7.77 (m, 1H), 6.59 (br s, 1H), 6.24 (br s, 1H) Reference Example 9 8-Chloropyrido[3,4-d]pyrimidin-4(3H)-one (Compound R9) 3-Amino-2-chloroisonicotinamide (170 mg, 0.99 mmol) obtained by the method described in Journal of Heterocyclic Chemistry, 2001, 38, 99 was stirred in ethyl triethyl orthoformate (3.0 mL) at 150° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and a diethyl ether/ethyl acetate (1/1) mixed solvent was added thereto, and the resulting solid was collected by filtration, whereby the title Compound R9 (148 mg, yield: 82%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 12.8 (br s, 1H), 8.42 (d, J=5.1 Hz, 1H), 8.30 (s, 1H), 7.95 (d, J=5.1 Hz, 1H) Reference Example 10 7,8-Dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (Compound R10) Ethyl 4-oxotetrahydro-2H-pyran-3-carboxylate (500 mg, 2.9 mmol) obtained by the method described in US2011/82138, formamidine acetate (300 mg, 2.9 mmol), and sodium methoxide (500 mg, 9.3 mmol) were refluxed in methanol (20 mL) for 6 hours. To the reaction mixture, water was added, and then, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated under reduced pressure, whereby the title Compound R10 (200 mg, yield: 45%) was obtained. ESI-MS m/z: 153 (M+H)+ Reference Example 11 4,7-Dichloropyrido [4,3-d]pyrimidine (Compound R11) Step 1: Methyl 4-amino-6-chloronicotinate (15 g, 80 mmol) obtained by the method described in US2012/184562 and sodium hydroxide (13 g, 322 mmol) were stirred in a mixed solution of methanol (100 mL) and water (50 mL) at room temperature for 12 hours. The reaction mixture was adjusted to pH 6 with a 6.0 mol/L aqueous hydrochloric acid solution, and the resulting solid was collected by filtration, whereby 4-amino-6-chloronicotinic acid (8.0 g, yield: 58%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 8.47 (s, 1H), 7.52 (br s, 2H), 6.75 (s, 1H) Step 2: 4-Amino-6-chloronicotinic acid (7.0 g, 41 mmol) obtained in Step 1 was stirred in thionyl chloride (100 mL) at 80° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, whereby crude 4-amino-6-chloronicotinoyl chloride was obtained. This compound was used in the subsequent reaction without particularly performing further purification. Step 3: The crude 4-amino-6-chloronicotinoyl chloride obtained in Step 2 was stirred in an aqueous ammonia solution (about 28%, 70 mL) at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate, and then, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography using a (dichloromethane/methanol) mixed solvent, whereby 4-amino-6-chloronicotinamide (4.5 g, yield: 72%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 8.37 (s, 1H), 7.97 (br s, 1H), 7.51 (br s, 2H), 7.24 (br s, 1H), 6.65 (s, 1H) Step 4: 4-Amino-6-chloronicotinamide (4.5 g, 25 mmol) obtained in Step 3 was stirred in trimethyl orthoformate (20 mL) at 150° C. for 5 hours. The reaction mixture was cooled to 0° C., and the resulting solid was collected by filtration, whereby 7-chloropyrido[4,3-d]pyrimidin-4(3H)-one (3.2 g, yield: 70%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 12.8 (br s, 1H), 9.10 (s, 1H), 8.34 (s, 1H), 7.73 (s, 1H) Step 5: 7-chloropyrido[4,3-d]pyrimidin-4(3H)-one (2.0 g, 11 mmol) obtained in Step 4 and N,N-dimethylaniline (0.1 mL) was refluxed in phosphorus oxychloride (60 mL) for 15 hours. After the reaction mixture was diluted with dichloromethane, ice water was added thereto, and the resulting mixture was extracted. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, whereby the crude title Compound R11 (1.7 g) was obtained. This compound was used in the subsequent reaction without particularly performing further purification. Reference Example 12 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (Compound 53) The title Compound 53 was synthesized according to the method described in Chemical & Pharmaceutical Bulletin 1990, 38(6), 1591. Example 1 2-[(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzamide (Compound 1) Step 1: 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (300 mg, 0.69 mmol) obtained by the method described in Chemical & Pharmaceutical Bulletin 1990, 38(6), 1591 was dissolved in DMF (3.0 mL), and sodium hydride (about 60 wt %, 33 mg) and methyl 2-(bromomethyl)-benzoate (190 mg, 0.83 mmol) were sequentially added thereto in an ice bath. After the resulting mixture was stirred at room temperature for 2 hours, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby methyl 2-[(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzoate (355 mg, yield: 88%) was obtained. ESI-MS m/z: 582 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.66 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.41-7.36 (m, 1H), 7.32-7.27 (m, 2H), 7.15-7.06 (m, 4H), 6.99-6.94 (m, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.52 (s, 2H), 4.57 (s, 2H), 4.22-4.15 (br m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), 3.50 (d, J=7.8 Hz, 2H), 3.12-3.02 (m, 2H), 2.18-2.08 (m, 1H), 1.96-1.87 (br m, 2H), 1.66-1.55 (br m, 2H) Step 2: Methyl 2-[3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzoate (100 mg, 0.17 mmol) obtained in Step 1 and lithium hydroxide monohydrate (12 mg, 0.52 mmol) were stirred in an ethanol (0.50 mL)/water (0.50 mL) mixed solvent at room temperature for 2 hours. To the reaction mixture, 3.0 mol/L hydrochloric acid was added under ice cooling, and the deposited solid was collected by filtration and dried under reduced pressure, whereby 2-[(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzoic acid (90 mg, yield: 92%) was obtained. 1H-NMR (400 MHz, DMSO-d6, δ): 13.16 (br s, 1H), 8.70 (s, 1H), 7.96 (d, J=6.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.36-7.32 (m, 1H), 7.30-7.18 (m, 3H), 7.13-7.08 (m, 1H), 7.02-6.94 (m, 2H), 6.51 (d, J=7.8 Hz, 1H), 5.38 (s, 2H), 4.70-4.50 (m, 4H), 3.97 (s, 3H), 3.92 (s, 3H), 3.48-3.36 (m, 4H), 2.26-2.19 (m, 1H), 1.92-1.84 (m, 2H), 1.49-1.39 (m, 2H) Step 3: 2-[(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzoic acid (40 mg, 0.07 mmol) obtained in Step 2, EDC hydrochloride (20 mg, 0.11 mmol), HOBt.H2O (16 mg, 0.11 mmol) and an aqueous ammonia solution (about 28%, 0.04 mL) were stirred in DMF (1.0 mL) at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 1 (35 mg, yield: 88%) was obtained. ESI-MS m/z: 567 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.65 (s, 1H), 7.58-7.53 (m, 1H), 7.33-7.28 (m, 1H), 7.28-7.24 (m, 2H), 7.23 (s, 1H), 7.20-7.16 (m, 1H), 7.11-7.09 (m, 1H), 7.07 (s, 1H), 7.01-6.97 (m, 1H), 6.84 (d, J=7.7 Hz, 1H), 6.65 (br s, 1H), 5.72 (br s, 1H), 5.34 (s, 2H), 4.53 (s, 2H), 4.21-4.11 (br m, 2H), 4.02 (s, 3H), 3.97 (s, 3H), 3.45 (d, J=7.3 Hz, 2H), 3.11-3.00 (m, 2H), 2.13-2.04 (m, 1H), 1.90-1.85 (m, 2H), 1.55-1.50 (m, 2H) Example 2 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-1-[(tetrahydrofuran-2-yl)methyl]-3,4-dihydroquinazolin-2(1H)-one (Compound 2) The title Compound 2 (95 mg, yield: 40%) was obtained in the same manner as in Example 1 using 2-(bromomethyl)tetrahydrofuran. ESI-MS m/z: 518 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.64 (s, 1H), 7.26-7.23 (m, 2H), 7.12-6.95 (m, 4H), 4.50 (d, J=14 Hz, 1H), 4.35 (d, J=14 Hz, 1H), 4.26-4.11 (m, 5H), 4.02 (s, 3H), 3.98 (s, 3H), 3.95-3.84 (m, 2H), 3.79-3.71 (m, 1H), 3.51-3.34 (m, 1H), 3.09-2.98 (m, 2H), 2.10-1.50 (m, 9H) Example 3 2-[(3-{[1-([1,3]Dioxo[4,5-g]quinazolin-8-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzo nitrile (Compound 3) [1,3]Dioxo[4,5-g]quinazolin-8(7H)-one (24 mg, 0.13 mmol) obtained by the method described in Journal of Medicinal Chemistry, 2010, 53, 8089, BOP (84 mg, 0.19 mmol) and DBU (58 mg, 0.38 mmol) were stirred in DMF (1.0 mL) at room temperature for 1 hour. Thereafter, Compound R2 (50 mg, 0.18 mmol) obtained in Reference Example 2 was added thereto, and the resulting mixture was stirred at 80° C. for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 3 (26 mg, yield: 39%) was obtained. ESI-MS m/z: 533 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.52-7.47 (m, 1H), 7.36-7.32 (m, 1H), 7.26-7.23 (m, 1H), 7.20 (s, 1H), 7.16-7.10 (m, 3H), 7.01-6.97 (m, 1H), 6.57 (d, J=7.8 Hz, 1H), 6.11 (s, 2H), 5.36 (s, 2H), 4.57 (s, 2H), 4.14-4.09 (br m, 2H), 3.50 (d, J=6.8 Hz, 2H), 3.06-2.99 (m, 2H), 2.14-2.07 (m, 1H), 1.94-1.88 (m, 2H), 1.65-1.61 (m, 2H) Example 4 2-[(3-{[1-(Benzo[d][1,2,3]triazin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzonitrile (Compound 4) The title Compound 4 (18 mg, yield: 29%) was obtained in the same manner as in Example 3 using Compound R2 and benzo[d][1,2,3]triazin-4(3H)-one. ESI-MS m/z: 490 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.26 (d, J=8.1 Hz, 1H), 7.94-7.87 (m, 2H), 7.77-7.67 (m, 2H), 7.54-7.47 (m, 1H), 7.37-7.24 (m, 2H), 7.16-7.10 (m, 2H), 7.02-6.96 (m, 1H), 6.58 (d, J=8.1 Hz, 1H), 5.35 (s, 2H), 4.57-4.54 (m, 4H), 3.50 (d, J=7.3 Hz, 2H), 3.34-3.23 (m, 2H), 2.25-2.18 (m, 1H), 2.02-1.94 (m, 2H), 1.72-1.59 (m, 2H) Example 5 2-[(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-6-(methylsulfonyl)-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)methyl]benzonitrile (Compound 5) Step 1: To a THF solution (10.0 mL) of 5-(methylsulfanyl)-2-nitrobenzoic acid (800 mg, 3.75 mmol), a borane-dimethyl sulfide complex (1.14 g, 15.0 mmol) was added at room temperature, and the resulting mixture was refluxed for 1.5 hours. The reaction mixture was cooled to 0° C., and hydrochloric acid (1.00 mol/L, 10.0 mL) was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent under reduced pressure was dissolved in chloroform (20.0 mL) and DMF (1.00 mL), and manganese dioxide (6.00 g, 69.0 mmol) was added thereto, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was treated with diatomaceous earth, and the solvent was evaporated under reduced pressure, thereby obtaining crude 5-(methylthio)-2-nitrobenzaldehyde. By using this crude compound, tert-butyl 4-{[6-(methylthio)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (850 mg, yield: 58%) was obtained in the same manner as in Reference Example 1. ESI-MS m/z: 392 (M+H)+ Step 2: Tert-butyl 4-{[6-(methylthio)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (400 mg, 1.02 mmol) obtained in Step 1 was dissolved in dichloromethane (10.0 mL), and a saturated aqueous sodium bicarbonate solution (10.0 mL) and meta-chloroperoxybenzoic acid (about 70 wt %, 630 mg) were sequentially added thereto in an ice bath, and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby tert-butyl 4-{[6-(methylsulfonyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (433 mg, quantitative yield) was obtained. ESI-MS m/z: 424 (M+H)+ Step 3: Tert-butyl 4-{[6-(methylsulfonyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-y l]methyl}piperidine-1-carboxylate (200 mg, 0.47 mmol) obtained in Step 2 was dissolved in ethyl acetate (3.0 mL), and a hydrochloric acid-ethyl acetate solution (4.0 mol/L, 3.5 mL) was added thereto in an ice bath. After the resulting mixture was stirred at room temperature for 2 hours, the solvent was evaporated under reduced pressure. To the resulting residue, 4-chloro-6,7-dimethoxyquinazoline (117 mg, 0.52 mmol) and diisopropylethylamine (183 mg, 1.4 mmol) were added, and the resulting mixture was refluxed in 2-propanol (5.0 mL) for 2 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby 3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-6-(methylsulfonyl)-3,4-dihydroquinazolin-2 (1H)-one (116 mg, yield: 48%) was obtained. ESI-MS m/z: 512 (M+H)+ Step 4: The title Compound 5 (23 mg, yield: 24%) was obtained in the same manner as in Example 1 using 3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-6-(methylsulfonyl)-3,4-dihydroquinazolin-2(1H)-one obtained in Step 3. ESI-MS m/z: 627 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.66 (s, 1H), 7.72-7.69 (m, 3H), 7.55-7.50 (m, 1H), 7.41-7.36 (m, 1H), 7.26-7.22 (m, 2H), 7.09 (s, 1H), 6.73-6.70 (m, 1H), 5.39 (s, 2H), 4.62 (s, 2H), 4.25-4.20 (m, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.52 (d, J=7.2 Hz, 2H), 3.15-3.07 (m, 2H), 3.03 (s, 3H), 2.24-2.11 (m, 1H), 1.94-1.90 (m, 2H), 1.66-1.55 (m, 2H) Example 6 3-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (Compound 6) Step 1: 3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (50 mg, 0.12 mmol) obtained by the method described in Chemical & Pharmaceutical Bulletin 1990, 38(6), 1591, copper(I) iodide (22 mg, 0.12 mmol), trans-1,2-cyclohexanediamine (13 mg, 0.12 mmol), 3-iodobenzonitrile (53 mg, 0.23 mmol) and tripotassium phosphate (49 mg, 0.23 mmol) were stirred in 1,4-dioxane (1.0 mL) at 100° C. for 5 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was treated with diatomaceous earth and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 6 (51 mg, yield: 82%) was obtained. ESI-MS m/z: 535 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.66 (s, 1H), 7.73-7.59 (m, 4H), 7.24 (s, 1H), 7.16-7.00 (m, 4H), 6.17 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 4.24-4.14 (br m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.47 (d, J=7.3 Hz, 2H), 3.10-3.06 (br m, 2H), 2.18-2.10 (m, 1H), 1.93-1.90 (m, 2H), 1.62-1.54 (m, 2H) Example 7 5-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-fluorobenzonitrile (Compound 7) The title Compound 7 (40 mg, yield: 63%) was obtained in the same manner as in Example 6 using 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 553 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.67 (s, 1H), 7.66-7.57 (m, 2H), 7.39-7.31 (m, 1H), 7.24 (s, 1H), 7.16-7.01 (m, 4H), 6.19 (d, J=8.4 Hz, 1H), 4.61 (s, 2H), 4.21-4.17 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.46 (d, J=7.0 Hz, 2H), 3.12-3.05 (m, 2H), 2.14-2.09 (m, 1H), 1.93-1.89 (m, 2H), 1.65-1.52 (m, 2H) Example 8 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-1-(3-nitrophenyl)-3,4-dihydroquinazolin-2(1H)-one (Compound 8) The title Compound 8 (40 mg, yield: 63%) was obtained in the same manner as in Example 6 using l-iodo-3-nitrobenzene. ESI-MS m/z: 555 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.67 (s, 1H), 8.32-8.27 (m, 1H), 8.26-8.23 (m, 1H), 7.74-7.66 (m, 2H), 7.26-7.24 (m, 1H), 7.17-7.01 (m, 4H), 6.20 (d, J=8.1 Hz, 1H), 4.63 (s, 2H), 4.24-4.15 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.48 (d, J=7.0 Hz, 2H), 3.15-3.03 (m, 2H), 2.20-2.08 (m, 1H), 1.97-1.88 (m, 2H), 1.66-1.49 (m, 2H) Example 9 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 9) The title Compound 9 (29 mg, yield: 47%) was obtained in the same manner as in Example 6 using 4-iodopicolinonitrile. ESI-MS m/z: 536 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.80 (d, J=5.2 Hz, 1H), 8.66 (s, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.66 (dd, J=5.2, 1.9 Hz, 1H), 7.24-7.07 (m, 5H), 6.39 (d, J=8.1 Hz, 1H), 4.59 (s, 2H), 4.23-4.15 (br m, 2H), 4.02 (s, 3H), 3.99 (d, J=3.3 Hz, 3H), 3.47 (d, J=7.0 Hz, 2H), 3.13-3.03 (m, 2H), 2.19-2.05 (m, 1H), 1.94-1.85 (m, 2H), 1.66-1.49 (m, 2H) Example 10 2-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)isonicotinonitrile (Compound 10) The title Compound 10 (580 mg, yield: 94%) was obtained in the same manner as in Example 6 using 2-iodoisonicotinonitrile. ESI-MS m/z: 536 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.78 (d, J=4.9 Hz, 1H), 8.66 (s, 1H), 7.86 (s, 1H), 7.55 (d, J=4.9 Hz, 1H), 7.25 (s, 1H), 7.17-7.03 (m, 4H), 6.27 (d, J=7.8 Hz, 1H), 4.62 (s, 2H), 4.24-4.14 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.48 (d, J=7.8 Hz, 2H), 3.12-3.03 (m, 2H), 2.20-2.08 (m, 1H), 1.97-1.85 (m, 2H), 1.67-1.52 (m, 2H) Example 11 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)pyrimidine-2-carbonitrile (Compound 11) Step 1: The title Compound 11 (8.0 mg, yield: 13%) was obtained in the same manner as in Example 6 using 3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one obtained by the method described in Chemical & Pharmaceutical Bulletin 1990, 38 (6), 1591 and 4-bromopyrimidine-2-carbonitrile. ESI-MS m/z: 537 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.77 (d, J=5.9 Hz, 1H), 8.66 (s, 1H), 8.19 (d, J=5.9 Hz, 1H), 7.31-7.21 (m, 4H), 7.14 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 4.49 (s, 2H), 4.22-4.14 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.50 (d, J=7.8 Hz, 2H), 3.12-3.01 (m, 2H), 2.13-2.03 (m, 1H), 1.89-1.79 (m, 2H), 1.64-1.52 (m, 2H) Example 12 5-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (Compound 12) Step 1: 5-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}1,2-dihydropyridine-3-carbonitrile (80 mg, yield: 51%) was obtained in the same manner as in Example 6 using Compound R3 obtained in Reference Example 3. ESI-MS m/z: 682 (M+H)+ Step 2: 5-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}1,2-dihydropyridine-3-carbonitrile (80 mg, 0.12 mmol) obtained in Step 1 and trifluoroacetic acid (740 mg, 6.5 mmol) were stirred in dichloromethane (1.0 mL) for 5 hours under ice cooling. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a methanol/chloroform mixed solvent), whereby the title Compound 12 (20 mg, yield: 31%) was obtained. ESI-MS m/z: 552 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.66 (s, 1H), 7.93 (d, J=2.7 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H), 7.25 (s, 1H), 7.21-7.14 (m, 2H), 7.10-7.04 (m, 2H), 6.44 (d, J=8.1 Hz, 1H), 4.58 (s, 2H), 4.24-4.16 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.46 (d, J=7.3 Hz, 2H), 3.15-3.04 (m, 2H), 2.18-2.09 (m, 1H), 1.94-1.85 (m, 2H), 1.66-1.51 (m, 2H) Example 13 3-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzenesulfonamide (Compound 13) Step 1: Tert-butyl 3-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)phenylsulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate (98 mg, yield: 86%) was obtained in the same manner as in Example 6 using Compound R4 obtained in Reference Example 4. ESI-MS m/z: 820 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.66 (s, 1H), 8.08-8.04 (m, 1H), 7.99-7.97 (m, 1H), 7.66-7.62 (m, 2H), 7.24 (s, 1H), 7.14-6.99 (m, 4H), 6.18-6.14 (m, 1H), 5.28 (s, 2H), 4.59 (s, 2H), 4.21-4.11 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.61-3.55 (m, 2H), 3.46 (d, J=7.0 Hz, 2H), 3.13-3.03 (m, 2H), 2.16-2.06 (m, 1H), 1.95-1.87 (m, 2H), 1.65-1.53 (m, 2H), 1.37-1.28 (m, 9H), 0.90-0.85 (m, 2H), −0.03 (s, 9H) Step 2: The title Compound 13 (25 mg, yield: 37%) was obtained in the same manner as in Step 2 of Example 12 using tert-butyl 3-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)phenylsulfonyl{[2-(trimethylsilyl)ethoxy]methyl}carbamate obtained in Step 1. ESI-MS m/z: 589 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.64 (s, 1H), 7.96-7.90 (m, 2H), 7.65-7.59 (m, 1H), 7.56-7.52 (m, 1H), 7.24 (s, 1H), 7.14-6.97 (m, 4H), 6.20-6.15 (m, 1H), 5.16 (br s, 2H), 4.61 (s, 2H), 4.22-4.13 (m, 2H), 4.01 (s, 3H), 3.97 (s, 3H), 3.45 (d, J=7.3 Hz, 2H), 3.13-3.03 (m, 2H), 2.18-2.07 (m, 1H), 1.94-1.85 (m, 2H), 1.64-1.49 (m, 2H) Example 14 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinamide (Compound 14) Step 1: Ethyl 4-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinate (235 mg, yield: 70%) was obtained in the same manner as in Example 6 using ethyl 4-iodopicolinate. ESI-MS m/z: 555 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.89 (d, J=5.1 Hz, 1H), 8.67 (s, 1H), 8.17 (s, 1H), 7.59 (d, J=5.1 Hz, 1H), 7.28-7.03 (m, 5H), 6.31 (d, J=8.1 Hz, 1H), 4.61 (s, 2H), 4.49 (q, J=7.1 Hz, 2H), 4.25-4.14 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.48 (d, J=7.3 Hz, 2H), 3.14-3.01 (m, 2H), 2.20-2.06 (m, 1H), 1.97-1.85 (m, 2H), 1.63-1.55 (m, 2H), 1.44 (t, J=7.1 Hz, 3H) Step 2: The title Compound 14 (40 mg, yield: 80%) was obtained in the same manner as in Example 1 using ethyl 4-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinate obtained in Step 1. ESI-MS m/z: 554 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.71 (d, J=5.1 Hz, 1H), 8.66 (s, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.86 (br s, 1H), 7.62 (dd, J=5.1, 2.0 Hz, 1H), 7.23 (s, 1H), 7.17-7.01 (m, 4H), 6.32 (d, J=8.1 Hz, 1H), 5.71 (br s, 1H), 4.59 (s, 2H), 4.23-4.14 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.47 (d, J=7.3 Hz, 2H), 3.15-3.04 (m, 2H), 2.19-2.06 (m, 1H), 1.96-1.85 (m, 2H), 1.66-1.51 (m, 2H) Example 15 2-Cyano-4-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzoic acid (Compound 15) Step 1: 2-Bromo-5-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (630 mg, yield: 89%) was obtained in the same manner as in Example 6 using 2-bromo-5-iodobenzonitrile. ESI-MS m/z: 613 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.66 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.47 (dd, J=8.4, 2.6 Hz, 1H), 7.23 (s, 1H), 7.16-7.04 (m, 4H), 6.22 (d, J=8.1 Hz, 1H), 4.60 (s, 2H), 4.21-4.16 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.46 (d, J=7.0 Hz, 2H), 3.13-3.03 (m, 2H), 2.17-2.07 (m, 1H), 1.94-1.87 (m, 2H), 1.61-1.54 (m, 2H) Step 2: 2-Bromo-5-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (200 mg, 0.33 mmol) obtained in Step 1, palladium acetate (7.3 mg, 0.03 mmol), 1,3-bis(diphenylphosphino)propane (DPPP) (130 mg, 0.03 mmol), potassium carbonate (90 mg, 0.65 mmol) and 1-propanol (3.0 mL) were stirred in DMF (1.0 mL) under a carbon monoxide atmosphere (atmospheric pressure) at 80° C. for 4 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was treated with diatomaceous earth, and then, the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (an ethyl acetate/heptane mixed solvent), whereby propyl 2-cyano-4-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzoate (175 mg, yield: 86%) was obtained. ESI-MS m/z: 621 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.65 (s, 1H), 8.28-8.25 (m, 1H), 7.84-7.82 (m, 1H), 7.73-7.69 (m, 1H), 7.23 (s, 1H), 7.18-7.02 (m, 4H), 6.23-6.20 (m, 1H), 4.61 (s, 2H), 4.41 (t, J=6.6 Hz, 2H), 4.22-4.15 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.49-3.44 (m, 2H), 3.13-3.03 (m, 2H), 2.18-2.08 (m, 1H), 1.94-1.83 (m, 2H), 1.64-1.53 (m, 2H), 1.28-1.24 (m, 2H), 1.07 (t, J=7.5 Hz, 3H) Step 3: The title Compound 15 (24 mg, yield: 16%) was obtained in the same manner as in Step 2 of Example 1 using propyl 2-cyano-4-(3-{[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1 (2H)-yl)benzoate obtained in Step 2. ESI-MS m/z: 579 (M+H)+, 1H-NMR (300 MHz, DMSO-d6, δ): 8.59 (s, 1H), 8.30 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.01 (d, J=1.8 Hz, 1H), 7.77 (dd, J=8.4, 2.2 Hz, 1H), 7.28-7.15 (m, 3H), 7.13-6.98 (m, 2H), 6.16 (d, J=8.1 Hz, 1H), 4.62 (s, 2H), 4.41-4.30 (m, 2H), 3.94 (s, 3H), 3.89 (s, 3H), 3.40-3.19 (m, 4H), 2.16-2.13 (m, 1H), 1.86-1.82 (m, 2H), 1.43-1.39 (m, 2H) Example 16 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-1-(tetrahydro-2H-pyran-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Compound 16) Step 1: Tert-butyl 4-[(2-aminobenzylamino)methyl]-piperidine-1-carboxylate (1.0 g, 3.1 mmol) obtained in Step 2 of Reference Example 1 was dissolved in methanol (50 mL), and in an ice bath, tetrahydro-4H-pyran-4-one (627 mg, 6.3 mmol) and sodium borohydride (481 mg, 12 mmol) were added thereto, and the resulting mixture was stirred for 2 hours, and thereafter further stirred at room temperature for 2 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby crude tert-butyl 4-{[2-(tetrahydro-2H-pyran-4-ylamino)benzylamide]methyl}piperidine-1-carboxylate was obtained. This compound was dissolved in dioxane (50 mL), and 1,1′-carbonyldiimidazole (0.4 g, 2.5 mmol) was added thereto, and the resulting mixture was stirred at 100° C. for 2 days. To the reaction mixture, water was added, and the resulting mixture was extracted with ethyl acetate. Then, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by preparative reverse-phase HPLC (an acetonitrile/water mixed solvent), whereby tert-butyl 4-{[2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (50 mg, yield: 4%) was obtained. ESI-MS m/z: 430 (M+H)+ Step 2: The title Compound 16 (10 mg, yield: 8%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-{[2-oxo-1-(tetrahydro-2H-pyran-4-yl)-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1. ESI-MS m/z: 518 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.65 (s, 1H), 7.36-7.26 (m, 2H), 7.19-7.06 (m, 4H), 4.29 (s, 2H), 4.28-4.17 (m, 3H), 4.17-4.07 (m, 2H), 4.03 (s, 3H), 3.90 (s, 3H), 3.60-3.45 (m, 2H), 3.40 (d, J=7.2 Hz, 2H), 3.16-3.05 (m, 2H), 2.86-2.72 (m, 2H), 2.17-1.96 (m, 1H), 1.93-1.72 (m, 4H), 1.65-1.42 (m, 2H) Example 17 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)azetidin-3-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 17) The title Compound 17 (12 mg, yield: 13%) was obtained in the same manner as in Step 3 of Example 5 after performing a treatment according to Reference Example 1 using 2-nitrobenzaldehyde and tert-butyl 3-(aminomethyl)azetidine-1-carboxylate. ESI-MS m/z: 508 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.81 (d, J=4.8 Hz, 1H), 8.51 (s, 1H), 7.81-7.80 (m, 1H), 7.64-7.63 (m, 1H), 7.23-7.09 (m, 5H), 6.37 (d, J=8.0 Hz, 1H), 4.68-4.61 (s, 4H), 4.36-4.32 (m, 2H), 4.01 (s, 3H), 3.94 (s, 3H), 3.84 (d, J=8.0 Hz, 2H), 3.32-3.23 (m, 1H) Example 18 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)-4-hydroxypiperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 18) Step 1: Tert-butyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (3.1 g, 13 mmol) obtained by the method described in WO2005/000837 was dissolved in methanol (150 mL), and 2-nitrobenzaldehyde (2.0 g, 13 mmol) and sodium cyanoborohydride (1.3 g, 26 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 12 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. A residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-hydroxy-4-[(2-nitrobenzylamino)methyl]piperidine-1-carboxylate (2.2 g, yield: 40%) was obtained. 1H-NMR (400 MHz, CDCl3, δ): 7.97 (dd, J=8.0, 0.8 Hz, 1H), 7.64-7.45 (m, 3H), 5.32 (s, 1H), 4.10 (s, 2H), 3.86 (br s, 2H), 3.18 (t, J=12 Hz, 2H), 2.59 (s, 2H), 1.55-1.40 (m, 13H) Step 2: The title Compound 18 (14 mg, yield: 17%) was obtained by performing the same treatments as in Reference Example 1, Step 3 of Example 5 and Example 6 sequentially using tert-butyl 4-hydroxy-4-[(2-nitrobenzylamino)methyl]piperidine-1-carboxylate obtained in Step 1. ESI-MS m/z: 552 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.89 (s, 1H), 8.53 (s, 1H), 8.22 (d, J=7.6 Hz, 1H), 7.42-7.34 (m, 4H), 7.22 (s, 1H), 7.10 (s, 1H), 7.06 (d, J=3.2 Hz, 1H), 6.80 (dd, J=7.6, 3.2 Hz, 1H), 4.39 (s, 2H), 3.92 (s, 3H), 3.90 (s, 3H), 3.77-3.72 (m, 2H), 3.51-3.49 (m, 2H), 3.26 (s, 2H), 1.89 (br s, 4H) Example 19 4-{3-[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-ylamino]-2-oxo-3,4-dihydroquinolin-1(2H)-yl}picolinonitrile (Compound 19) Step 1: 3-Amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (490 mg, 2.5 mmol) obtained by the method described in WO2004/98589, tert-butyl 4-oxopiperidine-1-carboxylate (590 mg, 3.0 mmol), triacetoxy sodium borohydride (1.6 g, 7.4 mmol), triethylamine (300 mg, 3.0 mmol) and acetic acid (0.1 mL) were stirred overnight in 1,2-dichloroethane (20 mL) at room temperature. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the organic layer was treated with diatomaceous earth. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby tert-butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)piperidine-1-carboxylate (626 mg, yield: 74%) was obtained. ESI-MS m/z: 346 (M+H)+ Step 2: Tert-butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)piperidine-1-carboxylate (0.64 g, 1.9 mmol) obtained in Step 1 and diisopropylethylamine (599 mg, 4.6 mmol) were dissolved in tetrahydrofuran (7.0 mL), and trifluoroacetic anhydride (778 mg, 3.7 mmol) was added thereto at 0° C. After the resulting mixture was stirred at room temperature for 30 minutes, a saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby tert-butyl 4-[2,2,2-trifluoro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide]piperidine-1-carboxylate (644 mg, yield: 79%) was obtained. ESI-MS m/z: 442 (M+H)+ Step 3: N-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]-2,2,2-trifluoro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (226 mg, yield: 98%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-[2,2,2-trifluoro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide]piperidine-1-carboxylate (192 mg, 0.43 mmol) obtained in Step 2. ESI-MS m/z: 530 (M+H)+ Step 4: N-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]-2,2,2-trifluoro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (226 mg, 0.427 mmol) obtained in Step 3 and lithium hydroxide monohydrate (36 mg, 0.85 mmol) were stirred overnight in a methanol/water mixed solvent (1/1, 4.0 mL) at 60° C. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (a chloroform/methanol mixed solvent), whereby 3-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-ylamino]-3,4-dihydroquinolin-2(1H)-one (132 mg, yield: 71%) was obtained. ESI-MS m/z: 434 (M+H)+ Step 5: The title Compound 19 (12 mg, yield: 19%) was obtained in the same manner as in Example 6 using 3-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-ylamino]-3,4-dihydroquinolin-2(1H)-one obtained in Step 4 and 4-iodopicolinonitrile. ESI-MS m/z: 536 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.83 (d, J=6.0 Hz, 1H), 8.67 (s, 1H), 7.70-7.69 (m, 1H), 7.53-7.51 (m, 1H), 7.34-7.32 (m, 1H), 7.27 (s, 1H), 7.21-7.14 (m, 2H), 7.10 (s, 1H), 6.50 (d, J=11 Hz, 1H), 4.17-4.11 (m, 2H), 4.03 (s, 3H), 3.99 (s, 3H), 3.77 (dd, J=13, 6.0 Hz, 1H), 3.22-3.01 (m, 5H), 1.73-1.67 (m, 2H), 1.28-1.24 (m, 2H) Example 20 3-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (Compound 20) Step 1: Isatoic anhydride (5.0 g, 31 mmol) was dissolved in 1,4-dioxane (40 mL), and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (6.6 g, 31 mmol) and diisopropylethylamine (8.3 g, 64 mmol) were added thereto, and the resulting mixture was stirred at 80° C. for 2 hours. After the reaction mixture was concentrated under reduced pressure, water was added thereto, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, whereby tert-butyl 4-[(2-aminobenzamide)methyl]piperidine-1-carboxylate (10.2 g, quantitative yield) was obtained. 1H-NMR (300 MHz, CDCl3, δ): 7.32-7.29 (m, 1H), 7.23-7.17 (m, 1H), 6.69-6.60 (m, 2H), 6.27 (br s, 1H), 5.50 (br s, 2H), 4.15-4.08 (m, 2H), 3.32-3.27 (m, 2H), 2.73-2.64 (m, 2H), 1.76-1.70 (m, 3H), 1.20-1.10 (m, 2H) Step 2: Tert-butyl 4-[(2-aminobenzamide)methyl]piperidine-1-carboxylate (500 mg, 1.5 mmol) obtained in Step 1 was dissolved in 1,2-dichloroethane (4.0 mL), and diisopropylethylamine (388 mg, 3.0 mmol) and DMAP (9.2 mg, 0.08 mmol) were added thereto. After the resulting mixture was cooled to 0° C., ethyl chloroformate (195 mg, 1.8 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-{[2-(ethoxycarbonylamino)benzamide]methyl}piperidine-1-carboxylate (577 mg, yield: 95%) was obtained. 1H-NMR (300 MHz, CDCl3, δ): 10.4 (br s, 1H), 8.36 (dd, J=8.4, 0.9 Hz, 1H), 7.49-7.40 (m, 2H), 7.04-6.98 (m, 1H), 6.36-6.34 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.17-4.09 (m, 2H), 3.33 (br s, 2H), 2.74-2.66 (m, 2H), 1.75-1.71 (m, 3H), 1.46 (s, 9H), 1.31 (t, J=7.2 Hz, 3H), 1.21-1.11 (m, 2H) Step 3: Tert-butyl 4-{[2-(ethoxycarbonylamino)benzamide]methyl}piperidine-1-carboxylate (0.47 g, 1.2 mmol) obtained in Step 2 and potassium hydroxide (390 mg, 7.0 mmol) were refluxed in ethanol (12 mL) for 30 minutes. To the reaction mixture, water was added, and the resulting mixture was cooled to 0° C., and then neutralized with dilute hydrochloric acid. Then, the resulting solid was collected by filtration, whereby tert-butyl 4-[(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate (343 mg, yield: 82%) was obtained. 1H-NMR (400 MHz, CDCl3, δ): 9.00 (br s, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.65-7.60 (m, 1H), 7.25-7.23 (m, 1H), 7.06-7.04 (m, 1H), 4.13-4.10 (m, 2H), 4.00 (d, J=6.8 Hz, 2H), 2.70-2.64 (m, 2H), 2.04 (br s, 1H), 1.67-1.62 (m, 2H), 1.45 (s, 9H), 1.39-1.27 (m, 2H) Step 4: 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}quinazoline-2,4(1H,3H)-dione (414 mg, yield: 98%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-[(2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 3. 1H-NMR (400 MHz, CDCl3, δ): 9.57 (br s, 1H), 8.66 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 7.65-7.61 (m, 1H), 7.28-7.24 (m, 2H), 7.10-7.09 (m, 2H), 4.20-4.11 (m, 4H), 4.02 (s, 3H), 3.99 (s, 3H), 3.07-3.01 (m, 2H), 2.24 (br s, 1H), 1.91-1.88 (m, 2H), 1.74-1.65 (m, 2H) Step 5: 3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}quinazoline-2,4(1H,3H)-dione (30 mg, 0.07 mmol) obtained in Step 4, 3-cyanophenylboronic acid (39 mg, 0.27 mmol), copper(II) acetate (49 mg, 0.27 mmol) and triethylamine (27 mg, 0.27 mmol) were mixed and stirred in dichloromethane (1.5 mL) at room temperature for 5 hours, and thereafter further stirred overnight at 35° C. The reaction mixture was treated with diatomaceous earth, and the solvent was evaporated under reduced pressure. Then, the resulting residue was purified by preparative thin-layer chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 20 (18 mg, yield: 48%) was obtained. ESI-MS m/z: 549 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.64 (s, 1H), 8.29 (dd, J=7.5, 1.5 Hz, 1H), 7.88-7.84 (m, 1H), 7.78-7.73 (m, 1H), 7.70-7.69 (m, 1H), 7.65-7.62 (m, 1H), 7.56-7.50 (m, 1H), 7.34-7.27 (m, 2H), 7.18-7.10 (m, 1H), 6.50 (d, J=8.1 Hz, 1H), 4.23-4.13 (m, 4H), 4.00 (s, 3H), 3.99 (s, 3H), 3.10-3.02 (m, 2H), 2.24 (br s, 1H), 1.92-1.88 (m, 2H), 1.75-1.62 (m, 2H) Example 21 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-1(2H)-yl)picolinonitrile (Compound 21) The title Compound 21 (62 mg, yield: 60%) was obtained by performing the same treatments as in Reference Example 1, Step 3 of Example 5 and Example 6 sequentially using 3-aminoisonicotinaldehyde. ESI-MS m/z: 537 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.85 (d, J=5.4 Hz, 1H), 8.66 (s, 1H), 8.36 (d, J=4.8 Hz, 1H), 7.85-7.84 (m, 1H), 7.76 (s, 1H), 7.65-7.62 (m, 1H), 7.24 (s, 1H), 7.14 (d, J=4.8 Hz, 1H), 7.08 (s, 1H), 4.63 (s, 2H), 4.22-4.18 (m, 2H), 4.02 (s, 3H), 3.98 (s, 3H), 3.48 (d, J=7.5 Hz, 2H), 3.13-3.05 (m, 2H), 2.16-2.08 (m, 1H), 1.90-1.86 (m, 2H), 1.65-1.53 (m, 2H) Example 22 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile (Compound 22) Step 1: Ethyl (3-formylpyridin-2-yl)carbamate (150 mg, 0.77 mmol) obtained by the method described in US2007/259850 and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (182 mg, 0.85 mmol) were stirred in methanol (2.0 mL) at 60° C. for 2 hours. After the reaction mixture was cooled to room temperature, sodium borohydride (35 mg, 0.93 mmol) was added thereto, and the resulting mixture was stirred for 40 minutes. Toluene (3.0 mL) and acetic acid (0.5 mL) were added thereto, and the resulting mixture was stirred at 110° C. for 3 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-[(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate (246 mg, yield: 92%) was obtained. 1H-NMR (400 MHz, DMSO-d6, δ): 9.58 (s, 1H), 8.07 (d, J=4.0 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 6.92-6.89 (m, 1H), 4.44 (s, 2H), 3.93-3.90 (m, 2H), 3.20 (d, J=7.6 Hz, 2H), 2.67 (br s, 2H), 1.89 (br s, 1H), 1.58-1.56 (m, 2H), 1.39-1.37 (m, 11H) Step 2: The title Compound 22 (45 mg, yield: 61%) was obtained by performing the same treatments as in Step 3 of Example 5 and Example 6 sequentially using tert-butyl 4-[(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methy 1]piperidine-1-carboxylate obtained in Step 1. ESI-MS m/z: 537 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.79 (d, J=6.0 Hz, 1H), 8.66 (s, 1H), 8.18-8.11 (m, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.57 (dd, J=6.0, 2.0 Hz, 1H), 7.51-7.49 (m, 1H), 7.24-7.23 (m, 1H), 7.08-7.00 (m, 2H), 4.62 (s, 2H), 4.22-4.19 (m, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.49 (d, J=7.6 Hz, 2H), 3.12-3.07 (m, 2H), 2.14 (br s, 1H), 1.92-1.89 (m, 2H), 1.64-1.55 (m, 2H) Example 23 4-(6-Fluoro-2-oxo-3-{[1-(pyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile (Compound 23) Step 1: Tert-butyl 4-[(6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate (876 mg, yield: 63%) was obtained in the same manner as in Reference Example 1 using 2-amino-5-fluoronicotinaldehyde. ESI-MS m/z: 365 (M+H)+ Step 2: Tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate (588 mg, quantitative yield) was obtained in the same manner as in Example 6 using tert-butyl 4-[(6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 1 and 4-iodopicolinonitrile. ESI-MS m/z: 467 (M+H)+ Step 3: The title Compound (34 mg, yield: 17%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-fluoro-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 2 and 4-chloropyrido[3,4-d]pyrimidine obtained by the method described in US2006/199804. ESI-MS m/z: 496 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 9.31 (s, 1H), 8.80-8.77 (m, 2H), 8.56 (d, J=5.9 Hz, 1H), 7.98 (d, J=2.7 Hz, 1H), 7.73 (t, J=1.1 Hz, 1H), 7.61 (dd, J=5.9, 0.9 Hz, 1H), 7.55 (dd, J=5.4, 2.3 Hz, 1H), 7.29 (dd, J=7.5, 2.9 Hz, 1H), 4.63 (s, 2H), 4.50 (d, J=14 Hz, 2H), 3.48 (d, J=7.2 Hz, 2H), 3.25-3.18 (m, 2H), 2.25-2.17 (m, 1H), 1.94 (t, J=6.6 Hz, 2H), 1.57 (m, 2H) Example 24 4-(3-{[1-(6,7-Dimethoxyquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropteridin-1(2H)-yl)picolinonitrile (Compound 24) The title Compound 24 (60 mg, yield: 84%) was obtained by performing the same treatments as in Reference Example 1, Step 3 of Example 5 and Example 6 sequentially using 3-aminopyrazine-2-carboxaldehyde. ESI-MS m/z: 538 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.82 (d, J=5.1 Hz, 1H), 8.66 (s, 1H), 8.24 (d, J=2.4 Hz, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.73 (d, J=2.1 Hz, 1H), 7.55 (dd, J=5.1, 2.1 Hz, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 4.79 (s, 2H), 4.23-4.18 (m, 2H), 4.02 (s, 3H), 3.99 (s, 3H), 3.54 (d, J=7.2 Hz, 2H), 3.13-3.05 (m, 2H), 2.16 (br s, 1H), 1.94-1.90 (m, 2H), 1.68-1.56 (m, 2H) Example 25 4-(4-{[1-(3-Cyanophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylic acid (Compound 25) Step 1: 3-{[1-(7-Bromoquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (9.0 g, yield: 54%) was obtained in the same manner as in Step 3 of Example 5 using Compound R1 obtained in Reference Example 1 and 7-bromo-4-chloroquinazoline. ESI-MS m/z: 452 (M+H)+ Step 2: 3-(3-{[1-(7-Bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (0.6 g, yield: 60%) was obtained in the same manner as in Example 6 using 3-{[1-(7-bromoquinazolin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one obtained in Step 1 and 3-iodobenzonitrile. ESI-MS m/z: 553 (M+H)+ Step 3: Propyl 4-(4-{[1-(3-cyanophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylate (1.6 g, yield: 50%) was obtained in the same manner as in Step 2 of Example 15 using 3-(3-{[1-(7-bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile obtained in Step 2. ESI-MS m/z: 561 (M+H)+ Step 4: The title Compound 25 (1.0 g, yield: 68%) was obtained in the same manner as in Step 2 of Example 1 using propyl 4-(4-{[1-(3-cyanophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylate obtained in Step 3. ESI-MS m/z: 519 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 9.03 (s, 1H), 8.91 (s, 1H), 8.23 (d, J=6.0 Hz, 1H), 7.87 (d, J=6.6 Hz, 1H), 7.80-7.62 (m, 4H), 7.21-7.09 (m, 2H), 7.09-6.99 (m, 1H), 6.21 (d, J=6.0 Hz, 1H), 4.65 (s, 2H), 4.63 (d, J=10 Hz, 2H), 3.49 (d, J=1.6 Hz, 2H), 3.37-3.27 (m, 2H), 2.39-2.13 (m, 1H), 2.08-1.91 (m, 2H), 1.81-1.61 (m, 2H) Example 26 4-(4-{[1-(3-Cyanophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)-N-methylquinazoline-7-carboxamido (Compound 26) The title Compound 26 (36 mg, yield: 23%) was obtained in the same manner as in Step 3 of Example 1 using Compound 25 obtained in Example 25 and methylamine. ESI-MS m/z: 532 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.73 (s, 1H), 8.15 (s, 1H), 7.93 (s, 2H), 7.79-7.62 (m, 4H), 7.17-7.01 (m, 3H), 6.41 (br s, 1H), 6.19 (d, J=4.5 Hz, 1H), 4.63 (s, 2H), 4.47 (d, J=13 Hz, 2H), 3.48 (d, J=7.2 Hz, 2H), 3.26-3.11 (m, 2H), 3.09 (d, J=4.8 Hz, 3H), 2.25-2.07 (m, 1H), 2.04-1.85 (m, 2H), 1.68-1.41 (m, 2H) Example 27 4-[3-({1-[7-(4-Methylpiperazine-1-carbonyl)quinazolin-4-yl]piperidin-4-yl}methyl)-2-oxo-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile (Compound 27) Step 1: Tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (578 mg, yield: 74%) was obtained in the same manner as in Example 6 using tert-butyl 4-(2-oxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)piperidine-1-carboxylate obtained in Step 3 of Reference Example 1 and 4-iodopicolinonitrile. ESI-MS m/z: 448 (M+H)+ Step 2: 4-[2-Oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile dihydrochloride (94 mg, quantitative yield) was obtained in the same manner as in Step 4 of Reference Example 1 using tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1. ESI-MS m/z: 348 (M+H)+ Step 3: Tert-butyl 4-(4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylate (22 mg, yield: 6.4%) was obtained in the same manner as in Example 3 using 4-[2-oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1 (2H)-yl]picolinonitrile dihydrochloride obtained in Step 2 and Compound R5 obtained in Reference Example 5. ESI-MS m/z: 576 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.80 (d, J=5.1 Hz, 1H), 8.75 (s, 1H), 8.49 (d, J=1.8 Hz, 1H), 7.98 (dd, J=8.6, 1.6 Hz, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.84 (d, J=1.8 Hz, 1H), 7.66 (dd, J=5.3, 2.0 Hz, 1H), 7.14 (dq, J=5.3, 18 Hz, 3H), 6.38 (d, J=8.4 Hz, 1H), 4.59 (s, 2H), 4.39 (d, J=13 Hz, 2H), 3.47 (d, J=7.3 Hz, 2H), 3.15 (t, J=12 Hz, 2H), 2.16 (dt, J=4.6, 14 Hz, 1H), 1.91 (d, J=11 Hz, 2H), 1.68-1.51 (m, 11H) Step 4: After tert-butyl 4-(4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylate (22 mg, 0.038 mmol) obtained in Step 3 was stirred in a trifluoroacetic acid (0.18 mL)/dichloromethane (0.20 mL) mixed solvent at room temperature for 1.5 hours, the solvent was evaporated under reduced pressure. By using the resulting residue and 1-methylpiperazine, the title Compound 27 (7.4 mg, yield: 32%) was obtained in the same manner as in Step 3 of Example 1. ESI-MS m/z: 602 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.81 (d, J=5.0 Hz, 1H), 8.73 (s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.84 (d, J=1.4 Hz, 2H), 7.65 (dd, J=5.2, 2.0 Hz, 1H), 7.47 (dd, J=8.6, 1.4 Hz, 1H), 7.20-7.09 (m, 3H), 6.38 (d, J=8.2 Hz, 1H), 4.60 (s, 2H), 4.39 (d, J=13 Hz, 2H), 3.86 (br s, 2H), 3.92-3.76 (m, 4H), 3.15 (t, J=12 Hz, 2H), 2.54 (br s, 2H), 2.43-2.30 (m, 5H), 2.21-2.11 (m, 1H), 1.91 (d, J=11.3 Hz, 2H), 1.58 (dd, J=21, 12 Hz, 2H) Example 28 4-(4-{[1-(2-Cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxamido (Compound 28) The title Compound 28 (19 mg, yield: 43%) was obtained in the same manner as in Step 4 of Example 27 using tert-butyl 4-(4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)quinazoline-7-carboxylate obtained in Step 3 of Example 27 and ammonium chloride. ESI-MS m/z: 519 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.88 (d, J=5.6 Hz, 1H), 8.64 (s, 1H), 8.29 (d, J=1.6 Hz, 2H), 8.20 (d, J=1.6 Hz, 1H), 8.02-8.00 (m, 1H), 7.94-7.91 (m, 1H), 7.82 (dd, J=5.2, 2.0 Hz, 1H), 7.64 (s, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.15-7.06 (m, 2H), 6.36 (d, J=7.2 Hz, 1H), 4.64 (s, 2H), 4.35-4.32 (m, 2H), 3.39-3.33 (m, 2H), 3.21-3.15 (m, 2H), 2.16 (br s, 1H), 1.83-1.80 (m, 2H), 1.48-1.43 (m, 2H) Example 29 4-(4-{[1-(3-Cyanophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-7-oxide (Compound 29) Step 1: 3-{[1-(Pyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (83 mg, yield: 48%) was obtained in the same manner as in Example 3 using Compound R1 and 4-hydroxypyrido[3,4-d]pyrimidine. ESI-MS m/z: 375 (M+H)+ Step 2: 3-{[1-(Pyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (598 mg, 1.6 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), and meta-chloroperoxybenzoic acid (about 70 wt %, 394 mg) was added thereto, and the resulting mixture was stirred at 0° C. for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative reverse-phase HPLC (an acetonitrile/water mixed solvent), whereby 4-{4-[(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidin-1-yl}pyrido[3,4-d]pyrimidine-7-oxide (133 mg, yield: 21%) was obtained. ESI-MS m/z: 391 (M+H)+ Step 3: The title Compound 29 (32 mg, yield: 21%) was obtained in the same manner as in Example 6 using 4-{4-[(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidin-1-yl}pyrido[3,4-d]pyrimidine-7-oxide obtained in Step 2. ESI-MS m/z: 492 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.70 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 8.08-8.05 (m, 1H), 7.66-7.59 (m, 5H), 7.15-7.00 (m, 3H), 6.18 (d, J=8.1 Hz, 1H), 4.61 (s, 2H), 4.43-4.39 (m, 2H), 3.46 (d, J=7.5 Hz, 2H), 3.26-3.19 (m, 2H), 2.25-2.18 (m, 1H), 1.97-1.94 (m, 2H), 1.64-1.47 (m, 2H) Example 30 4-(3-{[1-(Imidazo[1,2-a]pyrazin-8-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 30) The title Compound 30 (12 mg, yield: 19%) was obtained in the same manner as in Example 5 using 4-[2-oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile dihydrochloride obtained in Step 2 of Example 27 and 8-chloroimidazo[1,2-a]pyrazine. ESI-MS m/z: 465 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.80-8.78 (m, 1H), 7.84-7.83 (m, 1H), 7.67-7.65 (m, 1H), 7.53 (d, J=1.5 Hz, 1H), 7.48-7.47 (m, 2H), 7.33 (d, J=4.8 Hz, 1H), 7.19-7.07 (m, 3H), 6.40-6.37 (m, 1H), 5.48-5.43 (m, 2H), 4.56 (s, 2H), 3.39 (d, J=6.9 Hz, 2H), 3.10-3.00 (m, 2H), 2.17-2.10 (m, 1H), 1.88-1.85 (m, 2H), 1.52-1.38 (m, 2H) Example 31 4-(3-{[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 31) Step 1: 4-(2-Oxo-3-{[1-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (63 mg, yield: 67%) was obtained in the same manner as in Example 5 using 4-[2-oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile dihydrochloride obtained in Step 2 of Example 27 and 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine obtained by the method described in Organic Letters 2009, 11, 1999. 1H-NMR (300 MHz, CDCl3, δ): 8.86-8.84 (m, 1H), 8.40 (s, 1H), 7.89 (dd, J=2.4, 0.9 Hz, 1H), 7.71 (dd, J=5.4, 2.4 Hz, 1H), 7.25-7.13 (m, 4H), 6.57 (d, J=3.6 Hz, 1H), 6.45-6.42 (m, 1H), 5.63 (s, 2H), 4.86-4.82 (m, 2H), 4.62 (s, 2H), 3.61-3.55 (m, 2H), 3.45 (d, J=6.9 Hz, 2H), 3.20-3.11 (m, 2H), 2.30-2.17 (m, 1H), 1.94-1.91 (m, 2H), 1.54-1.41 (m, 2H), 0.99-0.91 (m, 2H), −0.05 (s, 9H) Step 2: The title Compound 31 (25 mg, yield: 64%) was obtained in the same manner as in Step 2 of Example 12 using 4-(2-oxo-3-{[1-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile obtained in Step 1. ESI-MS m/z: 465 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 10.0 (br s, 1H), 8.80 (d, J=5.7 Hz, 1H), 8.32 (s, 1H), 7.84-7.83 (m, 1H), 7.67-7.64 (m, 1H), 7.19-7.05 (m, 4H), 6.50 (d, J=3.3 Hz, 1H), 6.40-6.37 (m, 1H), 4.84-4.79 (m, 2H), 4.57 (s, 2H), 3.40 (d, J=6.9 Hz, 2H), 3.16-3.08 (m, 2H), 2.25-2.12 (m, 1H), 1.90-1.86 (m, 2H), 1.49-1.36 (m, 2H) Example 32 4-(3-{[1-(5-Methoxypyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 32) Step 1: 3-{[1-(6-Chloro-5-methoxypyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (504 mg, yield: 73%) was obtained in the same manner as in Example 5 using 4-[2-oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile dihydrochloride obtained in Step 2 of Example 27 and 4,6-dichloro-5-methoxypyrimidine. ESI-MS m/z: 388 (M+H)+ Step 2: 3-{[1-(6-Chloro-5-methoxypyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (100 mg, 0.26 mmol) obtained in Step 1, palladium-carbon (10 wt %, 27 mg) and triethylamine (52 mg, 0.52 mmol) were mixed and stirred in ethyl acetate (3.0 mL) under a hydrogen atmosphere (atmospheric pressure) at room temperature for 3 hours. The reaction mixture was treated with diatomaceous earth, and the solvent was evaporated under reduced pressure. To the resulting residue, diethyl ether was added, and the resulting solid was collected by filtration, whereby 3-{[1-(5-methoxypyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (82 mg, yield: 90%) was obtained. ESI-MS m/z: 354 (M+H)+ Step 3: The title Compound 32 (72 mg, yield: 86%) was obtained in the same manner as in Example 6 using 3-{[1-(5-methoxypyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one obtained in Step 2 and 4-iodopicolinonitrile. ESI-MS m/z: 456 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.79 (d, J=5.6 Hz, 1H), 8.32 (s, 1H), 7.88-7.83 (m, 2H), 7.66-7.64 (m, 1H), 7.19-7.08 (m, 3H), 6.38 (d, J=7.6 Hz, 1H), 4.59-4.56 (m, 4H), 3.85 (s, 3H), 3.39 (d, J=6.8 Hz, 2H), 2.91-2.85 (m, 2H), 2.09-2.04 (m, 1H), 1.81-1.78 (m, 2H), 1.45-1.31 (m, 2H) Example 33 4-(3-{[1-(6-Aminopyrimido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 33) Step 1: Compound R1 (841 mg, 3.0 mmol), 4,6-dichloropyrido[3,4-d]pyrimidine (716 mg, 3.6 mmol) obtained by the method described in Bioorganic & Medicinal Chemistry Letters, 2001, 11, 1401, and diisopropylethylamine (2.3 g, 18 mmol) were stirred in 2-propanol (8.0 mL) at 100° C. for 6 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby 3-[1-(6-chloropyrimido[3,4-d]pyrimidin-4-yl)piperidin-4-yl methyl]-3,4-dihydroquinazolin-2(1H)-one (600 mg, yield: 49%) was obtained. ESI-MS m/z: 409 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 9.09 (s, 1H), 8.73 (s, 1H), 7.66 (s, 1H), 7.58 (br s, 1H), 7.21-7.15 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.93 (m, 1H), 6.74-6.70 (m, 1H), 4.51 (s, 2H), 4.49-4.41 (m, 2H), 3.44 (d, J=7.7 Hz, 2H), 3.27-3.18 (m, 2H), 2.22-2.11 (m, 1H), 1.98-1.89 (m, 2H), 1.63-1.49 (m, 2H) Step 2: 4-(3-{[1-(6-Chloropyrimido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (370 mg, yield: 74%) was obtained in the same manner as in Example 6 using 3-[1-(6-chloropyrimido[3,4-d]pyrimidin-4-yl)piperidin-4-yl methyl]-3,4-dihydroquinazolin-2(1H)-one obtained in Step 1 and 4-iodopicolinonitrile. ESI-MS m/z: 511 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 9.10 (s, 1H), 8.81 (d, J=5.9 Hz, 1H), 8.74 (s, 1H), 7.84-7.83 (m, 1H), 7.67-7.64 (m, 2H), 7.21-7.09 (m, 3H), 6.41-6.37 (m, 1H), 4.59 (s, 2H), 4.48-4.43 (m, 2H), 3.46 (d, J=7.3 Hz, 2H), 3.27-3.18 (m, 2H), 2.24-2.16 (m, 1H), 1.98-1.90 (m, 2H), 1.61-1.48 (m, 2H) Step 3: 4-(3-{[1-(6-Chloropyrimido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (300 mg, 0.59 mmol) obtained in Step 2, Tris(dibenzylideneacetone)dipalladium(0) (Pd2dba3) (27 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9, 9-dimethylxanthene (Xantphos) (68 mg, 0.12 mmol), cesium carbonate (268 mg, 0.82 mmol) and benzophenone imine (128 mg, 0.71 mmol) were stirred in a 1,4-dioxane (3.0 mL)/toluene (3.0 mL) mixed solvent at 100° C. for 6 hours. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby crude 4-[3-({l-[6-(diphenylmethyleneamino)pyrimido[3,4-d]pyrimidin-4-yl]piperidin-4-yl}methyl)-2-oxo-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile (44 mg) was obtained. Step 4: To a THF solution (0.5 mL) of the crude 4-[3-({1-[6-(diphenylmethyleneamino)pyrimido[3,4-d]pyrimidin-4-yl]piperidin-4-yl}methyl)-2-oxo-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile (40 mg) obtained in Step 3, concentrated hydrochloric acid (12 mol/L, 0.02 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture, a saturated aqueous sodium bicarbonate solution was added, and the resulting mixture was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 33 (8.4 mg, yield: 3%) was obtained. ESI-MS m/z: 492 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.92 (s, 1H), 8.81 (d, J=4.9 Hz, 1H), 8.56 (s, 1H), 7.84 (s, 1H), 7.69-7.62 (m, 1H), 7.23-7.09 (m, 3H), 6.65 (s, 1H), 6.38 (d, J=7.8 Hz, 1H), 4.67-4.56 (m, 4H), 4.36-4.27 (m, 2H), 3.50-3.45 (m, 2H), 3.11-3.01 (m, 2H), 2.19-2.08 (m, 1H), 1.94-1.85 (m, 2H), 1.63-1.50 (m, 2H) Example 34 4-(2-Oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 34) 4-[2-Oxo-3-(piperidin-4-ylmethyl)-3,4-dihydroquinazolin-1(2H)-yl]picolinonitrile dihydrochloride (61 mg, 0.15 mmol) obtained in Step 2 of Example 27, 5-chloropyrido[4,3-d]pyrimidin-4(3H)-one (58 mg, 0.32 mmol) obtained by the method described in Synthesis, 2010, 42, 30, and diisopropylethylamine (827 mg, 0.64 mmol) were mixed and stirred in NMP (2.0 mL) at 150° C. for 1 hour using a microwave reactor (manufactured by CEM Corporation) at 300 W. After the solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (a chloroform/methanol mixed solvent), whereby the title Compound 34 (67 mg, yield: 86%) was obtained. ESI-MS m/z: 493 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 10.7 (br s, 1H), 8.80 (d, J=5.4 Hz, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.08 (s, 1H), 7.86-7.85 (m, 1H), 7.68 (d, J=2.1, 5.1 Hz, 1H), 7.22-7.07 (m, 3H), 6.96 (d, J=5.1 Hz, 1H), 6.38 (d, J=7.8 Hz, 1H), 4.58 (s, 2H), 4.03-3.99 (m, 2H), 3.45 (d, J=7.2 Hz, 2H), 3.04-2.96 (m, 2H), 2.06 (br s, 1H), 1.84-1.80 (m, 2H), 1.69-1.61 (m, 2H) Example 35 4-(2-Oxo-3-{[1-(6-oxo-6,7-dihydro-5H-pyrimido[4,5-b][1,4]oxazin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 35) The title Compound 35 (21 mg, yield: 19%) was obtained in the same manner as in Example 5 using Compound R6 obtained in Reference Example 6. ESI-MS m/z: 497 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.81-8.79 (m, 1H), 8.26 (s, 1H), 7.83 (s, 1H), 7.66-7.65 (m, 1H), 7.34 (br s, 1H), 7.20-7.10 (m, 3H), 6.38 (d, J=7.5 Hz, 1H), 4.83 (s, 2H), 4.57 (s, 2H), 3.76-3.72 (m, 2H), 3.44-3.42 (m, 2H), 3.00-2.93 (m, 2H), 2.02 (br s, 1H), 1.89-1.85 (m, 2H), 1.58-1.46 (m, 2H) Example 36 4-(2-Oxo-1-{[1-(8-oxo-8,9-dihydro-7H-purin-6-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 36) The title Compound 36 (67 mg, yield: 63%) was obtained in the same manner as in Example 34 using 6-chloro-7H-purin-8 (9H)-one (84 mg, 0.49 mmol) obtained by the method described in WO2007/125315. ESI-MS m/z: 482 (M+H)+, 1H-NMR (300 MHz, DMSO-d6, δ): 11.4 (s, 1H), 10.7 (s, 1H), 8.86 (d, J=5.4 Hz, 1H), 8.18-8.17 (m, 1H), 8.06 (s, 1H), 7.19-7.79 (m, 1H), 7.28 (d, J=6.9 Hz, 1H), 7.17-7.05 (m, 2H), 6.35 (d, J=7.8 Hz, 1H), 4.60 (s, 2H), 4.23-4.19 (d, J=13 Hz, 2H), 3.32-3.30 (m, 2H), 2.93-2.85 (m, 2H), 2.01 (br s, 1H), 1.71-1.67 (m, 2H), 1.24-1.16 (m, 2H) Example 37 4-(3-{[1-(7-Morpholinoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 37) Step 1: 4-(3-{[1-(7-Bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1 (2H)-yl)picolinonitrile (200 mg, yield: 67%) was obtained in the same manner as in Example 5 using 7-bromo-4-chloroquinazoline. ESI-MS m/z: 554 (M+H)+ Step 2: 4-(3-{[1-(7-Bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (200 mg, 0.36 mmol) obtained in Step 1, morpholine (63 mg, 0.72 mmol), Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (Pd2dba3.CHCl3) (37 mg, 0.04 mmol), Xantphos (21 mg, 0.04 mmol) and cesium carbonate (235 mg, 0.72 mmol) were stirred overnight in 1,4-dioxane (10 mL) at 100° C. The reaction mixture was cooled to room temperature, and then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative reverse-phase HPLC (an acetonitrile/water mixed solvent), whereby the title Compound 37 (50 mg, yield: 24%) was obtained. ESI-MS m/z: 561 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.87 (d, J=5.2 Hz, 1H), 8.45 (s, 1H), 8.20 (d, J=1.6 Hz, 1H), 7.83-7.75 (m, 2H), 7.30 (d, J=5.1 Hz, 2H), 7.15-7.08 (m, 2H), 6.99 (d, J=2.4 Hz, 1H), 6.36 (d, J=8.0 Hz, 1H), 4.64 (s, 2H), 4.22-4.19 (m, 2H), 3.77 (t, J=4.8 Hz, 4H), 3.38-3.33 (m, 6H), 3.10-3.04 (m, 2H), 2.08 (br s, 1H), 1.80-1.78 (m, 2H), 1.45-1.37 (m, 2H) Example 38 4-(2-Oxo-3-{[1-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 38) The title Compound 38 (50 mg, yield: 47%) was obtained in the same manner as in Example 34 using 5-bromo-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one obtained by the method described in WO2005/85226. ESI-MS m/z: 481 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.78 (d, J=6.0 Hz, 1H), 7.85-7.83 (m, 2H), 7.64 (dd, J=6.0, 2.0 Hz, 1H), 7.18-7.07 (m, 4H), 6.44 (d, J=8.4 Hz, 1H), 6.36 (d, J=8.0 Hz, 1H), 4.55 (s, 2H), 4.44-4.41 (m, 2H), 3.38-3.36 (m, 2H), 2.96-2.91 (m, 2H), 2.09 (br s, 1H), 1.82-1.79 (m, 2H), 1.34-1.26 (m, 2H) Example 39 4-(2-Oxo-3-{[1-(3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 39) The title Compound 39 (50 mg, yield: 46%) was obtained in the same manner as in Example 34 using Compound R7 obtained in Reference Example 7. ESI-MS m/z: 482 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 11.0 (br s, 1H), 8.79 (d, J=5.4 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.65 (dd, J=5.4, 1.8 Hz, 1H), 7.19-7.08 (m, 5H), 6.38 (d, J=9.8 Hz, 1H), 5.17-5.13 (m, 2H), 4.56 (s, 2H), 3.39 (d, J=7.2 Hz, 2H), 3.06-2.99 (m, 2H), 2.13 (br s, 1H), 1.87-1.83 (m, 2H), 1.46-1.32 (m, 2H) Example 40 3-(4-{[1-(2-Cyanopyridin-4-yl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)-2-fluoroisonicotinamide (Compound 40) The title Compound 40 (50 mg, yield: 46%) was obtained in the same manner as in Example 34 using Compound R8 obtained in Reference Example 8. ESI-MS m/z: 486 (M+H)+, 1H-NMR (270 MHz, CDCl3, δ): 8.79 (d, J=5.1 Hz, 1H), 8.07 (d, J=5.1 Hz, 1H), 7.83 (d, J=1.9 Hz, 1H), 7.65 (dd, J=5.1, 1.9 Hz, 1H), 7.31-7.27 (m, 1H), 7.19-7.07 (m, 3H), 6.49 (br s, 1H), 6.38 (d, J=8.1 Hz, 1H), 5.92 (br s, 1H), 4.57 (s, 2H), 4.05-4.00 (m, 2H), 3.42 (d, J=8.1 Hz, 2H), 2.95-2.87 (m, 2H), 2.03 (br s, 1H), 1.84-1.80 (m, 2H), 1.55-1.50 (m, 2H) Example 41 4-(3-{[1-(7-Aminopyrido[3,2-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 41) Step 1: 4-(3-{[1-(7-Bromopyrido[3,2-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (89 mg, yield: 90%) was obtained in the same manner as in Step 1 of Example 37 using 7-bromo-4-chloropyrido[3,2-d]pyrimidine. ESI-MS m/z: 555 (M+H)+ Step 2: Tert-butyl 4-(4-{[1-(2-cyanopyridin-4-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,2-d]pyrimidin-7-ylcarbamate (87 mg, yield: 92%) was obtained in the same manner as in Step 3 of Example 33 using 4-(3-{[1-(7-bromopyrido[3,2-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile obtained in Step 1 and tert-butyl carbamate. ESI-MS m/z: 555 (M+H)+ Step 3: The title Compound 41 (20 mg, yield: 28%) was obtained in the same manner as in Step 4 of Example 33 using tert-butyl 4-(4-{[1-(2-cyanopyridin-4-yl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,2-d]pyrimidin-7-ylcarbamate obtained in Step 2. ESI-MS m/z: 492 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.79 (d, J=5.4 Hz, 1H), 8.44 (s, 1H), 8.20 (d, J=2.4 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.65 (dd, J=5.1, 1.8 Hz, 1H), 7.19-7.07 (m, 4H), 6.38 (d, J=7.5 Hz, 1H), 5.62-5.58 (m, 2H), 4.57 (s, 2H), 4.23 (br s, 2H), 3.40 (d, J=6.9 Hz, 2H), 3.17-3.10 (m, 2H), 2.19 (br s, 1H), 1.89-1.84 (m, 2H), 1.52-1.42 (m, 2H) Example 42 4-(2-Oxo-3-{[1-(4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-8-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 42) The title Compound 42 (13 mg, yield: 25%) was obtained in the same manner as in Example 34. ESI-MS m/z: 493 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 11.5 (br s, 1H), 8.79 (d, J=4.8 Hz, 1H), 8.25 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.85 (d, J=1.5 Hz, 1H), 7.65 (dd, J=5.7, 1.8 Hz, 1H), 7.46 (d, J=5.1 Hz, 1H), 7.19-7.07 (m, 3H), 6.38 (d, J=7.5 Hz, 1H), 4.63-4.59 (m, 4H), 3.43 (d, J=7.5 Hz, 2H), 3.04-2.96 (m, 2H), 2.07 (br s, 1H), 1.86-1.82 (m, 2H), 1.70-1.57 (m, 2H) Example 43 3-(3-{[1-(7,8-Dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile (Compound 43) Step 1: 3-{[1-(7,8-Dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one (40 mg, yield: 11%) was obtained in the same manner as in Example 3 using Compound R1 obtained in Reference Example 1 and Compound R10 obtained in Reference Example 10. ESI-MS m/z: 380 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.57 (s, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.0 Hz, 1H), 7.00-6.90 (m, 1H), 6.85 (s, 1H), 6.69 (d, J=8.0 Hz, 1H), 4.56 (s, 2H), 4.51 (s, 2H), 4.08 (t, J=6.0 Hz, 2H), 3.79 (d, J=13 Hz, 2H), 3.50 (d, J=7.2 Hz, 2H), 3.00-2.85 (m, 4H), 2.10-1.95 (m, 1H), 1.80-1.70 (m, 2H), 1.50-1.35 (m, 2H) Step 2: The title Compound 43 (26 mg, yield: 26%) was obtained in the same manner as in Example 6 using 3-{[1-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one obtained in Step 1 and 3-iodobenzonitrile. ESI-MS m/z: 481 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.44 (s, 1H), 7.96-7.86 (m, 2H), 7.73 (t, J=7.8 Hz, 1H), 7.70-7.63 (m, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12-7.06 (m, 1H), 7.05-6.95 (m, 1H), 6.07 (d, J=8.0 Hz, 1H), 4.61 (s, 2H), 4.52 (s, 2H), 3.97 (t, J=6.2 Hz, 2H), 3.76 (d, J=13 Hz, 2H), 3.41-3.20 (m, 2H), 2.88 (t, J=12 Hz, 2H), 2.77 (t, J=6.0 Hz, 2H), 2.11-1.92 (m, 1H), 1.79-1.45 (m, 2H), 1.36-1.19 (m, 2H) Example 44 5-(3-{[1-(6-Acetyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-fluorobenzonitrile (Compound 44) Step 1: Tert-butyl 4-(4-{[2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (150 mg, yield: 59%) was obtained in the same manner as in Example 3 using Compound R1 obtained in Reference Example 1 and tert-butyl 4-oxo-3,5,7,8-tetrahydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate obtained by the method described in WO2010/066684. ESI-MS m/z: 479 (M+H)+, 1H-NMR (300 MHz, CDCl3, δ): 8.57 (s, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.08-6.93 (m, 2H), 6.80 (s, 1H), 6.69 (d, J=8.1 Hz, 1H), 4.51 (s, 2H), 4.44 (s, 2H), 3.89-3.85 (m, 2H), 3.74 (br s, 2H), 3.39-3.34 (m, 2H), 2.95 (br s, 4H), 2.07 (br s, 1H), 1.88-1.84 (m, 2H), 1.50 (br s, 11H) Step 2: Tert-butyl 4-(4-{[2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (800 mg, 1.7 mmol) obtained in Step 1 was stirred in hydrochloric acid-dioxane (4.0 mol/L, 20 mL) at room temperature for 2 hours. Then, the solvent was evaporated under reduced pressure, whereby crude 3-{[1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2 (1H)-one hydrochloride (600 mg) was obtained. This compound was used in the subsequent reaction without particularly performing further purification. Step 3: The crude 3-{[1-(5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2 (1H)-one hydrochloride (100 mg) obtained in Step 2, acetyl chloride (25 mg, 0.25 mmol) and triethylamine (40 mg, 0.4 mmol) were stirred in dichloromethane (5.0 mL) at room temperature for 5 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was evaporated under reduced pressure, the resulting residue was purified by preparative reverse-phase HPLC (an acetonitrile/water mixed solvent), whereby 3-{[1-(6-acetyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(H)-one (20 mg, yield: 19%) was obtained. ESI-MS m/z: 421 (M+H)+, 1H-NMR (400 MHz, CDCl3, δ): 8.56 (s, 1H), 7.22-7.18 (m, 1H), 7.09-7.07 (m, 1H), 7.02-6.96 (m, 1H), 6.69 (br s, 2H), 4.58 (s, 2H), 4.43 (s, 2H), 3.93-3.86 (m, 2H), 3.80-3.73 (m, 2H), 3.44-3.36 (m, 2H), 2.98-2.93 (m, 4H), 2.19 (s, 3H), 2.08 (br s, 1H), 1.86-1.83 (m, 2H), 1.53-1.44 (m, 2H) Step 4: The title Compound 44 (44 mg, yield: 34%) was obtained in the same manner as in Example 6 using 3-{[1-(6-acetyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-2(1H)-one obtained in Step 3 and 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 540 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.46 (s, 1H), 8.03-8.02 (m, 1H), 7.81-7.65 (m, 2H), 7.25 (d, J=7.2 Hz, 1H), 7.10 (t, J=7.6 Hz, 1H), 7.01 (t, J=7.2 Hz, 1H), 6.14 (d, J=8.0 Hz, 1H), 4.70 (s, 2H), 4.62-4.45 (m, 2H), 3.81-3.74 (m, 4H), 3.32 (br s, 2H), 2.93-2.87 (m, 4H), 2.07-2.04 (m, 4H), 1.91-1.84 (m, 2H), 1.38-1.24 (m, 2H) Example 45 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxamido (Compound 45) Step 1: Tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (400 mg, yield: 61%) was obtained in the same manner as in Example 6 using Compound R1 obtained in Reference Example 1 and 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 465 (M+H)+ Step 2: 5-(3-{[1-(6-Chloropyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-fluorobenzonitrile (100 mg, yield: 30%) was obtained in the same manner as in Example 3 using tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1 and 6-chloropyrido[3,4-d]pyrimidin-4(3H)-one obtained by the method described in WO2005/16926. ESI-MS m/z: 528 (M+H)+ Step 3: Propyl 4-(4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxylate (150 mg, yield: 53%) was obtained in the same manner as in Step 2 of Example 15 using 5-(3-{[1-(6-chloropyrido[3,4-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydroquinazolin-1(2H)-yl)-2-fluorobenzonitrile obtained in Step 2. Step 4: 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxylic acid (1.0 mg, yield: 1%) was obtained in the same manner as in Step 3 of Example 15 using propyl 4-(4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxylate obtained in Step 3. ESI-MS m/z: 538 (M+H)+ Step 5: 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxylic acid (20 mg, 0.04 mmol) obtained in Step 4 was mixed with ammonium chloride (6.0 mg, 0.12 mmol), HATU (21 mg, 0.06 mmol), and diisopropylethylamine (14 mg, 0.12 mmol) in THF (4.0 mL) and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative reverse-phase HPLC (an acetonitrile/water mixed solvent), whereby the title Compound 45 (11 mg, 54%) was obtained. ESI-MS m/z: 537 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 9.15 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 8.04-8.02 (m, 1H), 7.81-7.66 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.13-7.10 (m, 1H), 7.04-7.01 (m, 1H), 6.15 (d, J=8.0 Hz, 1H), 4.65 (s, 2H), 4.50 (d, J=13 Hz, 2H), 3.45-3.20 (m, 4H), 2.20 (br s, 1H), 1.89-1.86 (m, 2H), 1.51-1.29 (m, 2H) Example 46 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[3,4-d]pyrimidine-6-carboxamido (Compound 46) Step 1: Tert-butyl 4-[(2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate (2.0 g, yield: 62%) was obtained in the same manner as in Reference Example 1 using 3-aminopicolinaldehyde. ESI-MS m/z: 347 (M+H)+ Step 2: Tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate (400 mg, yield: 54%) was obtained in the same manner as in Example 6 using tert-butyl 4-[(2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-3(4H)-yl)methy 1]piperidine-1-carboxylate obtained in Step 1 and 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 466 (M+H)+ Step 3: The title Compound (13 mg, yield: 71%) was obtained in the same manner as in Example 45 using tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[3,2-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 2. ESI-MS m/z: 538 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 9.14 (s, 1H), 8.72 (s, 1H), 8.46 (s, 1H), 8.26 (s, 1H), 8.17 (dd, J=4.8, 1.2 Hz, 1H), 8.06 (dd, J=6.0, 2.8 Hz, 1H), 7.89-7.65 (m, 2H), 7.70 (t, J=9.0 Hz, 1H), 7.15 (dd, J=8.4, 3.6 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 4.73 (s, 2H), 4.50 (d, J=13 Hz, 2H), 3.49-3.20 (m, 4H), 2.35-2.13 (m, 1H), 1.89 (d, J=11 Hz, 2H), 1.53-1.30 (m, 2H) Example 47 2-Fluoro-5-(2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile (Compound 47) Step 1: Tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate (350 mg, yield: 52%) was obtained in the same manner as in Example 6 using tert-butyl 4-[(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 1 of Example 22 and 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 466 (M+H)+ Step 2: The title Compound 47 (40 mg, yield: 56%) was obtained in the same manner as in Example 34 using tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1 and 5-chloropyrido[4,3-d]pyrimidin-4(3H)-one. ESI-MS m/z: 511 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 12.1 (s, 1H), 8.23 (d, J=5.2 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J=5.2 Hz, 1H), 7.94 (dd, J=6.0, 2.4 Hz, 1H), 7.74-7.66 (m, 2H), 7.61 (t, J=8.8 Hz, 1H) 7.04 (dd, J=8.0, 4.8 Hz, 1H), 6.82 (d, J=5.2 Hz, 1H), 4.64 (s, 2H), 3.90-3.87 (m, 2H), 3.35-3.33 (m, 2H), 2.87 (t, J=8.4 Hz, 2H), 1.99 (br s, 1H), 1.73-1.70 (m, 2H), 1.43-1.38 (m, 2H) Example 48 4-(6-Methoxy-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinamide (Compound 48) Step 1: Tert-butyl 4-[(6-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate (1.5 g, yield: 73%) was obtained in the same manner as in Reference Example 1 using 5-methoxy-2-nitrobenzaldehyde. ESI-MS m/z: 376 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 8.97 (s, 1H), 6.75-6.69 (m, 3H), 4.38 (s, 2H), 3.93-3.90 (m, 2H), 3.90 (s, 3H), 3.18 (d, J=7.2 Hz, 2H), 2.68 (br s, 2H), 1.84 (br s, 1H), 1.58-1.55 (m, 2H), 1.39 (s, 9H), 1.07-1.00 (m, 2H) Step 2: Tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate (580 mg, yield: 76%) was obtained in the same manner as in Example 6 using tert-butyl 4-[(6-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 1 and 4-iodopyridine-2-carbonitrile. ESI-MS m/z: 478 (M+H)+ Step 3: 4-(6-Methoxy-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (300 mg, yield: 47%) was obtained in the same manner as in Example 36 after performing a treatment in the same manner as in Step 4 of Reference Example 1 using tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-methoxy-2-oxo-1,2-dihydroquinazolin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 2. ESI-MS m/z: 523 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 12.1 (s, 1H), 8.82 (d, J=5.2 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 8.17 (s, 1H), 8.11 (s, 1H), 7.80 (d, J=5.2 Hz, 1H), 6.91 (s, 1H), 6.82 (d, J=5.2 Hz, 1H), 6.75-6.73 (m, 1H), 6.39-6.37 (m, 1H), 4.57 (s, 2H), 3.89-3.77 (m, 2H), 3.73 (s, 3H), 3.34-3.32 (m, 2H), 2.89-2.83 (m, 2H), 1.96 (br s, 1H), 1.67-1.66 (m, 2H), 1.43-1.34 (m, 2H) Step 4: 4-(6-Methoxy-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (80 mg, 0.15 mmol) obtained in Step 3 and lithium hydroxide monohydrate (14 mg, 0.33 mmol) were stirred in a tetrahydrofuran-water mixed solvent (1/1, 3.0 mL) at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative reverse-phase HPLC, whereby the title Compound 48 (34 mg, yield: 40%) was obtained. ESI-MS m/z: 541 (M+H)+, 1H-NMR (400 MHz, DMSO-d6+D2O, δ): 8.73 (d, J=5.2 Hz, 1H), 8.32-8.17 (m, 2H), 8.08 (s, 1H), 7.94 (s, 1H), 7.74-7.69 (m, 1H), 7.62 (d, J=4.4 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.82 (d, J=5.6 Hz, 1H), 6.76-6.66 (m, 1H), 6.21 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 3.83 (d, J=13 Hz, 2H), 3.67 (s, 3H), 3.31 (d, J=7.2 Hz, 2H), 2.92-2.80 (m, 2H), 2.05-1.82 (m, 1H), 1.76-1.58 (m, 2H), 1.45-1.27 (m, 2H) Example 49 4-(6-Fluoro-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinonitrile (Compound 49) Step 1: Tert-butyl 4-[(6-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate (720 mg, yield: 73%) was obtained in the same manner as in Reference Example 1 using 5-fluoro-2-nitrobenzaldehyde. ESI-MS m/z: 364 (M+H)+ Step 2: Tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl]methyl}piperidine-1-carboxylate (500 mg, yield: 78%) was obtained in the same manner as in Example 6 using tert-butyl 4-[(6-fluoro-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 1 and 4-iodopicolinonitrile. ESI-MS m/z: 466 (M+H)+ Step 3: The title Compound 49 (80 mg, yield: 54%) was obtained in the same manner as in Example 34 after performing a treatment in the same manner as in Step 4 of Reference Example 1 using tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-6-fluoro-2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl]methyl}piperidine-1-carboxylate obtained in Step 2. ESI-MS m/z: 511 (M+H)+, 1H-NMR (300 MHz, DMSO-d6, δ): 9.87 (br s, 1H), 8.86 (d, J=5.1 Hz, 1H), 8.27-8.14 (m, 2H), 8.11 (s, 1H), 7.85-7.77 (m, 1H), 7.25-7.15 (m, 1H), 7.04-6.91 (m, 1H), 6.81 (d, J=5.4 Hz, 1H), 6.46-6.34 (m, 1H), 4.61 (s, 2H), 3.87 (d, J=13 Hz, 2H), 3.45-3.21 (m, 2H), 2.86 (t, J=12 Hz, 2H), 2.08-1.82 (m, 1H), 1.78-1.61 (m, 2H), 1.51-1.29 (m, 2H) Example 50 N-[4-(4-{[1-(2-Cyanopyridin-4-yl)-2-oxo-1,2-dihydropyrido[2, 3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl) quinazolin-6-yl]acetamide (Compound 50) Step 1: Tert-butyl 4-[(2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate (2.0 g, 5.8 mmol) obtained in Step 1 of Example 22, 4-iodopicolinonitrile (2.0 g, 8.7 mmol), copper(I) oxide (3.4 g, 24 mmol) and tripotassium phosphate (2.6 g, 12 mmol) were stirred in DMA (20 mL) at 120° C. for 7 hours. The reaction mixture was diluted with dichloromethane and extracted by adding water thereto. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (a dichloromethane/methanol mixed solvent), whereby tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate (1.6 g, yield: 61%) was obtained. 1H-NMR (300 MHz, DMSO-d6, δ): 8.83 (d, J=5.4 Hz, 1H), 8.12 (d, J=1.5 Hz, 1H), 8.05 (dd, J=5.4, 1.5 Hz, 1H), 7.75 (dd, J=5.4, 2.1 Hz, 1H), 7.69 (d, J=7.2 Hz, 1H), 7.09 (dd, J=7.2, 2.1 Hz, 1H), 4.62 (s, 2H), 4.10-3.80 (m, 2H), 3.45-3.15 (m, 2H), 2.90-2.50 (m, 2H), 2.00-1.75 (m, 1H), 1.70-1.50 (m, 2H), 1.38 (s, 9H), 1.15-0.90 (m, 2H) Step 2: 4-(3-{[1-(6-Bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile (100 mg, yield: 76%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-{[1-(2-cyanopyridin-4-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 1 and 6-bromo-4-chloroquinazoline. ESI-MS m/z: 555 (M+H)+ Step 3: The title Compound 50 (25 mg, yield: 26%) was obtained in the same manner as in Step 3 of Example 33 using 4-(3-{[1-(6-bromoquinazolin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-1(2H)-yl)picolinonitrile obtained in Step 2 and acetamide. ESI-MS m/z: 534 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 10.3 (s, 1H), 8.84 (d, J=5.2 Hz, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.15 (s, 1H), 8.07 (d, J=4.8 Hz, 1H), 7.85-7.77 (m, 4H), 7.13-7.10 (m, 1H), 4.68 (s, 2H), 4.27-4.23 (m, 2H), 3.42 (d, J=6.8 Hz, 2H), 3.08 (t, J=13 Hz, 2H), 2.12 (br s, 4H), 1.87-1.84 (m, 2H), 1.51-1.45 (m, 2H) Example 51 4-(6-Cyano-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-1(2H)-yl)picolinamide (Compound 51) Step 1: Tert-butyl 4-{[(5-bromo-2-nitrobenzyl)amino]methyl}piperidine-1-carboxylate (7.0 g, yield: 63%) was obtained in the same manner as in Step 1 of Reference Example 1 using 5-bromo-2-nitrobenzaldehyde. 1H-NMR (300 MHz, CDCl3, δ): 7.84 (d, J=8.4 Hz, 2H), 7.60-7.50 (m, 1H), 5.30 (s, 1H), 4.22-4.05 (m, 2H), 4.03 (s, 2H), 2.79-2.60 (m, 2H), 2.52 (d, J=6.6 Hz, 2H), 1.80-1.50 (m, 3H), 1.46 (s, 9H), 1.22-1.02 (m, 2H) Step 2: Tert-butyl 4-{[(5-bromo-2-nitrobenzyl)amino]methyl}piperidine-1-carboxylate (3.0 g, 7.0 mmol) obtained in Step 1, zinc (1.5 mg), zinc cyanide (540 mg, 4.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) were stirred in DMF (100 mL) at 100° C. for 12 hours. To the reaction mixture, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Then, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (a hexane/ethyl acetate mixed solvent), whereby tert-butyl 4-{[(5-cyano-2-nitrobenzyl)amino]methyl}piperidine-1-carboxylate (1.2 g, yield: 46%) was obtained. 1H-NMR (300 MHz, CDCl3, δ): 8.09 (s, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.80-7.68 (m, 1H), 4.25-4.00 (m, 4H), 3.50 (s, 1H), 2.71 (t, J=12 Hz, 2H), 2.54 (d, J=3.3 Hz, 2H), 1.80-1.60 (m, 2H), 1.75-1.51 (m, 1H), 1.47 (s, 9H), 1.29-1.01 (m, 2H) Step 3: Tert-butyl 4-[(6-cyano-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate (600 mg, yield: 70%) was obtained in the same manner as in Reference Example 1 using tert-butyl 4-{[(5-cyano-2-nitrobenzyl)amino]methyl}piperidine-1-carboxylate obtained in Step 2. 1H-NMR (300 MHz, CDCl3, δ): 7.58 (s, 1H), 7.52-7.41 (m, 1H), 7.34 (s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.48 (s, 2H), 4.25-4.01 (m, 2H), 3.45-3.25 (m, 2H), 2.80-2.59 (m, 2H), 2.00-1.55 (m, 3H), 1.45 (s, 9H), 1.33-1.10 (m, 2H) Step 4: Tert-butyl 4-{[6-cyano-1-(2-cyanopyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl]methyl}piperidine-1-carboxylate (220 mg, yield: 57%) was obtained in the same manner as in Example 6 using tert-butyl 4-[(6-cyano-2-oxo-1,2-dihydroquinazolin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 3 and 4-iodopicolinonitrile. ESI-MS m/z: 473 (M+H)+ Step 5: 1-(2-Cyanopyridin-4-yl)-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-6-carbonitrile (55 mg, yield: 26%) was obtained by performing the same treatments as in Step 4 of Reference Example 1 and Example 34 sequentially using tert-butyl 4-{[6-cyano-1-(2-cyanopyridin-4-yl)-2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl]methyl}piperidine-1-carboxylate obtained in Step 4. ESI-MS m/z: 518 (M+H)+, 1H-NMR (300 MHz, DMSO-d6, δ): 12.1 (br s, 1H), 8.91 (d, J=5.1 Hz, 1H), 8.25-8.18 (m, 2H), 8.10 (s, 1H), 7.86-7.73 (m, 2H), 7.62-7.52 (m, 1H), 6.81 (d, J=5.4 Hz, 1H), 6.46 (d, J=5.4 Hz, 1H), 4.67 (s, 2H), 3.88 (d, J=13 Hz, 2H), 3.40-3.27 (m, 2H), 2.95-2.78 (m, 2H), 2.05-1.85 (m, 1H), 1.77-1.63 (m, 2H), 1.49-1.30 (m, 2H) Step 6: The title Compound 51 (28 mg, yield: 74%) was obtained in the same manner as in Step 4 of Example 48 using 1-(2-cyanopyridin-4-yl)-2-oxo-3-{[1-(4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-5-yl)piperidin-4-yl]methyl}-1,2,3,4-tetrahydroquinazoline-6-carbonitrile obtained in Step 5. ESI-MS m/z: 536 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 12.1 (br s, 1H), 8.81 (d, J=5.2 Hz, 1H), 8.22 (d, J=5.2 Hz, 2H), 8.10 (s, 1H), 8.00 (s, 1H), 7.78 (s, 2H), 7.28-7.66 (m, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.82 (d, J=5.2 Hz, 1H), 6.33 (d, J=8.4 Hz, 1H), 4.68 (s, 2H), 3.88 (d, J=13 Hz, 2H), 3.34-3.32 (m, 2H), 2.87 (m, 2H), 2.05-1.93 (m, 1H), 1.82-1.62 (m, 2H), 1.45-1.29 (m, 2H) Example 52 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[4,3-d]pyrimidine-7-carboxamido Step 1: Tert-butyl 4-[(2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)methy 1]piperidine-1-carboxylate (3.6 g, yield: 61%) was obtained in the same manner as in Reference Example 1 using 4-aminonicotinaldehyde. ESI-MS m/z: 347 (M+H)+ Step 2: Tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate (450 mg, yield: 70%) was obtained in the same manner as in Step 1 of Example 50 using tert-butyl 4-[(2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl)methyl]piperidine-1-carboxylate obtained in Step 1 and 2-fluoro-5-iodobenzonitrile. ESI-MS m/z: 449 (M+H)+ Step 3: 5-(3-{[1-(7-Chloropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-1(2H)-yl)-2-fluorobenzonitrile (300 mg, 23%) was obtained in the same manner as in Step 3 of Example 5 using tert-butyl 4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidine-1-carboxylate obtained in Step 2 and Compound R11 obtained in Reference Example 11. ESI-MS m/z: 529 (M+H)+ Step 4: Propyl 4-(4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[4,3-d]pyrimidine-7-carboxylate (130 mg, yield: 53%) was obtained in the same manner as in Step 2 of Example 15 using 5-(3-{[1-(7-chloropyrido[4,3-d]pyrimidin-4-yl)piperidin-4-yl]methyl}-2-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-(2H)-yl)-2-fluorobenzonitrile obtained in Step 3. ESI-MS m/z: 581 (M+H)+ Step 5: 4-(4-{[1-(3-Cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[4,3-d]pyrimidine-7-carboxylic acid (35 mg, yield: 30%) was obtained in the same manner as in Step 3 of Example 15 using propyl 4-(4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[4,3-d]pyrimidine-7-carboxylate obtained in Step 4. ESI-MS m/z: 539 (M+H)+, 1H-NMR (400 MHz, DMSO-d6, δ): 9.32 (s, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 8.20 (d, J=5.6 Hz, 1H), 8.15-8.05 (m, 2H), 7.89-7.72 (m, 1H), 7.72 (t, J=9.0 Hz, 1H), 6.17 (d, J=5.6 Hz, 1H), 4.71 (s, 2H), 4.57 (d, J=13 Hz, 2H), 3.49-3.20 (m, 4H), 2.31-2.12 (m, 1H), 1.88 (d, J=10 Hz, 2H), 1.51-1.33 (m, 2H) Step 6: The title Compound 52 (12 mg, yield: 34%) was obtained in the same manner as in Step 5 of Example 45 using 4-(4-{[1-(3-cyano-4-fluorophenyl)-2-oxo-1,2-dihydropyrido[4,3-d]pyrimidin-3(4H)-yl]methyl}piperidin-1-yl)pyrido[4,3-d]pyrimidine-7-carboxylic acid obtained in Step 5. ESI-MS m/z: 538 (M+H)+, 1H-NMR (300 MHz, DMSO-d6, δ): 9.23 (s, 1H), 8.65 (s, 1H), 8.33 (s, 1H), 8.25-8.13 (m, 2H), 8.08 (s, 1H), 8.11-8.00 (m, 1H), 7.85 (s, 1H), 7.85-7.62 (m, 2H), 6.13 (d, J=5.4 Hz, 1H), 4.67 (s, 2H), 4.54 (d, J=12 Hz, 2H), 3.58-3.00 (m, 4H), 2.25-2.12 (m, 1H), 1.85 (d, J=12 Hz, 2H), 1.51-1.30 (m, 2H) Example 53 Tablets Compound 53 Tablets having the following ingredients are prepared according to the conventional manner. Compound 53 (40 g), lactose (286.8 g) and potato starch (60 g) are mixed, and a 10% aqueous hydroxypropyl cellulose solution (120 g) is added thereto. The resulting mixture is kneaded, granulated, dried, and then sized according to the conventional manner, whereby granules for tableting are prepared. Magnesium stearate (1.2 g) is added thereto and mixed therewith, and the resulting mixture is tableted using a tablet press with a pestle having a diameter of 8 mm (model RT-15, manufactured by Kikusui Seisakusho Ltd.), whereby tablets (containing 20 mg of the active ingredient per tablet) are obtained. TABLE 8 Formulation Compound 53 20 mg Lactose 143.4 mg Potato starch 30 mg Hydroxypropyl cellulose 6 mg Magnesium stearate 0.6 mg 200 mg INDUSTRIAL APPLICABILITY According to the present invention, a fused-ring heterocyclic compound or a pharmaceutically acceptable salt thereof, which has a Wnt signaling inhibitory activity, and is useful as a therapeutic and/or preventive agent for, for example, cancer, pulmonary fibrosis, fibromatosis, osteoarthritis, and the like, and the like can be provided.",C07D40114,C07D40114,20160129,20170926,20160616,66417.0
1,14990359,ACCEPTED,METHOD AND TERMINAL FOR SELECTING AP,"There is provided a method for selecting an access point (AP), the method performed by a user equipment. The method may comprise: receiving a prioritized list with respect to APs, the prioritized list includes at least one of roaming consortium information, a network address identifier (NAI), a public land mobile network (PLMN) identifier; scanning at least one or more APs in the vicinity thereby generating an available list which includes at least one or more service set identifiers (SSIDs) and roaming consortium information; acquiring at least one or more NAIs from the roaming consortium information in the available list using pre-stored mapping information; comparing the acquired NAI with the NAI in the prioritized list to select a proper AP.","1-15. (canceled) 16. A method for selecting an access point (AP), the method performed by a user equipment and comprising: scanning at least one or more APs in the vicinity; generating an available list including at least one or more of a service set identifiers (SSID) and roaming consortium information, which are acquired from the scanning, wherein, if an any AP searched from the scanning corresponds to a hotspot 2.0 based AP, the available list includes both of the SSID and the roaming consortium information; acquiring at least one or more network address identifiers (NAIs) from the roaming consortium information included in the available list based on pre-stored mapping information; and selecting an any AP, based on a comparison of the at least one or more acquired NAI with at least one or more NAIs in a prioritized list with respect to APs. 17. The method of claim 16, further comprising receiving the prioritized list with respect to APs, the prioritized list including at least one of: roaming consortium information, the at least one or more NAIs, and a public land mobile network (PLMN) identifier. 18. The method of claim 17, wherein the acquiring of the NAI includes: extracting an organization unique identifier (OUI) from the roaming consortium information included in the available list; and acquiring an NAI corresponding to the extracted OUI based on the pre-stored mapping information. 19. The method of claim 18, wherein the pre-stored mapping information includes an NAI and a PLMN ID corresponding to an OUI. 20. The method of claim 19, further comprising comparing the PLMN ID acquired from the pre-stored mapping information and the PLMN ID in the prioritized list with each other. 21. The method of claim 20, further comprising: performing an association to a corresponding AP, when an NAI and a PLMN ID which match the NAI and the PLMN ID in the prioritized list are present; and performing authentication by using the PLMN ID. 22. The method of claim 16, wherein the scanning includes: acquiring information on a load and an installation place of the at least one or more APs; excluding any AP which does not match a predetermined condition from the available list; and adding any AP which matches the predetermined condition into the available list. 23. The method of claim 22, wherein the predetermined condition includes at least one of: a condition for the load of the AP and a condition for the load for the installation place of the AP. 24. The method of claim 17, wherein the prioritized list is received from an access network discovery and selection function (ANDSF). 25. A terminal, comprising: a transceiver; and processor configured to: scan at least one or more APs in the vicinity; generate an available list including at least one or more of a service set identifiers (SSID) and roaming consortium information, which are acquired from the scanning, wherein, if an any AP searched from the scanning corresponds to a hotspot 2.0 based AP, the available list includes both of the SSID and the roaming consortium information; acquire at least one or more network address identifiers (NAIs) from the roaming consortium information included in the available list based on pre-stored mapping information; and select an any AP, based on a comparison of the at least one or more acquired NAI with at least one or more NAIs in a prioritized list with respect to APs. 26. The terminal of claim 25, wherein the processor is further configured to receive the prioritized list with respect to APs, the prioritized list includes at least one of roaming consortium information, the at least one or more NAIs, and a public land mobile network (PLMN) identifier. 27. The terminal of claim 26, wherein the acquiring of the processor includes: extracting an organizational unique identifier (OUI) from the roaming consortium information in the available list; and acquiring an NAI corresponding to the extracted OUI by using the pre-stored mapping information. 28. The terminal of claim 27, wherein the pre-stored mapping information includes an NAI and a PLMN ID corresponding to an OUI. 29. The terminal of claim 28, wherein the processor is further configured to compare the PLMN ID acquired from the mapping information and the PLMN ID in the prioritized list with each other. 30. The terminal of claim 29, wherein the processor is further configured to: perform an association to a corresponding AP when an NAI and a PLMN ID which match the NAI and the PLMN ID in the prioritized list are present; and perform authentication by using the PLMN ID. 31. The terminal of claim 25, wherein the scanning of the processor includes: acquiring information on a load and an installation place of the at least one or more APs; excluding any AP which does not match a predetermined condition from the available list; and adding any AP which matches the predetermined condition into the available list. 32. The terminal of claim 31, wherein the predetermined condition includes at least one of: a condition for the load of the AP and a condition for the load for the installation place of the AP.","<SOH> BACKGROUND OF THE INVENTION <EOH>Field of the Invention The present invention relates to a method and a terminal for selecting an access point (AP). Discussion of the Related Art A 3GPP that establishes a technology standard of a 3 rd generation mobile communication system has started a research into long term evolution/system architecture evolution (LTE/SAE) technology as part of an effort to optimize and improve performance of 3 GPP technologies from the end of 2004 in order to cope with various forums and new technologies associated with 4 th generation mobile communication. SAE that is progressed around 3GPP SA WG2 is a research into network technology to determine a structure of a network with an LTE work of a 3GPP TSG RAN and support mobility between model networks and one of key standardization issues of the 3GPP. This is a work for developing a 3GPP system to a system that supports various wireless access technologies based on an IP and the work has been progressed for the purpose of an optimized packet based system that minimizes a transmission delay with a further improved data transmission capability. An SAE higher-level reference model defined in the 3GPP SA WG2 includes a non-roaming case and a roaming case of various scenarios, and a detailed content may be referred in TS 23.401 and TS 23.402 which are 3GPP standard documents. A network structure diagram of FIG. 1 shows schematic reconfiguration of the SAE higher-level reference model. FIG. 1 is a Structural Diagram of an Evolved Mobile Communication Network. One of largest features of the network structure of FIG. 1 is based on a 2 tier model of eNodeB of an evolved UTRAN and a gateway of a core network and although accurately matches each other, the eNodeB 20 has functions of NodeB and RNC of an existing UMTS system and the gateway has an SGSN/GGSN function of the existing system. Another key feature is that a control plane and a user plane between an access network and the core network are exchanged to different interfaces. In the existing UMTS system, one lu interface exists between an RNC and an SGSN, while a mobility management entity (MME) 51 that undertakes processing of a control signal has a structure separated from a gateway (GW), and as a result, two interfaces of S1-MME and S1-U are respectively used. The GW includes a serving-gateway (hereinafter, referred to as ‘S-GW’) 52 and a packet data network gateway (hereinafter, referred to as ‘PDN-GW’ or ‘P-GW’) 53 . Meanwhile, in recent years, congestion of a core network of a mobile communication provider has been aggravated with an explosive increase of data. As a scheme for relieving the aggravated congestion, there is a discussion intended to offload data of a user terminal to a wired network without passing through a core network of a provider. As a result of such a discussion, technologies such as IP flow mobility and seamless offload (IFOM), multi access PDN connectivity (MAPCON), etc. for supporting multiple radio access have been proposed. The MAPCON technology establishes PDN connections through their preferred radio access such as 3GPP access or Wi-Fi access and transmits data through the PDN connections. The IFOM technology allows a PDN connection to use 3GPP access and Wi-Fi access simultaneously and transmits data through their preferred access. FIG. 2A is an Exemplary Diagram Illustrating an Example of IFOM Technology. Referring to FIG. 2A , the IFOM provides the same PDN connection through various different accesses simultaneously. The IFOM provides offloading to a seamless WLAN. Further, the IFOM transfers an IP flow of one same PDN connection from one access to another access. FIG. 2B is an Exemplary Diagram Illustrating an Example of MAPCON Technology. As known with reference to FIG. 2B , the MAPCON technology easily connects IP flows of various PDN connections to other APNs through different access systems. According to the MAPCON technology, a UE 10 may create a new PDN connection on an access which is not previously used. Alternatively, the UE 10 may create a new PDN connection to one selected from various accesses which are previously used. Alternatively, the UE 10 may transfer all or some of all PDN connections which are already connected to another access. Technology associated with Wi-Fi interworking includes traffic offloading technology and technology associated with WLAN selection. That is, technology in which a terminal can automatically select a WLAN is standardized (3GPP TS 24.234) and an associated operation is described below. First, the terminal searches neighboring Wi-Fi to create a list of available WLANs. This is a list of SSIDs expressing the WLANs. The created list and a preferred WLAN list are compared with each other to select the most preferred WLAN in the created list. An ANQP query is transmitted to the selected WLAN to acquire PLMN information which is providable by the WLAN. The most preferred PLMN (for example, Home PLMN) is selected by comparing the acquired PLMN information to preferred PLMN information which is stored in advance and is used to access to the corresponding PLMN through an authentication process. FIG. 3 Illustrates an Environment in which a General AP and a Recently Discussed Hotspot 2.0 AP are Present. An traditional HotSpot meant that a Wi-Fi service is provided to an unspecific majority in a public place where a floating population is large. However, with a recent explosive increase in a bandwidth usage, it is difficult to sufficiently provide a bandwidth required as 3 rd generation or 4 th generation mobile communication technology now. In particular, in a commercial area in which a population is dense during the daytime, bandwidth management is actually impossible and a HotSpot 2.0 that makes a mobile communication network in a population dense area interwork with a Wi-Fi network to provide a Vertical Handoff service is researched in order to solve such a problem. The HotSpot 2.0 as a standard developed in Wi-Fi Alliance (WFA) aims at simplifying and automating access to a public Wi-Fi network. A mobile terminal aims at recognizing which AP among various neighboring access points is suitable for a usage purpose thereof and authenticating the corresponding AP from a remote service provider by using appropriate credentials. To this end, the respective APs is allowed to provide new various information, and information indicating whether a specific service provider is connectable, a HotSpot provider, a roaming consortium, Venue information (Venue Group, Venue Type), configuration information can be provided. Herein, the roaming consortium is a group of service providers that make a roaming agreement. Numerous service set identifiers (SSIDs) that are managed for each roaming consortium may be present according to the roaming consortium and a 3GPP provider who cooperates with the roaming consortium may not know all of numerous SSIDs. Accordingly, a HotSpot 2.0 AP 40 c provides roaming consortium information to increase efficiency of management instead of the numerous SSIDs. The roaming consortium information is constituted by a list of a service provider or a company or an agency that made a roaming agreement with the service provider. Herein, information of each company or agency is expressed as an organizational unique identifier (OUI). That is, the roaming consortium information is configured in a list form of OUI 1 , OUI 2 , . . . , OUI_n. Herein, the OUI can be used by being registered in IEEE, and is information which is unique for each agency. Further, the HotSpot 2.0 AP 40 c may provide BSS load information or bandwidth information (for example, WAN Metrics). Meanwhile, as illustrated, under a situation in which the hotspot 2.0 AP 40 c and general APs 40 a and 40 b coexist, the UE 10 receives SSID information from the general APs 40 a and 40 b and the roaming consortium information from the hotspot 2.0 AP 40 c. However, since a 3GPP release 11 based UE 10 which has been developed up to now may select only the general APs 40 a and 40 b based on only the SSID and may not read the roaming consortium information, the UE 10 may not select the hotspot 2.0 AP 40 c. In detail, the UE 10 provides only SSID information in order to select the AP in a 3GPP network in prior art. According to 3GPP release 11, AP selection, that is, WLAN selection has been developed aiming at selecting a public land mobile network (PLMN). As a result, the UE 10 receives SSIDs broadcasted from the APs 40 a and 40 b to create an available list and thereafter, accesses respective APs in order of the SSIDs selected by comparing a preference list stored in advance and information on the created list and reads PLMN list information supported by the APs. The PLMN information is also compared with a preference PLMN list to select a PLMN having the highest preference. When the PLMN selection is completed, the AP is accessed by using the corresponding SSID to access the corresponding PLMN. As described above, since the 3GPP release 11 based UE 10 which has been developed up to now may select only the general APs 40 a and 40 b based on only the SSID and may not select the hotspot 2.0 AP 40 c.","<SOH> SUMMARY OF THE INVENTION <EOH>The present disclosure has been made in an effort to allow a UE to correctly select an AP. In detail, the present disclosure has been made in an effort to provide a scheme that allows a recently developed Hotspot 2.0 to be used even in a 3GPP network system. In particular, the present disclosure has been made in an effort to enhance a method for selecting an AP by using information provided by a Hotspot 2.0 AP. In one aspect, there is provided a method for selecting an access point (AP), the method performed by a user equipment. The method may comprise: receiving a prioritized list with respect to APs, the prioritized list includes at least one of roaming consortium information, a network address identifier (NAI), a public land mobile network (PLMN) identifier; scanning at least one or more APs in the vicinity thereby generating an available list which includes at least one or more service set identifiers (SSIDs) and roaming consortium information; acquiring at least one or more NAIs from the roaming consortium information in the available list using pre-stored mapping information; comparing the acquired NAI with the NAI in the prioritized list to select a proper AP. The acquiring of the NAI may include: extracting an organization unique identifier (OUI) from the roaming consortium information in the available list; and acquiring an NAI corresponding to the extracted OUI by using the pre-stored mapping information. The pre-stored mapping information may include an NAI and a PLMN ID corresponding to an OUI. The method may further comprise: comparing the PLMN ID acquired from the mapping information and the PLMN ID in the preference list with each other. The method may further comprise: associating, when an NAI and a PLMN ID which match the NAI and the PLMN ID in the preference list are present, a corresponding AP; and performing authentication by using the PLMN ID. The scanning may include: receiving information on a load and an installation place of the corresponding AP through the AP scanning; excluding an AP which does not match a predetermined condition from the available list; and filling the AP which matches the predetermined condition in the available list. The predetermined condition may include at least one of a condition for the load of the AP and a condition for the load for the installation place of the AP. an entity in a network providing the preference list is an access network discovery and selection function (ANDSF). In one aspect, there is provided a terminal comprising: a transmitting/receiving unit receiving a prioritized list with respect to APs from an entity in a network, the prioritized list includes at least one of a roaming consortium information, a network address identifier (NAI), and a public land mobile network (PLMN) identifier; and a processor scanning APs in the vicinity thereby generating an available list including a service set identifier (SSID) and the roaming consortium information, acquiring an NAI from the roaming consortium information in the available list, and comparing the acquired NAI with an NAI in the preference list. According to the present disclosure, a UE that supports a Hotspot 2.0 AP can effectively select an AP. Further, according to the present disclosure, a time required to select the AP can be significantly reduced.","This application claims the benefit of priority of U.S. Provisional applications No. 61/753,939 filed on Jan. 18, 2013, No. 61/767,196 filed on Feb. 20, 2013, No. 61/807,301 filed on Apr. 1, 2013, No. 61/818,916 filed on May 3, 2013, No. 61/821,667 filed on May 9, 2013, and No. 61/821,725 filed on May 10, 2013, of which are incorporated by reference in their entirety herein. BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to a method and a terminal for selecting an access point (AP). Discussion of the Related Art A 3GPP that establishes a technology standard of a 3rd generation mobile communication system has started a research into long term evolution/system architecture evolution (LTE/SAE) technology as part of an effort to optimize and improve performance of 3 GPP technologies from the end of 2004 in order to cope with various forums and new technologies associated with 4th generation mobile communication. SAE that is progressed around 3GPP SA WG2 is a research into network technology to determine a structure of a network with an LTE work of a 3GPP TSG RAN and support mobility between model networks and one of key standardization issues of the 3GPP. This is a work for developing a 3GPP system to a system that supports various wireless access technologies based on an IP and the work has been progressed for the purpose of an optimized packet based system that minimizes a transmission delay with a further improved data transmission capability. An SAE higher-level reference model defined in the 3GPP SA WG2 includes a non-roaming case and a roaming case of various scenarios, and a detailed content may be referred in TS 23.401 and TS 23.402 which are 3GPP standard documents. A network structure diagram of FIG. 1 shows schematic reconfiguration of the SAE higher-level reference model. FIG. 1 is a Structural Diagram of an Evolved Mobile Communication Network. One of largest features of the network structure of FIG. 1 is based on a 2 tier model of eNodeB of an evolved UTRAN and a gateway of a core network and although accurately matches each other, the eNodeB 20 has functions of NodeB and RNC of an existing UMTS system and the gateway has an SGSN/GGSN function of the existing system. Another key feature is that a control plane and a user plane between an access network and the core network are exchanged to different interfaces. In the existing UMTS system, one lu interface exists between an RNC and an SGSN, while a mobility management entity (MME) 51 that undertakes processing of a control signal has a structure separated from a gateway (GW), and as a result, two interfaces of S1-MME and S1-U are respectively used. The GW includes a serving-gateway (hereinafter, referred to as ‘S-GW’) 52 and a packet data network gateway (hereinafter, referred to as ‘PDN-GW’ or ‘P-GW’) 53. Meanwhile, in recent years, congestion of a core network of a mobile communication provider has been aggravated with an explosive increase of data. As a scheme for relieving the aggravated congestion, there is a discussion intended to offload data of a user terminal to a wired network without passing through a core network of a provider. As a result of such a discussion, technologies such as IP flow mobility and seamless offload (IFOM), multi access PDN connectivity (MAPCON), etc. for supporting multiple radio access have been proposed. The MAPCON technology establishes PDN connections through their preferred radio access such as 3GPP access or Wi-Fi access and transmits data through the PDN connections. The IFOM technology allows a PDN connection to use 3GPP access and Wi-Fi access simultaneously and transmits data through their preferred access. FIG. 2A is an Exemplary Diagram Illustrating an Example of IFOM Technology. Referring to FIG. 2A, the IFOM provides the same PDN connection through various different accesses simultaneously. The IFOM provides offloading to a seamless WLAN. Further, the IFOM transfers an IP flow of one same PDN connection from one access to another access. FIG. 2B is an Exemplary Diagram Illustrating an Example of MAPCON Technology. As known with reference to FIG. 2B, the MAPCON technology easily connects IP flows of various PDN connections to other APNs through different access systems. According to the MAPCON technology, a UE 10 may create a new PDN connection on an access which is not previously used. Alternatively, the UE 10 may create a new PDN connection to one selected from various accesses which are previously used. Alternatively, the UE 10 may transfer all or some of all PDN connections which are already connected to another access. Technology associated with Wi-Fi interworking includes traffic offloading technology and technology associated with WLAN selection. That is, technology in which a terminal can automatically select a WLAN is standardized (3GPP TS 24.234) and an associated operation is described below. First, the terminal searches neighboring Wi-Fi to create a list of available WLANs. This is a list of SSIDs expressing the WLANs. The created list and a preferred WLAN list are compared with each other to select the most preferred WLAN in the created list. An ANQP query is transmitted to the selected WLAN to acquire PLMN information which is providable by the WLAN. The most preferred PLMN (for example, Home PLMN) is selected by comparing the acquired PLMN information to preferred PLMN information which is stored in advance and is used to access to the corresponding PLMN through an authentication process. FIG. 3 Illustrates an Environment in which a General AP and a Recently Discussed Hotspot 2.0 AP are Present. An traditional HotSpot meant that a Wi-Fi service is provided to an unspecific majority in a public place where a floating population is large. However, with a recent explosive increase in a bandwidth usage, it is difficult to sufficiently provide a bandwidth required as 3rd generation or 4th generation mobile communication technology now. In particular, in a commercial area in which a population is dense during the daytime, bandwidth management is actually impossible and a HotSpot 2.0 that makes a mobile communication network in a population dense area interwork with a Wi-Fi network to provide a Vertical Handoff service is researched in order to solve such a problem. The HotSpot 2.0 as a standard developed in Wi-Fi Alliance (WFA) aims at simplifying and automating access to a public Wi-Fi network. A mobile terminal aims at recognizing which AP among various neighboring access points is suitable for a usage purpose thereof and authenticating the corresponding AP from a remote service provider by using appropriate credentials. To this end, the respective APs is allowed to provide new various information, and information indicating whether a specific service provider is connectable, a HotSpot provider, a roaming consortium, Venue information (Venue Group, Venue Type), configuration information can be provided. Herein, the roaming consortium is a group of service providers that make a roaming agreement. Numerous service set identifiers (SSIDs) that are managed for each roaming consortium may be present according to the roaming consortium and a 3GPP provider who cooperates with the roaming consortium may not know all of numerous SSIDs. Accordingly, a HotSpot 2.0 AP 40c provides roaming consortium information to increase efficiency of management instead of the numerous SSIDs. The roaming consortium information is constituted by a list of a service provider or a company or an agency that made a roaming agreement with the service provider. Herein, information of each company or agency is expressed as an organizational unique identifier (OUI). That is, the roaming consortium information is configured in a list form of OUI1, OUI2, . . . , OUI_n. Herein, the OUI can be used by being registered in IEEE, and is information which is unique for each agency. Further, the HotSpot 2.0 AP 40c may provide BSS load information or bandwidth information (for example, WAN Metrics). Meanwhile, as illustrated, under a situation in which the hotspot 2.0 AP 40c and general APs 40a and 40b coexist, the UE 10 receives SSID information from the general APs 40a and 40b and the roaming consortium information from the hotspot 2.0 AP 40c. However, since a 3GPP release 11 based UE 10 which has been developed up to now may select only the general APs 40a and 40b based on only the SSID and may not read the roaming consortium information, the UE 10 may not select the hotspot 2.0 AP 40c. In detail, the UE 10 provides only SSID information in order to select the AP in a 3GPP network in prior art. According to 3GPP release 11, AP selection, that is, WLAN selection has been developed aiming at selecting a public land mobile network (PLMN). As a result, the UE 10 receives SSIDs broadcasted from the APs 40a and 40b to create an available list and thereafter, accesses respective APs in order of the SSIDs selected by comparing a preference list stored in advance and information on the created list and reads PLMN list information supported by the APs. The PLMN information is also compared with a preference PLMN list to select a PLMN having the highest preference. When the PLMN selection is completed, the AP is accessed by using the corresponding SSID to access the corresponding PLMN. As described above, since the 3GPP release 11 based UE 10 which has been developed up to now may select only the general APs 40a and 40b based on only the SSID and may not select the hotspot 2.0 AP 40c. SUMMARY OF THE INVENTION The present disclosure has been made in an effort to allow a UE to correctly select an AP. In detail, the present disclosure has been made in an effort to provide a scheme that allows a recently developed Hotspot 2.0 to be used even in a 3GPP network system. In particular, the present disclosure has been made in an effort to enhance a method for selecting an AP by using information provided by a Hotspot 2.0 AP. In one aspect, there is provided a method for selecting an access point (AP), the method performed by a user equipment. The method may comprise: receiving a prioritized list with respect to APs, the prioritized list includes at least one of roaming consortium information, a network address identifier (NAI), a public land mobile network (PLMN) identifier; scanning at least one or more APs in the vicinity thereby generating an available list which includes at least one or more service set identifiers (SSIDs) and roaming consortium information; acquiring at least one or more NAIs from the roaming consortium information in the available list using pre-stored mapping information; comparing the acquired NAI with the NAI in the prioritized list to select a proper AP. The acquiring of the NAI may include: extracting an organization unique identifier (OUI) from the roaming consortium information in the available list; and acquiring an NAI corresponding to the extracted OUI by using the pre-stored mapping information. The pre-stored mapping information may include an NAI and a PLMN ID corresponding to an OUI. The method may further comprise: comparing the PLMN ID acquired from the mapping information and the PLMN ID in the preference list with each other. The method may further comprise: associating, when an NAI and a PLMN ID which match the NAI and the PLMN ID in the preference list are present, a corresponding AP; and performing authentication by using the PLMN ID. The scanning may include: receiving information on a load and an installation place of the corresponding AP through the AP scanning; excluding an AP which does not match a predetermined condition from the available list; and filling the AP which matches the predetermined condition in the available list. The predetermined condition may include at least one of a condition for the load of the AP and a condition for the load for the installation place of the AP. an entity in a network providing the preference list is an access network discovery and selection function (ANDSF). In one aspect, there is provided a terminal comprising: a transmitting/receiving unit receiving a prioritized list with respect to APs from an entity in a network, the prioritized list includes at least one of a roaming consortium information, a network address identifier (NAI), and a public land mobile network (PLMN) identifier; and a processor scanning APs in the vicinity thereby generating an available list including a service set identifier (SSID) and the roaming consortium information, acquiring an NAI from the roaming consortium information in the available list, and comparing the acquired NAI with an NAI in the preference list. According to the present disclosure, a UE that supports a Hotspot 2.0 AP can effectively select an AP. Further, according to the present disclosure, a time required to select the AP can be significantly reduced. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a structural diagram of an evolved mobile communication network. FIG. 2A is an exemplary diagram illustrating an example of IFOM technology. FIG. 2B is an exemplary diagram illustrating an example of MAPCON technology. FIG. 3 illustrates an environment in which a general AP and a recently discussed hotspot 2.0 AP are present. FIGS. 4A and 4B illustrate a network control entity for selecting an access network. FIG. 5 is an exemplary diagram illustrating an environment assumed in this specification. FIG. 6 is a flowchart illustrating a scheme according to a first exemplary embodiment presented in this specification under the environment illustrated in FIG. 5. FIG. 7 is a flowchart illustrating a scheme according to a second exemplary embodiment presented in this specification under the environment illustrated in FIG. 5. FIG. 8 is a flowchart illustrating a scheme according to a third exemplary embodiment presented in this specification under the environment illustrated in FIG. 5. FIG. 9 is a configuration block diagram of a UE 100 and an ANDSF 600 according to the present disclosure. DETAILED DESCRIPTION OF THE EMBODIMENTS Hereinafter, terms used in the specification will be defined in brief in order to assist understanding the present invention before a description referring the accompanying drawings. UMTS: means a 3rd generation mobile communication network as an abbreviation of a Universal Mobile Telecommunication System EPS: Means a core network supporting a long term evolution (LTE) network as an abbreviation of Evolved Packet System. Network evolved from the UMTS PDN (Public Data Network): An independent network at which a server providing a service is positioned APN (Access Point Name): Provided to UE as a name of an access point managed in the network. That is, the APN indicates a name (string) of the PDN. The corresponding PDN for transmitting and receiving data is decided based on the name of the access point. NodeB: Installed outdoor as a base station of the UMTS network and a cell coverage scale corresponds to a macro cell. eNodeB: Installed outdoor as a base station of an evolved packet system (EPS) and the cell coverage scale corresponds to the macro cell. MME: Serves to control each entity in the EPS in order to provide a session for the UE and mobility as an abbreviation of Mobility Management Entity. Session: The session is a passage for data transmission and the unit thereof may be PDN, bearer, IP flow unit, or the like. The respective units may be divided into a whole unit (APN or PDN unit) of a target network, a unit (Bearer unit) divided as a QoS therein, and a destination IP address unit. PDN connection: Indicates connection from the terminal to the PDN, that is, association (connection) between the terminal expressed as the IP address and the PDN expressed as the APN. The PDN connection means connection between entities (terminal—PDN GW) in the core network so as to form the session. UE Context: UE context information used to manage the UE in the network, that is, context information constituted by a UE id, mobility (present location, and the like), an attribute (QoS, priority, and the like) of the session Service Set ID (SSID): an identifier of a WLAN AP defined in the IEEE 802.11 ANDSF (Access Network Discovery and Selection Function): As one network entity, a policy is provided to discover and select access which the terminal can use by the unit of the provider Brief Description of Technology Presented in Specification Meanwhile, hereinafter, schemes presented in the specification will be described below in brief. First, a 3GPP based access network discovery and selection function (ANDSF) performs a network search function and a data management and control function for providing selective assistance data according to a provider policy. The existing ANDSF needs to designate an ID of a WLAN in order to decide access preference and the ID may be provided only in a form of a service set identifier. However, an ANDSF enhanced according to an embodiment of the present invention may provide a preference list defined by using information provided an Hotspot 2.0 AP which has been recently developed. For example, a preference list is constituted by a network address ID (for example, a network address identifier (NAI) realm) of a provider or a roaming consortium organizational identifier (OI) in addition to the SSID. The NAI realm information is address information of a character string pattern such as attwireless.com. Both information of the OUI and the NAI realm is different individual information having different formats, but a service provider may express itself by using the two formats due to the common point of expressing service providers. FIGS. 4A and 4B Illustrate a Network Control Entity for Selecting an Access Network. As known with reference to FIG. 4A, the ANDSF may be present in a home public land mobile network (hereinafter, ‘HPLMN’) of a UE 100. Further, as known with reference to FIG. 4B, the ANDSF may be present even in a visited public land mobile network (hereinafter, referred to as ‘VPLMN’) of the UE 100. As such, when the ANDSF is positioned on the home network, the ANDSF may be called H-ANDSF 610 and when the ANDSF is positioned on the visited network, the ANDSF may be called V-ANDSF 620. Hereinafter, the ANDSF 600 is commonly called the H-ANDSF 610 or the V-ANDSF 620. The ANDSF may respond to a request of the UE to access network discovery information and further, transmit information as necessary even though there is no request from the UE. The ANDSF may provide information on an inter-system mobility policy, information for discovery of the access network, and information on an inter-system routing, for example, a routing rule. The information on the routing, for example, the routing rule may include an AccessTechnology, an AccessId, AccessNetworkPriority, and the like. Technology called the ANDSF is started as technology that provides a policy for mobility between heterogeneous network. However, according to a disclosure of the specification, when legacy APs and the Hotspot 2.0 APs are present in plural, ANDSF provides information for the UE to select any AP. A detailed example will be described with reference to FIG. 5. FIG. 5 is an Exemplary Diagram Illustrating an Environment Assumed in this Specification. FIG. 6 is a Flowchart Illustrating a Scheme According to a First Exemplary Embodiment Presented in this Specification Under the Environment Illustrated in FIG. 5. As known with reference to FIG. 5, it is assumed that general APs 400a and 400b are present and several Hotspot 2.0 APs 400c, 400d, and 400e are present. As illustrated, the general APs 400a and 400b broadcast the SSID. The hotspot 2.0 APs 400c, 400d, and 400e broadcast roaming consortium information as well as SSID. Further, the hotspot APs 400c, 400d, and 400e provide information on an access network type regarding whether each hotspot AP 400c, 400d, or 400e is private, public, free, or personal. Further, the hotspot APs 400c, 400d, and 400e may provide venue information. For example, the hotspot APs 400c, 400d, and 400e may provide place type information regarding whether an installation space is, for example, a school, a hospital, a hotel, an office, a home, or the like. The hotspot APs 400c, 400d, and 400e are connected with access network query protocol based servers 800a, 800b, and 800c illustrated, respectively. The ANQP based servers 800a, 800b, and 800c provide the NAI realm according to a request. Hereinafter, information provided through Hotspot 2.0 technology which is organized will be illustrated in Table 1 below. TABLE 1 Information provided through Information broadcasted in AP ANQP based server 1. SSID 1. Roaming Consortium ID list 2. Roaming Consortium ID 2. NAI Realm list 3. Venue information (Venue Group, Venue Type) 4. BSS Load information Meanwhile, according to related art, the ANDSF 600 provides only SSID information for selecting an access network, for example, an AP. However, according to embodiments presented in the specification, the ANDSF 600 may provide the preference list using the roaming consortium information or the NAI realm information in addition to the SSID. The preference list is illustrated in Table 2. TABLE 2 PrioritizedAccess AccessTechnology AccessId SecondaryAccessId AccessNetworkPriority NAI Realm Roaming Consortium ID The preference list illustrated in Table 2 above shows preferred accesses which are arranged. The preferred accesses may include access technology, an access ID, a secondary access ID, an access network priority, NAI realm, a roaming consortium ID, and the like. The NAI realm and the roaming consortium ID may be designated in plural and expressed according to the priority. Then, as illustrated in FIG. 6, the UE 100 acquires information from several APs 400a, 400b, 400c, 400d, and 400e and compares the information with the information in the preference list to select any one AP. In detail, if a predetermined AP among several APs 400a, 400b, 400c, 400d, and 400e is the hotspot 2.0 AP (S110), the UE 100 acquires the broadcasted SSID and roaming consortium ID (S120). Subsequently, the UE 100 creates an available list by using the acquired information (for example, the SSID or the roaming consortium ID) (S130). In addition, the UE 100 compares the SSID or the roaming consortium ID in the available list with the SSID or the roaming consortium ID in the preference list illustrated in FIG. 6 (S140). According to a result of the comparison, if the matched SSID is the highest priority, PLMN information is acquired by accessing the corresponding AP (S170). Subsequently, a public land mobile network (PLMN) ID acquired from the corresponding AP and information of a preferred PLMN list are compared with each other (S180). When the PLMN ID is matched, the PLMN is selected and authentication is performed (S190). On the contrary, according to the comparison result (S140), if the roaming consortium ID which is matched has the highest priority, the NAI realm information is requested and acquired from the ANQP based servers 800a, 800b, and 800c of the corresponding AP (S150). Subsequently, the acquired NAI realm and the NAI realm in the preference list are compared with each other (S160). When the NAI realm is matched, the authentication is performed by using the NAI realm (S190). As described above, under an environment in which the general APs 400a and 400b, and the hotspot 2.0 APs 400c, 400d, and 400e coexist, information broadcasted by the respective APs may be different from each other and the UE 100 may select any one AP according to the preference list provided by the ANDSF 600. However, according to the first embodiment, in order to select and access the hotspot 2.0 AP, the NAI realm is queried to the ANQP based servers 800a, 800b, and 800c and acquired and thereafter, compared with the NAI realm in the preference list provided by the ANDSF 600. However, a time required to query and acquire the NAI realm is relatively longer than a time required to acquire the SSID. In the worst case, when the number of hotspot 2.0 APs is considerably large, quite a long time may be taken to query and acquire the NAI realm to the ANQP based servers of all APs. Meanwhile, the hotspot 2.0 APs 400c, 400d, and 400e provide various additional information, the venue information (Venue Group and Venue Type), BSS load information, and the like, but according to the first embodiment, the information may not be used in selecting the AP. For example, even though an AP having a large load may be allowed not to be selected when load information is used, the information may not be used in the first embodiment. Accordingly, other embodiments capable of solving a disadvantage of the first embodiment will be described. A method according to other embodiments will be summarized below in brief in order to assist understanding. As one method, the UE 100 may store the preference list for the SSID or the roaming consortium ID (OUI) in advance in order to rapidly select the AP. As another method, since the NAI realm represents the network address ID of the provider and the OUI in the roaming consortium ID represents information on each company or agency, the NAI realm and the OUI have a correspondence relationship. For example of a company in LG, the OUI may be LGI and the NAI realm may be LG.com. Accordingly, when the UE 100 stores mapping information indicating the correspondence relationship in advance and thereafter, receives the preference list from the ANDSF server, the NAI realm in the corresponding preference list is converted into the OUT according to the mapping information and compared with the OUI in the roaming consortium broadcasted from the hotspot 2.0 AP to select an AP to be accessed. Subsequently, the PLMN ID is acquired from the accessed AP and a best PLMN or service provider is selected and authenticated. As another method, the UE 100 stores service provider information (for example, NAI realm(s) and PLMN ID) which is accessible for each OUI in advance, rapidly selects the AP by using the stored information, and moreover, completes even authentication. FIG. 7 is a Flowchart Illustrating a Scheme According to a Second Exemplary Embodiment Presented in this Specification Under the Environment Illustrated in FIG. 5. First, according to the IEEE 802.11 standard, since the roaming consortium ID is defined as “each OI (Organizational Identifier) identifies an SSP (Subscription Service Provider) or group of SSPs (i.e, a roaming consortium)” and the OI is expressed as the OUI, the OUI may be acquired through the roaming consortium ID. Further, for example, since the OUI is expressed as LGI and the NAI realm is expressed as LG.com, the second embodiment enables more rapid AP selection by using the correspondence relationship between the NAI realm and the OUI. That is, according to the second embodiment, an appropriate AP may be selected even without directly using the ANQP query to the AP by appropriately using broadcasted information. First, when an associated AP fails to access at the time of attempting access by selecting the best PLMN or service provider, another AP is associated to attempt access again by selecting the best PLMN or the service provider. As such, an AP to be access is selected depending on only the broadcasted information to increase a probability of acquiring a best result within a short time. Further, the NAI realm is not queried and requested from an ANQP server of an AP not to be actually accessed, and as a result, unnecessary signaling generation may be reduced. Meanwhile, according to the second embodiment, the ANDSF exemplarily provides an enhanced preference list illustrated in Table 3. As known with reference to Table 3, the enhanced preference list may include a list (for example, Operator_Controlled_WLAN_Specific_identifier_List) for selecting the AP (that is, the WLAN) and a list (for example, Operator_Controlled_PLMN_Selector_for_WLAN_access_List) for selecting the PLMN. Unlike Table 2, in Table 3, the roaming consortium ID is included in the list for selecting the AP (that is, the WLAN) and the NAI realm is included in the list for selecting the PLMN. TABLE 3 Operator_Controlled_WLAN_Specific_identifier_List SSID Roaming Consortium ID Priority Operator_Controlled_PLMN_Selector_for_WLAN_access_List NAI Realm PLMN_ID Priority The list (for example, Operator_Controlled_WLAN_Specific_identifier_List) for selecting the AP (that is, the WLAN) is used to select an AP which the UE 100 will associate. The list for selecting the AP (that is, the WLAN) may include at least one of the SSID and the roaming consortium ID, and any of them can take precedence over the other one according to the priority. If the priority is not designated, the priority may be substituted with an order disclosed in the list. Alternatively, the NAI realm may be described instead of the roaming consortium ID. In this case, as described above, the mapping information indicating the corresponding relationship between the OUI and the NAI realm in the roaming consortium information is required. That is, the mapping information may be provided by a server or stored in a terminal through the provider or network configuration. The mapping information may include the PLMN ID in addition to the correspondence relationship between the OUI and the NAI realm. Meanwhile, plural PLMN ids and NAI realms may be described in the list for selecting the PLMN and a priority among the plural PLMN ids and NAI realms may be decided by the priority. The list is intended to be used for selecting the PLMN, but alternatively, may be referred even when the UE 100 creates the available list. That is, the UE 100 may extract/estimate the roaming consortium ID by using the NAI realm information of the list for selecting the PLMN and thus, select an AP to be first associated by using the OUI. In this case, the priorities of the list for selecting the AP (that is, the WLAN) and the list are equally used or any one list may be preferentially used. According to the second embodiment, an overall process is progressed by an order of a scanning process (S210 to S230), an AP selecting process (S240), and a PLMN selecting process (S250 to S270) are progressed in sequence. Each process will be described below. In the scanning process (S210 to S230), the UE 100 acquires only the SSID in the case of not the Hotspot 2.0 AP but the legacy AP (S215), acquires the SSID and the roaming consortium information (including the OUI) broadcasted from the Hotspot 2.0 AP (S220), and creates the available list (S230). For example, an example of the available list created when three neighboring hotspot 2.0 APs 400c, 400d, and 400e are searched like the environment illustrated in FIG. 5 is illustrated below. TABLE 4 Ex.) Available WSID list: (SSID2,OUI2), (SSID4, OUI4), (SSID6, OUI6) Next, when the AP selecting process (S240) is described, the UE 100 first compares the information in the available list and information defined in the list for selecting the AP (that is, the WLAN) of Table 3 for each priority. For example, it is assumed that the list (WLAN_Specific_identifier_List) for selecting the AP (that is, the WLAN) is illustrated as an example in a table below. TABLE 5 Ex.) WLAN_Specific_identifier_List: (—,OUI1), (—, OUI2), (SSID3, OUI3), (SSID4, —) Since a part expressed as ‘−’ is not designated, the part is analyzed as any. When the available list exemplified above and the list for selecting the AP (that is, the WLAN) exemplified above are compared with each other, an AP is selected in order of (−, OUI2) and (SSID4, −). Next, the PLMN selecting process (S250 to S270) will be described below. First, the UE 100 converts the roaming consortium information in the available list for the selected AP into the NAI realm by using the mapping information (S250). As described above, the OUI in the roaming consortium information may represent the service provider or a group thereof. That is, since one OUI represents various service providers, one OUI is associated with various service providers. Accordingly, when the AP supports a specific OUI, the UE 100 may access a service provider network associated with the OUI. In this case, the authentication process (S290) to be described below is performed in order to access the service provider network, and the NAI realm and the PLMN ID information acquired through the mapping information may be used in the authentication process (S290) to be described below. The mapping information may be transferred in the network or stored in the terminal in advance in a form of a policy or set-up. A table below illustrates an example thereof. TABLE 6 OUI_i = {ServiceProvider_1(NAI_11, NAI_12,PLMN_id_13...), ServiceProvider_2(NAI_21, NAI_22, ...), ... , ServiceProvider_n(NAI_n1, NAI_n2,...)} Alternatively, when there is no mapping information, the NAI realm and the PLMN ID may be acquired by querying to the ANQP 800a, 800b, or 800c of each AP. Then, the UE 100 compares the NAI realm acquired from the ANQP 800a, 800b, or 800c of each AP with the NAI realm/PLMN ID in the list (for example, Operator_Controlled_PLMN_Selector_for WLAN_access_List) for the NAI realm in the preference list, that is, the PLMN (S260). When the NAI realm/PLMN ID is matched, the UE 100 associates the NAI realm/PLMN ID to the corresponding AP, the UE 100 performs authentication, for example, AAA authentication (S290). However, when the NAI realm/PLMN ID of the corresponding AP does not match the NAI realm/PLMN ID in the preference list, the aforementioned processes are repeated with respect to another AP in the available list. Meanwhile, the UE 100 may appropriately modify the NAI by considering the situation of the Home PLMN or the Visited PLMN at the time of performing the authentication. That is, the UE 100 selects a service provider which is preferred in the corresponding OUI, and modifies the NAI according to the PLMN so that the UE accesses to the PLMN. Meanwhile, when the UE 100 selects the specific AP as described above, the service provider is thereafter selected by comparing the NAI realm and when the same preference is provided, the service provider may be selected by using individual preference lists. Further, like an OUI_i list illustrated in Table 6 above, several service providers may be arranged with respect to one OUI and the priority may be given to the order. In a general case, if a Home provider of the UE 100 is included in the corresponding roaming consortium, the UE 100 hopes accessing primarily by using the Home provider and even in remaining cases, a service provider which is preferred may be selected according to a roaming agreement. Accordingly, the authentication may be performed according to the corresponding order. The corresponding home provider may be preferred by using an indicator or a setting value in order to preferentially select the home provider. Further, the OUI_i list is stored based on a record which is succeeded after access through method 1 and thereafter, may be used at the time of an attempt. Optionally, the UE 100 may perform authentication by an option below by using the service provider (NAI realm) acquired through the query to the ANQP server 800a, 800b, or 800c by accessing the AP in the order of the preference OUI. A predetermined service provider (NAI realm) among the service providers in the OUI having the highest preference is selected and authenticated. (without a priority list of the service provider) The service provider having the highest preference is selected among the service providers in the OUI having the highest preference (the priority list of the service provider which is preferred for each OUI is used). Authentication is performed with the service provider having the highest priority among the service providers (NAI realms) that receive responses from the ANQP 800a, 800b, and 800c of the APs of all OUIs (a priority list of common service providers is used). In this case, Home or the PLMN preferred during roaming may be designated and selected. According to the second embodiment illustrated in FIG. 7 as above, when N APs are present therearound, the number of operating times may be reduced as illustrated in Table 7 below. First, the scanning process is performed similarly to N neighboring APs. The number of querying times to the ANQP server requires average N/twice because the NAI realm information or the PLMN information is acquired by arbitrary visitation in the case of the method by the first embodiment. However, according to the second embodiment, the access is performed by considering the priority in the OUI information acquired from the broadcasted roaming consortium ID. In this case, when a correlation between the OUI in the mapping information and the NAI realm or the PLMN is high (that is, when the correlation is 1), the access is performed only once. When the correlation is low, since the method is the same as the existing method even in the worst case, the access may be performed at N/twice. The average number is set as N/4, but when the available list is substantially searched, it is possible that the successful access can be achieved with one or two times of trial. TABLE 7 Full search Present invention # of Scanning N N # of ANQP (when N/2 N/2 OUI/Realm, PLMN id has no correlation) # of ANQP (when OUI/ N/2 1 Realm, PLMN id has a strong correlation) # of ANQP (an N/2 N/4 average of two above cases) FIG. 8 is a flowchart illustrating a scheme according to a third exemplary embodiment presented in this specification under the environment illustrated in FIG. 5. In the third embodiment, an AP selection is enhanced by using state information. As described above, the Hotspot 2.0 APs 400a, 400c, and 400e broadcast various information indicating a state or a feature of the AP, for example, venue information (Venue Group and Venue Type), BSS load information and the like. Therefore, according to the third embodiment, the UE 100 considers broadcasted additional information and when the additional information does not match a predetermined condition, the UE 100 excludes the APs from the available list. The predetermined condition may be expressed as follows. TABLE 8 Venue Type:any BSS Load < 70 In detail, referring to FIG. 8, the UE 100 acquires various information indicating the state or feature from the hotspot 2.0 APs 400a, 400c, and 400e, for example, the venue information (Venue Group and Venue Type), the BSS load information, and the like in addition to the SSID and the roaming consortium information according to the third embodiment. In addition, the UE 100 excludes the AP that does not match the predetermined condition while creating the available list (S330). As such, the available list may be more simplified by excluding the AP which does not match the condition. Meanwhile, when the load information is used among the aforementioned various additional information, the UE 100 may select a less-loaded AP. When there is no less-loaded AP, another radio access technology (RAT) may be alternatively selected. Since other processes illustrated in FIG. 8 are similar as the processes of FIG. 7, a detailed description thereof will be omitted. Contents which have been described up to now will be organized as below. The present specification addresses the key issue of “Support WLAN access through roaming agreements. However, it is applicable also to scenarios where WLAN access is provided without roaming agreements. The present specification proposes to extend the ANDSF selection policies to support also selection policies based on the Realms and/or the Organizational Unique Identifiers (OUIs) which are supported by Hotspot 2.0 compliant WLAN networks. The ANDSF may send policies to UE based on Realms and/or OUIs to indicate for example that “WLANs that interwork with Realm=PartnerX.com have the highest access priority”. The UE uses the Realms and/or OUIs as an alternative way (instead of using SSID) to identify and prioritize the discovered WLAN access networks. A Hotspot 2.0 compliant UE is capable to discover the Realms and/or OUIs supported by a specific WLAN access network prior to association by using the applicable discovery procedures (e.g. based on the ANQP protocol) and/or by receiving the beacon transmissions of APs (some OUIs are included in the AP beacon messages). Roaming consortium OI is an identifier representing an SSP (Subscription service provider) or group of SSPs. One or more service providers can be members of one roaming consortium OI. When a WLAN AP is selected based on roaming consortium OI, a preferred service provider should be derived from the roaming consortium. Therefore, the ANDSF MO is enhanced so that a roaming consortium OI has a list of preferred 3GPP service providers (e.g. realms) including Home PLMN. This list is used by the UE to select a preferred service provider which is related to the preferred roaming consortium. That is, once a preferred roaming consortium is selected, a preferred service provider is selected from the members of the preferred roaming consortium. This can be done by comparing the service providers captured from the WLAN AP and the preferred service provider list of the roaming consortium OI. If a service provider is selected, the UE (i) constructs a NAI (e.g. decorated NAI for VPLMN) when it attempts EAP-AKA authentication over a selected WLAN access network. This allows a UE to select the preferred 3GPP service provider to authenticate with upon selecting WLAN based, among other information, on the list of roaming consortium that the UE may discover from the WLAN AP, e.g. by means of HS2.0 ANQP query or beacon message if the AP is HS2.0 capable. The methods described above may be implemented by hardware. The implementation of the hardware will be described with reference to FIG. 9. FIG. 9 is a Configuration Block Diagram of a UE 100 and an ANDSF 600 According to the Present Disclosure. As illustrated in FIG. 9, the UE 100 includes a storage means 101, a controller 102, and a transmitting/receiving unit 103. In addition, the ANDSF 600 includes a storage means 601, a controller 602, and a transmitting/receiving unit 603. The storage means 101 and 601 stores the aforementioned methods. The controllers 102 and 112 control the storage means 101 and 601 and the transmitting/receiving units 103 and 603. In detail, the controllers 102 and 602 execute the methods stored in the storage means 101 and 601. In addition, the controllers 102 and 602 transmit the aforementioned signals through the transmitting/receiving units 103 and 603. Although preferable embodiments of the present invention has been exemplarily described as above, the scope of the present invention is limited to only the specific embodiments, and as a result, various modifications, changes, or enhancements of the present invention can be made within the spirit of the present invention and the scope disclosed in the appended claims.",H04W4820,H04W4820,20160107,20180717,20170713,61702.0
2,15003726,PENDING,COMPOSITIONS AND METHODS FOR TREATMENT OF CANCER USING BACTERIA,"Provided herein are compositions comprising substantially non-viable Gram-negative bacterial organisms that have a substantial reduction in endotoxin activity and/or pyrogenicity and methods for treating a cancer using the same. Also provided are methods for treating cancer provided herein, comprising administering to a mammal diagnosed with cancer, substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity, in an amount sufficient to inhibit growth or metastasis of the cancer. An additional method is provided comprising administering viable or non-viable Gram-negative bacterial organisms that have a genetic defect that results in a substantial loss of lipopolysaccharide within the outer membrane of the bacteria. Further provided are methods for reducing endotoxin activity and/or pyrogenicity in Gram-negative bacteria comprising treatment with polymyxin and glutaraldehyde.","1. A composition comprising intact and substantially non-viable Gram-negative bacterial cells having at least about 80% reduction in endotoxin activity and at least 90% reduction in pyrogenicity as compared to corresponding wild-type Gram-negative bacterial cells. 2. (canceled) 3. The composition of claim 1, wherein at least about 90% of the bacterial cells are non-viable. 4. The composition of claim 3, wherein about 100% of the bacterial cells are non-viable. 5. (canceled) 6. The composition of claim 1, wherein the endotoxin activity is reduced by about 90%. 7. The composition of claim 6, wherein the pyrogenicity is reduced by about 95%. 8. A method for treating a cancer comprising administering to a mammal diagnosed as having a cancer an amount of the composition of claim 1, wherein the amount administered is sufficient to inhibit growth or metastasis of the cancer. 9. The composition of claim 1, wherein the bacterial cells are made substantially non-viable by treatment with radiation. 10. The composition of claim 1, wherein the bacterial cells are treated with an antibiotic that inactivates endotoxin. 11. The composition of claim 10, wherein said antibiotic is selected from the group consisting of polymyxin B and polymyxin E. 12. The composition of claim 1, wherein the bacterial cells are treated with an antibiotic known to disrupt the biosynthesis of KDO2-Lipid IVA. 13. The composition of claim 1, wherein the bacterial cells comprise a genetic defect that disrupts the biosynthesis of KDO2-Lipid IVA sufficient to substantially reduce endotoxin activity and pyrogenicity. 14. The composition of claim 1, wherein the bacterial cells comprise a genetic mutation that prevents O-acylation of KDO2-Lipid IVA sufficient to substantially reduce endotoxin activity and pyrogenicity. 15. The composition of claim 14, wherein the defect is in the msbB or lpxM loci. 16. The method of claim 8, wherein the cancer is a solid tumor. 17. The method of claim 8, wherein the mammal is further administered an antagonist of an immune function inhibiting T-cell receptor or T-cell receptor ligand selected from the group consisting of CTLA-4, PD-1, PD-L1 and PD-L2. 18. The method of claim 8, wherein the mammal is further administered an agonist of an immune function stimulating T-cell receptor selected from the group consisting of GITR, 4-1BB, CD40 and OX40. 19. The method of claim 8, wherein the mammal is further administered a chemotherapeutic agent. 20. The method of claim 19, wherein the chemotherapeutic agent is cyclophosphamide. 21. The method of claim 8, wherein the mammal is further administered a cytokine. 22. The method of claim 8, wherein the bacterial cells are Salmonella. 23. The method of claim 8, wherein the bacterial cells are Escherichia. 24-28. (canceled) 29. The composition of 1, wherein the bacterial cells are Salmonella. 30. The composition of 1, wherein the bacterial cells are Escherichia. 31. A method for treating a cancer, comprising: treating Gram-negative bacterial cells with an antibiotic under conditions to reduce viability, endotoxin activity and pyrogenicity of the cells without loss of cell integrity, to obtain a plurality of intact and substantially non-viable Gram-negative bacterial cells with substantial reduction in endotoxin activity and pyrogenicity as compared to untreated bacterial cells, and administering the plurality of intact and substantially non-viable Gram-negative bacterial cells to a cancer patient.","<SOH> BACKGROUND <EOH>The association of cancer regression in patients undergoing bacterial infection was observed and reported at least as early as 1868. The systemic administration of live attenuated Salmonella organisms to solid tumor bearing animals was reported to result in tumor therapy. See, e.g., U.S. Pat. No. 6,685,935 and Pawelek et al., (Lancet Oncol. 4(9):548-56, 2003). Also, intravesical (non-systemic) administration of attenuated Gram-positive mycobacteria (BCG) is approved in the United States for the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder. Improvements in tumor therapy using live Gram-negative Salmonella have also been reported for certain auxotrophic mutants. See e.g., Hoffman et al., (Amino Acids 37:509-521, 2009, U.S. Patent publication 20090300779 (Zhao et al.), and Zhao et al. (Proc. Natl. Acad. Sci. (USA) 102(3):775-760, 2005). Salmonella having deletions in the msbB locus have been prepared which express LPS lacking terminal myristoylation of lipid A in the outer membrane. TNF-alpha induction in mice and swine treated with these msbB- Salmonella strains was 33% and 14% of the amount induced by wild-type bacteria, respectively. See e.g., Low et al., Nature 17:37-41, 1999 and U.S. Pat. No. 7,354,592 (Bermudes et al.). Administration of such live organisms, including strain VNP20009, has been reported to inhibit the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA-MB-231 grown in mice (Luo et al., Oncol. Res. 12(11-12):501-508, 2001). Salmonella strain VNP20009 has also been reported to improve the anti-tumor efficacy of the chemotherapeutic agent cyclophosphamide at both a maximum tolerated dose and with a low-dose metronomic regimen (Jia et al., Int. J. Cancer 121(3):666-674, 2007). Conditional mutants of Gram-negative bacteria that cannot produce Lipid A and that lack LPS in the outer membrane have been prepared but have been reported to be toxic to the organism. For example, mutational inhibition of synthesis of 3-deoxy-D-manno-octulosonate (Kdo) or mutational inhibition of incorporation of Kdo molecules into lipid IV A prevents lipid A and LPS synthesis and localization of LPS precursors to the outer membrane of Gram-negative bacteria. Lipid IV A is an LPS precursor that lacks glycosylation. Activation of these mutations leads to loss of bacterial viability (Rick et al., Proc. Natl. Acad. Sci. USA 69(12):3756-3760, 1972, Belunis et al. J. Biol. Chem. 270(46):27646-27652, 1995, and Taylor et al. J. Biol. Chem. 275(41):32141-32146, 2000). It is also possible to inhibit Kdo incorporation into lipid IV A , synthesis of lipid A and localization to the outer membrane through the use of exogenously added compounds. Goldman et al. (J Bacteriol. 170(5):2185-91, 1988) describe antibacterial agents that specifically inhibit CTP:CMP-3-deoxy-D-manno-octulosonate cytidylyltransferase activity, thereby blocking the incorporation of 2-keto 3-deoxy-D-manno-octulosonate (Kdo) into lipid IV A of Gram-negative organisms. As LPS synthesis ceased, molecules similar in structure to lipid IV A were found to accumulate, and bacterial growth ceased. The authors concluded that addition of Kdo to LPS precursor lipid species IV A is the major pathway of lipid A-Kdo 2 formation in both S. typhimurium LT2 and Escherichia coli ( E. coli ). More recently, mutants of Gram-negative bacteria have been prepared that lack LPS, including lipid A or 6-acyl lipidpolysaccharide, in the outer membrane but maintain viability. For example, U.S. Patent publication 2010/0272758 reports an E. coli K-12 strain KPM22 that is defective in synthesis of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo). KPM22 has an outer membrane (OM) composed predominantly of lipid IV A . Viability of these organisms was achieved by the presence of a second-site suppressor that facilitates transport of lipid IV A from the inner membrane to the outer membrane. This suppressor is reported to relieve toxic side-effects of lipid IV A accumulation in the inner membrane and provide sufficient amounts of LPS precursors to support OM biogenesis. The LPS precursor produced by this strain lacks endotoxin activity, as determined by its inability to induce TNF-alpha secretion by human mononuclear cells at LPS precursor doses of up to 1 μg/mL. See also, Mamat et al., (Mol Microbiol. 67(3):633-48, 2008). Dose-limiting side effects associated with infection and septic shock significantly limit systemic administration of live bacteria to cancer patients. This limitation has been associated with wildtype bacteria (see e.g., Wiemann and Starnes, Pharmac. Ther. 64:529-564, 1994 for review), and has also been associated with genetically attenuated bacteria, which proliferate selectively in tumor tissue and express modified lipid A (see e.g., Toso et al., J. Clin. Oncol. 20(1):142-152, 2002). These limitations have led to the use of heat killed bacteria for cancer therapy. See e.g., Havas et al. (Med. Oncol. & Tumour Pharmacother. 10(4):145-158, 1993), Ryoma et al. (Anticancer Res. 24:3295-3302, 2004), Maletzki et al. (Clin. Develop. Immunol. 2012:1-16, 2012), U.S. Pat. No. 8,034,359 B2 (Gunn), European Patent No. EP 1,765,391 B1 (Gunn), and for review, Wiemann and Starnes (Pharmac. Ther. 64:529-564, 1994). However, non-infectious, killed bacteria still induce significant dose-limiting toxicities associated with LPS-derived endotoxin and other cell constituents, which are pyrogenic and can produce symptoms of septic shock. Thus, further improvements in treating cancer with bacteria are needed.","<SOH> SUMMARY <EOH>Provided herein are compositions and methods for treating cancer in a mammal (e.g., a human), diagnosed as having cancer, by administering to that mammal an amount of Gram-negative bacteria wherein the bacteria are (i) non-viable or substantially non-viable in the mammal, (ii) have a substantial reduction in endotoxin activity and/or pyrogenicity, and (iii) are administered in an amount sufficient to inhibit the growth or metastatic potential of the cancer. In some embodiments, the Gram-negative bacteria are rendered non-viable or substantially non-viable prior to administration to the mammal by treatment with (i) radiation, (ii) a chemical sterilant, (iii) an antibiotic that inactivates endotoxin (e.g., polymyxin B or polymyxin E), or (iv) an antibiotic that disrupts the biosynthesis of KDO2-Lipid IV A . Alternatively, or in addition to, any one or more of the foregoing treatments, the Gram-negative bacteria further comprises a genetic defect that disrupts or partially disrupts the biosynthesis of KDO2-Lipid IV A or prevents the O-acylation of KDO2-Lipid IV A . Genetic defects that disrupt or partially disrupt the O-acylation of KDO2-Lipid IV A include, for example, defects which functionally disrupt the msbB and lpxM loci. In one aspect of the disclosure, compositions comprise substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity and a pharmaceutically acceptable excipient. In one embodiment, the Gram-negative bacteria are made non-viable by treatment with glutaraldehyde. In another embodiment, the endotoxin activity and/or pyrogenicity is reduced by treatment with polymyxin B or polymyxin E. In a further embodiment, the endotoxin activity and/or pyrogenicity is reduced by treatment with glutaraldehyde. In another aspect, methods are provided to treat a mammal diagnosed as having cancer which included administering an amount of substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity, wherein the amount administered is sufficient to inhibit growth or metastasis of the cancer. In another aspect, the disclosure provides methods for treating cancer in a mammal (e.g., a human), diagnosed as having cancer, by administering to that mammal an amount of Gram-negative bacteria wherein the bacteria are viable, may or may not be attenuated, and have a genetic defect that results in a substantial or total loss of lipopolysaccharide within the outer membrane of the bacteria and wherein the amount administered is sufficient to inhibit the growth or metastatic potential of the cancer. In one embodiment, the disclosure provides a method for treating a cancer comprising administering to a mammal diagnosed as having cancer an amount of viable or non-viable Gram-negative bacterial organisms that have a genetic defect that results in a substantial loss of lipopolysaccharide within the outer membrane of the bacteria, wherein the amount administered is sufficient to inhibit growth of the cancer. In some embodiments, the genetic defect disrupts or partially disrupts the biosynthesis of KDO2-Lipid IV A or prevents the O-acylation of KDO2-Lipid IV A . In some embodiments, the cancer is a solid tumor. In other embodiments, the mammal is further administered a chemotherapeutic agent including, for example, cyclophosphamide. In other embodiments, the mammal is further administered an antagonist of an immune function-inhibiting receptor or receptor agonist including, for example, inhibiting the function of a T-cell receptor or T-cell receptor ligand (e.g., CTLA-4, PD-1, PD-L1, and PD-L2). In other embodiments, the mammal is further administered an agonist of an immune function-stimulating receptor including, for example, agonists that stimulate a T-cell receptor. Suitable receptor targets include, for example, GITR, 4-1BB, CD40, and OX40. In other embodiments, the mammal is further administered an immune function-stimulating cytokine including, for example, interferon-alpha, interferon-beta, interferon-gamma, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12. In some embodiments, the Gram-negative bacteria are Salmonella or Escherichia. In another embodiment, the disclosure provides for methods of killing and reducing endotoxin activity and/or pyrogenicity in Gram-negative bacteria by treating the bacteria with polymyxin B and glutaraldehyde. In one embodiment, viability is reduced to 0% and the endotoxin activity or pyrogenicity is reduced by about 90% or 96%.","CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 14/139,063, filed Dec. 23, 2013, which application claims the benefit under 35 U.S.C. §119(e) to U.S. provisional application 61/748,369 filed Jan. 2, 2013, both of which are hereby incorporated by reference. FIELD This disclosure relates to compositions comprising Gram-negative bacteria and methods for treating cancer by administering the same. BACKGROUND The association of cancer regression in patients undergoing bacterial infection was observed and reported at least as early as 1868. The systemic administration of live attenuated Salmonella organisms to solid tumor bearing animals was reported to result in tumor therapy. See, e.g., U.S. Pat. No. 6,685,935 and Pawelek et al., (Lancet Oncol. 4(9):548-56, 2003). Also, intravesical (non-systemic) administration of attenuated Gram-positive mycobacteria (BCG) is approved in the United States for the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder. Improvements in tumor therapy using live Gram-negative Salmonella have also been reported for certain auxotrophic mutants. See e.g., Hoffman et al., (Amino Acids 37:509-521, 2009, U.S. Patent publication 20090300779 (Zhao et al.), and Zhao et al. (Proc. Natl. Acad. Sci. (USA) 102(3):775-760, 2005). Salmonella having deletions in the msbB locus have been prepared which express LPS lacking terminal myristoylation of lipid A in the outer membrane. TNF-alpha induction in mice and swine treated with these msbB-Salmonella strains was 33% and 14% of the amount induced by wild-type bacteria, respectively. See e.g., Low et al., Nature 17:37-41, 1999 and U.S. Pat. No. 7,354,592 (Bermudes et al.). Administration of such live organisms, including strain VNP20009, has been reported to inhibit the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA-MB-231 grown in mice (Luo et al., Oncol. Res. 12(11-12):501-508, 2001). Salmonella strain VNP20009 has also been reported to improve the anti-tumor efficacy of the chemotherapeutic agent cyclophosphamide at both a maximum tolerated dose and with a low-dose metronomic regimen (Jia et al., Int. J. Cancer 121(3):666-674, 2007). Conditional mutants of Gram-negative bacteria that cannot produce Lipid A and that lack LPS in the outer membrane have been prepared but have been reported to be toxic to the organism. For example, mutational inhibition of synthesis of 3-deoxy-D-manno-octulosonate (Kdo) or mutational inhibition of incorporation of Kdo molecules into lipid IVA prevents lipid A and LPS synthesis and localization of LPS precursors to the outer membrane of Gram-negative bacteria. Lipid IVA is an LPS precursor that lacks glycosylation. Activation of these mutations leads to loss of bacterial viability (Rick et al., Proc. Natl. Acad. Sci. USA 69(12):3756-3760, 1972, Belunis et al. J. Biol. Chem. 270(46):27646-27652, 1995, and Taylor et al. J. Biol. Chem. 275(41):32141-32146, 2000). It is also possible to inhibit Kdo incorporation into lipid IVA, synthesis of lipid A and localization to the outer membrane through the use of exogenously added compounds. Goldman et al. (J Bacteriol. 170(5):2185-91, 1988) describe antibacterial agents that specifically inhibit CTP:CMP-3-deoxy-D-manno-octulosonate cytidylyltransferase activity, thereby blocking the incorporation of 2-keto 3-deoxy-D-manno-octulosonate (Kdo) into lipid IVA of Gram-negative organisms. As LPS synthesis ceased, molecules similar in structure to lipid IVA were found to accumulate, and bacterial growth ceased. The authors concluded that addition of Kdo to LPS precursor lipid species IVA is the major pathway of lipid A-Kdo2 formation in both S. typhimurium LT2 and Escherichia coli (E. coli). More recently, mutants of Gram-negative bacteria have been prepared that lack LPS, including lipid A or 6-acyl lipidpolysaccharide, in the outer membrane but maintain viability. For example, U.S. Patent publication 2010/0272758 reports an E. coli K-12 strain KPM22 that is defective in synthesis of 3-deoxy-d-manno-oct-2-ulosonic acid (Kdo). KPM22 has an outer membrane (OM) composed predominantly of lipid IVA. Viability of these organisms was achieved by the presence of a second-site suppressor that facilitates transport of lipid IVA from the inner membrane to the outer membrane. This suppressor is reported to relieve toxic side-effects of lipid IVA accumulation in the inner membrane and provide sufficient amounts of LPS precursors to support OM biogenesis. The LPS precursor produced by this strain lacks endotoxin activity, as determined by its inability to induce TNF-alpha secretion by human mononuclear cells at LPS precursor doses of up to 1 μg/mL. See also, Mamat et al., (Mol Microbiol. 67(3):633-48, 2008). Dose-limiting side effects associated with infection and septic shock significantly limit systemic administration of live bacteria to cancer patients. This limitation has been associated with wildtype bacteria (see e.g., Wiemann and Starnes, Pharmac. Ther. 64:529-564, 1994 for review), and has also been associated with genetically attenuated bacteria, which proliferate selectively in tumor tissue and express modified lipid A (see e.g., Toso et al., J. Clin. Oncol. 20(1):142-152, 2002). These limitations have led to the use of heat killed bacteria for cancer therapy. See e.g., Havas et al. (Med. Oncol. & Tumour Pharmacother. 10(4):145-158, 1993), Ryoma et al. (Anticancer Res. 24:3295-3302, 2004), Maletzki et al. (Clin. Develop. Immunol. 2012:1-16, 2012), U.S. Pat. No. 8,034,359 B2 (Gunn), European Patent No. EP 1,765,391 B1 (Gunn), and for review, Wiemann and Starnes (Pharmac. Ther. 64:529-564, 1994). However, non-infectious, killed bacteria still induce significant dose-limiting toxicities associated with LPS-derived endotoxin and other cell constituents, which are pyrogenic and can produce symptoms of septic shock. Thus, further improvements in treating cancer with bacteria are needed. SUMMARY Provided herein are compositions and methods for treating cancer in a mammal (e.g., a human), diagnosed as having cancer, by administering to that mammal an amount of Gram-negative bacteria wherein the bacteria are (i) non-viable or substantially non-viable in the mammal, (ii) have a substantial reduction in endotoxin activity and/or pyrogenicity, and (iii) are administered in an amount sufficient to inhibit the growth or metastatic potential of the cancer. In some embodiments, the Gram-negative bacteria are rendered non-viable or substantially non-viable prior to administration to the mammal by treatment with (i) radiation, (ii) a chemical sterilant, (iii) an antibiotic that inactivates endotoxin (e.g., polymyxin B or polymyxin E), or (iv) an antibiotic that disrupts the biosynthesis of KDO2-Lipid IVA. Alternatively, or in addition to, any one or more of the foregoing treatments, the Gram-negative bacteria further comprises a genetic defect that disrupts or partially disrupts the biosynthesis of KDO2-Lipid IVA or prevents the O-acylation of KDO2-Lipid IVA. Genetic defects that disrupt or partially disrupt the O-acylation of KDO2-Lipid IVA include, for example, defects which functionally disrupt the msbB and lpxM loci. In one aspect of the disclosure, compositions comprise substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity and a pharmaceutically acceptable excipient. In one embodiment, the Gram-negative bacteria are made non-viable by treatment with glutaraldehyde. In another embodiment, the endotoxin activity and/or pyrogenicity is reduced by treatment with polymyxin B or polymyxin E. In a further embodiment, the endotoxin activity and/or pyrogenicity is reduced by treatment with glutaraldehyde. In another aspect, methods are provided to treat a mammal diagnosed as having cancer which included administering an amount of substantially non-viable Gram-negative bacteria having a substantial reduction in endotoxin activity and/or pyrogenicity, wherein the amount administered is sufficient to inhibit growth or metastasis of the cancer. In another aspect, the disclosure provides methods for treating cancer in a mammal (e.g., a human), diagnosed as having cancer, by administering to that mammal an amount of Gram-negative bacteria wherein the bacteria are viable, may or may not be attenuated, and have a genetic defect that results in a substantial or total loss of lipopolysaccharide within the outer membrane of the bacteria and wherein the amount administered is sufficient to inhibit the growth or metastatic potential of the cancer. In one embodiment, the disclosure provides a method for treating a cancer comprising administering to a mammal diagnosed as having cancer an amount of viable or non-viable Gram-negative bacterial organisms that have a genetic defect that results in a substantial loss of lipopolysaccharide within the outer membrane of the bacteria, wherein the amount administered is sufficient to inhibit growth of the cancer. In some embodiments, the genetic defect disrupts or partially disrupts the biosynthesis of KDO2-Lipid IVA or prevents the O-acylation of KDO2-Lipid IVA. In some embodiments, the cancer is a solid tumor. In other embodiments, the mammal is further administered a chemotherapeutic agent including, for example, cyclophosphamide. In other embodiments, the mammal is further administered an antagonist of an immune function-inhibiting receptor or receptor agonist including, for example, inhibiting the function of a T-cell receptor or T-cell receptor ligand (e.g., CTLA-4, PD-1, PD-L1, and PD-L2). In other embodiments, the mammal is further administered an agonist of an immune function-stimulating receptor including, for example, agonists that stimulate a T-cell receptor. Suitable receptor targets include, for example, GITR, 4-1BB, CD40, and OX40. In other embodiments, the mammal is further administered an immune function-stimulating cytokine including, for example, interferon-alpha, interferon-beta, interferon-gamma, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12. In some embodiments, the Gram-negative bacteria are Salmonella or Escherichia. In another embodiment, the disclosure provides for methods of killing and reducing endotoxin activity and/or pyrogenicity in Gram-negative bacteria by treating the bacteria with polymyxin B and glutaraldehyde. In one embodiment, viability is reduced to 0% and the endotoxin activity or pyrogenicity is reduced by about 90% or 96%. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1 and 2 demonstrate that incubation of E. coli with polymyxin B (PMB) reduces the level of bacterial cell-associated endotoxin activity and cell viability. This is further described in Example 2. FIGS. 3 and 4 demonstrate that incubation of E. coli with glutaraldehyde (GA) reduces the level of bacterial cell-associated endotoxin activity and cell viability, as further described in Example 3. FIG. 5 depicts transmission electron microscope images of E. coli untreated (FIG. 5A), treated with 1,000 μg/mL PMB (FIG. 5B), 1% GA (FIG. 5C), or both PMB and GA (FIG. 5D), demonstrating that the bacteria remain intact after all treatments, as further described in Example 4. FIG. 6 depicts a graph showing the dose-dependent effect of PMB+GA-treated E. coli on the growth of subcutaneous murine B16F10 melanoma in mice, as further described in Example 7. FIG. 7 shows a graph showing the dose-dependent effect of untreated and 1% GA-treated E. coli on the growth of subcutaneous murine B16F10 melanoma in mice, as further described in Example 8. FIGS. 8A and 8B illustrate graphs showing the dose-dependent effect of PMB+GA-treated E. coli without and with metronomic cyclophosphamide (FIG. 8A) or anti-murine CTLA-4 antibody (FIG. 8B) on the growth of subcutaneous CT26 murine colorectal carcinoma in mice, as further described in Example 9. DETAILED DESCRIPTION Provided herein are compositions comprising non-viable Gram-negative bacterial organisms and that have substantial reduction in endotoxin and/or pyrogenic activity and methods to treat cancer, comprising administering to a mammal suffering from cancer an amount of non-viable Gram-negative bacterial organisms that have a substantial reduction in endotoxin or pyrogenic activity, wherein the amount administered is sufficient to inhibit growth or metastasis of the cancer. Possible mechanism(s) responsible for anti-tumor activity mediated by bacteria include selective proliferation of live bacterial organisms in tumor tissue and stimulation of host immune responses, in particular via LPS (endotoxin)-mediated induction of tumoricidal cytokine release from host mononuclear cells. However, the proliferation of live bacteria and LPS (endotoxin)-mediated induction of cytokines (even with LPS attenuated by msbB mutation), are believed responsible for dose-limiting toxicity associated with treatment of mammals with live bacteria. Toso et al. (J. Clin. Oncol. 20(1):142-152, 2002) treated cancer patients with live msbB-attenuated Salmonella and dose-limiting toxicities included bacteremia and side-effects associated with cytokine release. Proliferation of bacteria in tumor tissue was lower and sensitivity to cytokine-mediated toxicities was higher than seen in human tumor xenograft models in mice. It is believed that systemic proliferation by viable bacteria and/or cytokine-related toxicities, mediated in part by LPS lacking one secondary acyl chain, may prevent administration of safe and effective doses of live, attenuated Gram-negative bacteria to some mammals (such as humans) other than mice, which are known to be relatively resistant to bacterial infection and associated septic consequences of cytokine induction. Although not wishing to be bound by theory, it is believed that killed or non-viable Gram-negative organisms with substantially reduced endotoxin activity and/or pyrogenicity can be administered to cancer patients in amounts that are less toxic and more effective to treat the cancer as compared to using live or viable organisms, which proliferate in each patient's normal and tumor tissues in a variable manner that cannot be controlled by the practitioner, either proliferating insufficiently to produce a therapeutic effect or proliferating too much, thereby producing unacceptable toxicity. It is also believed that killed or non-viable Gram-negative organisms with substantially reduced endotoxin activity and/or pyrogenicity can be administered to cancer patients in amounts that are less toxic and more effective to treat the cancer as compared to using killed bacteria that express wildtype levels of endotoxin activity and/or pyrogenicity. It is also believed that viable Gram-negative organisms having a genetic defect in the formation of LPS that results in a substantial reduction in the amount of glycosylated Lipid A and LPS in the outer membrane of the bacteria can be effective in the treatment of cancer whether administered alive and attenuated, so as to prevent further proliferation in the mammalian host, or as killed organisms. Although such organisms lack functional LPS molecules that cause endotoxic shock as well as provide a stimulus to the host's immune system, it is believed that there are other features of the Gram-negative bacteria that will stimulate the host's innate or combined innate and adaptive immune responses to achieve tumor cell killing or tumor growth inhibition. In one embodiment, the Gram-negative organisms used in cancer therapy, as disclosed herein, do not contain DNA that encodes or expresses non-bacterial proteins (e.g., tumor-specific antigens). The Gram-negative organisms, therefore, are not a cancer vaccine in that they do not directly induce a specific immunological response against a tumor antigen. Instead, these organism function as an adjuvant or biological response modifier (BRM) that may generally stimulate the host innate immune response and possibly indirectly an adaptive anti-tumor immune response. In some embodiments, the Gram-negative organisms are injected directly in or near the site of the tumor, or are injected systemically and accumulate in or near the tumor. The increased innate immune response against the organisms then may secondarily become directed against the tumor. In addition, or alternatively, immune responses against the organisms may stimulate or activate pre-existing tumor antigen-specific immune cells capable of participating in an adaptive anti-tumor response. In an alternative embodiment, the Gram-negative organisms express DNA that encodes for expression of non-bacterial proteins including, for example, tumor-specific antigens or immune system stimulating proteins. Here again, the organisms may be injected in or near the tumor site, or systemically, and induce an innate or adaptive immune response against the organism, the tumor-specific antigen, or both. As used herein, the term tumor specific antigen refers to an antigen that is expressed by a tumor but is not expressed by any normal cells from the organism from which the tumor was derived. The term tumor-associated antigen refers to an antigen that is expressed by a tumor but may also be expressed in a limited manner by normal cells from the organism from which the tumor was derived. The limited manner of expression may reflect a lower level of expression in normal cells than the tumor, expression by a limited type of normal cell or expression by normal cells only during fetal development (i.e., a fetal antigen). As used herein, an antigen is any molecule that can be recognized by an immune response, either an antibody or by an immune cell (e.g., T cell). As used herein the terms “adjuvant” and “biological response modifier” refer to any substance that enhances an immune response to an antigen, tumor or tumor-associated cell. Thus, an adjuvant or biological response modifier is used to stimulate the immune system to respond more vigorously to a foreign antigen or a disease-causing or disease-associated cell expressing a new antigen, or structurally altered or abnormal level of an existing antigen. However, in some embodiments, recombinant forms of Gram-negative bacteria that express, e.g., tumor specific or tumor-associated antigens or human immune activation proteins such as cytokines or chemokines are contemplated for use in the disclosed methods. In an alternative embodiment, purified immune activation proteins such as cytokines or chemokines are mixed with the Gram-negative organisms prior to administration, or are administered before or after the Gram-negative organisms. As used herein the term mammal includes any mammal such as a human, dog, cat, cow, sheep, and the like. A preferred mammal is a human. The term “Gram-negative bacteria” refers to bacteria that do not retain the initial basic dye stain (e.g., crystal violet) that is part of the procedure known as the Gram stain. In an exemplary Gram stain, cells are first fixed to a slide by heat and stained with a basic dye (e.g., crystal violet), which is taken up by both Gram-negative and Gram-positive bacteria. The slides are then treated with a mordant (e.g., Gram's iodine), which binds to basic dye (e.g. crystal violet) and traps it in the cell. The cells are then washed with acetone or alcohol, and then counterstained with a second dye of different color (e.g., safranin). Gram-positive organisms retain the initial violet stain, while Gram-negative organisms are decolorized by the wash solvent organic and hence show the counterstain. Exemplary Gram-negative bacteria include, but are not limited to, Escherichia spp., Shigella spp., Salmonella spp., Campylobacter spp., Neisseria spp., Haemophilus spp., Aeromonas spp., Francisella spp., Yersinia spp., Klebsiella spp., Bordetella spp., Legionella spp., Corynebacteria spp., Citrobacter spp., Chlamydia spp., Brucella spp., Pseudomonas spp., Helicobacter spp. and Vibrio spp. Within gram-negative organisms are the Enterobacteriaceae, a large family that includes, along with many harmless symbionts, many well-known pathogens, such as Salmonella, E. coli, Yersinia pestis, Klebsiella and Shigella, Proteus, Enterobacter, Serratia, and Citrobacter. Members of the Enterobacteriaceae have been referred to as enterobacteria, as several members live in the intestines of animals. Enterobacteriaceae are rod-shaped, typically 1-5 μm in length. They are facultative anaerobes, fermenting sugars to produce lactic acid and various other end products. Most also reduce nitrate to nitrite and generally lack cytochrome C oxidase. Most have many flagella for motility, but some are nonmotile. Enterobacteriaceae are nonspore-forming. The term “vector” refers to a nucleic acid molecule, which is capable of transporting another nucleic acid to which it is linked as a single piece of nucleic acid. Vectors capable of directing the expression of genes to which they are operatively linked are referred to herein as “expression vectors.” The term “expression system” as used herein refers to a combination of components that enable sequences in an expression vector to be transcribed into RNA, folded into structural RNA, or translated into protein. The expression system may be an in vitro expression system, such as is commercially available or readily made according to known methods, or may be an in vivo expression system, such as a eukaryotic or prokaryotic host cell that contains the expression vector. In general, expression vectors useful in recombinant DNA techniques can be “plasmids” which refer generally to circular double stranded DNA that, in their vector form, is not bound to the bacterial chromosome. Other expression vectors well known in the art also can be used in expression systems (e.g., cosmid, phagemid and bacteriophage vectors). The term “nucleic acid” refers to polynucleotides or oligonucleotides such as deoxyribonucleic acid (DNA), and, where appropriate, ribonucleic acid (RNA). The term should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs and as applicable to the embodiment being described, single (sense or antisense) and double-stranded polynucleotides. The term “modulation” as used herein refers to both upregulation (i.e., activation or stimulation (e.g., by agonizing or potentiating)) and downregulation (i.e., inhibition or suppression (e.g., by antagonizing, decreasing or inhibiting)). The term “inducible” refers in particular to gene expression which is not constitutive but which takes place in response to a stimulus (e.g., temperature, heavy metals or other medium additive). A. Candidate Bacterial Organisms Candidate bacterial organisms that may be employed by the methods herein are Gram-negative and are derived from those that have endotoxin activity as wildtype organisms. Exemplary Gram-negative bacteria include, but are not limited to, Escherichia spp., Shigella spp., Salmonella spp., Campylobacter spp., Neisseria spp., Haemophilus spp., Aeromonas spp., Francisella spp., Yersinia spp., Klebsiella spp., Bordetella spp., Legionella spp., Corynebacteria spp., Citrobacter spp., Chlamydia spp., Brucella spp., Pseudomonas spp., Helicobacter spp. and Vibrio spp. Candidate Gram negative organisms also may be those that fall in the Enterobacteriaceae, Pseudomonadaceae, Neisseriaceae, Veillonellaceae, Bacteroidaceae, Vibrionaceae, Pasteurellaceae, and Fusobacteriaceae families. In some embodiments, the candidate organism is a species of Salmonella or Escherichia spp. One candidate Salmonella organism, VNP20009, has been described by Luo et al., Oncol Res. 12(11-12):501-8, 2001. VNP20009 is a genetically modified strain of Salmonella typhimurium with deletions in the msbB and purI loci. Intravenous administration at doses ranging from 1×104 to 3×106 cfu/mouse of live VNP20009 to tumor bearing mice inhibited the growth of subcutaneously implanted B16F10 murine melanoma, and the human tumor xenografts Lox, DLD-1, A549, WiDr, HTB177, and MDA-MB-231. VNP20009, given intravenously also inhibited the growth of lung metastases in these animals. See also, U.S. Pat. No. 7,354,592 (Bermudes et al.). Another candidate Salmonella organism is SL3235 described by Eisenstein et al. Med. Oncol. 12(2):103-8, 1995. SL3235 is an attenuated strain of Salmonella that when administered live can cure plasmacytoma tumor growing in mice. Further candidate Salmonella include auxotrophic mutants reported by Hoffman et al., Amino Acids 37:509-521, 2009. The S. typhimurium A1-R mutant is auxotrophic for leu-arg and has high anti-tumor virulence. In vitro, A1-R infects tumor cells and causes nuclear destruction. A1-R administration treats metastatic human prostate and breast tumors orthotopically implanted in nude mice. A1-R administered intravenously (i.v.) to nude mice with primary osteosarcoma and lung metastasis is effective, especially against metastasis. A1-R also was reported effective against pancreatic cancer liver metastasis when administered intrasplenically to nude mice. See also U.S. Patent publication 20090300779 (Zhao et al.), and Zhao et al. (Proc. Natl. Acad. Sci. (USA) 102(3):775-760, 2005). A variety of Gram-negative organisms suitable for the treatment of solid tumors are reported in U.S. Pat. No. 6,685,935 (Pawelek et al.). These organisms are referred to as super-infective as they replicate preferentially in the tumor after administration. Included are super-infective, tumor-specific mutants of Salmonella spp., e.g., Salmonella typhimurium. Also described are super-infective, tumor-specific mutants of Salmonella spp. containing a suicide gene such as thymidine kinase from Herpes simplex virus, cytosine deaminase from E. coli, or human microsomal p450 oxidoreductase. See also Pawelek et al., (Lancet Oncol. 4(9):548-56, 2003). In one embodiment, E. coli is selected as the organism. One particular strain contemplated is E. coli strain 2617-143-312, (Migula) Castellani and Chalmers (ATCC® 13070™). Additional E. coli strains which may be used include MG1655 (ATCC® 47076) and KY8284 (ATCC® 21272). The Gram-negative organisms used in the methods herein need not be recombinant organisms that contain or express DNA foreign to the wildtype form of the organism. However, in some embodiments, the organisms may be modified to express some non-native molecules. For example, U.S. Pat. No. 7,452,531 reports preparation and use of attenuated tumor-targeted bacteria vectors for the delivery of one or more primary effector molecule(s) to the site of a solid tumor. According to the method, effector molecules, which may be toxic when administered systemically to a host, can be delivered locally to tumors by attenuated tumor-targeted bacteria with reduced toxicity to the host. Specifically, the attenuated tumor-targeted bacteria can be a facultative aerobe or facultative anaerobe which is modified to encode one or more primary effector molecule(s). The primary effector molecule(s) include members of the TNF cytokine family, anti-angiogenic factors, and cytotoxic polypeptides or peptides. The primary effector molecules of the disclosure are useful, for example, to treat a solid tumor cancer such as a carcinoma, melanoma, lymphoma, sarcoma, or metastases derived from these tumors. B. Reducing Bacterial Endotoxin Activity Various methods may be used to reduce endotoxin activity and/or pyrogenicity of bacterial organisms. As used herein, the term “endotoxin activity” refers to portions of Gram-negative bacteria that can cause toxicity, including pyrogenicity and septic shock. The toxic effects attributed to endotoxin have been found to be associated with the glycosylated lipid A portion of a lipopolysaccharide molecule present in or derived from the outer membrane of Gram-negative bacteria. The term “Lipopolysaccharide” (LPS) refers to large molecules consisting of a lipid and a polysaccharide (glycophospholipid) joined by a covalent bond. LPS comprises three parts: 1) O antigen; 2) Core oligosaccharide, and 3) Lipid A. The O-antigen is a repetitive glycan polymer attached to the core oligosaccharide, and comprises the outermost domain of the LPS molecule. Core oligosaccharide attaches directly to lipid A and commonly contains sugars such as heptose and 3-deoxy-D-mannooctulosonic acid (also known as KDO, keto-deoxyoctulosonate). Lipid A is a phosphorylated glucosamine disaccharide linked to multiple fatty acids. The fatty acids anchor the LPS into the bacterial membrane, and the rest of the LPS projects from the cell surface. Bacterial death may result if LPS is mutated or removed. Endotoxin activity resides in the lipid A domain portion of LPS. When bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the circulation, causing fever (pyrogenicity), diarrhea, and a potentially fatal shock (called endotoxic or septic shock). Toxicity of LPS is expressed by lipid A through the interaction with B-cells and macrophages of the mammalian immune system, a process leading to the secretion of proinflammatory cytokines, mainly tumor necrosis factor (TNF), which may have fatal consequences for the host. Lipid A also activates human T-lymphocytes (Th-1) “in vitro” as well as murine CD4+ and CD8+ T-cells “in vivo”, a property which allows the host's immune system to mount a specific, anamnestic IgG antibody response to the variable-size carbohydrate chain of LPS. On these bases, LPS has been recently recognized as a T-cell dependent antigen “in vivo”. Endotoxin activity can be measured by methods well known in the art, including, for example, the Limulus Amebocyte Lysate (LAL) assay, which utilizes blood from the horseshoe crab, can detect very low levels of LPS. The presence of endotoxin activity will result in coagulation of the limulus blood lysate due to amplification via an enzymatic cascade. Gel clotting, turbidometric, and chromogenic forms of the LAL assay are commercially available. See, e.g., Lonza, Allendale, N.J., and Clongen Labs, Germantown, Md. Enzyme linked immunoadsorbent assay (ELISA)-based endotoxin activity assays are also known such as the EndoLISA® from Hyglos, Munich area of Germany. This assay employs an LPS specific phage protein attached to the solid phase to capture LPS, and following a wash step, the presence of LPS is determined by addition of recombinant Factor C, which when activated by LPS, cleaves a compound that then emits fluorescence. Factor C, present in the Limulus amebocyte lysate, normally exists as a zymogen, and is the primer of the coagulation cascade that occurs in the LAL test. Endotoxin activity can also be measured by evaluating induction of TNF-alpha secretion, either from primary peripheral blood mononuclear cells in vitro, or by treating an animal with the suspected source of endotoxin and measuring TNF-alpha levels in plasma, obtained from the animal after approximately 1 to 4 hours. Primary mammalian peripheral blood mononuclear cells can be purchased from companies such as Lonza (Allendale, N.J., USA). TNF-alpha levels in cell supernatant or plasma can be determined with ELISA kits, such as those available from Thermo Scientific (Rockford, Ill., USA), Abcam (Cambridge, Mass., USA) or eBioscience (San Diego, Calif., USA). Endotoxin activity can also be assessed in vivo by measuring pyrogenicity (rectal temperature increase) in rabbits in response to intravenously administered organisms or derivatives thereof. The endotoxin activity and/or pyrogenicity of Gram-negative organisms may be substantially reduced as compared to that of the wildtype organism. A substantial reduction in endotoxin activity is preferably more than about 70%, more than about 75%, more than about 80%, more than about 85%, more than about 90%, more than 95% and more than about 99%. Various methods are available to reduce the endotoxin activity of Gram-negative organisms. The methods include treatment of the organisms with an agent that binds to LPS or disrupts its formation, or by genetically manipulating the bacterial organism to modify LPS or inhibit LPS formation. In one embodiment, reduction in endotoxin activity or pyrogenicity is achieved by treating the bacterial organisms with an antibiotic that inactivates endotoxin. A suitable such antibiotic is polymyxin B or polymyxin E. For example, Cooperstock et al., Infect Immun. 1981 July; 33(1):315-8, report that Polymyxin B treatment can reduce the inflammatory reactivity of LPS in vaccines of Gram-negative bacteria including Bordetella pertussis, E. coli, Haemophilus influenzae, and Pseudomonas aeruginosa. It is within the skill of one in the art to determine the amount of antibiotic and conditions for treatment. In one embodiment, the polymyxin, either polymyxin B or E, may be employed at a concentration of approximately 3 micrograms to 5,000 micrograms per 1×107 to 5×1010 bacteria per milliliter. In another embodiment, the concentration of polymyxin may be from about 200 micrograms to 5,000 micrograms per 1×107 to 5×1010 bacteria per milliliter. In one embodiment, the antibiotic is applied to the bacteria for 10 minutes to 4 hours or from about 30 minutes to about 3 hours. In one embodiment, the bacteria are grown in the presence of magnesium (Mg) in the form of MgCl2 and treated with polymyxin in the presence of MgCl2, as well as at a temperature suitable to maintain the bacteria's integrity. In one embodiment, the concentration of MgCl2 in the growth medium is from about 0.5 mM to about 5.0 mM, or about 2 mM, and the concentration of MgCl2 in the treatment medium is from about 5.0 mM to about 30 mM, or about 20 mM. In one embodiment, the temperature of the treatment medium is from about 2° C. to about 10° C., or about 4° C. Bacterial integrity is determined by efficiency of recovery in a well-defined pellet after centrifugation at 3,000×g for 10 minutes, and by electron microscopy. In a preferred embodiment, bacterial recovery after treatment and wash is greater than about 80% and the bacteria appear intact by electron microscopy. In another embodiment, reduction in endotoxin activity is achieved by treating the bacterial organisms with an antibiotic known to disrupt the biosynthesis of KDO2-Lipid IVA. For example, Goldman et al., J Bacteriol. 170(5):2185-91, 1988 describe antibacterial agents, including antibacterial agent III, which specifically inhibit CTP:CMP-3-deoxy-D-manno-octulosonate cytidylyltransferase activity and which are useful to block the incorporation of 3-deoxy-D-manno-octulosonate (KDO) into LPS of Gram-negative organisms. As LPS synthesis ceased, bacterial growth ceased. The addition of KDO to LPS precursor species lipid IVA is the major pathway of lipid A-KDO formation in both S. typhimurium and E. coli. In one embodiment, the antibiotic is antibacterial agent III and Gram-negative bacteria are treated with a suitable amount, such as, for example 5 micrograms per milliliter to 500 micrograms per milliliter for a suitable time, for example 2 to 8 hours. A reduction in endotoxin activity may be achieved by introducing a genetic defect into the organism. The term “defect” as used herein, with regard to a gene or expression of a gene, means that the gene is different from the normal (wildtype) gene or that the expression of the gene is at a reduced level of expression compared to that of the wildtype gene. The defective gene may result from a mutation in that gene, or a mutation that regulates the expression of that gene. (e.g., transcriptional or post-transcriptional) In one embodiment, a reduction in endotoxin activity may be achieved by introducing a genetic defect that disrupts the biosynthesis of KDO2-Lipid IVA. For example, Woodard et al., U.S. Patent publication 20100272758, report viable non-toxic Gram-negative bacteria (e.g., E. coli) substantially lacking LPS within the outer membrane. The authors describe E. coli K-12 strain KPM22 as defective in synthesis of 3-deoxy-d-manno-octulosonic acid (Kdo). KPM22 has an outer membrane (OM) composed predominantly of lipid IVA, an LPS precursor that lacks glycosylation. Viability of the organisms is achieved by the presence of a second-site suppressor that transports lipid IVA from the inner membrane (IM) to the outer membrane. This suppressor is reported to relieve toxic side-effects of lipid IVA accumulation in the inner membrane and provide sufficient amounts of LPS precursors to support OM biogenesis. See also, Mamat et al., (Mol Microbiol. 67(3):633-48, 2008). In another embodiment, Bramhill et al., U.S. Patent Publication 2011-0224097, describe viable Gram-negative bacteria comprising outer membranes that substantially lack a ligand, such as Lipid A or 6-acyl lipopolysaccharide that acts as an agonist of TLR4/MD2. According to Bramhill, the bacteria may comprise reduced activity of arabinose-5-phosphate isomerases and one or more suppressor mutations, for example in a transporter thereby increasing the transporters capacity to transport Lipid IVA, or in membrane protein YhjD. One or more genes (e.g., IpxL, IpxM, pagP, IpxP, and/or eptA) may be substantially deleted and/or one or more enzymes (e.g., LpxL, LpxM, PagP, LpxP, and/or EptA) may be substantially inactive. In another embodiment, a reduction in endotoxin activity may be achieved by introducing a genetic defect that prevents synthesis of Kdo. For example, Rick et al., (Proc Natl Acad Sci USA. 69(12):3756-60, 1972) report an auxotrophic mutant of Salmonella typhimurium that is defective in the synthesis of the 3-deoxy-D-mannooctulosonate (ketodeoxyoctonate) region of the LPS and requires D-arabinose-5-phosphate for growth. The mutant defect was due to an altered ketodeoxyoctonate-8-phosphate synthetase (kdsA) with an apparent K(m) for D-arabinose-5-phosphate 35-fold higher than that of the parental enzyme. This caused the mutant strain to be dependent on exogenous D-arabinose-5-phosphate both for growth and for synthesis of a complete LPS. In another example, Belunis et al., (J. Biol. Chem. 270(46):27646-27652, 1995) disrupted the Kdo transferase (kdtA) gene in E. coli, which prevented incorporation of Kdo into lipid IVA. This mutation was lethal, but could be rescued by the conditional presence of a temperature-sensitive plasmid encoding kdtA. The development of conditional mutants in the Kdo synthesis pathway allows for growth of the bacteria, followed by transfer to the non-permissive condition, resulting in sufficient growth or survival to produce non-viable bacteria with significantly reduced endotoxin activity. In addition to LPS-derived endotoxin, various other constituents of Gram-negative organisms can induce or contribute to pyrogenicity and septic shock, including outer membrane proteins, fimbriae, pili, lipopeptides, and lipoproteins (reviewed by Jones, M., Int. J. Pharm. Compd., 5(4):259-263, 2001). Pyrogenicity can be measured by a rabbit method, well known in the art, involving assessment of rectal temperature after intravenous administration of putative pyrogens. It has been found that treatment of a Gram-negative organism with a combination of polymyxin B and glutaraldehyde produced a 30-fold reduction in pyrogenicity, as measured in rabbits. In one embodiment, 1,000 micrograms per milliliter (μg/mL) of polymyxin B and 1% glutaraldehyde was employed to produce a 30-fold reduction in pyrogenicity, as measured in rabbits. The pyrogenicity is reduced by a combination of polymyxin B reaction with LPS and glutaraldehyde reactivity with LPS and/or other bacterial constituents. The glutaraldehyde serves a dual role in this setting by also killing the bacteria. Thus, in one embodiment is provided a method of reducing endotoxin activity and pyrogenicity of and killing a Gram-negative bacterial microorganism by treating said bacteria with a combination of 1,000 μg/mL polymyxin B and 1% glutaraldehyde. In another embodiment, the Gram-negative bacteria are treated with a combination of polymyxin B at a dose range between about 3 μg/mL to about 1,000 μg/mL and glutaraldehyde at a dose range between about 0.1% to about 1.0%. In a further embodiment, the dose range of polymyxin B is between about 100 μg/mL to about 1,000 μg/mL and glutaraldehyde is at a dose range between about 0.5% to about 1.0%. Additionally, Gram-negative bacteria may be treated, for example with a dose range of polymyxin B between about 1,000 μg/mL to about 3,000 μg/mL and glutaraldehyde is at a dose range between about 0.5% to about 1.0%. In another aspect, Gram-negative bacteria maybe treated, for example with a dose range of polymyxin B between about 3,000 μg/mL to about 5,000 μg/mL and glutaraldehyde is at a dose range between about 0.5% to about 2.0%. In one embodiment, the endotoxin activity is reduced by about 70%, or about 75%, or about 80%, or about 85%, or about 90%, or about 92%, and pyrogenicity is reduced by about 75%, or about 80%, or about 85%, or about 90%, or about 95%, or about 97%. C. Rendering Bacteria Non-Viable Bacteria for administration according to the methods of the disclosure are rendered non-viable or substantially non-viable either prior to administration or become so upon administration. What is meant by “non-viable” is that the organisms are killed by treatment with an exogenous agent, and/or contain a mutation that results in an inability of the organisms to survive in a mammalian host. Substantially non-viable bacteria are strains that have had their viability reduced by at least 80%, 85%, 90%, 95%, 99%, or more. In preferred embodiments for bacteria that are not killed or not completely killed, the bacteria are further treated or modified such that they cannot proliferate within a mammalian host. In some embodiments where LPS is substantially not produced, it is contemplated that non-viable, attenuated, or viable bacteria are administered. Preferred methods of rendering bacteria non-viable are treatment with a compound that binds to LPS, thereby blocking its endotoxin activity, or treatment with a compound that interferes with LPS biosynthesis. In both cases, LPS binding and interference with LPS synthesis, viability is reduced as a result of permeabilization of the cell envelope. Another approach is to grow bacterial strains with conditional mutations in the LPS biosynthesis pathway that are suppressed during growth and then transfer to a non-permissive condition which activates the mutation and disrupts LPS biosynthesis. In each instance, the procedure applied is one that renders the bacteria non-viable by, determining in each setting, the optimal time of treatment or dose of compound, such that viability has been substantially lost with retention of significant bacterial cell integrity. In the case where non-viability is less than 100%, bacteria can be used which contain a mutation preventing further proliferation of viable bacteria in a mammalian host (e.g. a diaminopimelic acid auxotroph, as described by Bukhari and Taylor, J. Bacteriol. 105(3):844-854, 1971 and Curtiss et al., Immunol. Invest. 18(1-4):583-596, 1989). If alternative or additional methods of rendering bacteria non-viable are desired, a preferred method for killing bacteria is ionizing radiation (gamma rays or electron beam), but could also be done by other standard sterilization methods such as moist or dry heat, sterilant gas or vapor (see, e.g., Shintani et al., Biocontrol Science, 16(3):85-94, 2011). Additional non-standard methods of terminal sterilization that could be used include chemical treatment such as a chemical sterilant, and are summarized by Rutala and Weber (Emerg. Infect. Dis. 7(2):348-353, 2001) and Yaman (Curr. Opin. Drug Discov. Develop. 4(6):760-763, 2001). Examples of chemical gas, vapor and liquid sterilants include ethylene oxide gas (EOG), chlorine dioxide, vaporous phase of liquid hydrogen peroxide (VHP), formaldehyde, glutaraldehyde (e.g., ≧0.05% for ≧10 minutes), ortho-phthalaldehyde (OPA) (e.g. ≧0.1% for ≧5 minutes), and phenol. Methods that kill bacteria may affect the integrity of the organism. For example, the addition of heat may damage bacterial integrity, as opposed to the use of radiation. Reference to a bacterial organism as used herein includes the fully intact organism and partially degraded forms of the organism that may arise when the organisms are killed, but does not extend to subcellular fractions of the organisms that have become separated from other cellular components, such as a cell wall fraction (preparation) or a cell wall skeleton (see e.g., U.S. Pat. No. 4,436,727), cytoplasmic fraction, and the like. D. Compositions In one embodiment, is provided a composition comprising non-viable Gram-negative bacterial organisms having a substantial reduction in endotoxin and/or pyrogenic activity and a pharmaceutically acceptable excipient. In another embodiment, at least about 80% of the organisms are non-viable or at least about 90% of the organisms are non-viable, or about 100% of the organisms are non-viable. In one embodiment, the organisms have their viability reduced by about 80%, or by about 85%, or by about 90%, or by about 95%, or by about 100%. In one embodiment, the endotoxin and/or pyrogenic activity is reduced by about 70%, or by about 75%, or by about 80%, or by about 85%, or by about 90%, or by about 95%. The composition may contain any contemplated amount of non-viable or viability-reduced organisms in combination with any contemplated reduction in endotoxin or pyrogenic toxicity. In another embodiment, the composition comprises at least about 100% non-viable organisms having at least about 95% reduced endotoxin activity and pyrogenicity. Compositions described herein may be formulated in a variety of ways for use in the methods described herein. In one embodiment, the composition comprises the organisms as described throughout and a pharmaceutically acceptable carrier. “Pharmaceutically acceptable carriers” refers to any diluents, excipients, or carriers that may be used in the compositions. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field. They are selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. The pharmaceutical compositions may be manufactured by methods well known in the art such as microbial growth in fermenters, followed by concentration and washing by centrifugation, filtration or dialysis, conventional granulating, mixing, dissolving, encapsulating, lyophilizing, or emulsifying processes, among others. Compositions may be produced in various forms, including granules, precipitates, or particulates, powders, including freeze dried, rotary dried or spray dried powders, amorphous powders, injections, emulsions, elixirs, suspensions or solutions. Formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. Pharmaceutical compositions may be prepared as liquid suspensions or solutions using a sterile liquid, such as oil, water, alcohol, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents or emulsifying agents, may be added for oral or parenteral administration. Suspensions may include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids, such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as poly(ethyleneglycol), petroleum hydrocarbons, such as mineral oil and petrolatum, and water may also be used in suspension formulations. The compositions are formulated for pharmaceutical administration to a mammal, preferably a human being. Such pharmaceutical compositions of the invention may be administered in a variety of ways, including parenterally. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Sterile injectable forms of the compositions may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation. Compositions may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. E. Methods for Treating Cancer Cancers suitable for treatment by the methods herein include generally carcinomas, leukemias or lymphomas, and sarcomas. Carcinomas may be of the anus, biliary tract, bladder, breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, kidney, gallbladder and bile ducts, small intestine, urinary tract, female genital tract, male genital tract, endocrine glands, thyroid, and skin. Other suitable cancers include carcinoid tumors, gastrointestinal stromal tumors, head and neck tumors, unknown primary tumors, hemangiomas, melanomas, malignant mesothelioma, multiple myeloma, and tumors of the brain, nerves, eyes, and meninges. In some embodiments, the cancers to be treated form solid tumors, such as carcinomas, sarcomas, melanomas and lymphomas. Cancer therapy, as described herein is achieved by administering an amount of Gram-negative (live or dead as appropriate) organisms that is sufficient to inhibit growth or metastasis of the cancer. As employed herein, the phrase “a sufficient amount,” refers to a dose (or series of doses) sufficient to impart a beneficial effect on the recipient thereof. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the type of cancer being treated, the severity of the cancer, the activity of the specific organism or combined composition, the route of administration, the rate of clearance of the organism or combined composition, the duration of treatment, the drugs (if any) used in combination with the organism, the age, body weight, sex, diet, and general health of the subject, and like factors well known in the medical arts and sciences. Various general considerations taken into account in determining the “therapeutically effective amount” are known to those of skill in the art and are described, e.g., in Gilman et al., eds., Goodman And Gilman's: The Pharmacological Bases of Therapeutics, 8th ed., Pergamon Press, 1990; and Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Co., Easton, Pa., 1990. Dosage levels typically fall in the range of about 0.001 up to 100 mg/kg/day; with levels in the range of about 0.05 up to 10 mg/kg/day being generally applicable for compounds. Dosage levels for administered organisms typically fall in the range of about 106 to 1012 per m2. A composition can be administered parenterally, such as intravascularly, intravenously, intraarterially, intramuscularly, subcutaneously, orally or the like. Bacterial organisms can be administered parenterally, such as intravascularly, intravenously, intraarterially, intramuscularly, subcutaneously, intraperitoneally, or intravesically. A therapeutically effective dose can be estimated by methods well known in the art. Cancer animal models such as immune-competent mice with murine tumors or immune-compromised mice (e.g. nude mice) with human tumor xenografts are well known in the art and extensively described in many references incorporated for reference herein. Such information is used in combination with safety studies in rats, dogs and/or non-human primates in order to determine safe and potentially useful initial doses in humans. Additional information for estimating dose of the organisms can come from studies in actual human cancer. For example, Toso et al. (J Clin Oncol. 20(1):142-52, 2002) report a phase I clinical trial in which live VNP20009 was administered to patients with metastatic melanoma. Patients received 30-minute intravenous bolus infusions containing 10(6) to 10(9) cfu/m(2) of VNP20009. The maximum-tolerated dose was 3×10(8) cfu/m(2). Dose-limiting toxicity was observed in patients receiving 1×10(9) cfu/m(2), which included thrombocytopenia, anemia, persistent bacteremia, hyperbilirubinemia, diarrhea, vomiting, nausea, elevated alkaline phosphatase, and hypophosphatemia. The organisms may be administered as a pharmaceutically acceptable formulation. The term “pharmaceutically acceptable” means a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected organism or combined compound without causing any undesirable biological effects or interacting in a deleterious manner with any of other administered agents. This is more thoroughly described above. The term “treating” a subject for a condition or disease, as used herein, is intended to encompass curing, as well as ameliorating at least one symptom of the condition or disease. Cancer patients are treated if the patient is cured of the cancer, the cancer goes into remission, survival is lengthened in a statistically significant fashion, time to tumor progression is increased in a statistically significant fashion, there is a reduction in lymphocytic or hematopoietic tumor burden based on standard criteria established for each type of lymphocytic or hematopoietic malignancy, or solid tumor burden has been decreased as defined by response evaluation criteria in solid tumors (RECIST 1.0 or RECIST 1.1, Therasse et al. J Natl. Cancer Inst. 92(3):205-216, 2000 and Eisenhauer et al. Eur. J. Cancer 45:228-247, 2009). As used herein, “remission” refers to absence of growing cancer cells in the patient previously having evidence of cancer. Thus, a cancer patient in remission is either cured of their cancer or the cancer is present but not readily detectable. Thus, cancer may be in remission when the tumor fails to enlarge or to metastesize. Complete remission as used herein is the absence of disease as indicated by diagnostic methods, such as imaging, such as x-ray, MRI, CT and PET, or blood or bone marrow biopsy. When a cancer patient goes into remission, this may be followed by relapse, where the cancer reappears. The term “substantially” unless indicated otherwise means greater than about 80%, greater than about 90%, greater than about 95% and greater than about 99%. F. Combinations for Treating Cancer The methods of cancer therapy described herein may employ administration of Gram-negative organisms together with one or more antagonists of receptors or ligands that negatively modulate the host immune response. Antagonists may be directed to PD-1, PD-L1 or CTLA-4 and typically are administered intravenously, for example at a dose range of about 0.03 milligram per kilogram to about 30 milligram per kilogram every 1 to 4 weeks. Programmed cell death protein 1 (PD-1) is a protein that in humans is encoded by the PDCD1 gene. PD-1 has also been designated as CD279 (cluster of differentiation 279). PD-1 is a type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. See, e.g., Ishida et al., EMBO J. 11 (11): 3887-95, 1992. The proteins contain an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites within in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif. This suggests that PD-1 negatively regulates TCR signaling. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages. PD-1 is a broad negative regulator of immune responses. PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. See, e.g., Freeman et al., J. Exp. Med. 192 (7):1027-34, 2000 and Latchman et al., Nat. Immunol. 2(3): 261-8, 2001. PD-L1 is a 40 kDa type 1 transmembrane protein that has been reported to play a major role in suppressing the immune system during pregnancy, tissue allografts, autoimmune disease and hepatitis. PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling. The formation of a PD-1 receptor/PD-L1 ligand complex transmits an inhibitory signal which reduces the proliferation of CD8+ T cells (during an immune response) at the lymph nodes and PD-1 also can control the accumulation of foreign antigen specific T cells in the lymph nodes through apoptosis. PD-L2 expression is more restricted and is expressed mainly by dendritic cells and a few tumor lines. CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4), also known as CD152 (Cluster of differentiation 152), is a protein receptor that downregulates the immune system. CTLA-4 is expressed on the surface of helper, effector and immunoregulatory T-cells, which lead the cellular immune attack on antigens. The T cell can be turned on by stimulating the CD28 receptor or turned off by stimulating the CTLA-4 receptor. CTLA-4, like that of the T-cell costimulatory protein, CD28, bind to CD80 and CD86, also called B7-1 and B7-2, respectively, on antigen-presenting cells. T-cell activation through the T-cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules. Enhancing or prolonging T-cell activation has been achieved by monoclonal antibodies (mAbs) to CTLA-4 and PD-1. Ipilimumab and tremelimumab are monoclonal antibodies that inhibit CTLA-4, and have been shown to induce or enhance anti-tumor immune responses leading to durable anti-tumor effects. Ipilimumab (also known as MDX-010 or MDX-101), marketed in the U.S. under the name Yervoy, is sold by Bristol Myers Squibb for the treatment of unresectable or metastatic malignant melanoma. BMS-936558 (MDX-1106) is a monoclonal antibody against PD-1 and has exhibited significant anti-tumor activity in human clinical trials. See, e.g., Brahmer et al., J. Clin. Oncol., 28(19):3167-3175, 2010, Brahmer et al., N. Engl. J. Med., 366(26):2455-2465, 2012; and Lipson et al., Clin. Can. Res. 19(2):462-468, 2013. Inhibition of CTLA-4 also may be achieved by a fusion protein (CTLA4Ig) made up of CTLA-4 and Fc of immunoglobulin (Ig) heavy chain. See, e.g., Park et al., Pharm Res. 20(8):1239-48, 2003. An additional important negative regulator of the immune response in the tumor microenvironment is the signal transducer and activator of transcription (STAT) signal responsive transcription factor STAT3. Activity of this factor is elevated in tumor and associated immune cells. STAT3 activity in tumor cells contributes to enhanced survival, proliferation, invasion and metastasis, as well as stimulation of angiogenesis. Elevated STAT3 activity in immune cells leads to accumulation and activation of immunosuppressive cells, such as Treg, Th17 and myeloid derived suppressor cells within the tumor microenvironment. See e.g., Rébé et al. (JAK-STAT 2(1):e23010-1-10, 2013) for review. The widely used type 2 diabetes drugs metformin and phenformin have been shown to have antitumor activity and the mechanism is thought to include inhibition of STAT3 activity, resulting in decreased anti-tumor immunosuppression. See e.g., Deng et al., (Cell Cycle 11(2):367-376, 2012), Hirsch et al., (Proc. Natl. Acad. Sci., USA 110(3):972-977, 2013), Appleyard et al., (British J Cancer 106:1117-1122, 2012), Jiralerspong et al., (J Clin Oncol. 27(20):3297-3302, 2009), and Del Barco et al., (Oncotarget 2(12):896-917, 2011) for review. The methods of cancer therapy described herein may employ administration of Gram-negative organisms together with an inhibitor of STAT3 expression or activity. Such inhibitors may include metformin and phenformin. Metformin maybe administered, for example at a dose range of between about 50 milligrams to about 1,000 milligrams, usually 1 to 3 times per day. Phenformin is typically administered at a dose range of between about 20 milligrams to about 800 milligrams 1 to 2 times per day. The methods of cancer therapy described herein may also employ administration of Gram-negative organisms together with one or more agonists of receptors or ligands that positively modulate the host immune response. Agonists directed to 4-1BB (CD137), GITR, CD40 or OX40 (CD134) and can be administered, for example intravenously at a dose range of between about 0.03 milligram per kilogram to about 30 milligram per kilogram every 1 to 4 weeks. Glucocorticoid inducible tumor necrosis factor receptor (TNFR)-related protein (GITR), 4-1BB (CD137), CD40 and OX40 (CD134) are costimulatory TNFR family members that are expressed on regulatory and effector T cells as well as on other cells of the immune system. Activation of these proteins leads to stimulation or enhancement of immune function. Activating monoclonal antibodies for each of these proteins have exhibited anti-tumor activity in preclinical models and have entered clinical development. See, e.g., Melero et al., Clin. Cancer Res. 15(5):1507-1509, 2009, Garber, JNCI 103(14):1079-1082, 2011, Khong et al., Int. Rev. Immunol. 31(4):246-266, 2012, Vinay and Kwon, Mol. Cancer Ther. 11(5):1062-1070, 2012, Snell et al., Immunol. Rev. 244(1):197-217, 2011, and So et al., Cytokine Growth Factor Rev. 19(3-4):253-262, 2008. The methods of cancer therapy described herein may also employ administration of Gram-negative organisms together with one or more chemotherapeutic agents. Such agents may include cyclophosphamide. It is contemplated that when cyclophosphamide is used in the methods described herein, it may administered in a dose of between 5 mg/m2 to 750 mg/m2 intravenously or orally daily or every 21 days. Alternatively, cyclophosphamide may be administered, for example, in a metronomic regimen at a dose of between 5 mg to 100 mg orally daily. See, for example, Jia et al., Int. J. Cancer 121(3):666-674, 2007. Stimulation of anti-tumor immune responses has been demonstrated with various cytokines. See, for example, Smyth et al., Immunological Rev. 202:275-293, 2004 and Kim-Schulze, Surg. Oncol. Clin N. Am. 16:793-818, 2007 for reviews. The methods of cancer therapy described herein may also employ administration of Gram-negative organisms together with recombinantly expressed or isolated and purified cytokines, such as interferon-alpha, interferon-beta, interferon-gamma, granulocyte-macrophage colony-stimulating factor, interleukin-2, and interleukin-12. The methods of cancer therapy described herein may also employ Gram-negative bacteria administered together with recombinantly expressed or isolated and purified interferon-alpha. The interferon-alpha may be administered either subcutaneously, intramuscularly, or intravenously at a dose range of between about 3×105 to about 3×108 IU 1, 3, 5 or 7 times per week. In another embodiment, Gram-negative bacteria may be administered together with interferon-beta. In certain embodiments, the interferon-beta will be administered subcutaneously or intravenously at a dose range of between about 0.01 milligrams to about 5 milligrams either once a week or every other day. Interferon-gamma may also be co-administered. In one embodiment, the interferon-gamma may be administered either subcutaneously or intravenously at a dose range of between about 1×105 IU to about 1×109 IU either once or daily. In additional methods, interleukins (e.g. interleukin-2, and interleukin-12) may be co-administered. In one embodiment, interleukins may be administered intravenously in a dose of between about 1×104 to about 1×107 IU once per week or up to three times a day in combination with Gram-negative bacteria. Additional methods include Gram-negative bacteria being administered, for example with Granulocyte-macrophage colony-stimulating factor either subcutaneously, intradermal, or intravenously typically at a dose range of between about 5 micrograms to about 5 milligrams, either daily or monthly. In any of the combination treatments noted throughout, it is contemplated the organisms may be administered before or after the additional cancer treatment. They may also be administered concurrently. The following examples serve to illustrate the present disclosure. These examples are in no way intended to limit the scope of the disclosure. EXAMPLES Example 1 Optimal conditions for inactivation of lipopolysaccharide-associated endotoxin activity and bacterial cell killing by polymyxin B without loss of cell integrity are determined for each bacterial strain by incubating concentrated late log bacteria (109 to 1011 per mL) at 37° C. in phosphate buffered saline (PBS) with 1-100 μg/mL of polymyxin B for various times between 2 minutes and 6 hours. Viability is determined by serial dilution plating of control and treated bacterial suspensions on growth-compatible agar plates, followed by overnight incubation and colony counting. Cell integrity is determined by visual (microscope) examination and analysis of absorbance at 600 nm. Endotoxin activity is determined by the Limulus Amebocyte Lysate (LAL) assay. Soluble or excess polymyxin and cell debris, including soluble endotoxin, are removed by centrifugation-mediated washing with 0.9% NaCl (normal saline). Alternatively, optimal conditions for isolation of intact, non-viable bacteria with defective LPS, resulting from a conditional mutation, are determined as described for polymyxin treatment, except that bacteria are grown in LB (Lysogeny broth) medium under the non-permissive condition and removed at various times, followed by analysis and processing as described for polymyxin treatment. Polymyxin-treated bacteria or saline-washed late log phase LPS mutant/defective bacteria are freeze-dried using trehalose as the cryoprotectant (see, e.g., Leslie et al., App. Environment. Microbiol. 61(10):3592-3597, 1995; Gu et al., J. Biotech. 88:95-105, 2001 and American Type Culture Collection Bacterial Culture Guide). If desired, bacterial viability is further reduced by treatment with ionizing radiation at a dose sufficient to reduce viability to 0%, without loss of bacterial integrity. Freeze-dried bacteria are resuspended in sterile water prior to use in anti-tumor studies. PBS-washed murine tumor cells (B16 and B16F10 melanoma, CT-26 colorectal carcinoma, Panc02 pancreatic carcinoma or Lewis Lung carcinoma (105-107 cells, depending on cell line) are implanted subcutaneously on the back of shaved C57BL/6 mice. Mice are randomized and treatment is initiated when tumors can be first palpated, when tumors have reached an average volume of 75 mm3, or when tumors have reached an average volume of 300 mm3 (as estimated by caliper measurement). Resuspended bacteria are injected once to twice per week via the tail vein or intraperitoneally (i.p.) at individual doses ranging from 103 to 1010 per 0.1-0.2 mL injection volume. Antibody antagonists or agonists directed to T-cell receptors are administered i.p. at individual doses of 3-100 micrograms once to twice per week. Cyclophosphamide is administered i.p. at up to 150 mg/kg every other day for 5 days (MTD dosing) or at 25 mg/kg per day in the drinking water (metronomic dosing). Mice are weighed twice per week and clinical observations are recorded. Tumor measurements (by caliper) are carried out twice per week and mice are humanely sacrificed if/when tumors reach 1,000 mm3, become necrotic or if ≧15% weight loss is observed. Tumors are removed and weighed, and minimal necropsy is carried out with sacrificed mice. Mice may be re-challenged with tumor cell implantation if long-term tumor regression or cures are observed. Example 2 In Example 2, E. coli strain 2617-143-312 (Migula) Castellani and Chalmers (ATCC® 13070™) were used. This non-hazardous Gram-negative bacterium requires exogenous diaminopimelic acid (DAP) for growth. Since mammals do not make DAP, this bacterial strain is not viable and cannot cause infections in mammals. In addition, the DAP auxotrophy can be used to monitor contamination during in vitro studies. Bacteria were grown to late log phase (based on O.D.600) in LB Miller broth with 2 mM MgCl2, 0.5% glucose and 1 mM DAP at 37° C. with constant shaking at 300 rpm. The culture was washed three times by centrifugation at 2,000×g for 15 minutes and resuspension in 4° C. LB Miller broth containing 20 mM MgCl2, 0.5% glucose and 0.1 mM DAP (PMB treatment medium). Final resuspension was made at 2×1010 bacteria per mL, based on an O.D.600 of 1 being equal to 1.12×109 bacteria per mL. Individual aliquots of the culture were incubated without and with various concentrations of Polymyxin B (PMB) (Calbiochem #5291) for 1 hour at 4° C. with constant stirring. Bacteria were then washed three times with 4° C. fresh PMB treatment medium by centrifugation at 3,000×g for 10 minutes and resuspended at 2×109 bacteria per mL. Bacteria recovery efficiency was monitored by following O.D.600. Bacteria recovery after PMB treatment and wash was greater than 90% for all samples treated with up to 300 μg/mL PMB, and exceeded 80% for treatment with 1,000 μg/mL PMB. In FIG. 1, endotoxin activity was determined by analyzing serial dilutions of untreated and treated bacterial cultures with the Limulus Amebocyte Lysate (LAL) Endosafe Endochrome-K kinetic assay kit (Charles River Endosafe, Charleston, S.C.). Untreated cultures typically contained approximately 50-100 endotoxin units per 1×106 bacteria. Similar endotoxin reductions were observed for treatment with 1,000 μg/mL PMB in four independent experiments (average=17% of untreated). In FIG. 2, bacterial viability was determined by serially diluting and plating each sample on LB Miller agar plates containing 2 mM MgCl2, 0.5% glucose, with and without 1 mM DAP (to monitor viability and contamination, respectively). Plates were incubated overnight at 37° C., the number of colonies on each plate was determined, and then viability was calculated by multiplying the number of colonies on each plate by the dilution factor. The total number of bacteria in each suspension was calculated by multiplying the O.D.600 by the conversion factor of 1.12×109 bacteria/mL per O.D.600 of 1. Viability (% Live Bacteria) was calculated as the percent of viable bacteria/mL relative to the total number of bacteria. Treatment with 1,000 μg/mL PMB reduced bacteria viability to 0%. In subsequent scale-up experiments 1,000 μg PMB reduced viability to an average of 11% in four independent experiments. Example 3 The experiments were carried out as described in Example 2, except that pre-treatment washes, glutaraldehyde (GA) treatment and post-treatment washes were carried out with phosphate-buffered saline (PBS; Mg and Ca-free) pH 7.5, containing 20 mM MgCl2. Bacteria recovery after GA treatment, at all concentrations tested, was typically 80-100%. FIG. 3 demonstrates that treatment with 1% GA reduced endotoxin activity by 96%. A 2-liter scale-up experiment with 1% GA treatment produced an endotoxin activity reduction of 82%, relative to the untreated culture. Treatment with GA consistently produced 100% bacteria kill at doses above 0.05%, as demonstrated in FIG. 4. Combination of 1,000 μg/mL PMB treatment followed by 1% GA treatment using 2 liters of late log phase culture produced bacteria with 0% viability and a 92% (12-fold) reduction in endotoxin activity, relative to the untreated culture (Table 1). Example 4 In Example 4, bacteria were grown and treated with 1,000 μg/mL PMB, 1% GA or both as described in the protocols for Examples 2 and 3. Samples were diluted with PBS, pH 7.5 containing 1% GA (if not previously exposed to GA) and fixed for 10 minutes. Twenty-five microliter droplets containing the bacteria were placed on parafilm and then covered with a 100 mesh formvar+carbon EM grid (EMS, Hatfield, Pa.), which was pre-coated with 0.1% poly-L-lysine. Samples were allowed to adhere for 10 minutes and then the grids were washed briefly three times by placement on 200 microliter water droplets. The grids were negatively stained by placement for 1 minute on 100 microliter droplets of 2% uranyl acetate in water. Excess stain was blotted away with 3M filter paper, followed by air drying. Samples were visualized using an FEI Tecnai Spirit G2 BioTWIN transmission electron microscope equipped with a bottom mount Eagle 4k (16 megapixel) digital camera (magnifications 1,200× and 11,000×). The images in FIGS. 5B, 5C, and 5D confirm that PMB and/or GA treatments carried out according to the present methods leave the bacteria intact, which is a desirable result. A polysaccharide capsule is visible (fuzzy surface) on the untreated bacteria (FIG. 5A), but appears to have been removed or matted down in all treated bacteria (FIGS. 5B, 5C, and 5D). Example 5 For Example 5, E. coli were grown and treated with 1,000 μg/mL PMB plus 1% GA, and viability and endotoxin levels were determined as described for Examples 2 and 3. After final washing, untreated and PMB+GA-treated bacteria were resuspended in 50% PBS, pH 7.5, 0.5 mM MgCl2, 12% trehalose at a concentration of 1.1×1011 bacteria per mL, aliquoted, flash frozen and stored at −80° C. The pyrogenicity threshold was determined essentially as described in the United States Pharmacopeia, Chapter 151. Adult female New Zealand White rabbits weighing at least 2.0 kg were used. All animals were conditioned with a sham test not more than 7 days prior to the pyrogen test. Dose range-finding was carried out with one rabbit per dose and these results were subsequently confirmed with two rabbits per dose. Bacteria were diluted into sterile saline for injection. All doses were delivered via the intravenous route in a volume of 10 mL. The lowest concentration of test agent that produced a temperature increase of 0.5-1.0° C. at any time point within three hours of test agent administration was considered to represent the pyrogenicity threshold. Rectal temperatures were recorded at baseline and at 30 minute intervals between 1 and 3 hours following injection of test agent. Saline-diluted vehicle used for storage of untreated and treated E. coli was shown not to be pyrogenic. Administration of 3×104 untreated bacteria to two rabbits produced temperature increases of 0.8 and 1.0° C. Administration of 3×105 PMB+GA-treated bacteria did not produce a temperature increase of more than 0.1° C., but administration of 9×105 PMB+GA-treated bacteria to two rabbits produced temperature increases of 0.7 and 1.0° C., demonstrating a pyrogenicity threshold difference of 30×-fold. It is likely that PMB neutralizes only lipopolysaccharide-mediated pyrogenic activity. Whereas, GA may neutralize pyrogenicity mediated by lipopolysaccharide, as well as by other constituents of the bacteria. Table 1 demonstrates the pyrogenicity (febrile reaction) threshold for untreated bacteria and bacteria treated with both 1,000 μg/mL PMB and 1% GA, as measured by a standard in vivo rabbit test. The results are compared to endotoxin levels determined with the in vitro LAL assay, demonstrating that although PMB+GA treatment reduces endotoxin levels by 12-fold, pyrogenicity mediated by the same sample is reduced by 30-fold, compared to untreated bacteria. TABLE 1 Pyrogenicity Live Endotoxin Activity Threshold Treatment Bacteria LAL Assay Rabbit Assay No 83% 44.7 Units/106 Bacteria 3 × 104 Bacteria Treatment PMB + GA 0% 3.6 Units/106 Bacteria 9 × 105 Bacteria Max Reduction 12X 30X Example 6 In Example 6, E. coli were grown and treated with 1,000 μg/mL Polymyxin B plus 1% GA as described in the protocols for Examples 2 and 3. Frozen stocks of untreated and treated bacteria were thawed rapidly at 37° C. and either diluted at least 10-fold into sterile saline for injection (i.v. doses ≦3×109 bacteria) or centrifuged at 3,000×g for 10 minutes and resuspended in sterile saline for injection (i.v. doses ≧5×109). Bacteria or vehicles were injected i.v. via the tail vein in a volume of 100 microliters. Eight week old C57BL/6 or BALB/c female mice were used and acclimated for at least 7 days prior to studies. Mortality and clinical observations were performed once or twice per day. Additional observations were made at the time of and 1-4 hours after injections. Lack of toxicity by vehicles was confirmed. Cage side observations included but were not limited to the following: Changes in skin, fur, eyes, mucous membranes, gait, posture, and response to handling occurrence of secretions/excretions or other evidence of autonomic activity such as lacrimation, piloerection, unusual respiratory patterns; presence of seizures; changes in general alertness; stereotype behaviors such as excessive grooming and repetitive circling; unusual behaviors (self-mutilating); development of lumps/bumps (tumor, abscess, etc.); development of signs of stress and/or respiratory symptoms; observation of the injection sites for signs of irritation and inflammation; changes in food and water consumption and urine and feces output. Bacteria administration for multiple-dose studies was carried out twice per week for two weeks (4 treatments). Evaluation of toxicity included monitoring of animal weight. The mice used in the multiple-dose study reported for PMB+GA-treated bacteria at 1×109 were tumor-bearing. All other mice reported in Table 2 were non-tumor bearing. TABLE 2 Bacterial Single Dose Multiple (4) Dose Treatment Dose Observations Observations Untreated 3 × 108 Slightly lethargic at Slightly lethargic at 1-4 hr 1-4 hr 1 × 109 Lethargic at 1-4 hr Lethargic at 1-4 hr, 2 of 3 mice dead after 4th dose 5 × 109 Lethargic at 1-48 hr ND* Dead by 72 hr 1 × 1010 Dead by 18 hr ND PMB + 1 × 109 Slightly lethargic at Slightly lethargic at 1-4 hr, GA 1-4 hr ruffled fur 3 × 109 Lethargic at 1-4 hr Slightly lethargic, lethargic or ruffled fur up to 4 hr post treatment 5 × 109 Lethargic at 1-4 hr Slightly lethargic, lethargic or ruffled fur up to 4 hr post treatment 1 × 1010 Severely lethargic, Lethargic, slightly 1 of 3 mice dead by lethargic, ruffled fur and/or 24 hr shallow breathing *ND = not determined Example 7 In Example 7, 1,000 μg/mL PMB+1% GA-treated bacteria (DB103) were prepared as described in the protocols for Examples 2 and 3. Eight week old female C57BL/6J mice were shaved at the injection site and injected subcutaneously on the right flank with 2×105B16F10 murine melanoma cells (ATCC CRL-6475). Treatments were started via tail vein i.v. administration three days later and continued twice per week for a total of 5 treatments. DB103 in 50% PBS, pH 7.5, 0.5 mM MgCl2, 12% trehalose at a concentration of 1.1×1011 per mL were diluted 11-fold (1×109 dose) or 220-fold (5×107 dose) with sterile saline and injected in a final volume of 100 microliters. The stock vehicle was diluted 11-fold for the vehicle control treatment group. Tumors were measured with calipers twice weekly and tumor volume was determined using the formula (length×width2)/2. No compound-related deaths were observed. All animals developed tumors, with the exception of two animals treated with 1×109 DB103. Transient body weight loss of up to 3% (low dose group) and 7% (high dose group) was observed, but recovered after the last treatment (FIG. 6). Example 8 For Example 8, E. coli (untreated and 1% GA-treated) were prepared as described in the protocols for Examples 2 and 3. The experiment was carried out as described in the protocol for Example 7, except that treatment was started on day 11 when tumors were just palpable. Group measurements were not recorded after day 24 for most groups because a subset of animals in each of these groups had to be euthanized due to tumor burden. Tumors formed in all animals. Maximum weight loss in the 1×109 GA group was 11%. Toxicity precluded administration of 1×109 untreated E. coli (see Table 2). Example 9 In Example 9, 1,000 μg PMB+1% GA-treated bacteria (DB103) were prepared as described in the protocols for Examples 2 and 3. The experiment was carried out as described in the protocol for Example 7, except that 1×105 murine CT26 colorectal carcinoma cells were injected subcutaneously in the right flank of BALB/c mice. DB103 treatments were started via tail vein i.v. administration three days later and continued twice per week for a total of 6 treatments. Cyclophosphamide (LKT Laboratories, #C9606) was administered via the drinking water continuously, starting on day 3, at ˜20 mg/kg/day (0.133 mg/mL in water). Anti-murine CTLA-4 antibody (BioXcell #BE0164), 100 μg in 200 microliters PBS, was administered i.p. on days 3, 6 and 9. Clinical observations and mortality were recorded daily. Tumors were measured with calipers twice weekly and tumor volume was determined with the formula (length×width2)/2. Tumors formed in all mice in the vehicle group. No weight loss and no compound-related deaths were observed in any group. The data for the vehicle, low dose and high dose DB103 groups is the same in FIGS. 8A and 8B. All patents and publications mentioned in the specification are indicative of the levels of those of ordinary skill in the art to which the disclosure pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. The disclosure illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising,” “consisting essentially of” and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the claims. Thus, it should be understood that although the present disclosure has been specifically described by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this disclosure as defined by the appended claims. Other embodiments are set forth within the following claims.",A61K3574,A61K3574,20160121,,20160714,70962.0
3,15005424,ACCEPTED,Germanium FinFETs with Metal Gates and Stressors,An integrated circuit structure includes an n-type fin field effect transistor (FinFET) and a p-type FinFET. The n-type FinFET includes a first germanium fin over a substrate; a first gate dielectric on a top surface and sidewalls of the first germanium fin; and a first gate electrode on the first gate dielectric. The p-type FinFET includes a second germanium fin over the substrate; a second gate dielectric on a top surface and sidewalls of the second germanium fin; and a second gate electrode on the second gate dielectric. The first gate electrode and the second gate electrode are formed of a same material having a work function close to an intrinsic energy level of germanium.,"1. A method comprising: forming a first germanium-containing fin higher than top surfaces of Shallow Trench Isolation (STI) regions, wherein the STI regions are on opposite sides of the first germanium-containing fin and extend into a silicon substrate, and the first germanium-containing fin has a first germanium atomic percentage; forming a first gate stack on a middle portion of the first germanium-containing fin, with an end portion of the first germanium-containing fin exposed; etching the end portion of the first germanium-containing fin to form a recess; and re-growing a first source/drain region in the recess, wherein the first source/drain region has a second germanium atomic percentage lower than the first germanium atomic percentage. 2. The method of claim 1, wherein the first gate stack and the first source/drain region are parts of an n-type Fin Field Effect Transistor (FinFET). 3. The method of claim 1, wherein the first source/drain region extends below the top surfaces of the STI regions to contact a portion of the silicon substrate, with the portion of the silicon substrate extending between and at a same level as the STI regions. 4. The method of claim 1, wherein the first germanium-containing fin is free from silicon. 5. The method of claim 1 further comprising forming a p-type Fin Field Effect Transistor (FinFET) comprising: when the first germanium-containing fin is formed, simultaneously forming a second germanium-containing fin over the silicon substrate. 6. The method of claim 5 further comprising: forming a second gate stack on a middle portion of the second germanium-containing fin, with an end portion of the second germanium-containing fin exposed; etching the end portion of the second germanium-containing fin to form an additional recess; and re-growing a second source/drain region in the additional recess, wherein the second source/drain region has a third germanium atomic percentage higher than the first germanium atomic percentage. 7. The method of claim 6, wherein each of the forming the first gate stack and the forming the second gate stack comprises: forming a gate dielectric on a top surface and sidewalls of a respective one of the first germanium-containing fin and the second germanium-containing fin; and forming a gate electrode over the gate dielectric, wherein the gate electrode of the first gate stack and the gate electrode of the second gate stack are formed of a same material having a work function between about 4.25 eV and about 4.4 eV. 8. The method of claim 1, wherein the forming the first germanium-containing fin comprises: recessing a top portion of the silicon substrate between the STI regions to form an additional recess; re-growing a germanium-containing semiconductor material in the additional recess; and recessing the STI regions. 9. The method of claim 1 further comprising forming gate spacers on sidewalls of the first germanium-containing fin, wherein in the etching the end portion of the first germanium-containing fin, the middle portion of the first germanium-containing fin is protected by the first gate stack and the gate spacers. 10. A method comprising: forming Shallow Trench Isolation (STI) regions extending into a substrate, with the substrate comprising silicon; forming a first germanium fin and a second germanium fin higher than portions of the STI regions on opposite sides of respective ones of the first and the second germanium fins, wherein both the first and the second germanium fins have a first germanium atomic percentage; forming an n-type Fin Field Effect Transistor (FinFET) comprising: forming a first gate dielectric on a top surface and sidewalls of the first germanium fin; forming a first gate electrode over the first gate dielectric; etching a portion of the first germanium fin to form a first recess; and growing a first source/drain region comprising germanium in the first recess, with the first source/drain region having a second germanium atomic percentage lower than the first germanium atomic percentage, and the first source/drain region extends below top surfaces of the STI regions to contact the substrate; and forming a p-type FinFET comprising: forming a second gate dielectric on a top surface and sidewalls of the second germanium fin; forming a second gate electrode over the second gate dielectric; etching a portion of the second germanium fin to form a second recess; and growing a second source/drain region comprising germanium in the second recess, with the second source/drain region having a third germanium atomic percentage higher than the first germanium atomic percentage, wherein the second source/drain region extends below the top surfaces of the STI regions to contact the substrate, and wherein the first gate electrode and the second gate electrode are formed of a same material having a work function between 4.25 eV and 4.4 eV. 11. The method of claim 10, wherein the first and the second germanium fins are free from silicon. 12. The method of claim 10, wherein the first gate electrode and the second gate electrode are formed simultaneously, and are formed of a same metallic material. 13. The method of claim 10, wherein the growing the second source/drain region comprises growing germanium tin (GeSn). 14. The method of claim 10 further comprising: forming a third germanium fin underlying the first gate electrode, wherein the third germanium fin is physically separated from, and electrically connected to, the first germanium fin; and forming a fourth germanium fin underlying the second gate electrode, wherein the fourth germanium fin is physically separated from, and electrically connected to, the second germanium fin. 15. A method comprising: forming Shallow Trench Isolation (STI) regions extending into a substrate; forming a p-type Fin Field Effect Transistor (FinFET) comprising: forming a first germanium fin over the substrate, wherein the first germanium fin is a germanium fin without being doped with silicon; forming a first gate dielectric on a top surface and sidewalls of the first germanium fin; forming a first metal gate over the first gate dielectric; and growing a first source/drain region adjacent to the first metal gate; and forming an n-type FinFET comprising: forming a second germanium fin over the substrate, wherein the second germanium fin is a germanium fin without being doped with silicon; forming a second gate dielectric on a top surface and sidewalls of the second germanium fin; forming a second metal gate over the second gate dielectric, wherein the first metal gate and the second metal gate are formed simultaneously; and growing a second source/drain region adjacent to the second metal gate, wherein the second source/drain region comprises silicon germanium, with a germanium atomic percentage in the second source/drain region being lower than a germanium atomic percentage in the second germanium fin, wherein the second source/drain region extends below top surfaces of the STI regions to contact the substrate. 16. The method of claim 15, wherein the first germanium fin and the second germanium fin are formed simultaneously in a same epitaxial growth. 17. The method of claim 15, wherein the forming the first source/drain region of the p-type FinFET comprises growing a III-V compound semiconductor material. 18. The method of claim 15, wherein the forming the first source/drain region of the p-type FinFET comprises growing germanium tin (GeSn). 19. The method of claim 15, wherein the first metal gate and the second metal gate are formed of a same material having a work function between 4.25 eV and 4.4 eV. 20. The method of claim 15, wherein the first germanium fin and the second germanium fin are free from silicon.","<SOH> BACKGROUND <EOH>The speeds of metal-oxide-semiconductor (MOS) transistors are closely related to the drive currents of the MOS transistors, which drive currents are further closely related to the mobility of charges. For example, NMOS transistors have high drive currents when the electron mobility in their channel regions is high, while PMOS transistors have high drive currents when the hole mobility in their channel regions is high. Germanium is a commonly known semiconductor material. The electron mobility and hole mobility of germanium are greater (2.6 times and 4 times, respectively) than that of silicon, which is the most commonly used semiconductor material in the formation of integrated circuits. Hence, germanium is an excellent material for forming integrated circuits. An additional advantageous feature of germanium is that germanium's hole and electron motilities have a greater stress sensitivity than that of silicon. For example, FIG. 1 illustrates the hole mobility of germanium and silicon as a function of uni-axial compressive stresses. It is noted that with the increase in the compressive stress, the hole mobility of germanium increases at a faster rate than silicon, indicating that germanium-based PMOS devices have a greater potential to have high drive currents than silicon-based PMOS devices. Similarly, FIG. 2 illustrates the electron mobility of germanium and silicon as functions of uni-axial tensile stresses. It is noted that with the increase in the tensile stress, the electron mobility of germanium increases at a faster rate than that of silicon, indicating that germanium-based NMOS devices have a greater potential to have high drive currents than silicon-based NMOS devices. Germanium, however, also suffers from drawbacks. The bandgap of germanium is 0.66 eV, which is smaller than the bandgap of silicon (1.12 eV). This means that the substrate leakage currents of germanium-based MOS devices are high. In addition, the dielectric constant of germanium is 16, and is greater than the dielectric constant of silicon (11.9). Accordingly, the drain-induced barrier lowering (DIBL) of germanium-based MOS devices is also higher than that of silicon-based MOS devices.","<SOH> SUMMARY <EOH>In accordance with one aspect of the embodiment, an integrated circuit structure includes an n-type fin field effect transistor (FinFET) and a p-type FinFET. The n-type FinFET includes a first germanium fin over a substrate; a first gate dielectric on a top surface and sidewalls of the first germanium fin; and a first gate electrode on the first gate dielectric. The p-type FinFET includes a second germanium fin over the substrate; a second gate dielectric on a top surface and sidewalls of the second germanium fin; and a second gate electrode on the second gate dielectric. The first gate electrode and the second gate electrode are formed of a same material having a work function close to an intrinsic energy level of germanium. Other embodiments are also disclosed.","This application is a continuation of U.S. patent application Ser. No. 12/831,903, entitled “Germanium FinFETs with metal Gates and Stressors,” filed Jul. 7, 2010, which application claims the benefit of U.S. Provisional Application No. 61/245,547, filed on Sep. 24, 2009, and entitled “Germanium FinFETs with Metal Gates and Stressors,” which applications are hereby incorporated herein by reference. TECHNICAL FIELD This application relates generally to integrated circuit structures, and more particularly to the structures of fin field effect transistors (FinFETs) and the methods of forming the same. BACKGROUND The speeds of metal-oxide-semiconductor (MOS) transistors are closely related to the drive currents of the MOS transistors, which drive currents are further closely related to the mobility of charges. For example, NMOS transistors have high drive currents when the electron mobility in their channel regions is high, while PMOS transistors have high drive currents when the hole mobility in their channel regions is high. Germanium is a commonly known semiconductor material. The electron mobility and hole mobility of germanium are greater (2.6 times and 4 times, respectively) than that of silicon, which is the most commonly used semiconductor material in the formation of integrated circuits. Hence, germanium is an excellent material for forming integrated circuits. An additional advantageous feature of germanium is that germanium's hole and electron motilities have a greater stress sensitivity than that of silicon. For example, FIG. 1 illustrates the hole mobility of germanium and silicon as a function of uni-axial compressive stresses. It is noted that with the increase in the compressive stress, the hole mobility of germanium increases at a faster rate than silicon, indicating that germanium-based PMOS devices have a greater potential to have high drive currents than silicon-based PMOS devices. Similarly, FIG. 2 illustrates the electron mobility of germanium and silicon as functions of uni-axial tensile stresses. It is noted that with the increase in the tensile stress, the electron mobility of germanium increases at a faster rate than that of silicon, indicating that germanium-based NMOS devices have a greater potential to have high drive currents than silicon-based NMOS devices. Germanium, however, also suffers from drawbacks. The bandgap of germanium is 0.66 eV, which is smaller than the bandgap of silicon (1.12 eV). This means that the substrate leakage currents of germanium-based MOS devices are high. In addition, the dielectric constant of germanium is 16, and is greater than the dielectric constant of silicon (11.9). Accordingly, the drain-induced barrier lowering (DIBL) of germanium-based MOS devices is also higher than that of silicon-based MOS devices. SUMMARY In accordance with one aspect of the embodiment, an integrated circuit structure includes an n-type fin field effect transistor (FinFET) and a p-type FinFET. The n-type FinFET includes a first germanium fin over a substrate; a first gate dielectric on a top surface and sidewalls of the first germanium fin; and a first gate electrode on the first gate dielectric. The p-type FinFET includes a second germanium fin over the substrate; a second gate dielectric on a top surface and sidewalls of the second germanium fin; and a second gate electrode on the second gate dielectric. The first gate electrode and the second gate electrode are formed of a same material having a work function close to an intrinsic energy level of germanium. Other embodiments are also disclosed. BRIEF DESCRIPTION OF THE DRAWINGS For a more complete understanding of the embodiments, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which: FIG. 1 illustrates the hole mobilities of germanium and silicon as functions of uni- axial compressive stresses; FIG. 2 illustrates the electron mobilities of germanium and silicon as functions of uni-axial tensile stresses; FIGS. 3 through 9 are perspective views and cross-sectional views of intermediate stages in the manufacturing of germanium-based FinFETs in accordance with an embodiment; FIGS. 10-12 are perspective views and a cross-sectional view of multiple-fin FinFETs; and FIG. 13 illustrates the energy bands of germanium. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS The making and using of the embodiments of the disclosure are discussed in detail below. It should be appreciated, however, that the embodiments provide many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed are merely illustrative of specific ways to make and use the embodiments, and do not limit the scope of the disclosure. A novel fin field-effect transistor (FinFET) embodiment and the method of forming the same are presented. The intermediate stages of manufacturing the embodiment are illustrated. The variations of the embodiment are discussed. Throughout the various views and illustrative embodiments, like reference numbers are used to designate like elements. Referring to FIG. 3, an integrated circuit structure is formed. The integrated circuit structure includes substrate 20, which may be a silicon substrate, a germanium substrate, or a substrate formed of other semiconductor materials. Substrate 20 may be doped with a p-type or an n-type impurity. Isolation regions such as shallow trench isolation (STI) regions 22 may be formed in or over substrate 20. Germanium fins 124 and 224 are formed above the top surfaces of STI regions 22. In an exemplary embodiment, germanium fins 124 and 224 are formed by recessing top portions of substrate 20 between neighboring STI regions 22 to form recesses, and re-growing germanium in the recesses. Top portions of STI regions 22 may then be removed, while bottom portions of STI regions 22 are not removed, so that the top portion of the re-grown germanium between neighboring STI regions 22 becomes germanium fins. Germanium fins 124 and 224 may have a germanium atomic percentage greater than about 50 percent, for example. In an embodiment, fins 124 and 224 are formed of pure germanium. In alternative embodiments, fins 124 and 224 are formed of silicon germanium. Germanium fins 124 and 224 may have channel dopings. Germanium fin 124 may be doped with a p-type impurity such as boron, while germanium fin 224 may be doped with an n-type impurity such as phosphorous. The channel doping of germanium fins 124 and 224 may be lower than about 5E17/cm3, or as low as about 1E17/cm3. In an exemplary embodiment, the aspect ratios of germanium fins 124 and 224 (the ratio of heights H to widths W), may be greater than about 1, or even greater than about 5. Substrate 20 includes a portion in NMOS device region 100 and a portion in PMOS device region 200. Germanium fins 124 and 224 are in NMOS device region 100 and PMOS device region 200, respectively. Referring to FIG. 4, gate dielectric layer 32 and gate electrode layer 34 are deposited in both NMOS device region 100 and PMOS device region 200 and over germanium fins 124 and 224. In an embodiment, gate dielectric layer 32 is formed of a high-k dielectric material. The exemplary high-k materials may have k values greater than about 4.0, or even greater than about 7.0, and may include aluminum-containing dielectrics such as Al2O3, HfAlO, HfAlON, AlZrO, Hf-containing materials such as HfO2, HfSiOx, HfAlOx, HfZrSiOx, HfSiON, and/or other materials such as LaAlO3 and ZrO2. Gate electrode layer 34 is formed on gate dielectric layer 32, and may comprise metal. Gate electrode layer 34 may have a work function close to an intrinsic level (a middle level, which is about 4.33 eV) of the conduction band of germanium (4 eV) and the valance band of germanium (4.66 eV). In an embodiment, the work function of gate electrode layer 34 is between about 4.15 eV and about 4.5 eV, or even between about 4.25 eV and about 4.4 eV. Exemplary materials of gate electrode layer 34 include TixNy, TaxNy, Al, TaxCy, Pt, multi-layers thereof, and combinations thereof, with x and y being positive values. Gate electrode layer 34 and gate dielectric layer 32 are then patterned to form gate stacks, as is shown in FIG. 5. The gate stack in NMOS device region 100 includes gate electrode 134 and gate dielectric 132. The gate stack in PMOS device region 200 includes gate electrode 234 and gate dielectric 232. Each of germanium fins 124 and 224 thus has portions that are uncovered by the gate stacks. Referring to FIG. 6, gate spacers 136 and 236 may be formed. The exposed portions of germanium fins 124 and 224 not covered by gate dielectrics 132 and 232, gate electrodes 134 and 234, and gate spacers 136 and 236 are then removed (recessed), while the covered portion of germanium fins 124 and 224 are not removed. The removal may be performed by a dry etch. The spaces left by the removed portions of fins 124 and 224 are referred to as recesses 140 and 240, respectively, hereinafter. Recesses 140 and 240 may have bottoms level with top surfaces 35 of STI regions 22. Alternatively, the bottoms of recesses 140 and 240 may be lower than top surfaces 35 of STI regions 22, as illustrated in FIGS. 6. FIG. 7 (and subsequent FIGS. 8 and 9) illustrates a cross-sectional view of the structure shown in FIG. 6, wherein the cross-sectional view of NMOS device region 100 is obtained in a vertical plane crossing line 7-7 in FIG. 6, while the cross-sectional view of PMOS device region 200 is obtained in a vertical plane crossing line 7′-7′ in FIG. 6. It is noted that although FIG. 7 and subsequent FIGS. 8 and 9 illustrate that the cross-sectional views of NMOS device region 100 and PMOS devices 200 are in a same plane, they may actually be in different planes. Next, as shown in FIG. 8, PMOS region 200 is covered, for example, by photo resist 241, and source and drain (referred to as source/drain hereinafter) regions 142 are epitaxially grown in recesses 140 by selective epitaxial growth (SEG). Source/drain regions 142 are also alternatively referred to as source/drain stressors 142, and may have a lattice constant smaller than the lattice constant of germanium fin 124. In an exemplary embodiment, source/drain regions 142 comprise SiGe, and are formed using plasma enhanced chemical vapor deposition (PECVD), or other commonly used methods. The precursors may include Si-containing gases such as SiH4 and Ge-containing gases such as GeH4, and the partial pressures of the Si-containing gases and Ge-containing gases are adjusted to modify the atomic ratio of germanium to silicon. In an embodiment, the resulting source/drain regions 142 include between about 20 and about 60 atomic percent silicon. In alternative embodiments, source/drain region 142 may be formed of silicon carbon (SiC) or silicon with no carbon and/or germanium added. N-type impurities, such as phosphorous and/or arsenic, may be in-situ doped when the epitaxial growth proceeds. With the lattice constant of source/drain region 142 being smaller than that of germanium fin 124, source/drain regions 142 apply a tensile stress to germanium fin 124, which forms the channel region of the resulting n-type FinFET 150. After the epitaxial growth of source/drain regions 142, photo resistor 241 is removed. Referring to FIG. 9, NMOS device region 100 is covered, for example, by photo resist 141. Source/drains regions 242, which may also be referred to as a source/drain stressors 242, are epitaxially grown in recesses 240. Source/drain regions 242 may have a lattice constant greater than the lattice constant of germanium fin 224. Again, source/drain regions 242 may be formed using PECVD. In an embodiment, source/drain regions 242 comprise GeSn. In alternative embodiments, source/drain region 242 may be formed of compound semiconductor materials comprising group III and group V materials (referred to as III-V semiconductor materials hereinafter), such as InGaAs, InP, GaSb, InAs, AlSb, InSb, and the like. With the lattice constant of source/drain region 242 being greater than that of germanium fin 224, source/drain regions 242 apply a compressive stress to germanium fin 224, which forms the channel region of the resulting PMOS FinFET 250. After the epitaxial growth of source/drain regions 242, photo resistor 141 is removed. During the epitaxial process for forming source/drain regions 142 and 242, n-type impurities (such as phosphorous) and p-type impurities (such as boron), respectively, may be doped with the proceeding epitaxial processes. The impurity concentration may be between about 5×1020/cm3 and about 1×1021/cm3. In alternative embodiments, no p-type and n-type impurities are doped, while the doping of source/drain regions 142 and 242 are performed in implantation steps after the formation of source/drain regions 142 and 242. Next, silicide/germanide regions (not shown) may be formed on source/drain regions 142 and 242 by reacting source/drain regions 142 and 242 with a metal(s) to reduce the contact resistances. The formation details of silicide/germanide regions are known in the art, and hence are not repeated herein. Through the above-discussed process steps, n-type FinFET 150 and PMOS FinFET 250 are formed. In the above-discussed embodiments, single-fin FinFETs were discussed. Alternatively, the concept of the disclosure may be applied to multi-fin FinFETs. FIGS. 10 through 12 illustrate a cross-sectional view and perspective views of multi-fin FinFETs. Unless specified otherwise, like reference numerals are used to represent like elements. The materials of the elements shown in FIGS. 10-12 are thus not repeated herein. FIG. 10 illustrates a cross sectional view of an integrated circuit including n-type FinFET 150, PMOS FinFET 250, and dummy fin structures 350, including dummy fins 324, which are formed on substrate 320. Substrate 320 may be a germanium substrate or a silicon substrate. N-type FinFET 150 is formed on a p-well, and includes multiple germanium fins 124. Gate electrode 134 is formed over multiple germanium fins 124, so that multiple germanium fins 124 become the fins of a single n-type FinFET 150. Gate dielectrics 132 are formed between germanium fins 124 and gate electrode 134. Similarly, PMOS FinFET 250 is formed on an n-well, and includes multiple germanium fins 224. Gate electrode 234 is formed over multiple germanium fins 224, so that multiple germanium fins 224 become the fins of a single PMOS FinFET 250. Gate dielectrics 232 are formed between germanium fins 124 and gate electrode 134. In addition, dummy fins, which are not used in any FinFETs, are also formed to reduce the pattern-loading effect in the formation of germanium fins 124 and 224. With multiple fins used in a single FinFET, the drive current of the FinFET can be further increased. Since there is a lattice mismatch between germanium and silicon, it is easier achieve a high quality (with lower defect density) for a germanium epitaxy layer grown from a fin with a smaller fin width than from a fin with a greater fin width. FIGS. 11 and 12 illustrate perspective views of multiple FinFETs. The like elements in FIG. 11 can be found in FIG. 10. The FinFET may either be n-type FinFET 150 or PMOS FinFET 250, and hence is denoted as 150/250. In FIG. 11, source/drain regions (stressors) 142/242 are grown from germanium fins 124/224, and are discrete regions. In FIG. 12, source/drain regions (stressors) 142/242 grown from germanium fins 124/224 merge with each other. FIG. 13 illustrates the energy bands of germanium. It is noted that germanium has a conduction band Ec equal to 4 eV, a valence band Ev equal to 4.66 eV, and an intrinsic level Ei (which is (Ec+Ev)/2) equal to 4.33 eV. Therefore, the intrinsic level Ei and the conduction band Ec have an energy difference equal to about 330 mV, and the intrinsic level Ei and the valence band Ev have an energy difference equal to about 330 mV. The 330 mV energy difference may be utilized to simplify the formation of metal gates for n-type germanium FinFETs and p-type germanium FinFETs. Since in germanium FinFETs, the fully depleted channel results in the reduction in threshold voltages Vt, band-edge work functions are no longer needed. Instead, near-mid-bandgap work functions are needed to shift the threshold voltages Vt to target values accurately. Accordingly, for germanium-based FinFETs, with the work functions of metal gates of both n-type germanium FinFETs and p-type germanium FinFETs being close to the intrinsic level of about 4.33 eV, the requirements for optimizing the work functions of n-type FinFETs and p-type FinFETs can both be satisfied, even when a same metallic material is used forming the gates of n-type FinFETs and p-type FinFETs. In addition to the above-discussed advantageous features, the embodiments of the disclosure have several other advantageous features. By forming germanium-based FinFETs, the drive currents of n-type FinFETs and p-type FinFETs can be improved due to the high electron and hole mobilities of germanium. The leakage currents may also be reduced due to the reduced junction areas of FinFETs compared to planar MOS devices. Although the embodiments and their advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the embodiments as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, and composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed, that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the disclosure. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps. In addition, each claim constitutes a separate embodiment, and the combination of various claims and embodiments are within the scope of the disclosure.",H01L218256,H01L218256,20160125,20170704,20160602,57821.0
4,14905065,ACCEPTED,MILK FAT GLOBULE EPIDERMAL GROWTH FACTOR 8 REGULATES FATTY ACID UPTAKE,"Methods and compositions for regulating fatty acid uptake and/or decreasing gastric motility in an animal are provided. The method comprises administering an antagonist of integrin αvβ3 or αvβ5 to an animal in an amount sufficient to reduce fatty acid uptake in the animal, thereby reducing fatty acid uptake in the animal. In some embodiments, the antagonist is an antibody. Also provided is a method of increasing fatty acid uptake and/or gastric motility in an animal.","1. A method of reducing fatty acid uptake in an animal, the method comprising, administering an antagonist of integrin αvβ3 or αvβ5 to an animal in an amount sufficient to reduce fatty acid uptake in the animal, thereby reducing fatty acid uptake in the animal. 2. The method of claim 1, wherein the animal is a human. 3. The method of claim 1, wherein the antagonist is an antibody. 4. The method of claim 3, wherein the antibody specifically binds to αvβ3. 5. The method of claim 3, wherein the antibody specifically binds to αvβ5. 6. The method of claim 3, wherein the antibody is a humanized or chimeric antibody. 7. The method of claim 1, wherein the antibody binds the same epitope as ALULA (the antibody produced by the hybridoma deposited under ATCC Deposit No. PTA-5817). 8. The method of claim 1, wherein the animal is obese. 9. The method of claim 1, wherein the antagonist is administered intravenously, subcutaneously, intramuscularly, rectally, or orally. 10. A method of increasing fatty acid uptake and/or decreasing gastric motility in an animal, the method comprising, administering a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8, to an animal in an amount sufficient to increase fatty acid uptake and/or to decrease gastric motility in the animal. 11. The method of claim 10, wherein the Mfge8 is human Mfge8 (SEQ ID NO:1) or is at least 80% identical to (i) SEQ ID NO:1 or (ii) an integrin-binding portion of SEQ ID NO:1. 12. The method of claim 10, wherein the animal is human. 13. The method of claim 10, wherein the animal is under two or one years or under six, five, four, three, two, or one months old. 14. The method of claim 10, wherein the animal is a premature human infant. 15. The method of claim 10, wherein the animal is diabetic or has cystic fibrosis. 16. The method of claim 10, wherein the polypeptide is administered intravenously, subcutaneously, intramuscularly, rectally, or orally. 17. (canceled) 18. (canceled) 19. A composition comprising a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8. 20. (canceled) 21. The composition of claim 19, wherein the composition is selected from the group consisting of a powder, a tablet, a capsule, a lozenge, a chewing gum, a food product, a supplemented beverage, or a medical food. 22. The composition of claim 19, further comprising a bovine milk protein, a soy protein, betalactoglobulin, whey, soybean oil or starch. 23. (canceled) 24. The method of claim 3, wherein the antibody is a humanized version of the ALULA antibody.","<SOH> BACKGROUND OF THE INVENTION <EOH>Obesity is a central feature of the metabolic syndrome, which leads to significant morbidity and mortality by increasing the risk of diabetes and cardiovascular disease. The absorption of dietary triglycerides with subsequent storage in adipose tissue is a key step in the development of obesity (Berk, P. D., et al., J Biol Chem 274, 28626-28631 (1999); Berk, P. D., et al., J Biol Chem 272, 8830-8835 (1997)). Under physiological conditions, cellular uptake of fatty acids occurs primarily through protein-mediated pathways consisting of a number of fatty acid transporters expressed in tissue-specific patterns (Stump, D. D., Fan, X. & Berk, P. D., J Lipid Res 42, 509-520 (2001); Anderson, C. M. & Stahl, A., Mol Aspects Med 34, 516-528 (2013)). Translocation of these transporters from the cytosol to the cell membrane is the major mechanism through which the rate of fatty acid uptake can be acutely regulated in response to dietary and metabolic cues (Stahl, A. et al., Developmental cell 2, 477-488 (2002); Luiken, J. J., et al., Am J Physiol Endocrinol Metab 282, E491-495 (2002); Luiken, J. J., et al., Diabetes 52, 1627-1634 (2003)). Fatty acid transporter translocation is regulated systemically by hormones and locally by muscle contraction (Stahl, A. et al., Developmental cell 2, 477-488 (2002); Luiken, J. J., et al., Am J Physiol Endocrinol Metab 282, E491-495 (2002); Luiken, J. J., et al., Diabetes 52, 1627-1634 (2003)). Mfge8 is an integrin ligand (Hanayama, R., et al., Nature 417, 182-187 (2002)) that is highly expressed in the adipose tissue of mice on a high-fat diet (HFD) (Aoki, N. et al., Endocrinology 148, 3850-3862 (2007)). Both the expression of Mfge8 and the integrin receptors for Mfge8 are increased in the adipose tissue of obese humans (Henegar, C. et al., Genome Biol 9, R14 (2008)).","<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>Methods of reducing fatty acid uptake in an animal are provided. In some embodiments, the method comprises administering an antagonist of integrin αvβ3 or αvβ5 to an animal in an amount sufficient to reduce fatty acid uptake in the animal, thereby reducing fatty acid uptake in the animal. In some embodiments, the animal is a human. In some embodiments, the antagonist is an antibody In some embodiments, the antibody specifically binds to αvβ3. In some embodiments, the antibody specifically binds to αvβ5 In some embodiments, the antibody is a humanized or chimeric antibody. In some embodiments, the antibody binds the same epitope as ALULA (the antibody produced by the hybridoma deposited under ATCC Deposit No. PTA-5817). In some embodiments, the animal is obese. In some embodiments, the animal has reduced insulin sensitivity. In some embodiments, the animal is insulin resistant. In some embodiments, the antagonist is administered intravenously, intraperitoneally, subcutaneously, intramuscularly, rectally, or orally. Also provides is a method of increasing fatty acid uptake and/or gastric motility in an animal. In some embodiments, the method comprises administering a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8, to an animal in an amount sufficient to increase fatty acid uptake and/or to gastric motility in the animal. In some embodiments, the Mfge8 is human Mfge 8 (SEQ ID NO:1) or is at least 80% identical to (i) SEQ ID NO:1 or (ii) an integrin-binding portion of SEQ ID NO:1. In some embodiments, the animal is human. In some embodiments, the animal (e.g., human) is under two or one years or under six, five, four, three, two, or one months old. In some embodiments, the animal is a premature human infant. In some embodiments, the animal is diabetic or has cystic fibrosis. In some embodiments, the polypeptide is administered intravenously, intraperitoneally, subcutaneously, intramuscularly, rectally, or orally. In some embodiments, the polypeptide is administered as a component of a composition selected from the group consisting of a powder, a tablet, a capsule, a lozenge, a chewing gum, a food product, a supplemented beverage, or a medical food. In some embodiments, the food product is infant formula. Also provided is a composition comprising a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8. In some embodiments, the Mfge8 is human Mfge 8 (SEQ ID NO:1) or is at least 80% identical to (i) SEQ ID NO:1 or (ii) an integrin-binding portion of SEQ ID NO:1. In some embodiments, the composition is selected from the group consisting of a powder, a tablet, a capsule, a lozenge, a chewing gum, a food product, a supplemented beverage, or a medical food. In some embodiments, the composition further comprises a bovine milk protein, a soy protein, betalactoglobulin, whey, soybean oil or starch. In some embodiments, said supplemented beverage is a member selected from the group consisting of an infant formula, follow-on formula, toddler's beverage, milk, fruit juice, and fruit-based drink.","CROSS REFERENCE TO RELATED APPLICATIONS The present application claims priority to U.S. Provisional Application No. 61/856,475, filed Jul. 19, 2013 and U.S. Provisional Application No. 61/873,134, filed Sep. 3, 2013, the disclosures of which are herein incorporated by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION Obesity is a central feature of the metabolic syndrome, which leads to significant morbidity and mortality by increasing the risk of diabetes and cardiovascular disease. The absorption of dietary triglycerides with subsequent storage in adipose tissue is a key step in the development of obesity (Berk, P. D., et al., J Biol Chem 274, 28626-28631 (1999); Berk, P. D., et al., J Biol Chem 272, 8830-8835 (1997)). Under physiological conditions, cellular uptake of fatty acids occurs primarily through protein-mediated pathways consisting of a number of fatty acid transporters expressed in tissue-specific patterns (Stump, D. D., Fan, X. & Berk, P. D., J Lipid Res 42, 509-520 (2001); Anderson, C. M. & Stahl, A., Mol Aspects Med 34, 516-528 (2013)). Translocation of these transporters from the cytosol to the cell membrane is the major mechanism through which the rate of fatty acid uptake can be acutely regulated in response to dietary and metabolic cues (Stahl, A. et al., Developmental cell 2, 477-488 (2002); Luiken, J. J., et al., Am J Physiol Endocrinol Metab 282, E491-495 (2002); Luiken, J. J., et al., Diabetes 52, 1627-1634 (2003)). Fatty acid transporter translocation is regulated systemically by hormones and locally by muscle contraction (Stahl, A. et al., Developmental cell 2, 477-488 (2002); Luiken, J. J., et al., Am J Physiol Endocrinol Metab 282, E491-495 (2002); Luiken, J. J., et al., Diabetes 52, 1627-1634 (2003)). Mfge8 is an integrin ligand (Hanayama, R., et al., Nature 417, 182-187 (2002)) that is highly expressed in the adipose tissue of mice on a high-fat diet (HFD) (Aoki, N. et al., Endocrinology 148, 3850-3862 (2007)). Both the expression of Mfge8 and the integrin receptors for Mfge8 are increased in the adipose tissue of obese humans (Henegar, C. et al., Genome Biol 9, R14 (2008)). DEFINITIONS An integrin “antagonist” is any agent that competes with an endogenous integrin ligand for available ligand binding sites on an integrin. A “therapeutic dose,” “therapeutic amount,” “therapeutically effective amount,” or “effective amount” of a molecule antagonist is an amount of the molecule that prevents, alleviates, abates, or reduces the severity of symptoms of a disease or condition to be treated, e.g., a condition involving fatty acid uptake in a patient. As used herein, the terms “treat” and “prevent” are not intended to be absolute terms. Treatment can refer to any delay in onset, amelioration of symptoms, improvement in patient survival, reduction of tissue damage, etc. Indeed, in some embodiments, treatment according to the invention can result in reversal of the disease. Similarly, prevention can refer to any delay in onset or, depending on context, reduction in severity of symptoms. The effect of treatment can be compared to an individual or pool of individuals not receiving the treatment, or to the same patient, e.g., before treatment. The term “subject” is used broadly herein to refer to any individual that is considered for treatment. Typically, the subject is a human or some other mammal (e.g., an agricultural animal such as a cattle, pigs, sheep, horses, or goats or a pet such as a dog or a cat). The term “antibody” refers to a polypeptide encoded by an immunoglobulin gene or functional fragments thereof that specifically binds and recognizes an antigen. The recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon, and mu constant region genes, as well as the myriad immunoglobulin variable region genes. Light chains are classified as either kappa or lambda. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The terms “variable heavy chain,” “VH,” or “VH” refer to the variable region of an immunoglobulin heavy chain, including an Fv, scFv, dsFv or Fab; while the terms “variable light chain,” “VL” or “VL” refer to the variable region of an immunoglobulin light chain, including of an Fv, scFv, dsFv or Fab. Examples of antibody functional fragments include, but are not limited to, complete antibody molecules, antibody fragments, such as Fv, single chain Fv (scFv), complementarity determining regions (CDRs), VL (light chain variable region), VH (heavy chain variable region), Fab, F(ab)2′ and any combination of those or any other functional portion of an immunoglobulin peptide capable of binding to target antigen (see, e.g., FUNDAMENTAL IMMUNOLOGY (Paul ed., 4th ed. 2001). Various antibody fragments can be obtained by a variety of methods, for example, digestion of an intact antibody with an enzyme, such as pepsin; or de novo synthesis. Antibody fragments are often synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., (1990) Nature 348:552). The term “antibody” also includes bivalent or bispecific molecules, diabodies, triabodies, and tetrabodies. Bivalent and bispecific molecules are described in, e.g., Kostelny et al. (1992) J. Immunol. 148:1547, Pack and Pluckthun (1992) Biochemistry 31:1579, Hollinger et al. (1993), PNAS. USA 90:6444, Gruber et al. (1994) J Immunol. 152:5368, Zhu et al. (1997) Protein Sci. 6:781, Hu et al. (1996) Cancer Res. 56:3055, Adams et al. (1993) Cancer Res. 53:4026, and McCartney, et al. (1995) Protein Eng. 8:301. “Single chain Fv (scFv)” or “single chain antibodies” refers to a protein wherein the VH and the VL regions of a scFv antibody comprise a single chain which is folded to create an antigen binding site similar to that found in two chain antibodies. Methods of making scFv antibodies have been described in e.g., Ward et al., Exp Hematol. (5):660-4 (1993); and Vaughan et al., Nat Biotechnol. 14(3):309-14 (1996). Single chain Fv (scFv) antibodies optionally include a peptide linker of no more than 50 amino acids, generally no more than 40 amino acids, preferably no more than 30 amino acids, and more preferably no more than 20 amino acids in length. In some embodiments, the peptide linker is a concatamer of the sequence Gly-Gly-Gly-Gly-Ser, e.g., 2, 3, 4, 5, or 6 such sequences. However, it is to be appreciated that some amino acid substitutions within the linker can be made. For example, a valine can be substituted for a glycine. Additional peptide linkers and their use are well-known in the art. See, e.g., Huston et al., Proc. Nat'l Acad. Sci. USA 8:5879 (1988); Bird et al., Science 242:4236 (1988); Glockshuber et al., Biochemistry 29:1362 (1990); U.S. Pat. No. 4,946,778, U.S. Pat. No. 5,132,405 and Stemmer et al., Biotechniques 14:256-265 (1993). As used herein, “chimeric antibody” refers to an immunoglobulin molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g., an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region, or portion thereof, having a different or altered antigen specificity; or with corresponding sequences from another species or from another antibody class or subclass. As used herein, “humanized antibody” refers to an immunoglobulin molecule in which CDRs from a donor antibody are grafted onto human framework sequences. Humanized antibodies may also comprise residues of donor origin in the framework sequences. The humanized antibody can also comprise at least a portion of a human immunoglobulin constant region. Humanized antibodies may also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. Humanization can be performed using methods known in the art (e.g., Jones et al., Nature 321:522-525; 1986; Riechmann et al., Nature 332:323-327, 1988; Verhoeyen et al., Science 239:1534-1536, 1988); Presta, Curr. Op. Struct. Biol. 2:593-596, 1992; U.S. Pat. No. 4,816,567), including techniques such as “superhumanizing” antibodies (Tan et al., J. Immunol. 169: 1119, 2002) and “resurfacing” (e.g., Staelens et al., Mol. Immunol. 43: 1243, 2006; and Roguska et al., Proc. Natl. Acad. Sci USA 91: 969, 1994). As used herein, “V-region” refers to an antibody variable region domain comprising the segments of Framework 1 (F1), Complementarity Determining Region 1 (CDR1), F2, CDR2, and F3, including CDR3 and F4, which segments are added to the V-segment as a consequence of rearrangement of the heavy chain and light chain V-region genes during B-cell differentiation. A “V-segment” as used herein refers to the region of the V-region (heavy or light chain) that is encoded by a V gene. The V-segment of the heavy chain variable region encodes FR1-CDR1-FR2-CDR2 and FR3. For the purposes of this invention, the V-segment of the light chain variable region is defined as extending though FR3 up to CDR3. As used herein, the term “J-segment” refers to a subsequence of the variable region encoded comprising a C-terminal portion of a CDR3 and the FR4. An endogenous J-segment is encoded by an immunoglobulin J-gene. As used herein, “complementarity-determining region (CDR)” refers to one of the three hypervariable regions in each chain that interrupt the four “framework” regions established by the light and heavy chain variable regions. The CDRs are primarily responsible for binding to an epitope of an antigen. The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also typically identified by the chain in which the particular CDR is located. Thus, for example, a VH CDR3 is located in the variable domain of the heavy chain of the antibody in which it is found, whereas a VL CDR1 is the CDR1 from the variable domain of the light chain of the antibody in which it is found. The sequences of the framework regions of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three dimensional space. Thus, the position of the CDRs within the V region is relatively conserved between antibodies. The amino acid sequences and positions of the CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (IMGT), and AbM (see, e.g., Johnson et al., supra; Chothia & Lesk, 1987, Canonical structures for the hypervariable regions of immunoglobulins. J. Mol. Biol. 196, 901-917; Chothia C. et al., 1989, Conformations of immunoglobulin hypervariable regions. Nature 342, 877-883; Chothia C. et al., 1992, structural repertoire of the human VH segments J. Mol. Biol. 227, 799-817; Al-Lazikani et al., J. Mol. Biol 1997, 273(4)). Definitions of antigen combining sites are also described in the following: Ruiz et al., IMGT, the international ImMunoGeneTics database. Nucleic Acids Res., 28, 219-221 (2000); and Lefranc, M.-P. IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. January 1; 29(1):207-9 (2001); MacCallum et al, Antibody-antigen interactions: Contact analysis and binding site topography, J. Mol. Biol., 262 (5), 732-745 (1996); and Martin et al, Proc. Natl Acad. Sci. USA, 86, 9268-9272 (1989); Martin, et al, Methods Enzymol., 203, 121-153, (1991); Pedersen et al, Immunomethods, 1, 126, (1992); and Rees et al, In Sternberg M. J. E. (ed.), Protein Structure Prediction. Oxford University Press, Oxford, 141-172 1996). The phrase “specifically (or significantly or selectively) binds to” when referring to a given protein or peptide, refers to a binding reaction which is determinative of the presence of the protein in the presence of a heterogeneous population of proteins and other biologics. Thus, under designated immunoassay conditions, the specified antibodies or other antagonists bind to a particular protein (e.g., for an αvβ5-specific antibody, an αvβ5 integrin, β5, or portions thereof, or for an αvβ3-specific antibody, an χ, β3, or portions thereof) and do not bind in a significant amount to other proteins present in the sample. Specific binding to an antibody under such conditions may require an antibody that is selected for its specificity for a particular protein. For example, antibodies raised against an αvβ5 integrins or a β5 polypeptide can be further selected to obtain antibodies specifically immunoreactive with that protein and not with other proteins. In some embodiments, the specific antibody will also bind to polymorphic variants of the protein, e.g., proteins at least 80%, 85%, 90%, 95% or 99% identical to a sequence of interest. Generally, an αvβ5-specific antibody or an αvβ3-specific antibody binds to the β component of the integrin as αv has a number of different binding partners. However, as shown in the Example, an antibody specific for αv is effective in blocking fat uptake because the antibody targets both αvβ3 and αvβ5. “Specific” or “significant” binding are not intended to be absolute terms. For example, if an antibody does not significantly bind to a particular epitope, it binds with at least 5-fold, 8-fold, 10-fold, 20-fold, 50-fold, 80-fold, or 100-fold reduced affinity as compared to the epitope against which the antibody was raised. Binding affinity can be determined using techniques known in the art, e.g., ELISAs. Affinity can be expressed as dissociation constant (Kd or KD). A relatively higher Kd indicates lower affinity. Thus, for example, the Kd of an αvβ5-specific antibody for αvβ5 will typically be lower by a factor of at least 5, 8, 10, 15, 20, 50, 100, 500, 1000, or more than the Kd of the αvβ5-specific antibody with another protein. One of skill will understand how to design controls to indicate non-specific binding and compare relative binding levels. A variety of immunoassay formats may be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays, Western blots, or immunohistochemistry are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. See, Harlow and Lane Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, NY (1988) for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity. Typically, a specific or selective reaction will be at least twice the background signal or noise and more typically more than 10 to 100 times background. An agent that “specifically competes” for binding reduces the specific binding of an antibody to a polypeptide. A first antibody is considered to competitively inhibit binding of a second antibody, if binding of the second antibody to the antigen is reduced by at least 30%, usually at least about 40%, 50%, 60%, 75%, or at least about 90%, in the presence of the first antibody using any of the competitive binding assays known in the art (see, e.g., Harlow and Lane, supra). The term “equilibrium dissociation constant” or “affinity” abbreviated (Kd or KD), refers to the dissociation rate constant (kd, time−1) divided by the association rate constant (ka, time−1 M−1). Equilibrium dissociation constants can be measured using any known method in the art. Antibodies with high affinity have a monovalent affinity less than about 10 nM, and often less than about 500 pM or about 50 pM as determined by surface plasmon resonance analysis performed at 37° C. In some embodiments, the antibodies of the invention have an affinity (as measured using surface plasmon resonance), of less than 500 pM, typically less than about 100 pM, or even less than 25 pM. The terms “polypeptide,” “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues. The terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers. As used herein, the terms encompass amino acid chains of any length, including full length proteins (i.e., antigens), wherein the amino acid residues are linked by covalent peptide bonds. For example, the Mfge8 polypeptides described herein can contain one of more non-naturally-occurring amino acid. The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an α carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. “Amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes. The terms “peptidomimetic” and “mimetic” refer to a synthetic chemical compound that has substantially the same structural and functional characteristics of Mfge8 polypeptides or αvβ5 and/or αvβ5 antagonists. Peptide analogs are commonly used in the pharmaceutical industry as non-peptide drugs with properties analogous to those of the template peptide. These types of non-peptide compound are termed “peptide mimetics” or “peptidomimetics” (see, e.g., Fauchere, J. Adv. Drug Res. 15:29 (1986); Veber and Freidinger TINS p. 392 (1985); and Evans et al. J. Med. Chem. 30:1229 (1987)). Peptide mimetics that are structurally similar to therapeutically useful peptides may be used to produce an equivalent or enhanced therapeutic or prophylactic effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a biological or pharmacological activity), such as a naturally occurring αvβ5 ligand, but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of, e.g., —CH2NH—, —CH2S—, —CH2-CH2-, —CH═CH— (cis and trans), —COCH2-, —CH(OH)CH2-, and —CH2SO—. The mimetic can be either entirely composed of synthetic, non-natural analogues of amino acids, or, is a chimeric molecule of partly natural peptide amino acids and partly non-natural analogs of amino acids. The mimetic can also incorporate any amount of natural amino acid conservative substitutions as long as such substitutions also do not substantially alter the mimetic's structure and/or activity. As used herein, the terms “nucleic acid” and “polynucleotide” are used interchangeably. Use of the term “polynucleotide” includes oligonucleotides (i.e., short polynucleotides). This term also refers to deoxyribonucleotides, ribonucleotides, and naturally occurring variants, and can also refer to synthetic and/or non-naturally occurring nucleic acids (i.e., comprising nucleic acid analogues or modified backbone residues or linkages), such as, for example and without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, peptide-nucleic acids (PNAs), and the like. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions) and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and/or deoxyinosine residues (see, e.g., Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Cassol et al. (1992); Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). “Conservatively modified variants” applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode any given protein. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine Thus, at every position where an alanine is specified by a codon, the codon can be altered to any of the corresponding codons described without altering the encoded polypeptide. Such nucleic acid variations are “silent variations,” which are one species of conservatively modified variations. Every nucleic acid sequence herein which encodes a polypeptide also describes every possible silent variation of the nucleic acid. One of skill will recognize that each codon in a nucleic acid (except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan) can be modified to yield a functionally identical molecule. Accordingly, each silent variation of a nucleic acid that encodes a polypeptide is implicit in each described sequence. As to amino acid sequences, one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention. The following eight groups each contain amino acids that are conservative substitutions for one another: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (I), Leucine (L), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)). “Percentage of sequence identity” is determined by comparing two optimally aligned sequences over a comparison window, wherein the portion of the polynucleotide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (e.g., a polypeptide of the invention), which does not comprise additions or deletions, for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. The terms “identical” or percent “identity,” in the context of two or more nucleic acids or polypeptide sequences, refer to two or more sequences or subsequences that are the same sequences. Two sequences are “substantially identical” if two sequences have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 60% identity, optionally 65%, 70%, 75%, 80%, 85%, 90%, or 95% identity over a specified region, or, when not specified, over the entire sequence), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection. The invention provides polypeptides that are substantially identical to the polypeptides exemplified herein (e.g., any of SEQ ID NO: 1, 2, 3, 4, 5, or 6). Optionally, the identity exists over a region that is at least about 50 nucleotides in length, or more preferably over a region that is 100 to 500 or 1000 or more nucleotides in length, or the entire length of the reference sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are entered into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Default program parameters can be used, or alternative parameters can be designated. The sequence comparison algorithm then calculates the percent sequence identities for the test sequences relative to the reference sequence, based on the program parameters. A “comparison window”, as used herein, includes reference to a segment of any one of the number of contiguous positions selected from the group consisting of from 20 to 600, usually about 50 to about 200, more usually about 100 to about 150 in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. Methods of alignment of sequences for comparison are well known in the art. Optimal alignment of sequences for comparison can be conducted, e.g., by the local homology algorithm of Smith and Waterman (1970) Adv. Appl. Math. 2:482c, by the homology alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity method of Pearson and Lipman (1988) Proc. Nat'l. Acad. Sci. USA 85:2444, by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), or by manual alignment and visual inspection (see, e.g., Ausubel et al., Current Protocols in Molecular Biology (1995 supplement)). Two examples of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nuc. Acids Res. 25:3389-3402, and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence, which either match or satisfy some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al., supra). These initial neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits are extended in both directions along each sequence for as far as the cumulative alignment score can be increased. Cumulative scores are calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T, and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a wordlength (W) of 11, an expectation (E) or 10, M=5, N=−4 and a comparison of both strands. For amino acid sequences, the BLASTP program uses as defaults a wordlength of 3, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89:10915) alignments (B) of 50, expectation (E) of 10, M=5, N=−4, and a comparison of both strands. The BLAST algorithm also performs a statistical analysis of the similarity between two sequences (see, e.g., Karlin and Altschul (1993) Proc. Natl. Acad. Sci. USA 90:5873-5787). One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P(N)), which provides an indication of the probability by which a match between two nucleotide or amino acid sequences would occur by chance. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in a comparison of the test nucleic acid to the reference nucleic acid is less than about 0.2, more preferably less than about 0.01, and most preferably less than about 0.001. BRIEF SUMMARY OF THE INVENTION Methods of reducing fatty acid uptake in an animal are provided. In some embodiments, the method comprises administering an antagonist of integrin αvβ3 or αvβ5 to an animal in an amount sufficient to reduce fatty acid uptake in the animal, thereby reducing fatty acid uptake in the animal. In some embodiments, the animal is a human. In some embodiments, the antagonist is an antibody In some embodiments, the antibody specifically binds to αvβ3. In some embodiments, the antibody specifically binds to αvβ5 In some embodiments, the antibody is a humanized or chimeric antibody. In some embodiments, the antibody binds the same epitope as ALULA (the antibody produced by the hybridoma deposited under ATCC Deposit No. PTA-5817). In some embodiments, the animal is obese. In some embodiments, the animal has reduced insulin sensitivity. In some embodiments, the animal is insulin resistant. In some embodiments, the antagonist is administered intravenously, intraperitoneally, subcutaneously, intramuscularly, rectally, or orally. Also provides is a method of increasing fatty acid uptake and/or gastric motility in an animal. In some embodiments, the method comprises administering a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8, to an animal in an amount sufficient to increase fatty acid uptake and/or to gastric motility in the animal. In some embodiments, the Mfge8 is human Mfge 8 (SEQ ID NO:1) or is at least 80% identical to (i) SEQ ID NO:1 or (ii) an integrin-binding portion of SEQ ID NO:1. In some embodiments, the animal is human. In some embodiments, the animal (e.g., human) is under two or one years or under six, five, four, three, two, or one months old. In some embodiments, the animal is a premature human infant. In some embodiments, the animal is diabetic or has cystic fibrosis. In some embodiments, the polypeptide is administered intravenously, intraperitoneally, subcutaneously, intramuscularly, rectally, or orally. In some embodiments, the polypeptide is administered as a component of a composition selected from the group consisting of a powder, a tablet, a capsule, a lozenge, a chewing gum, a food product, a supplemented beverage, or a medical food. In some embodiments, the food product is infant formula. Also provided is a composition comprising a polypeptide comprising (i) Milk Fat Globule Epidermal Growth Factor 8 (Mfge8), or (ii) an integrin-binding portion of Mfge8. In some embodiments, the Mfge8 is human Mfge 8 (SEQ ID NO:1) or is at least 80% identical to (i) SEQ ID NO:1 or (ii) an integrin-binding portion of SEQ ID NO:1. In some embodiments, the composition is selected from the group consisting of a powder, a tablet, a capsule, a lozenge, a chewing gum, a food product, a supplemented beverage, or a medical food. In some embodiments, the composition further comprises a bovine milk protein, a soy protein, betalactoglobulin, whey, soybean oil or starch. In some embodiments, said supplemented beverage is a member selected from the group consisting of an infant formula, follow-on formula, toddler's beverage, milk, fruit juice, and fruit-based drink. BRIEF DESCRIPTION OF THE DRAWINGS FIGS. 1A-1I. Mfge8 mediates fatty acid uptake in adipocytes. (A) Fatty acid uptake in undifferentiated 3T3-L1 fibroblasts and differentiated 3T3-L1 adipocytes treated with the rMfge8 or RGE construct. N=4. (B) 3T3-L1 adipocyte triglyceride content after treatment with the rMfge8 or RGE construct (10 μg/ml). N=3. (C-F) Fatty acid uptake in Mfge8−/− primary adipocytes (C, N=7-9), differentiated primary Mfge8−/− adipocyte progenitors cells (D, N=3), and 3T3-L1 adipocytes (F, N=4) after incubation with mutated Mfge8 constructs (E). (G,H) Effect of integrin blocking antibodies on fatty acid uptake in Mfge8−/− adipocytes treated with rMfge8 (G, N=3-4) and in 3T3-L1 adipocytes (H, N=5). (I) Fatty acid uptake in β5−/− and β3−/− primary adipocytes with and without the addition of integrin blocking antibodies. N=4. *P<0.01, **P<0.001, ***P<0.0001. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. FIGS. 2A-2D. Mfge8 mediates fatty acid uptake in hepatocytes and cardiac myocytes. (A) Fatty acid uptake in primary Mfge8+/+ and Mfge8−/− hepatocytes, and Mfge8−/− hepatocytes treated with rMfge8 or RGE. N=6. (B) Fatty acid uptake in primary Mfge8+/+ and Mfge8−/− cardiac myocytes and Mfge8−/− cardiac myocytes treated with rMfge8 or RGE. N=6. (C) The effect of mutated Mfge8 constructs on fatty acid uptake by HepG2 cells. N=4. (D) The effect of integrin blocking antibodies (20 μg/mL) on fatty acid uptake in HepG2 cells treated with rMfge8. *P<0.01, **P<0.001, ***P<0.0001. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. FIGS. 3A-3K. Mfge8 mediates fatty acid uptake in the intestinal tract. (A) Triglyceride content of the small intestine in mice fasted for 8 hours. N=5. (B) Fatty acid uptake in primary Mfge8+/+ and Mfge8−/− enterocytes, and Mfge8−/− enterocytes treated with rMfge8 or RGE. N=8. (C) Serum triglycerides after oral gavage of Mfge8+/+ and Mfge8−/− mice with olive oil and Mfge8−/− mice with olive oil mixed with rMfge8 or RGE construct. N=3-5, *P<0.01, ***P<0.0001 when comparing Mfge8−/− with Mfge8+/+ mice, ̂̂P <0.01, ̂P <0.05 when comparing Mfge8−/− mice with Mfge8−/− treated with rMfge8, #P<0.01 when comparing Mfge8+/+ mice with Mfge8−/− treated with rMfge8. (D) Liver triglyceride levels 8 hours after olive oil gavage as described for FIG. 3C. N=3-5. (E) Serum free fatty acid levels in Mfge8+/+ and Mfge8−/− mice after olive oil gavage, N=4-5. (F) Effect of rMfge8 or RGE construct on serum triglycerides after olive oil gavage in Mfge8+/+ mice. N=4-5. (G) Fecal fatty acid levels in Mfge8+/+ and Mfge8−/− mice after gavage with BODIPY fatty acid analog. N=4-5. (H) Serum free fatty acid levels in Mfge8+/+ and Mfge8−/− mice after a 24 hour fast, N=4-5. (I-K) Effect of oral administration of integrin blocking antibodies prior to olive oil gavage on serum triglycerides levels (G, *P<0.01, **P<0.001, ***P <0.0001, when comparing αv antibody with control antibody, #P<0.01 when comparing 135 antibody with control antibody), and on small intestine (FIG. 3H) and liver triglyceride content (FIG. 3I) in Mfge8+/+ mice. N=4-5 for panels, I-K. #P<0.05, *P<0.01, **P <0.001, ***P<0.0001 where not previously specified. Data are expressed as mean±s.e.m. Each in vivo experiment was performed once. For in vitro experiments in panel B, each replicate represents an independent experiment. FIGS. 4A-4F. Mfge8 increases fatty acid uptake through an integrin-PI3K-AKT-dependent pathway. (A) Effect of rMfge8 (10 μg/mL) or insulin (10 μg/mL) with and without wortmannin (100 nM) on AKT phosphorylation. (B) Effect of wortmannin on fatty acid uptake in primary Mfge8+/+ and Mfge8−/− adipocytes and on Mfge8−/− adipocytes treated with rMfge8. N=7. *P<0.05, ***P<0.001. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. (C) Effect of mutated Mfge8 constructs on AKT and Rictor phosphorylation in 3T3-L1 adipocytes. (D) Effect of integrin blocking antibodies on AKT phosphorylation in 3T3-L1 adipocytes after treatment with rMfge8. (E) The effect of mutated Mfge8 constructs on phosphorylation of AKT and Rictor in HepG2 cells. (F) The effect of rMfge8 on AKT phosphorylation in the presence of integrin blocking antibodies in HepG2 cells. FIGS. 5A-5I. Mfge8 stimulates fatty acid uptake by inducing translocation of fatty acid transporters to the cell surface. (A-C) Plasma membrane and post membrane CD36 expression in primary Mfge8−/− and Mfge8+/+ adipocytes (A), hepatocytes (B), and enterocytes (C). Mfge8−/− cells were also incubated with rMfge8 or rMfge8 and wortmannin. (D-F) Effect of CD36 blocking antibody or control antibody on the ability of rMfge8 to increase fatty acid uptake in primary Mfge8−/− and Mfge8+/+ adipocytes (D), hepatocytes (E), and enterocytes (F), and on Mfge8+/+ adipocytes, hepatocytes, and enterocytes. N=3-4 for experiments with antibodies and 7-8 for experiments with and without rMfge8. (G) Effect of rMfge8 on fatty acid uptake in CD36+/+ and CD36−/− adipocytes. N=3 for experiments with CD36−/− cells and rMfge8 and 6 for experiments with Mfge8+/+ and Mfge8−/− cells, each replicate represents an independent experiment and data from different experiments were combined for statistical analysis. (H) Plasma membrane and post membrane expression of FATP1 in primary Mfge8−/− and Mfge8+/+ adipocytes, and Mfge8−/− adipocytes treated with rMfge8 or rMfge8 and wortmannin. (I) Effect of rMfge8 on fatty acid uptake in FATP1+/+ and FATP1−/− adipocytes. N=3, each replicate represents an independent experiment. *P<0.05, **P<0.001, ***P<0.0001. Data are expressed as mean±s.e.m. FIG. 6. Effect of integrin blocking antibodies on fatty acid uptake by Mfge8−/− adipocytes. Fatty acid uptake was measured in Mfge8−/− adipocytes in the presence of integrin blocking antibodies (20 μg/ml). N=4. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. FIGS. 7A-7C. Mfge8 does not regulate glucose homeostasis. (A) Serum glucose levels after gavage with a glucose bolus in Mfge8+/+ and Mfge8−/− mice and gavage of glucose mixed with rMfge8 in Mfge8−/− mice. N=4-5. (B) Effect of rMfge8 and insulin on glucose uptake in 3T3-L1 adipocytes. N=7-8, each replicate represents an independent experiment. (C) Effect of integrin blocking antibodies or control antibody on glucose adsorption by Mfge8+/+ mice after glucose gavage. N=4-5. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. *P<0.01. FIGS. 8A-8H demonstrates an effect of Mfge8 on gastric motility. (A,B) Smooth muscle strips from stomach of Mfge KO (knockout) mice have stronger contraction and thus can be rescued by addition of rMfge8. (C) Represents the same experiment as FIGS. 13A and B but using mice that only express Mfge8 in smooth muscle (dbl-means transgenic mice in the Mfge8 KO background that express Mfge8 in smooth muscle), have no Mfge8 (single-sgl), or are wild type. (D, E) Increased small intestinal transit time with rescue groups as above in Mfge8 KO mice. (F, G) More rapid gastric emptying in Mfge KO with same rescue as above. (H) Increased phosphorylation of MLCP meaning enhanced calcium sensitivity in Mfge8 KO mice. FIG. 9 shows that Mfge8 induces insulin resistance in 3T3-L1 adipocytes. Glucose uptake in 3T3-L1 adipocyte with and without 20 min treatment with recombinant Mfge8 or RGE (10 μg/ml) and insulin (1 μM) or both Mfge8 and insulin (n=8, P<0.05). Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. FIG. 10 illustrates that integrin receptor blockade enhances insulin sensitivity in primary adipocytes. Glucose uptake in Mfge8−/− and Mfge8+/+ primary adipocytes, with and without 20 min treatment with insulin (1 μM) and effect of pretreatment with integrin blocking antibodies (0.5 μg/g, IP, 15 min before insulin) on glucose uptake in Mfge8+/+ adipocytes. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=8, P<0.05). Pretreatment with αv, b3 or b5 integrin blocking antibody prior to insulin injection resulted in significantly lower serum glucose levels after insulin injection as compared with insulin injection alone. FIG. 11 shows that Mfge8 induces acute insulin resistance in vivo. 8-week-old Mfge8−/− and Mfge8+/+ control mice were fasted for 4 hours, then blood glucose was measured 15 min after IP injection of insulin (1 U/kg), saline, RGE (50 μg/kg) or a combination of insulin (1.5 U/Kg) and rMfge8 or RGE construct (50 μg/kg). Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=4, P<0.05). FIG. 12 shows that integrin blockade induces acute insulin sensitivity in vivo. 8-week-old Mfge8−/− and Mfge8+/+ control mice were fasted for 4 hours, then received blocking antibodies (0.5 μg per gram body weight)(αv (clone RMV-7) and βv (clone ALULA)) IP. 15 min prior insulin (1 U/kg) or saline, blood glucose was measured 15 min after IP injection of insulin (1 U/kg) or saline. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=4, P<0.05). FIGS. 13A-13G. Enhanced, antral smooth muscle contraction in Mfge8−/− mice. (A-C) Force of antral smooth muscle ring contraction with and without the addition of rMfge8 or RGE construct (A) or after in vivo induction of transgenic Mfge8 expression in Mfge8−/−sm+ mice in response to MCh. (C) Force of antral contraction with and without epithelium (denuded). Mfge8−/− mice have enhanced gastric emptying and more rapid small intestine transit time (SIT). (D-E) Gastric emptying was measured by the proportion of phenol red remaining in the stomach 15 minutes after gavage. N=7-10. (F-G) Small intestinal transit times after gavage with Carmine dye with subsequent evaluation at 15 minutes of dye migration along the intestinal tract. N=5-10 in C and 3-5 in D. For FIGS. 13E and 13G, Mfge8−/−sm+ and single transgenic controls were placed on doxycycline for 2 weeks prior to the experiments to induce Mfge8 production in the smooth muscle. *P<0.05, **P<0.01, ***P<0.001. FIGS. 14A-14D. Inhibition of PI3K prevents exaggerated Mfge8−/− antral ring contraction. (A) Antral rings were treated for 15 min with PI3K inhibitor wortmannin (Wort.100 nm) followed by assessment of contractile force in response to MCh. N=3-4. *** P<0.0001. (B) Mfge8 reduces AKT phosphorylation. Western blot of antral tissue treated for 30 minutes with or without rMfge8. (C) Wortmannin prevents RhoA activation. Western blot of antrum treated for 30 minutes with wortmannin (100 ng/ml) or Mfge8 and then with MCh for 15 minutes prior to quantifying active RhoA using a GST pull-down. (D) Mfge8 modulates PTEN activity. PTEN activity assay measuring conversion of PIP3 to PIP2 in freshly isolated antrum with and without rMfge8 or RGE construct (10 μg/ml) n=3-5. *P<0.05, **P<0.01, ***P<0.001. DETAILED DESCRIPTION OF THE INVENTION I. Introduction Surprisingly, it has been discovered that Milk Fat Globule Epidermal Growth Factor 8 (Mfge8) stimulates fatty acid uptake. In view of this discovery, Mfge8 and analogs thereof will be useful in stimulating fatty uptake in animals (including but not limited to humans) in need thereof. Individuals who will benefit from stimulated fatty acid uptake include but are not limited to premature infants, individuals with excessive gastric emptying, diabetics and those with cystic fibrosis. Conversely, blocking Mfge8 binding to integrin receptors αvβ3 or αvβ5 inhibits fatty acid uptake. Blocking fatty acid uptake is useful, for example, in weight loss. Accordingly, administration of antagonists of αvβ3 or αvβ5 is useful for inducing weight loss in animals (e.g., humans), and is particularly useful for obese individuals. In addition, administration of antagonists of αvβ3 or αvβ5 can also enhance insulin sensitivity and can be used to treat individuals with reduced insulin sensitivity or insulin resistance. II. Increasing MFGE8 Signaling As noted above, it has been discovered that Mfge8 increases fatty acid uptake in various organs. Accordingly, in some embodiments, a polypeptide comprising Mfge8, or a substantially identical sequence thereof, or an integrin-binding fragment thereof is administered to an animal, thereby increasing fatty acid uptake in the animal. In some embodiments, a Mfge8 polypeptide as described herein is administered to an individual suffering from fat malabsorption. In some aspects, an individual in need of increased fatty acid uptake/adsorption is treated with a Mfge8 polypeptide as described herein. In some aspects, the individual has excess gastric emptying or otherwise has difficulty extracting nutrients from food. In some embodiments, the individual is a premature infant (e.g., born prior to completion of gestation) or is otherwise nursing. In some embodiments, the individual is less than 1 or 2 years old. In some embodiments, the individual is less than 6, 5, 4, 3, 2, or 1 month old. Additional examples of individuals (e.g., suffering from fat malabsorption) to which Mfge8 polypeptides can be administered include individuals having cystic fibrosis, individuals who undergo gastric bypass surgery, individuals with a decrease in the small intestine lymphatics, individuals having altered duodenal pH (Zollinger-Ellison syndrome), individuals having improper emulsification after certain types of gastrectomy, individuals having rapid transit dumping syndrome, rapid transit dumping syndrome having acute abnormality in the intestinal lining, e.g., because of infections, antibiotics or alcohol abuse, rapid transit dumping syndrome having small bowel syndrome, rapid transit dumping syndrome having presence of a chronic abnormal intestinal lining, e.g., as a result of conditions such as Crohn's disease or Celiac disease, rapid transit dumping syndrome having improper intestinal environments, e.g., because of bacterial overgrowth or the presence of parasites in the digestive system, rapid transit dumping syndrome having inadequate gastric mixing, e.g., due to factors such as a fistula in the gastric environment or after a gastrostomy, rapid transit dumping syndrome having impaired movement of the enzymes in the body, individuals having intestinal lymphangiectasia, individuals having Whipple's Disease, rapid transit dumping syndrome having irritable bowel syndrome and/or inflammatory bowel disease, individuals having cancer (e.g., advanced cancer such as Stage III or Stage IV). A Mfge8 polypeptide as described herein is administered to an individual having pancreatic and biliary dysfunction, including but not limited to individuals having chronic pancreatitis, obstruction in the pancreatic duct, pancreatic cancer, resection of the pancreas, Shwachmann-Diamond syndrome, Johnson-Blizzard syndrome, or Pearson syndrome. A variety of polypeptides can be used according to the methods for increasing fatty acid uptake. In some embodiments, full-length native (or variants thereof) Mfge8 protein amino acid sequences are used in the methods described herein. In some embodiments, the polypeptides comprise a fragment (not the full-length native sequence) of the Mfge8 sequence, or a variant thereof, that retains the ability to bind to integrin αvβ3 or αvβ5. Binding of Mfge8 to the integrin receptors is through the RGD motif and thus in some embodiments the Mfge8 fragment will comprise at least RGD, and in some aspects at least 2, 4, 5, 10, or 20 native amino acids of Mfge8 on either side of the RGD motif. Thus, in some embodiments, the polypeptides comprise at least a fragment (e.g., at least 20, 40, 50, 100, 150, 200, 250 contiguous amino acids) of the native Mfge8 protein. The inventors have found that the sequence set forth in SEQ ID NO:4, which is a mouse Mfge8 sequence lacking the second discoidan domain but including all other native sequence, remains active. The full length mouse Mfge8 sequence is depicted in SEQ ID NO:3. In some aspects the Mfge8 protein or fragment thereof will be derived from the animal species to be treated. Thus, for example, if a human is to be treated, a human Mfge8 (e.g., SEQ ID NO:1) or fragment thereof is administered. As another example, if cattle are to be treated, a bovine Mfge8 (e.g., SEQ ID NO:5) or a fragment or substantially identical polypeptide thereof is used. While not required, in some embodiments, the Mfge8 polypeptides will include non-native Mfge8 protein flanking sequences. For example, a full-length Mge8 or an RGD-containing fragment of Mfge8 can be fused to one or more heterologous amino acids to form a fusion protein. Fusion partner sequences can include, but are not limited to, amino acid tags, non-L (e.g., D-) amino acids or other amino acid mimetics to extend in vivo half-life and/or protease resistance, targeting sequences or other sequences. In some embodiments, the MFGE8 polypeptides will comprise at least one non-naturally encoded amino acid. Methods of making and introducing a non-naturally-occurring amino acid into a protein are known. See, e.g., U.S. Pat. Nos. 7,083,970; and 7,524,647. The general principles for the production of orthogonal translation systems that are suitable for making proteins that comprise one or more desired unnatural amino acid are known in the art, as are the general methods for producing orthogonal translation systems. For example, see International Publication Numbers WO 2002/086075, entitled “METHODS AND COMPOSITION FOR THE PRODUCTION OF ORTHOGONAL tRNA-AMINOACYL-tRNA SYNTHETASE PAIRS;” WO 2002/085923, entitled “IN VIVO INCORPORATION OF UNNATURAL AMINO ACIDS;” WO 2004/094593, entitled “EXPANDING THE EUKARYOTIC GENETIC CODE;” WO 2005/019415, filed Jul. 7, 2004; WO 2005/007870, filed Jul. 7, 2004; WO 2005/007624, filed Jul. 7, 2004; WO 2006/110182, filed Oct. 27, 2005, entitled “ORTHOGONAL TRANSLATION COMPONENTS FOR THE VIVO INCORPORATION OF UNNATURAL AMINO ACIDS” and WO 2007/103490, filed Mar. 7, 2007, entitled “SYSTEMS FOR THE EXPRESSION OF ORTHOGONAL TRANSLATION COMPONENTS IN EUBACTERIAL HOST CELLS.” Each of these applications is incorporated herein by reference in its entirety. For discussion of orthogonal translation systems that incorporate unnatural amino acids, and methods for their production and use, see also, Wang and Schultz, (2005) “Expanding the Genetic Code.” Angewandte Chemie Int Ed 44: 34-66; Xie and Schultz, (2005) “An Expanding Genetic Code.” Methods 36: 227-238; Xie and Schultz, (2005) “Adding Amino Acids to the Genetic Repertoire.” Curr Opinion in Chemical Biology 9: 548-554; and Wang, et al., (2006) “Expanding the Genetic Code.” Annu Rev Biophys Biomol Struct 35: 225-249; Deiters, et al, (2005) “In vivo incorporation of an alkyne into proteins in Escherichia coli.” Bioorganic & Medicinal Chemistry Letters 15:1521-1524; Chin, et al., (2002) “Addition of p-Azido-L-phenylalanine to the Genetic Code of Escherichia coli.” J Am Chem Soc 124: 9026-9027; and International Publication No. WO2006/034332, filed on Sep. 20, 2005, the contents of each of which are incorporated by reference in their entirety. Additional details are found in U.S. Pat. No. 7,045,337; No. 7,083,970; No. 7,238,510; No. 7,129,333; No. 7,262,040; No. 7,183,082; No. 7,199,222; and No. 7,217,809. A “non-naturally encoded amino acid” refers to an amino acid that is not one of the common amino acids or pyrolysine or selenocysteine. Other terms that may be used synonymously with the term “non-naturally encoded amino acid” are “non-natural amino acid,” “unnatural amino acid,” “non-naturally-occurring amino acid,” and variously hyphenated and non-hyphenated versions thereof. The term “non-naturally encoded amino acid” also includes, but is not limited to, amino acids that occur by modification (e.g. post-translational modifications) of a naturally encoded amino acid (including but not limited to, the 20 common amino acids or pyrrolysine and selenocysteine) but are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. Examples of such non-naturally-occurring amino acids include, but are not limited to, N-acetylglucosaminyl-L-serine, N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine. A non-naturally encoded amino acid is typically any structure having any substituent side chain other than one used in the twenty natural amino acids. Because the non-naturally encoded amino acids of the invention typically differ from the natural amino acids only in the structure of the side chain, the non-naturally encoded amino acids form amide bonds with other amino acids, including but not limited to, natural or non-naturally encoded, in the same manner in which they are formed in naturally occurring polypeptides. However, the non-naturally encoded amino acids have side chain groups that distinguish them from the natural amino acids. For example, R optionally comprises an alkyl-, aryl-, acyl-, keto-, azido-, hydroxyl-, hydrazine, cyano-, halo-, hydrazide, alkenyl, alkynl, ether, thiol, seleno-, sulfonyl-, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino group, or the like or any combination thereof. Other non-naturally occurring amino acids of interest that may be suitable for use in the present invention include, but are not limited to, amino acids comprising a photoactivatable cross-linker, spin-labeled amino acids, fluorescent amino acids, metal binding amino acids, metal-containing amino acids, radioactive amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and/or photoisomerizable amino acids, amino acids comprising biotin or a biotin analogue, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and/or photocleavable amino acids, amino acids with an elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons, carbon-linked sugar-containing amino acids, redox-active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moiety. Exemplary non-naturally encoded amino acids that may be suitable for use in the present invention and that are useful for reactions with water soluble polymers include, but are not limited to, those with carbonyl, aminooxy, hydrazine, hydrazide, semicarbazide, azide and alkyne reactive groups. In some embodiments, non-naturally encoded amino acids comprise a saccharide moiety. Examples of such amino acids include N-acetyl-L-glucosaminyl-L-serine, N-acetyl-L-galactosaminyl-L-serine, N-acetyl-L-glucosaminyl-L-threonine, N-acetyl-L-glucosaminyl-L-asparagine and O-mannosaminyl-L-serine. Examples of such amino acids also include examples where the naturally-occurring N- or O-linkage between the amino acid and the saccharide is replaced by a covalent linkage not commonly found in nature—including but not limited to, an alkene, an oxime, a thioether, an amide and the like. Examples of such amino acids also include saccharides that are not commonly found in naturally-occurring proteins such as 2-deoxy-glucose, 2-deoxygalactose and the like. Another type of modification that can optionally be introduced into the MFGE8 polypeptide (e.g., within the polypeptide chain or at either the N- or C-terminal), e.g., to extend in vivo half-life, is PEGylation or incorporation of long-chain polyethylene glycol polymers (PEG). Introduction of PEG or long chain polymers of PEG increases the effective molecular weight of the present polypeptides, for example, to prevent rapid filtration into the urine. In some embodiments, a Lysine residue in the MFGE8 sequence is conjugated to PEG directly or through a linker. Such linker can be, for example, a Glu residue or an acyl residue containing a thiol functional group for linkage to the appropriately modified PEG chain. An alternative method for introducing a PEG chain is to first introduce a Cys residue at the C-terminus or at solvent exposed residues such as replacements for Arg or Lys residues. This Cys residue is then site-specifically attached to a PEG chain containing, for example, a maleimide function. Methods for incorporating PEG or long chain polymers of PEG are well known in the art (described, for example, in Veronese, F. M., et al., Drug Disc. Today 10: 1451-8 (2005); Greenwald, R. B., et al., Adv. Drug Deliv. Rev. 55: 217-50 (2003); Roberts, M. J., et al., Adv. Drug Deliv. Rev., 54: 459-76 (2002)), the contents of which is incorporated herein by reference. Other methods of polymer conjugations known in the art can also be used in the present invention. In some embodiments, poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) is introduced as a polymer conjugate with the MFGE8 proteins of the invention (see, e.g., WO2008/098930; Lewis, et al., Bioconjug Chem., 19: 2144-55 (2008)). In some embodiments, a phosphorylcholine-containing polymer conjugate with the MFGE8 proteins can be used in the present invention. Other biocompatible polymer conjugates can also be utilized. A more recently reported alternative approach for incorporating PEG or PEG polymers through incorporation of non-natural amino acids (as described above) can be performed with the present Mfge8 polypeptides. This approach utilizes an evolved tRNA/tRNA synthetase pair and is coded in the expression plasmid by the amber suppressor codon (Deiters, A, et al. (2004). Bio-org. Med. Chem. Lett. 14, 5743-5). For example, p-azidophenylalanine can be incorporated into the present polypeptides and then reacted with a PEG polymer having an acetylene moiety in the presence of a reducing agent and copper ions to facilitate an organic reaction known as “Huisgen [3+2]cycloaddition.” In certain embodiments, specific mutations of the MFGE8 proteins are contemplated so as to alter the glycosylation of the polypeptide. Such mutations may be selected so as to introduce or eliminate one or more glycosylation sites, including but not limited to, O-linked or N-linked glycosylation sites. In certain embodiments, the MFGE8 proteins have glycosylation sites and patterns unaltered relative to the naturally-occurring MFGE8 proteins. In certain embodiments, a variant of MFGE8 proteins includes a glycosylation variant wherein the number and/or type of glycosylation sites have been altered relative to the naturally-occurring MFGE8 proteins. In certain embodiments, a variant of a polypeptide comprises a greater or a lesser number of N-linked glycosylation sites relative to a native polypeptide. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. In certain embodiments, a rearrangement of N-linked carbohydrate chains is provided, wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Exemplary MFGE8 proteins variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) relative to the amino acid sequence of the naturally-occurring MFGE8 proteins. In certain embodiments, cysteine variants may be useful when MFGE8 proteins must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. In certain embodiments, cysteine variants have fewer cysteine residues than the native polypeptide. In certain embodiments, cysteine variants have an even number of cysteine residues to minimize interactions resulting from unpaired cysteines. In some embodiments, functional variants or modified forms of the MFGE8 proteins include fusion proteins of an MFGE8 protein of the invention and one or more fusion domains. Well known examples of fusion domains include, but are not limited to, polyhistidine, Glu-Glu, glutathione S transferase (GST), thioredoxin, protein A, protein G, an immunoglobulin heavy chain constant region (Fc), maltose binding protein (MBP), or human serum albumin. A fusion domain may be selected so as to confer a desired property. For example, some fusion domains are particularly useful for isolation of the fusion proteins by affinity chromatography. For the purpose of affinity purification, relevant matrices for affinity chromatography, such as glutathione-, amylase-, and nickel- or cobalt-conjugated resins are used. Many of such matrices are available in “kit” form, such as the Pharmacia GST purification system and the QLAexpress™ system (Qiagen) useful with fusion partners (e.g., His6; SEQ ID NO:7). As another example, a fusion domain may be selected so as to facilitate detection of the MFGE8 proteins. Examples of such detection domains include the various fluorescent proteins (e.g., GFP) as well as “epitope tags,” which are usually short peptide sequences for which a specific antibody is available. Well known epitope tags for which specific monoclonal antibodies are readily available include FLAG, influenza virus haemagglutinin (HA), and c-myc tags. In some cases, the fusion domains have a protease cleavage site, such as for Factor Xa or Thrombin, which allows the relevant protease to partially digest the fusion proteins and thereby liberate the recombinant proteins therefrom. The liberated proteins can then be isolated from the fusion domain by subsequent chromatographic separation. In certain embodiments, an MFGE8 protein is fused with a domain that stabilizes the MFGE8 protein in vivo (a “stabilizer” domain). By “stabilizing” is meant anything that increases serum half life, regardless of whether this is because of decreased destruction, decreased clearance by the kidney, or other pharmacokinetic effect. Fusions with the Fc portion of an immunoglobulin are known to confer desirable pharmacokinetic properties on a wide range of proteins. Likewise, fusions to human serum albumin can confer desirable properties. Other types of fusion domains that may be selected include multimerizing (e.g., dimerizing, tetramerizing) domains and functional domains (that confer an additional biological function, as desired). It is contemplated that the polypeptides, compositions, and methods of the present invention may be used to treat a mammal. As used herein a “mammal” to any mammal classified as a mammal, including humans, domestic and farm animals, and zoo, sports or pet animals, such as cattle (e.g. cows), horses, dogs, sheep, pigs, rabbits, goats, cats, etc. All embodiments described herein not specifically referring to another species should be understood to specifically apply to humans as well as more generally to mammals. The dose of a compound of the present invention for treating the above-mentioned diseases or disorders varies depending upon the manner of administration, the age and the body weight of the subject, and the condition of the subject to be treated, and ultimately will be decided by the attending physician or veterinarian. Such an amount of the compound as determined by the attending physician or veterinarian is referred to herein as an “effective amount.” Formulations suitable for administration include exipients, including but not limited to, aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In some embodiments, the Mfge8 polypeptides are formulated in micelles or liposomes. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial response in the subject over time. The dose will be determined by the efficacy of the particular protein employed and the condition of the subject, as well as the body weight or surface area of the area to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular protein or vector in a particular subject. Administration can be accomplished via single or divided doses. Formulations suitable for administration include aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, orally, rectally, nasally, topically, intravenously, intraperitoneally, or intrathecally. The formulations of polypeptides can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. The modulators can also be administered as part a of prepared food or drug. In general, any food or beverage that can be consumed by human infants or adults or animals may be used to make formulations containing the Mfge8 polypeptides described herein. Exemplary foods include those with a semi-liquid consistency to allow easy and uniform dispersal of the compositions. However, other consistencies (e.g., powders, liquids, etc.) can also be used without limitation. Accordingly, such food items include, without limitation, dairy-based products such as cheese, cottage cheese, yogurt, and ice cream. Processed fruits and vegetables, including those targeted for infants/toddlers, such as apple sauce or strained vegetables (e.g., peas and carrots, etc.), are also suitable for use in combination with the prebiotic and synbiotic compositions of the present invention. Both infant cereals such as rice- or oat-based cereals and adult cereals such as Musilix are also suitable for use in combination with the oligosaccharides of the present invention. In addition to foods targeted for human consumption, animal feeds may also be supplemented with the Mfge8 polypeptides as described herein. Alternatively, the Mfge8 polypeptide compositions can be used to supplement a beverage. Examples of such beverages include, without limitation, infant formula, follow-on formula, toddler's beverage, milk, fermented milk, fruit juice, fruit-based drinks, and sports drinks Many infant and toddler formulas are known in the art and are commercially available, including, for example, Carnation Good Start (Nestle Nutrition Division; Glendale, Calif.) and Nutrish A/B produced by Mayfield Dairy Farms (Athens, Tenn.). Other examples of infant or baby formula include those disclosed in U.S. Pat. No. 5,902,617. Other beneficial formulations of the compositions of the present invention include the supplementation of animal milks, such as cow's milk. Alternatively, the prebiotic and probiotic compositions of the present invention can be formulated into pills or tablets or encapsulated in capsules, such as gelatin capsules. Tablet forms can optionally include, for example, one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge or candy forms can comprise the compositions in a flavor, e.g., sucrose, as well as pastilles comprising the compositions in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art. The Mfge8 polypeptide formulations may also contain conventional food supplement fillers and extenders such as, for example, rice flour. In some embodiments, the Mfge8 polypeptide composition will further comprise a non-human protein, non-human lipid, non-human carbohydrate, or other non-human component. For example, in some embodiments, the compositions of the invention comprise a bovine (or other non-human) milk protein, a soy protein, a rice protein, betalactoglobulin, whey, soybean oil or starch. In some embodiments, the prebiotic or synbiotic composition will further comprise a non-bovine protein, non-bovine lipid, non-bovine carbohydrate, or other non-bovine component. III. Inhibiting MFGE8 Signaling Mfge8 is a ligand for both αvβ3 and αvβ5 integrins. As demonstrated below in Examples 1 and 2, administration of an antagonist antibody that binds the αv integrin subunit completely inhibited fat uptake in an animal and administration of an antibody specific for αvβ3 or administration of an antibody specific for αvβ5 partially decreases fat absorption. Accordingly, antagonizing the αvβ3 and/or αvβ5 integrin receptors is effective to reduce fat uptake and optionally for weight reduction in an individual. Co-administration of antagonists of αvβ3 and/or αvβ5 integrin receptors and insulin can be used to treat individuals with reduced insulin sensitivity. In particular, pretreatment with antagonists of αvβ3 and/or αvβ5 integrin receptors prior to insulin injection can significantly lower serum glucose levels, as compared to injection of insulin alone. Exemplary antagonists can be, for example, antagonist antibodies, e.g., antagonists antibodies that specifically bind to αvβ3 and/or αvβ5 integrin receptors. An exemplary αvβ5 antibody is “ALULA” (the antibody produced by the hybridoma deposited under ATCC Deposit No. PTA-5817). Alternatively, the αvβ3 and/or αvβ5 integrin receptor antagonists can be small molecules. See, e.g., PCT WO 2003/059872. In some embodiments, the antagonists are RGD-containing peptides or cyclic peptides. Examples of such peptides include, but are not limited to those described in Belvisi, L., et al., Mol Cancer Ther 4(11): (November 2005). Some antagonists are reviewed in Hsu, A R, et al., Recent Pat Anticancer Drug Discov. 2(2):143-58 (2007). In some embodiments, the αvβ3 and/or αvβ5 integrin receptor antagonists are administered to an individual that is overweight overweight (e.g., body mass index (BMI) greater or equal to 25 kg/m2) or is obese. In some embodiments, the αvβ3 and/or αvβ5 integrin receptor antagonists are administered to an individual with high (i.e., above average) level of fatty acids and triglycerides, and an individual with hyperlipidemia or dyslipidemia (e.g., an individual having cirrhosis or liver damage, hypothyroidism (underactive thyroid), nephrotic syndrome, a kidney disorder, or diabetes. In some embodiments, the αvβ3 and/or αvβ5 integrin receptor antagonists are administered to a pregnant individual or an individual with elevated levels of female hormones. In some embodiments, the αvβ3 and/or αvβ5 integrin receptor antagonists are administered to an individual with an elevated risk cardiovascular disease or stroke. In some embodiments, the αvβ3 and/or αvβ5 integrin receptor antagonists are administered to an individual with reduced insulin sensitivity or insulin resistance. The αvβ3 and/or αvβ5 integrin receptor antagonists can be formulated and administered as described above with regard to the Mfge8 polypeptides. For example, formulations suitable for administration include aqueous and non-aqueous solutions, isotonic sterile solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, orally, rectally, nasally, topically, intravenously, intraperitoneally, or intrathecally. The formulations of polypeptides can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials. Solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. The modulators can also be administered as part of a prepared food or drug. EXAMPLES Example 1 Mfge8 and Regulating Fat Storage and Lipid Homeostasis Fatty acids are integral mediators of energy storage, membrane formation, and cell signaling. The pathways that orchestrate uptake of fatty acids remain incompletely understood. Expression of the integrin ligand Mfge8 is increased in human obesity and in mice on a high-fat diet (HFD). The role of Mfge8 in obesity is unknown. We show here that Mfge8 promotes the development of obesity by facilitating cellular uptake of fatty acids. Mfge8 deficient (Mfge8−/−) mice absorb less dietary triglycerides and are protected from weight gain, steatohepatitis and obesity-associated insulin resistance on a HFD. Mfge8−/− cells have impaired fatty acid uptake in vitro. Mfge8 coordinates fatty acid uptake through αvβ3 and αvβ5 integrin-dependent phosphorylation of AKT by PI3 kinase and mTOR complex 2 leading to translocation of CD36 and FATP1 from cytosolic stores to the cell surface. Collectively, our results implicate a central role for Mfge8 in regulating fat storage and lipid homeostasis. Results Mfge8 Increases 3T3-L1 Adipocyte Fatty Acid Uptake and Triglyceride Storage To evaluate the effect of Mfge8 on fatty acid uptake, we quantified the effect of recombinant Mfge8 (rMfge8) on uptake of a BODIPY fatty acid analog (Liao, J. et al., J Lipid Res 46, 597-602 (2005)) by 3T3-L1 adipocytes. rMfge8 significantly increased fatty acid uptake in a dose-dependent fashion (FIG. 1A), while a recombinant construct with a point mutation changing the integrin-binding RGD sequence of Mfge8 to RGE (RGE) had no effect (FIG. 1A). 3T3-L1 cells treated with rMfge8, but not RGE, had significantly greater triglyceride content 2, 4, 6, and 8 days after treatment (FIG. 1B). These data indicate that Mfge8 increases fatty acid uptake and triglyceride stores in 3T3-L1 adipocytes through an integrin-dependent pathway. Mfge8−/− Adipocytes have Impaired Fatty Acid Uptake that is Rescued with rMfge8. We next evaluated whether fatty acid uptake was impaired in adipocytes from Mfge8−/− mice. Mfge8−/− primary adipocytes isolated from epididymal white adipose tissue (eWAT) and differentiated adipocyte progenitors isolated from subcutaneous white adipose tissue had significantly impaired fatty acid uptake (FIGS. 1C,D). rMfge8 rescued the decrease in fatty acid uptake in Mfge8−/− adipocytes and significantly increased WT fatty acid uptake (FIGS. 1C,D). In addition to an intact integrin-binding motif, the effect of recombinant protein required at least one of the discoidin domains of Mfge8 (FIGS. 1C,E,F). Treatment of 323-L1 adipocytes with cycloRGD did not induce an increase in AKT phosphorylation or fatty acid uptake. The Effect of Mfge8 on Fatty Acid Uptake is Mediated Through the αvβ5 and αvβ3 Integrins. Mfge8 is a ligand for the αvβ3 and αvβ5 integrins (Hanayama, R. et al., Nature 417, 182-187 (2002)). To determine whether Mfge8 mediated fatty acid uptake through these integrins, we evaluated the effects of integrin-blocking antibodies on the ability of rMfge8 to rescue impaired fatty acid uptake in Mfge8−/− adipocytes (FIG. 1G) and increase fatty acid uptake in 3T3-L1 adipocytes (FIG. 1H). Blocking antibody to the αv integrin subunit or both the β3 and β5 subunits completely inhibited and blocking antibodies to the β5 or the β3 integrin subunits partially inhibited the increase in fatty acid uptake induced by rMfge8 (FIGS. 1G,H). During 3T3-L1 differentiation from fibroblasts into adipocytes, Mfge8 expression increased, while expression of αv, β3 and β5 integrin subunits was stably persistent. β5−/− and β3−/− adipocytes had impaired fatty acid uptake which was further reduced with the addition of blocking antibody to the β3 integrin subunit in β5−/− adipocytes and vice versa. These data indicate that the αvβ3 and αvβ5 integrins mediate the effect of Mfge8 on fatty acid uptake. Mfge8 Regulates Hepatic and Cardiac Fatty Acid Uptake To determine whether the effect of Mfge8 on fatty acid uptake could be generalized to other tissues, we evaluated fatty acid uptake in hepatocytes and cardiac myocytes. Mfge8−/− hepatocytes and cardiac myocytes had impaired fatty acid uptake that was rescued with rMfge8 (FIGS. 2A,B). rMfge8 also increased fatty acid uptake in HepG2 cells, a human hepatocellular carcinoma cell line, in an integrin binding and discoidin domain dependent manner (FIGS. 2C,D). Mfge8 Mediates Fatty Acid Uptake and Absorption of Dietary Triglycerides in the Gastrointestinal Tract. The high expression of Mfge8 in breast milk (Newburg, D. S. et al., Lancet 351, 1160-1164 (1998)) led us to investigate a role for Mfge8 in intestinal fat absorption. We found significantly reduced small intestinal triglyceride content in Mfge8−/− mice (FIG. 3A) and reduced in vitro fatty acid uptake by Mfge8−/− primary enterocytes (FIG. 3B). Mfge8−/− mice had significantly lower serum triglyceride levels after olive oil gavage. Adding rMfge8, but not RGE, to olive oil significantly raised serum triglyceride levels (FIG. 3C). Liver triglyceride levels after gavage were significantly lower in Mfge8−/− mice and increased significantly with rMfge8 treatment (FIG. 3D). Serum fatty acid levels after olive oil gavage were also lower in Mfge8−/− mice (FIG. 3E). rMfge8 significantly increased WT serum triglyceride levels after olive oil gavage (FIG. 3F). There was no difference in serum glucose levels after glucose gavage when comparing Mfge8−/− and WT mice or in glucose uptake by 3T3-L1 adipocytes treated with rMfge8. To prove that Mfge8 deficiency led to fatty acid malabsorption, we administered a gavage of BODIPY fatty acid analog and measured fecal BODIPY content. Mfge8−/− mice had significantly greater fecal BODIPY levels (FIG. 3G). To separate the effects of impaired enteral absorption of fatty acids from impaired peripheral uptake of fatty acids on serum fatty acid levels, we measured serum free fatty acids after fasting mice for 24 hours. Mfge8−/− mice had significantly higher serum free fatty acids (FIG. 3H) indicating a defect in peripheral uptake of fatty acids after starvation-induced lipolysis. We next evaluated the ability of enteral integrin blockade to prevent fat absorption in WT mice. The administration of αv-blocking or β5-blocking antibody by gavage 30 minutes prior to receiving an olive oil bolus significantly reduced serum triglyceride levels, enterocyte triglyceride content, and hepatic triglyceride content (FIGS. 3I-K) while having no effect on glucose absorption (FIG. 7C). Mfge8 Stimulates Fatty Acid Uptake Through a PI3 Kinase-mTORC2-AKT-Dependent Pathway. PI3 kinase and AKT are integral parts of regulatory pathways in metabolism (Manning, B. D. & Cantley, L. C., Cell 129, 1261-1274 (2007); Li, X. et al., Nature 447, 1012-1016 (2007)). We therefore investigated whether the Mfge8-induced increase in fatty acid uptake was mediated through an AKT/PI3K axis. rMfge8 induced phosphorylation of AKT at serine 473 (s473) in 3T3-L1 cells and this effect was completely blocked by the PI3 kinase inhibitor wortmannin (FIG. 4A). Wortmannin also inhibited the ability of rMfge8 to increase fatty acid uptake in Mfge8−/− adipocytes treated with rMfge8 (FIG. 4B). AKT phosphorylation was dependent on an intact integrin binding motif and the presence of at least one discoidin domain (FIG. 4C) and was inhibited by blocking antibodies to the βv, β3, and β5 integrin subunits (FIG. 4D). mTOR Complex 2 (mTORC2) is the kinase complex primarily responsible for phosphorylation of AKT at s473 (Sarbassov, D. D. et al., Science 307, 1098-1101 (2005)). To determine whether Mfge8-induced AKT phosphorylation was mediated through mTORC2, we evaluated phosphorylation of rapamycin-insensitive companion of mTOR (Rictor) at threonine 1135. Rictor was phosphorylated by Mfge8 and phosphorylation required an intact integrin binding motif and at least one discoidin domain (FIG. 4C). Mfge8 also induced phosphorylation of AKT and Rictor in HepG2 cells by an integrin-dependent pathway (FIGS. 4E,F). Mfge8 Stimulates Fatty Acid Uptake by Inducing Translocation of CD36 and FATP1 to the Cell Surface. CD36 is a key mediator of fatty acid uptake (Ibrahimi, A. et al., Proc Natl Acad Sci USA 93, 2646-2651 (1996)) that is regulated by translocation from cytosolic stores to the cell surface (Glatz, J. F. et al., Physiol Rev 90, 367-417 (2010)). We therefore evaluated whether Mfge8 induced translocation of CD36 to the cell surface. In primary Mfge8−/− adipocytes, hepatocytes, and enterocytes there was a marked reduction in membrane CD36 (FIGS. 5A-C). The addition of rMfge8 increased membrane expression of CD36 in Mfge8−/− cells to WT levels, and this effect was completely inhibited by wortmannin. Incubation with a CD36 blocking antibody prevented rMfge8 from increasing fatty acid uptake in Mfge8−/− adipocytes, hepatocytes, and enterocytes (FIGS. 5D-F). Unlike WT adipocytes, rMfge8 did not significantly increase fatty acid uptake in CD36−/− adipocytes. FATP1 is a member of the FATP family and plays a key role in fatty acid transport in adipocytes. Like CD36, FATP1 is translocated from cytosolic pool to the cell surface for fatty acid transport (Stahl, A. et al., Developmental cell 2, 477-488 (2002)). Membrane expression of FATP1 was reduced in Mfge8−/− adipocytes, expression was increased by rMfge8, and this effect was inhibited by wortmannin (FIG. 5H). The addition of rMfge8 to FATP1−/− adipocytes did not significantly increase fatty acid uptake (FIG. 5I). Taken together, these data indicate that Mfge8 regulates fatty acid uptake by inducing translocation of the machinery of fatty acid uptake to the cell surface. Mfge8−/− Mice are Protected from Weight Gain on a HFD Due to Impaired Fat Absorption. To determine whether Mfge8-mediated fatty acid uptake contributes to the development of obesity in vivo, we evaluated weight gain in Mfge8−/− mice placed on a HFD. Male and female Mfge8−/− mice gained less weight as compared with controls over a 12 week period on a HFD. The eWAT of 20-week-old Mfge8−/− mice on a HFD weighed significantly less than control eWAT. There was a marked induction of Mfge8 protein in eWAT of WT mice on HFD. 20-week-old Mfge8−/− mice on a HFD or CD had smaller adipocytes and reduced hepatic triglyceride content (CD). The hearts of Mfge8−/− mice also had significantly reduced triglyceride content. To determine the body composition of Mfge8−/− mice on a HFD, we examined lean and fat mass using DEXA scanning 20-week old Mfge8−/− mice on HFD and 10- and 20-week old, but not 5-week-old, Mfge8−/− mice on a CD had significantly less total body fat and percent body fat. Since obesity is associated with insulin resistance, we performed insulin tolerance tests on Mfge8−/− mice. 20-week old Mfge8−/− mice on a HFD had increased insulin sensitivity compared to WT mice. 10-, but not 5-, week old Mfge8−/− mice on a CD had enhanced insulin sensitivity. To evaluate whether the decrease in body fat was secondary to impaired absorption of dietary fats, we measured stool triglyceride and energy content. Mfge8−/− mice on HFD had significantly higher stool triglyceride levels and caloric content as measured by bomb calorimetry. Mfge8−/− Mice are Protected from Obesity-Induced Adipose Tissue Inflammation Since obesity is associated with chronic inflammation (Weisberg, S. P. et al., J Clin Invest 112, 1796-1808 (2003)) and Mfge8 suppresses inflammation by multiple mechanisms (Kudo, M. et al., Proc Natl Acad Sci USA 110, 660-665 (2013)), we evaluated eWAT inflammation in Mfge8−/− mice on a HFD. There was a marked reduction in eWAT infiltrating macrophages by immunohistochemistry as well as a reduction in multiple immune populations as evaluated by flow cytometry in Mfge8−/− mice. Since Mfge8−/− mice develop age-dependent autoimmune disease (that is apparent at 40 weeks of age) (Hanayama, R. et al., Science 304, 1147-1150 (2004)), we evaluated whether 20-week old Mfge8−/− mice on a HFD had evidence of chronic immune activation that may have contributed to the decrease in body fat. We found no difference in the number or percent of activated splenic lymphocytes or total number of cells in the spleens of 20-week old Mfge8−/− mice on a HFD. Mfge8 Deficiency does not Alter Energy Expenditure We next examined whether differences in energy expenditure could account for the differences in body fat in Mfge8−/− mice. After 10 days on HFD, we placed 12-week-old Mfge8−/− and WT mice in clams metabolic cages for a period of 4 days. We found no difference in total oxygen consumption, oxygen consumption corrected for lean body mass, food intake, or ambulation when comparing Mfge8−/− and control mice. Finally, there was a modest increase in the respiratory exchange ratio in Mfge8−/− mice without changes in eWAT PGC1a expression. Collectively, these data indicate that the decrease in body fat in Mfge8−/− mice is not caused by exaggerated inflammation, an increase in energy expenditure, or an increase in fatty acid oxidation. Discussion The work presented here identifies a critical role for Mfge8 in regulating obesity through modulation of cellular uptake and storage of fatty acids. In the gastrointestinal tract, Mfge8 coordinates orderly absorption of dietary fats. Mfge8 deficiency leads to fat malabsorption, a reduction in total body fat, and protection from diet induced obesity (DIO). Importantly, Mfge8 also increases fatty acid uptake by adipocytes, cardiac myocytes and hepatocytes. While the in vivo sequelae of impaired fatty acid uptake by peripheral organs in Mfge8−/− mice is obscured by the malabsorption phenotype, the data suggests that under normal conditions (wild type mice and humans), Mfge8 is physiologically important for fat uptake in these tissues. This conclusion is supported by the following observations. Serum fatty acid levels are lower in Mfge8−/− mice after an olive oil bolus. However, when mice are fasted for 24 hours, serum fatty acid levels are significantly higher in Mfge8−/− mice consistent with impaired peripheral uptake of fatty acids released after catecholamine-induced lipolysis. There is a near 100-fold increase in adipose tissue Mfge8 expression when mice are placed on a HFD suggesting, as further discussed below, a key role for Mfge8 in persistent expansion of adipose tissue with progressive weight gain. Similarly, expression of Mfge8 and both the αv and β5 integrin subunits are significantly increased in the adipose tissue of obese humans (Henegar, C. et al., Genome Biol 9, R14 (2008)). Mfge8 induces translocation of FATP1 to the cell surface, a fatty acid transport protein that is lacking in the intestine, but present in adipocytes and cardiac myocytes. Fatty acid transporter translocation is a key regulatory step by which cellular uptake of fatty acids can be acutely modified in response to hormonal and metabolic cues (Bonen, A. et al., J Biol Chem 275, 14501-14508 (2000)). Insulin and muscle contraction increase fatty acid uptake in skeletal and cardiac muscle through this mechanism (Jain, S. S. et al., FEBS Lett 583, 2294-2300 (2009); Glatz, J. F. et al., Physiol Rev 90, 367-417 (2010)). The identification of additional regulatory pathways that modulate this process has been elusive. While both insulin and Mfge8 induce translocation of fatty acid transporters through PI3 kinase-dependent phosphorylation of AKT (Stahl, A. et al., Developmental cell 2, 477-488 (2002); Chabowski, A. et al., Am J Physiol Endocrinol Metab 287, E781-789 (2004)), there are some key differences between their roles in fatty acid uptake. In the gastrointestinal tract, Mfge8 mediates absorption of dietary triglycerides while insulin regulates nutrient deposition in tissues after absorption from the intestine. Another distinction is apparent in obese adipose tissue. While insulin promotes lipogenesis by inducing de novo triglyceride synthesis (Wakil, S. J. et al., Annu Rev Biochem 52, 537-579 (1983)), increasing fatty acid uptake (Stahl, A. et al., Developmental cell 2, 477-488 (2002)), and inhibiting lipolysis (Jensen, M. D. et al., Diabetes 38, 1595-1601 (1989)), obesity is associated with adipocyte insulin resistance (Smith, U., Int J Obes Relat Metab Disord 26, 897-904 (2002)). Adipocytes from diabetic patients have impaired downstream signaling after insulin receptor binding, resulting in reduced PI3 kinase activity (Rondinone, C. M. et al., Proc Natl Acad Sci USA 94, 4171-4175 (1997)). This raises an interesting paradox: how does insulin continue to promote adipocyte enlargement and obesity by stimulating cells that are known to be insulin-resistant? Our data raise the interesting possibility that the marked increase in adipocyte Mfge8 expression during obesity may supply the signal that promotes fatty acid uptake in insulin-resistant adipocytes, thereby perpetuating the adipose hypertrophy characteristic of obesity. Finally, unlike insulin, Mfge8 systemically induces fatty acid uptake without directly affecting glucose uptake, thereby providing a mechanism to dissociate regulation of these two major components of nutrient metabolism. The relative contribution of Mfge8-mediated CD36 translocation to increased fatty acid uptake induced by Mfge8 in different organ system is an area of active investigation. In adipocytes, our data indicate that Mfge8 regulates both FATP1 and CD36 translocation. The roles of CD36 and FATP1 in promoting fatty acid uptake are well established in adipocytes (Coburn, C. T. et al., J Biol Chem 275, 32523-32529 (2000); Wu, Q. et al., Mol Cell Riot 26, 3455-3467 (2006)), and cardiac myocytes (Coburn, C. T. et al., J Biol Chem 275, 32523-32529 (2000); Tanaka, T. et al., J Lipid Res 42, 751-759 (2001)) and are consistent with a model whereby the effect of Mfge8 on fatty acid uptake in these tissues is mediated through translocation of FATP1 and CD36 to the cell surface. Whether the effect of Mfge8 on fatty acid uptake in the intestinal tract is primarily mediated through CD36 is less clear. Absorption of dietary fats is a multistep process that begins with luminal breakdown of ingested triglycerides into free fatty acids that are subsequently taken up by enterocytes where they are re-esterified and secreted as chylomicrons (Bamba, V. & Rader, D. J., Gastroenterology 132, 2181-2190 (2007)). CD36 modulates both absorption of dietary fats and secretion of triglycerides by intestinal epithelial cells (Drover, V. A. et al., J Biol Chem 283, 13108-13115 (2008); Drover, V. A. et al., J Clin Invest 115, 1290-1297 (2005); Nassir, F. et al., J Biol Chem 282, 19493-19501 (2007)). The impairment in Mfge8−/− enterocyte fatty acid uptake in vitro and the increase in fecal energy content in Mfge8−/− mice suggest that the main effect of Mfge8 is to stimulate uptake of fatty acids rather than regulate secretion of chylomicrons. As we found in adipocytes, Mfge8 may interact with additional fatty acid transporters in the gastrointestinal tract leading to overlapping but not identical phenotypes in enteral fat absorption in Mfge8−/− and CD36−/− mice. While the protection from the DIO in Mfge8−/− mice is reminiscent of MGAT2−/− mice, MGAT2−/− mice have a delay in absorption rather than malabsorption of dietary fats. Yen, C. L. et al., Nat Med 15, 442-446 (2009)). Our work also identifies an important role for integrins in regulating lipid homeostasis. We show that both the αvβ3 and αvβ5 integrins induce AKT phosphorylation via PI3 kinase and mTORC2. Of note, integrins are overexpressed in many malignancies (Mizejewski, G. J., Proc Soc Exp Biol Med 222, 124-138 (1999)) and overexpression is important in the interaction of malignant cells with the extracellular matrix relative to both cancer growth and metastasis (Zhao, Y. et al., Cancer Res 67, 5821-5830 (2007)). Our data raise the possibility that integrin overexpression in malignancies may increase tumor cell fatty acid uptake. This may be particular importance in malignancies such as prostate cancer where cells preferentially metabolize fatty acids. (Liu, Y., Anticancer Res 30, 369-374 (2010)) and overexpress the αvβ3 integrin (Zheng, D. Q., Cancer Res 59, 1655-1664 (1999)). Our results provide a mechanism to explain the recent observations that Mfge8 is located in a region linked with susceptibility to obesity in humans (Rankinen, T. et al., Obesity (Silver Spring) 14, 529-644 (2006)) and that adipose expression of Mfge8 is increased in human obesity (Henegar, C. et al., Genome Biol 9, R14 (2008)). Collectively, our data indicate that Mfge8 ligation of integrin receptors regulates body fat content by regulating the uptake of fatty acids in the alimentary tract and in peripheral tissues. From the therapeutic viewpoint, this pathway can be targeted for the treatment of malabsorption syndromes or obesity. To our knowledge, we show the first evidence of a pathway that can augment absorption of dietary fats and serve as a target for the treatment of fat malabsorption. In addition, inhibition of the Mfge8-dependent pathway will provide a novel therapeutic target for the treatment of obesity that directly inhibits the molecular pathways of fat absorption in the gastrointestinal tract. A better understanding of the mechanisms that regulate fat uptake and storage is of significant interest in the light of the high morbidity, mortality and economic burden associated with obesity and obesity-related disease. Supplemental Methods Mice. All animal experiments were approved by the UCSF Institutional Animal Care and Use Committee in adherence to NIH guidelines and policies. In vivo studies were conducted with two different lines of mice deficient in Mfge8. Some studies were carried out on Mfge8−/− mice created by a gene disruption vector. These mice have been extensively characterized and have the same phenotypes as Mfge8−/− mice created by homologous recombination (Silvestre, J. S. et al., Nat Med 11, 499-506 (2005); Atabai, K. et al., Mol Biol Cell 16, 5528-5537 (2005)). Mice were backcrossed 10 generations into the C57bl/6 background and bred as Mfge8−/− breeding pairs and Mfge8+/+ breeding pairs. In a subset of studies, Mfge8−/− and Mfge8+/− breeding pairs were used to generate sibling littermates from the same cage. A second line of Mfge8 mice created by homologous recombination was obtained from RIKEN (Hanayama, R. et al., Nature 417, 182-187 (2002)). These mice were bred as Mfge8−/− and Mfge8+/− breeding pairs and used in some studies and as Mfge8−/− and Mfge8+/+ breeding pairs for studies used in FIGS. 3A-3K and, and for harvesting of all primary cells used in in vitro studies. All mice were age- (6-8 weeks of age unless otherwise noted) and sex-matched. β3−/− and β5−/− mice in the 129 SVEV strain have been previously described (Huang, X. et al., Mol Cell Blot 20, 755-759 (2000); Su, G. et al., Am J Respir Crit Care Med 185, 58-66 (2012)). CD36−/− mice were generously provided by Roy Silverstein and were in the C57bl/6 background. FAP1−/− mice were also in the C57bl/6 background (Wu, Q. et al., Mol Cell Biol 26, 3455-3467 (2006)). For FIGS. 3C-3I investigator were blinded to genotypes until statistical analysis of the data. Investigators were not blinded as to genotype in animal studies that involved weighing mice on a high-fat diet, obtaining insulin tolerance tests, and determining body composition by Dexa scan. Investigators were blinded to the mouse genotypes for the energy expenditure experiments which were done by a core facility. High-Fat Diet. 8 to 10 week-old mice were placed on a high-fat formula containing 60% fat calories (Research Diets, Inc.) for 12 weeks. The control diet contained 9% fat calories (PMI). Mice were housed in groups of 5 mice per cage for diet experiments including weights, insulin tolerance tests, Dexa scanning for body composition, adipocyte size quantification, and hepatic triglyceride content with each cage of 5 mice representing an independent experiment. Fluorescent Fatty Acid Uptake Assay. Uptake of fatty acids by differentiated 3T3-L1 adipocytes or primary mouse adipocytes was assessed using a QBT Fatty Acid Uptake Kit (Molecular Devices). Cells were plated in triplicate in 96-well plates at a concentration of 25,000 cells per well in 100 μl of DMEM/10% FCS. Plates were centrifuged at 1000 rpm for 4 minutes and incubated at 37° Celsius for 4-5 hours. Cells were then serum deprived for 1 hour before treatment with recombinant proteins for 30 minutes followed by the addition of QBT Fatty Acid Uptake solution. In experiments using function-blocking antibodies, antibodies against mouse integrins αv (clone RMV-7) (Takahashi, K. et al., J Immunol 145, 4371-4379 (1990))β3 (clone 2C9.G2; BD Biosciences) (Ashkar, S. et al., Science 287, 860-864 (2000)), 135 (clone ALULA) (Su, G. et al., American journal of respiratory cell and molecular biology 36, 377-386 (2007)), 131 (clone HA2/5; BD Biosciences, anti-rat with cross-reactivity with mouse (Zovein, A. C. et al., Developmental cell 18, 39-51 (2010)), CD36 (clone MF3; Abcam) (Helming, L. et al., Journal of cell science 122, 453-459 (2009)), human integrins αv (clone L230) (Thomas, G. J. et al., British journal of cancer 87, 859-867 (2002)), 133 (clone Axum-2) (Su, G. et al., Am J Respir Crit Care Med 185, 58-66 (2012)), 135 (clone ALULA), 131 (clone P5D2), cycloRGD and cycloRAD (BACHEM) were added to cells after serum deprivation and cells were incubated for 20 minutes at 4° Celsius prior to addition of recombinant proteins. Plates were incubated in a fluorescent plate reader at 37° Celsius and kinetic readings were acquired every 20 seconds for 30 minutes. Fluorescence values were plotted against time and data was expressed as relative fluorescent units per minutes×103. 3T3-L1 Cell/HepG2 Cell Culture. 3T3-L1 (Zen-Bio) fibroblasts were differentiated into adipocytes as described previously (Liao, J. et al., J Lipid Res 46, 597-602 (2005)). Briefly, 3T3-L1 fibroblasts were cultured to confluence on 10 cm tissue culture plates or in 6-well tissue culture dishes in DMEM supplemented with 10% FBS and 25 mM HEPES (normal medium). 2 days after reaching confluence, media was change and 3-isobutyl-1methylxanthine (Calbiochem), dexamethasone (Sigma), and insulin (Sigma) were added to the normal medium at concentrations of 0.5 mM, 1 μM, and 5 μg/mL, respectively, to induce adipocyte differentiation. After 2 days (and every 2 days thereafter), media was replaced with normal medium supplemented with 5 μg/mL insulin. Cells were harvested for use 6-10 days after differentiation. The human hepatocellular carcinoma cell line HepG2 was a generous gift of Dr. Ethan Weiss. Cells were propagated in Eagle's MEM supplemented with 10% fetal bovine serum. Olive Oil Gavage and Serum Triglyceride and Fatty Acid Content. 6-8 week-old mice were fasted for 4 hours and then gavaged with 15 μL olive oil per gram body weight. Mice had access to water but not food for the remainder of the experiment. In the experiments in FIGS. 3C and 3F, 50 μg/kg body weight of recombinant protein was mixed into olive oil and administered immediately to mice by gavage. In blocking antibody experiments, integrins αv (clone RMV-7) and 05 (clone ALULA) were administered by gavaging mice with 100 μL water containing 0.5 μg antibody per gram body weight 30 minutes before olive oil gavage. Triglyceride content of serum was assayed using a commercially available kit (Sigma-Aldrich) and fatty acid concentrations were quantified by Wako (Rabot, S. et al., FASEB J 24, 4948-4959 (2010)). Quantification of Liver, Intestinal, and Fecal Triglyceride Content. After experiments described above, samples from the left lobe of the liver and the proximal small intestine were isolated and rapidly frozen in liquid nitrogen for triglyceride content assays. Control mice were starved for 8 hours before their organs were harvested as above. Triglyceride content of the intestine (Uchida, A. et al., Front Physiol 3, 26) and liver (Kim, K. Y. et al., J Clin Invest 121, 3701-3712 (2011)) and fecal samples Kim, K. Y. et al., J Clin Invest 121, 3701-3712 (2011)) were quantified as described previously. Glucose Gavage and Blood Glucose Measurement. 6-8 week-old mice were fasted for 4 hours and then gavaged with 1.5 mg glucose per gram body weight. In the experiments in FIG. 7A, 50 μg/kg body weight of recombinant protein was mixed into glucose solution and administered immediately to mice by gavage. In blocking antibody experiments, integrins αv (clone RMV-7) and β5 (clone ALULA) were administered orally with 100 μL water containing 0.5 μg antibody per gram body weight 30 minutes before glucose gavage. Blood glucose levels were measured by sampling from the tail vein of mice from 0-60 minutes after glucose administered. Fecal Fatty Acid Content. 6-8 week-old mice were fasted for 4 hours and then gavaged with 2 μg BODIPY per gram body weight. Feces were collected from 20 minutes to 4 hours after BODIPY administered. 50 mg of feces was homogenized in PBS contained 30 mM HEPES, 57.51 mM MgCl2 and 0.57 mg/ml BSA with 0.5% SDS and sonicated for 30 seconds, and then centrifuged at 1000 g for 10 minutes. Supernatants were transferred to 96 well plates and Fluorescence values were measured immediately using a fluorescence microplate reader for endpoint reading (Molecular Devices). Primary Adipocyte, Hepatocyte, Enterocyte, and Adipocyte Progenitor Culture. Adipocytes. Primary mouse adipocytes were obtained from epididymal fat pads by collagenase digestion in Krebs-HEPES (KRBH) buffer followed by filtering through a 100 μm strainer which was then washed with an additional 7.5 mL KRBH buffer. Adipocytes were allowed to float to the top of the mixture for 5 minutes, and the solution under the adipocyte layer was removed with a syringe. The adipocytes were washed with 10 mL KRBH and again allowed to float to the surface, at which point the solution was again removed. This process was repeated for a total of 3 washes. After the last aspiration, adipocytes were resuspended in 0.5-1.0 mL and counted. Adipocyte Progenitors. Primary mouse adipocyte progenitors from the vascular stromal fraction were isolated and cultured as reported previously (Tseng et al., 2008). In brief, subcutaneous white adipose tissue was removed, minced and digested with 1 mg/ml collagenase for 45 min at 37° C. in DMEM/F12 medium containing 1% BSA and antibiotics. Digested tissues were filtered through sterile 150 μm nylon mesh and centrifuged at 250 g for 5 min. The floating fractions consisting of adipocytes were discarded and the pellets representing the stromal vascular fractions were resuspended in erythrocyte lysis buffer (154 mM NH4Cl, 10 mM KHCO3, 0.1 mM EDTA) for 10 min to remove red blood cells. The cells were further centrifuged at 500 g for 5 min, plated at 8×105 per well of a 24-well plate, and grown at 37° C. in DMEM/F12 supplemented with 10% FBS at 37° C. 2 days after cells reached 100% confluence, cells were treated with 1 μM rosiglitazone and 5 μg/mL insulin to induce terminal differentiation. Primary Hepatocytes. The liver was pre-perfused through the portal vein with calcium-free buffer (0.5 mM EDTA, HBSS without Ca2+ and Mg2+) and next perfused with collagenase (3.5 U/ml Collegenase II (Worthington) 25 mM HEPES, HBSS with Ca2+ and Mg2+). Parenchymal cells were purified by Percoll buffer (90% Percoll (Sigma), 1×PBS) at low-speed centrifugation (1500 rpm for 10 min). Viability of isolated hepatocytes was determined by Trypan blue staining (around 85%) and cell density was approximately 60% confluence. Cells were plated in collagen-I-coated dishes and cultured at 37° C. in a humidified atmosphere of 95% O2 and 5% CO2 in growth medium (Huang, P. et al., Nature 475, 386-389 (2011)). Primary Enterocytes. The proximal small intestine was collected from anesthetized mice, and the luminal contents were emptied, washed with 115 mM NaCl, 5.4 mM KCl, 0.96 mM NaH2PO4, 26.19 mM NaHCO3, and 5.5 mM glucose buffer, pH 7.4, and gassed for 30 minutes with 95% O2 and 5% CO2. The proximal small intestines were then filled with buffer containing 67.5 mM NaCl, 1.5 mM KCl, 0.96 mM NaH2PO4, 26.19 mM NaHCO3, 27 mM sodium citrate, and 5.5 mM glucose, pH 7.4, saturated with 95% O2 and 5% CO2, and incubated in a bath containing oxygenated saline at 37° C. with constant shaking After 15 minutes, the luminal solutions were discarded and the intestines were filled with buffer containing 115 mM NaCl, 5.4 mM KCl, 0.96 mM NaH2PO4, 26.19 mM NaHCO3, 1.5 mM EDTA, 0.5 mM dithiothreitol, and 5.5 mM glucose, pH 7.4, saturated with 95% O2 and 5% CO2, and bathed in saline as described above. After 15 minutes, the luminal contents were collected and centrifuged (1,500 rpm, 5 minutes, room temperature), and the pellets were resuspended in DMEM saturated with 95% O2 and 5% CO2=(Anwar, K. et al., J Lipid Res 48, 2028-2038 (2007)). Primary Cardiomyocytes. Hearts were immersed in ice-cold calcium-free perfusion buffer containing (in mmol/L) NaCl 120.4, KCl 14.7, KH2PO4 0.6, Na2HPO4 0.6, 5 MgSO4-7H2O 1.2, Na-HEPES 10, NaHCO3 4.6, taurine 30, butanedione monoxime (BDM) 10, glucose 5.5, and then perfused through the aorta with calcium-free perfusion buffer (3 ml/minutes) for 4 minutes, then switched to calcium-free digestion buffer (perfusion buffer containing collagenase II [2 mg/ml] from Worthington Biochemical) for 10 minutes. This was followed by perfusion with digestion buffer containing 100 μmol/L CaCl2 for another 8-10 minutes. Hearts were removed from the perfusion apparatus and placed in a 10 cm Petri dish containing 2 ml digestion buffer and 3 ml of stop buffer (perfusion buffer supplemented with 10% FBS). The atria were removed and the ventricles were pulled into 10-12 equally sized pieces. Tissue was then gently dispersed into cell suspension using plastic transfer pipettes. The cell suspension was collected in a 15 ml falcon tube, brought to 10 ml with stop buffer and centrifuged at 40×g for 3 minutes. Damaged myocytes and non-myocytes were removed by a series of washes in 10 ml stop buffer containing, sequentially, 100, 400, or 900 μmol/L CaCl2. Cardiomyocytes were pelleted by centrifugation at 40×g for 3 minutes after each wash and plated in laminin coated dishes (Smyth, J. W. et al., Circ Res 110, 978-989 (2012)). Recombinant Protein Production. Recombinant protein constructs were created and expressed in High 5 cells as previously described (Atabai, K. et al., J Clin Invest 119, 3713-3722 (2009)). For studies using different recombinant constructs the molar equivalent of 10 μg/mL of full-length recombinant Mfge8 was used for each construct. Western Blot. Following tissue preparation and SDS-PAGE, membranes were incubated with a polyclonal antibody against Akt (Cell Signaling Technology), or Rictor (Cell Signaling); Anti-PGC1 alpha antibody (abcam); a monoclonal antibody against Phospho-Akt Ser473 (Cell Signaling), Phospho-Rictor Thr1135 (Cell Signaling), GAPDH (Cell Signaling), or Mfge8 (R&D Systems). For evaluation of total AKT and total Rictor, membranes that been blotted for phospho-AKT and phospho-Rictor were stripped and reprobed. Plasma membrane and post-plasma membrane fractions were isolated as previously described (Nishiumi, S. & Ashida, H., Biosci Biotechnol Biochem 71, 2343-2346 (2007)). Immunohistochemistry. 5 μm sections were boiled for 15 minutes in 10 mM sodium citrate (pH 6) for antigen retrieval and blocked with H2O2 in methanol and subsequently 2% BSA. Rabbit anti-MAC2 antibody (Cedarlane, CL8942AP) directed against MAC2 was used at 1:3800 dilution in TBS and 0.5% tween, followed by a 1:200 biotinylated anti-rabbit secondary antibody (Vector), ABC reagent (Vector) and liquid diaminobenzidine substrate (Sigma). Morphometric Analysis. Paraffin embedded eWAT sections from 5 CD and 10 HFD mice were stained with H&E. For each section 5 high-power field (HPF) pictures were taken at 100× magnification. The average number of adipocytes per HPF for each section was counted and the diameter of each adipocyte was measured using Image-Pro Plus MDA. Investigators were blinded to genotype during quantification. Flow Cytometry. Epididymal fat pads were dissected, weighed, and placed in a buffered collagenase solution for homogenization using a GentleMACS tissue dissociator. Homogenized tissue was incubated at 37° C. on a rotating shaker at 250 rpm for 30 minutes, then passed through a 40 um strainer and rinsed with 10 mL ice-cold PBS. After a red blood cell lysis step, cells were stained for viability using a LIVE/DEAD aqua fixable stain kit (Invitrogen, Carlsbad, Calif.) and then for the following stains to identify macrophage subtype and eosinophil populations: CD45 (clone 30-F11, BioLegend, San Diego, Calif.), CD11b (clone M1/70, BioLegend), F4/80 (clone BM8, BioLegend), CD11c (clone N418, BioLegend), CD301 (clone ER-MP23, AbdSerotec, Oxford, United Kingdom), Siglec (clone E50-2440, BD Pharmingen, San Diego, Calif.). A second set of cells from the fat pads were similarly stained for viability and then with the following antibodies to identify lymphocyte populations: CD45, CD4 (clone RM4-4, BioLegend), CD44 (clone IM7, Ebioscience), CD62L (clone MEL-14, BD Pharmingen), and FoxP3 (clone FJK-16s, Ebioscience, San Diego, Calif.). Spleens were removed after sacrificing ironic within. The splenocytes were treated to lyse red blood cells and subsequently stained for viability and the lymphocyte markers detailed above. Flow cytometry was performed on a BD FACS flow cytometer and analyzed using FlowJo Software (Tree Star Inc., Ashland, Oreg.). Body Fat Analysis. Bone, lean, and fat mass analysis was performed with GE Lunar PIXImus II Dual Energy X-ray Absorptiometer. CLAMS Metabolic Cage Analysis. Mice were placed in single housing cages for 5 days prior to initiating experimental analysis for a period of 96 hours. Mice were on a HFD for 10 days prior to initiating the analysis. The following variables were measured: food and water intake, oxygen consumption (VO2) and carbon dioxide production (VCO2) (at 13 minute intervals), and locomotor activity. Infrared beams monitored movement in the X, Y, and Z directions. The data presented was from the last 48 hours of the analysis (Sutton, G. M. et al., Endocrinology 147, 2183-2196 (2006)). Measurements of Fecal Energy Content. Feces from mice on a HFD were freeze dried (samples from 2 mice were combined for each sample) and pulverized with a ceramic mortar and pestle. Caloric content of feces was measured with an 1108 Oxygen Combustion Bomb calorimeter. Insulin Tolerance Tests. For insulin tolerance test, mice were fasted for 5 hours after which they were injected with 1.5 U/kg of insulin IP. Blood was collected from the tail vein immediately before injection and then again after 15, 30, 60, and 90 minutes for evaluation of blood glucose. Statistical Analysis Data were assessed for normal distribution and similar variance between groups using Graphpad Prism 6.0. One-way ANOVA was used to make comparisons between multiple groups. When the ANOVA comparison was statistically significant (P<0.05), further pairwise analysis was performed using a Bonferroni t-test. 2-sided Student's t-test, Mann-Whitney t-test or unpaired t-test with Welch's correction was used for comparisons between 2 groups depending on the distribution and variance of the data. GraphPad Prism 6.0 was used for all statistical analysis. All data are presented as mean±s.e.m. Sample size for animal experiments were selected based on numbers typically used in the literature. There was no randomization of animals. Example 2 Mfge8 Modulates Glucose Uptake In Vitro and In Vivo This example illustrates that the administration of recombinant Mfge8 (rMfge8) induces acute insulin resistance in cultured adipocytes and in vivo, while the administration of αv or β5 integrin blocking antibodies significantly increased the effect of insulin on glucose uptake in vitro and in vivo. This example also shows that IP co-administration of rMfge8 and insulin in mice resulted in significantly higher serum glucose levels as compared with insulin injection alone. Furthermore, pretreatment with αv or β5 integrin blocking antibody prior to insulin injection resulted in significantly lower serum glucose levels after insulin injection as compared to insulin injection alone. FIG. 9 shows that Mfge8 induces insulin resistance in 3T3-L1 adipocytes. Glucose uptake in 3T3-L1 adipocyte with and without 20 min treatment with recombinant Mfge8 or RGE (10 μg/ml) and insulin (1 μM) or both mfge8 and insulin (n=8, P<0.05). Data are expressed as mean±s.e.m. Each replicate represents an independent experiment. FIG. 10 shows that integrin receptor blockade enhances insulin sensitivity in primary adipocytes. Glucose uptake in Mfge8−/− and Mfge8+/+ primary adipocytes, with and without 20 min treatment with insulin (1 μM) and effect of pretreatment with integrin blocking antibodies (0.5 μg/g, IP, 15 min before insulin) on glucose uptake in Mfge8+/+ adipocytes. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=8, P<0.05). Pretreatment with αv, b3 or b5 integrin blocking antibody prior to insulin injection resulted in significantly lower serum glucose levels after insulin injection as compared with insulin injection alone. FIG. 11 shows that Mfge8 induces acute insulin resistance in vivo. 8-week-old Mfge8−/− and Mfge8+/+ control mice were fasted for 4 hours, then blood glucose was measured 15 min after IP injection of insulin (1 U/kg), saline, RGE (50 μg/kg) or a combination of insulin (1.5 U/Kg) and rMfge8 or RGE construct (50 μg/kg). Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=4, P<0.05). FIG. 12 shows that integrin blockade induces acute insulin sensitivity in vivo. 8-week-old Mfge8−/− and Mfge8+/+ control mice were fasted for 4 hours, then received blocking antibodies (0.5 μg per gram body weight) (αv (clone RMV-7) and βv (clone ALULA)) IP. 15 min prior insulin (1 U/kg) or saline, blood glucose was measured 15 min after IP injection of insulin (1 U/kg) or saline. Data are expressed as mean±s.e.m. Each replicate represents an independent experiment (n=4, P<0.05). While recombinant Mfge8 (rMfge8) had no effect on baseline glucose uptake, rMfge8 significantly inhibited while αv or 05 integrin blocking antibodies significantly increased the effect of insulin on glucose uptake in both 3T3-L1 adipocytes and primary WT adipocytes. IP co-administration of rMfge8 and insulin in mice resulted in significantly higher while pretreatment with αv or 05 integrin blocking antibody prior to insulin injection resulted in significantly lower serum glucose levels after insulin injection as compared with insulin injection alone. These data indicate that Mfge8 acutely modulates the glucose uptake response to insulin. Co-injection of αv or 05 integrin blocking antibodies with insulin may reduce insulin requirements by approximately 50%. Systemic therapy with αv or 05 integrin blocking antibodies may enhance insulin sensitivity in at-risk populations of individuals. Glucose Uptake Assay. Uptake of fatty acids by primary cells and cell lines was assessed using the fluorescent D-glucose analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) (Invitrogen). 2-NBDG has been successfully used as an alternative to 2-deoxyglucose in the measurement of glucose uptake in multiple cell types. Cells were plated in triplicate in 96-well plates at a concentration of 25,000 cells per well in 100 μl of DMEM/10% FCS. Plates were centrifuged at 1000 rpm for 4 minutes and incubated at 37° C. for 4-5 hours. Cells were then serum deprived for 1 hour before treatment with recombinant proteins for 20 minutes followed by the addition of 2-NBDG (100 μM) for 10 min at 37° C. in a humidified atmosphere of 5% CO2. Reaction was stopped by adding a twofold volume of ice-cold PBS and the wells were washed again with ice-cold PBS three times. The fluorescent signal before (autofluorescence) and after adding 100 μM 2-NBDG was measured using fluorescent plate reader at 37° C. (Molecular Device using the 485 nmex and 520 nmemiss filter set). The net increase in fluorescence was normalized to the lowest signal (0 cells/well). In experiments using function-blocking antibodies, antibodies against mouse integrins αv (clone RMV-7), P3 (clone 2C9.G2; BD Biosciences), β5 (clone ALULA), β1 (clone HA2/5; BD Biosciences), anti-rat with cross-reactivity with mouse, were added to cells after serum deprivation and cells were incubated for 20 minutes prior to addition of recombinant proteins. Insulin Tolerance Test. Mice were fasted for 4 hours after which they were injected with 1.5 U/kg of insulin IP. Blood was collected from the tail vein immediately before injection and then again after 15, 30, 60, and 90 minutes for evaluation of blood glucose. Blood Glucose Measurement. In experiments using RGE or Mfge8 construct: mice received 50 μg/kg body weight of recombinant protein. In experiments using function-blocking antibodies: 6-8 week-old mice were fasted for 4 hours and then each mouse received 0.5 μg antibody (integrins αv (clone RMV-7) and (35 (clone ALULA)) per gram body weight in total volume of 200 μl, 15 minutes later each mouse received an insulin injection (1.5 U/kg, intraperitoneal injection (IP)). Blood glucose levels were measured by sampling from the tail vein of mice from 15 minutes after insulin administered. EXAMPLE Mfge8 Modulates Glucose Uptake In Vitro and In Vivo This example illustrates enhanced, antral smooth muscle contraction in Mfge8−/− mice. It also shows that PI3K inhibition prevented exaggerated Mfge8−/− antral ring contraction. FIGS. 13A-13C show the force of antral smooth muscle ring contraction with and without the addition of the rMfge8 or RGE construct (FIG. 13A) or after in vivo induction of transgenic Mfge8 expression in Mfge8−/−sm+ mice in response to MCh (FIG. 13B). FIG. 13C shows the force of antral contraction with and without epithelium (denuded). Mfge8−/− mice have enhanced gastric emptying and more rapid small intestine transit time (SIT). FIGS. 13D and 13E show that gastric emptying was measured by the proportion of phenol red remaining in the stomach 15 minutes after gavage. N=7-10. FIGS. 13F and 13G shows small intestinal transit times after gavage with Carmine dye with subsequent evaluation at 15 minutes of dye migration along the intestinal tract. N=5-10 in FIG. 13C and 3-5 in FIG. 13D. In FIGS. 13E and 13G, Mfge8−/−sm+ and single transgenic controls were placed on doxycycline for 2 weeks prior to the experiments to induce Mfge8 production in the smooth muscle. *P<0.05, **P<0.01, ***P<0.001. In FIG. 14A, the antral rings were treated for 15 min with PI3K inhibitor wortmannin (Wort.100 nm) followed by assessment of contractile force in response to MCh. N=3-4. *** P<0.0001. FIG. 14B shows that Mfge8 reduces AKT phosphorylation. Western blot of antral tissue were treated for 30 minutes with or without rMfge8. FIG. 14C shows that wortmannin prevents RhoA activation. Western blot of antrum were treated for 30 minutes with wortmannin (100 ng/ml) or Mfge8 and then with MCh for 15 minutes prior to quantifying active RhoA using a GST pull-down. FIG. 14D shows that Mfge8 modulates PTEN activity. PTEN activity assay measured the conversion of PIP3 to PIP2 in freshly isolated antrum with and without the rMfge8 or RGE construct (10 μg/ml) n=3-5. *P<0.05, **P<0.01, ***P<0.001. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.",C07K162848,C07K1628,20160114,20180626,20160602,69562.0
5,14995057,PENDING,Systems and Methods for Intra-Operative Image Analysis,"A system and method that acquire (i) at least a reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least an intraoperative image of the site after an implant has been affixed to the articulating bone. The system generates at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. The reference and intraoperative images are compared, and differences between the orientation of the articulating bone in the two images are utilized to analyze at least one of offset and length differential.","1. A system to analyze images at a surgical site within a patient, the surgical site including at least one skeletal bone and at least one articulating bone that has a longitudinal axis and articulates with the skeletal bone at a joint, the system comprising: an image capture module capable of acquiring (i) at least one reference image including one of a preoperative image of the surgical site and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one intraoperative image of the site after an implant has been affixed to the articulating bone, the implant having at least a skeletal component with a first center of rotation and an articulating bone component having a second center of rotation, the first and second centers of rotation being co-located in the intraoperative image; a landmark identification module capable of receiving the reference and intraoperative images and generating at least one reference landmark point on at least the articulating bone in the reference image and at least one intraoperative landmark point on at least the articulating bone in the intraoperative image; an image comparison module capable of identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image; and an analysis module capable of utilizing differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image to analyze at least one of offset and length differential of at least the articulating bone in the intraoperative image. 2. The system of claim 1 wherein the reference and intraoperative images are provided by the image capture module to the landmark identification module in a digitized format. 3. The system of claim 1 wherein the analysis module calculates a difference angle between the longitudinal axis of the femur in the reference image relative to the longitudinal axis of the femur in the intraoperative image and then estimates a corrected landmark point based on that difference angle. 4. The system of claim 3 wherein the analysis module estimates a corrected intraoperative landmark point by calculating a first radius between the estimated center of rotation and the intraoperative landmark and then selecting the corrected intraoperative landmark point at a second radius spaced at the difference angle from the first radius. 5. The system of claim 3 wherein the analysis module calculates length differential by estimating distance from the reference landmark point to a corrected intraoperative landmark point in a direction parallel to the longitudinal axis of the femur in the reference image. 6. The system of claim 3 wherein the analysis module calculates offset by estimating distance from the reference landmark point to a corrected intraoperative landmark in a direction perpendicular to the longitudinal axis of the femur in the reference image. 7. The system of claim 1 wherein (a) at least one of the image comparison module, the landmark identification module and the image comparison module identifies at least one stationary point on the skeletal bone in each of the reference image and intraoperative image, and (b) at least one of the image comparison module, the landmark identification module and the image comparison module aligns the reference image and intraoperative image according to at least the stationary point in each image. 8. The system of claim 7 wherein aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. 9. The system of claim 1 wherein the reference image and the intraoperative image are at least one of aligned and scaled relative to each other prior to the analysis module analyzing offset and length differential. 10. The system of claim 9 wherein at least two stationary points are generated on the skeletal bone in the reference image to establish a reference stationary base and at least two stationary points are generated on the skeletal bone in the intraoperative image to establish an intraoperative stationary base, and at least one of the image comparison module, the landmark identification module and the image comparison module utilizes the reference and intraoperative stationary bases to accomplish at least one of image alignment and image scaling. 11. The system of claim 9 wherein at least one of the image comparison module, the landmark identification module and the image comparison module provides at least relative scaling of one of the reference and intraoperative images to match the scaling of the other of the reference and intraoperative images. 12. A system to analyze images at a surgical site within a patient, the surgical site including at least one skeletal bone and at least one articulating bone that has a longitudinal axis and articulates with the skeletal bone at a joint, the system including a memory, a user interface including a display capable of providing at least visual guidance to a user of the system, and a processor, with the processor executing a program performing the steps of: acquiring (i) at least one digitized reference image including one of a preoperative image of the surgical site and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one digitized intraoperative image of the site after an implant has been affixed to the articulating bone, the implant having at least a skeletal component with a first center of rotation and an articulating bone component having a second center of rotation, the first and second centers of rotation being co-located in the intraoperative image; generating at least one reference landmark point on at least the articulating bone in the reference image and at least one intraoperative landmark point on at least the articulating bone in the intraoperative image; identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image; and utilizing differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in and the intraoperative image to analyze at least one of offset and length differential of at least the articulating bone in the intraoperative image. 13. The system of claim 12 wherein aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. 14. A method for analyzing images to quantify restoration of orthopaedic functionality at a surgical site within a patient, the surgical site including at least one skeletal bone and at least one articulating bone that has a longitudinal axis and articulates with the skeletal bone at a joint, the method comprising: acquiring (i) at least one reference image including one of a preoperative image of the surgical site and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one intraoperative image of the site after an implant has been affixed to the articulating bone, the implant having at least a skeletal component with a first center of rotation and an articulating bone component having a second center of rotation, the first and second centers of rotation being co-located in the intraoperative image; generating at least one reference landmark point on at least the articulating bone in the reference image and at least one intraoperative landmark point on at least the articulating bone in the intraoperative image; identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image; and utilizing differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image to analyze at least one of offset and length differential of at least the articulating bone in the intraoperative image. 15. The method of claim 14 wherein aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. 16. The method of claim 14 wherein the pelvis of the patient is selected as the skeletal bone and a femur is selected as the articulating bone, and the skeletal component of the implant is an acetabular cup and the articulating bone component includes a femoral stem pivotally connectable to the acetabular cup to establish the first center of rotation for the implant. 17. The method of claim 16 wherein the landmark point on the articulating bone is identified to have a known location relative to the greater trochanter on the femur of the patient. 18. The method of claim 14 wherein the reference and intraoperative images are acquired in a digitized format. 19. The method of claim 18 wherein the length differential is calculated by estimating distance from the reference landmark point to a corrected intraoperative landmark point in a direction parallel to the longitudinal axis of the femur in the reference image. 20. The method of claim 19 wherein the offset is calculated by estimating distance from the reference landmark point to a corrected intraoperative landmark in a direction perpendicular to the longitudinal axis of the femur in the reference image.","<SOH> BACKGROUND OF THE INVENTION <EOH>Orthopaedic surgeons have the option of utilizing computer-assisted navigation systems to provide intraoperative surgical guidance. For example, computer navigation can provide data on functional parameters such as leg length and offset changes during hip arthroplasty. The purported benefits of computer navigation include reduction of outliers and adverse outcomes related to intraoperative positioning of surgical hardware. Despite obvious clinical benefit, these systems have had limited adoption due to their expense, the learning curve and training requirements for surgeons and, for some systems, the additional procedure and time associated with hardware insertion into the patient. Surgeons that do not use these systems are limited to traditional techniques that are generally based on visual analysis and surgeon experience. However, these techniques are inconsistent, often leading to outliers in functional parameters which may affect patient satisfaction and implant longevity. Details of one such technique, specifically used in a minimally invasive hip arthroplasty technique referred to as the direct anterior approach, are mentioned in the description of a total hip arthroplasty surgery, by Matta et al. in “Single-incision Anterior Approach for Total hip Arthroplasty on an Orthopaedic Table”, Clinical Ortho. And Related Res. 441, pp. 115-124 (2005). The intra-operative technique described by Matta et al. is time-consuming and has a high risk of inaccuracy due to differences in rotation, magnification and/or scaling of various images, because the technique relies upon acquiring a preoperative and intraoperative image that are scaled and positioned equivalently. The technique also requires consistent patient positioning in the preoperative and intraoperative images, including positioning of the femur relative to the pelvis. Maintaining femoral position while performing hip arthroplasty can pose a significant and often unrealistic challenge to a surgeon that is focused on performing a procedure. The high risk of inaccurate interpretation using this technique has limited its utility in guiding surgical decision making. What appears to be a software implementation of this technique is described by Penenberg et al. in U.S. Patent Publication No. 2014/0378828, which is a continuation-in-part application of U.S. Pat. No. 8,831,324 by Penenberg. While the use of a computer system may facilitate some aspects of this technique, the underlying challenges to the technique are consistent with the challenges to Matta's approach, and limit the system's potential utility. The challenge of accounting for differences in femoral positioning, ever-present in existing non-invasive guidance technologies for hip arthroplasty, could be solved by developing a system and method that corrects for deviations between preoperative and intraoperative femoral positioning. It is therefore desirable to have a non-invasive system and method that provides intraoperative guidance and data by correcting for deviations in femoral positioning between preoperative and intraoperative images.","<SOH> SUMMARY OF THE INVENTION <EOH>An object of the present invention is to quantify restoration of orthopaedic functionality at a surgical site within a patient, even during a surgical procedure. Another object of the present invention is to provide image analysis and feedback information to enable better fracture reduction and/or optimal implant selection during the surgery. Yet another object of the present invention is to capture and preserve a digital record of patient results for data collection and quality improvements in surgical procedures. A still further object of the present invention is to improve the outcome of bone repositioning, fracture repair, and/or fixation within a patient. This invention results from the realization that postoperative change in offset and leg length can be accurately estimated during surgery by overlaying or otherwise comparing preoperative and intraoperative images that have been consistently scaled based on pelvic anatomy, generating consistent femoral landmarks in each image, and calculating the vector difference between femoral landmarks after correcting for possible differences in femoral positioning between the two images relative to the pelvis. This invention features a system to analyze images at a surgical site within a patient, the surgical site including at least one skeletal bone such as a pelvis and at least one articulating bone such as a femur that has a longitudinal axis and articulates with the skeletal bone at a joint. In one embodiment, the system includes an image capture module capable of acquiring (i) at least one reference image including one of a preoperative image of the surgical site and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least an intraoperative image of the site after an implant has been affixed to the articulating bone. A landmark identification module is capable of receiving the reference and intraoperative images and generates at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. An image comparison module is capable of identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. An analysis module is capable of utilizing differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image to analyze at least one of offset and length differential. In some embodiments, the first and second images are provided by the image capture module to the landmark identification module in a digitized format. In certain embodiments, the analysis module calculates a difference angle between the longitudinal axis of the femur in the reference image relative to the longitudinal axis of the femur in the intraoperative image and then estimates a corrected landmark point, such as a corrected intraoperative landmark point, based on that difference angle. In one embodiment, the analysis module estimates the corrected intraoperative landmark point by calculating a first radius between the estimated center of rotation and the intraoperative landmark and then selecting the corrected intraoperative landmark point at a second radius spaced at the difference angle from the first radius. In certain embodiments, the analysis module calculates length differential by estimating distance from the reference landmark point to the corrected intraoperative landmark point in a direction parallel to the longitudinal axis of the femur in the reference image, and/or calculates offset by estimating distance from the reference landmark point to the corrected intraoperative landmark in a direction perpendicular to the longitudinal axis of the femur in the reference image. In certain embodiments, at least one of the image comparison module, the landmark identification module and the image comparison module identifies at least one stationary point on the skeletal bone in each of the reference image and intraoperative image, and at least one of the image comparison module, the landmark identification module and the image comparison module aligns the reference image and intraoperative image according to at least the stationary point in each image. In one embodiment, aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. In some embodiments, the reference image and the intraoperative image are at least one of aligned and scaled relative to each other prior to the analysis module analyzing offset and length differential. In one embodiment, at least two stationary points are generated on the skeletal bone in the reference image to establish a reference stationary base and at least two stationary points are generated on the skeletal bone in the intraoperative image to establish an intraoperative stationary base, and at least one of the image comparison module, the landmark identification module and the image comparison module utilizes the reference and intraoperative stationary bases to accomplish at least one of image alignment and image scaling. In another embodiment, at least one of the image comparison module, the landmark identification module and the image comparison module provides at least relative scaling of one of the reference and intraoperative images to match the scaling of the other of the reference and intraoperative images. This invention also features a system including a memory, a user interface having a display capable of providing at least visual guidance to a user of the system, and a processor, with the processor executing a program performing the steps of acquiring (i) at least one digitized reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one digitized intraoperative image of the site after an implant has been affixed to the articulating bone. The processor receives the reference and intraoperative images and generates at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. The processor identifies (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. One or more differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image are utilized to analyze at least one of offset and length differential. This invention further features a method including acquiring (i) at least one reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one intraoperative image of the site after an implant has been affixed to the articulating bone. The method further includes receiving the reference and intraoperative images and generating at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. The method includes identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. One or more differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image are utilized to analyze at least one of offset and length differential. In some embodiments, aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. In certain embodiments, the pelvis of the patient is selected as the skeletal bone and a femur is selected as the articulating bone, and the skeletal component of the implant is an acetabular cup and the articulating bone component includes a femoral stem having a shoulder and pivotally connectable to the acetabular cup to establish the first center of rotation for the implant. The landmark point on the articulating bone is identified to have a known location relative to the greater trochanter on the femur of the patient.","CROSS-REFERENCE TO RELATED APPLICATION This application is a continuation-in-part application of U.S. patent application Ser. No. 14/630,300 filed 24 Feb. 2015, also referred to as “parent application”, and claims priority to U.S. Provisional Application No. 61/944,520 filed 25 Feb. 2014, U.S. Provisional Application No. 61/948,534 filed 5 Mar. 2014, U.S. Provisional Application No. 61/980,659 filed 17 Apr. 2014, U.S. Provisional Application No. 62/016,483 filed 24 Jun. 2014, U.S. Provisional Application No. 62/051,238 filed 16 Sep. 2014, U.S. Provisional Application No. 62/080,953 filed 17 Nov. 2014, and U.S. Provisional Application No. 62/105,183 filed 19 Jan. 2015. This application is also related to U.S. patent application Ser. No. 14/974,225, filed 18 Dec. 2015, by the present inventors. The entire contents of each of the above applications are incorporated herein by reference. FIELD OF THE INVENTION The invention relates to analysis of images of features within a patient and more particularly to accurately analyzing such images during surgery. BACKGROUND OF THE INVENTION Orthopaedic surgeons have the option of utilizing computer-assisted navigation systems to provide intraoperative surgical guidance. For example, computer navigation can provide data on functional parameters such as leg length and offset changes during hip arthroplasty. The purported benefits of computer navigation include reduction of outliers and adverse outcomes related to intraoperative positioning of surgical hardware. Despite obvious clinical benefit, these systems have had limited adoption due to their expense, the learning curve and training requirements for surgeons and, for some systems, the additional procedure and time associated with hardware insertion into the patient. Surgeons that do not use these systems are limited to traditional techniques that are generally based on visual analysis and surgeon experience. However, these techniques are inconsistent, often leading to outliers in functional parameters which may affect patient satisfaction and implant longevity. Details of one such technique, specifically used in a minimally invasive hip arthroplasty technique referred to as the direct anterior approach, are mentioned in the description of a total hip arthroplasty surgery, by Matta et al. in “Single-incision Anterior Approach for Total hip Arthroplasty on an Orthopaedic Table”, Clinical Ortho. And Related Res. 441, pp. 115-124 (2005). The intra-operative technique described by Matta et al. is time-consuming and has a high risk of inaccuracy due to differences in rotation, magnification and/or scaling of various images, because the technique relies upon acquiring a preoperative and intraoperative image that are scaled and positioned equivalently. The technique also requires consistent patient positioning in the preoperative and intraoperative images, including positioning of the femur relative to the pelvis. Maintaining femoral position while performing hip arthroplasty can pose a significant and often unrealistic challenge to a surgeon that is focused on performing a procedure. The high risk of inaccurate interpretation using this technique has limited its utility in guiding surgical decision making. What appears to be a software implementation of this technique is described by Penenberg et al. in U.S. Patent Publication No. 2014/0378828, which is a continuation-in-part application of U.S. Pat. No. 8,831,324 by Penenberg. While the use of a computer system may facilitate some aspects of this technique, the underlying challenges to the technique are consistent with the challenges to Matta's approach, and limit the system's potential utility. The challenge of accounting for differences in femoral positioning, ever-present in existing non-invasive guidance technologies for hip arthroplasty, could be solved by developing a system and method that corrects for deviations between preoperative and intraoperative femoral positioning. It is therefore desirable to have a non-invasive system and method that provides intraoperative guidance and data by correcting for deviations in femoral positioning between preoperative and intraoperative images. SUMMARY OF THE INVENTION An object of the present invention is to quantify restoration of orthopaedic functionality at a surgical site within a patient, even during a surgical procedure. Another object of the present invention is to provide image analysis and feedback information to enable better fracture reduction and/or optimal implant selection during the surgery. Yet another object of the present invention is to capture and preserve a digital record of patient results for data collection and quality improvements in surgical procedures. A still further object of the present invention is to improve the outcome of bone repositioning, fracture repair, and/or fixation within a patient. This invention results from the realization that postoperative change in offset and leg length can be accurately estimated during surgery by overlaying or otherwise comparing preoperative and intraoperative images that have been consistently scaled based on pelvic anatomy, generating consistent femoral landmarks in each image, and calculating the vector difference between femoral landmarks after correcting for possible differences in femoral positioning between the two images relative to the pelvis. This invention features a system to analyze images at a surgical site within a patient, the surgical site including at least one skeletal bone such as a pelvis and at least one articulating bone such as a femur that has a longitudinal axis and articulates with the skeletal bone at a joint. In one embodiment, the system includes an image capture module capable of acquiring (i) at least one reference image including one of a preoperative image of the surgical site and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least an intraoperative image of the site after an implant has been affixed to the articulating bone. A landmark identification module is capable of receiving the reference and intraoperative images and generates at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. An image comparison module is capable of identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. An analysis module is capable of utilizing differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image to analyze at least one of offset and length differential. In some embodiments, the first and second images are provided by the image capture module to the landmark identification module in a digitized format. In certain embodiments, the analysis module calculates a difference angle between the longitudinal axis of the femur in the reference image relative to the longitudinal axis of the femur in the intraoperative image and then estimates a corrected landmark point, such as a corrected intraoperative landmark point, based on that difference angle. In one embodiment, the analysis module estimates the corrected intraoperative landmark point by calculating a first radius between the estimated center of rotation and the intraoperative landmark and then selecting the corrected intraoperative landmark point at a second radius spaced at the difference angle from the first radius. In certain embodiments, the analysis module calculates length differential by estimating distance from the reference landmark point to the corrected intraoperative landmark point in a direction parallel to the longitudinal axis of the femur in the reference image, and/or calculates offset by estimating distance from the reference landmark point to the corrected intraoperative landmark in a direction perpendicular to the longitudinal axis of the femur in the reference image. In certain embodiments, at least one of the image comparison module, the landmark identification module and the image comparison module identifies at least one stationary point on the skeletal bone in each of the reference image and intraoperative image, and at least one of the image comparison module, the landmark identification module and the image comparison module aligns the reference image and intraoperative image according to at least the stationary point in each image. In one embodiment, aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. In some embodiments, the reference image and the intraoperative image are at least one of aligned and scaled relative to each other prior to the analysis module analyzing offset and length differential. In one embodiment, at least two stationary points are generated on the skeletal bone in the reference image to establish a reference stationary base and at least two stationary points are generated on the skeletal bone in the intraoperative image to establish an intraoperative stationary base, and at least one of the image comparison module, the landmark identification module and the image comparison module utilizes the reference and intraoperative stationary bases to accomplish at least one of image alignment and image scaling. In another embodiment, at least one of the image comparison module, the landmark identification module and the image comparison module provides at least relative scaling of one of the reference and intraoperative images to match the scaling of the other of the reference and intraoperative images. This invention also features a system including a memory, a user interface having a display capable of providing at least visual guidance to a user of the system, and a processor, with the processor executing a program performing the steps of acquiring (i) at least one digitized reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one digitized intraoperative image of the site after an implant has been affixed to the articulating bone. The processor receives the reference and intraoperative images and generates at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. The processor identifies (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. One or more differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image are utilized to analyze at least one of offset and length differential. This invention further features a method including acquiring (i) at least one reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one intraoperative image of the site after an implant has been affixed to the articulating bone. The method further includes receiving the reference and intraoperative images and generating at least one reference landmark point on at least one anatomical feature on the articulating bone in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. The method includes identifying (i) an estimation of at least the first center of rotation of the implant in at least one of the reference image and the intraoperative image and (ii) the longitudinal axis of the articulating bone in each of the reference image and intraoperative image. One or more differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image are utilized to analyze at least one of offset and length differential. In some embodiments, aligning includes overlaying one of the reference image and intraoperative image on the other of the reference image and intraoperative image. In certain embodiments, the pelvis of the patient is selected as the skeletal bone and a femur is selected as the articulating bone, and the skeletal component of the implant is an acetabular cup and the articulating bone component includes a femoral stem having a shoulder and pivotally connectable to the acetabular cup to establish the first center of rotation for the implant. The landmark point on the articulating bone is identified to have a known location relative to the greater trochanter on the femur of the patient. BRIEF DESCRIPTION OF THE DRAWINGS In what follows, preferred embodiments of the invention are explained in more detail with reference to the drawings, in which: FIG. 1 is a schematic image of a frontal, X-ray-type view of a pelvic girdle of a patient illustrating various known anatomical features; FIG. 2 is a schematic diagram illustrating how multiple types of user interfaces can be networked via a cloud-based system with data and/or software located on a remote server; FIG. 3 is a Flowchart G showing technique flow for both contralateral and ipsilateral analysis; FIG. 4 is a Flowchart W of several functions performed for hip analysis; FIG. 5 is an image of the right side of a patient's hip prior to an operation and showing a marker placed on the greater trochanter as a landmark or reference point; FIG. 6 is an image similar to FIG. 5 showing a reference line, drawn on (i) the pre-operative, ipsilateral femur or (ii) the contra-lateral femur, to represent the longitudinal axis of the femur; FIG. 7 is an image similar to FIG. 6 with a line drawn across the pelvic bone intersecting selected anatomical features; FIG. 8 is a schematic screen view of two images, the left-hand image representing a pre-operative view similar to FIG. 6 and the right-hand image representing an intra-operative view with a circle placed around the acetabular component of an implant to enable rescaling of that image; FIG. 9 is a schematic screen view similar to FIG. 8 indicating marking of the greater trochanter of the right-hand, intra-operative image as a femoral landmark; FIG. 10 is a schematic screen view similar to FIG. 9 with a reference line drawn on the intra-operative femur in the right-hand view; FIG. 11 is an image similar to FIGS. 7 and 10 with a line drawn across the obturator foramen in both pre- and intra-operative views; FIG. 12 is an overlay image showing the right-hand, intra-operative image of FIG. 11 superimposed and aligned with the left-hand, pre-operative image; FIG. 13 is an image similar to FIG. 11 with points marking the lowest point on the ischial tuberosity and points marking the obturator foramen and top of the pubic symphysis in both pre- and intra-operative views; FIG. 14 is an overlay image showing the right-hand, intra-operative image of FIG. 13 superimposed and aligned with the left-hand, pre-operative image utilizing triangular stable bases; FIG. 15 is a schematic combined block diagram and flow chart of an identification guidance module utilized according to aspects of the present invention; FIG. 16 is an image of a trial implant in a hip with the acetabular component transacted by a stationary base line and with two error analysis triangles; FIG. 17 is a flowchart showing the use of an ‘Image Overlay’ technique to calculate a postoperative change in offset and leg length according to an aspect of the present invention; FIG. 18 is a schematic diagram of an Image Analysis System according to the present invention; FIG. 19 is a schematic screen view of a preoperative image and an intraoperative image positioned side by side with digital annotations marking anatomic landmarks and stationary points on the images; FIG. 20 is a schematic screen view of the preoperative image and intraoperative image of FIG. 19 overlaid according to pelvic anatomy with generated femoral landmark points and error analysis according to another aspect of the present invention; FIG. 21 is a schematic diagram showing generation of a corrected landmark point and analysis of offset and length differential according to the present invention; FIG. 22 is a schematic screen view of a preoperative image and an intraoperative image positioned side by side with a grid and digital annotations to mark anatomic landmarks and other features on the images according to certain aspects of the present invention; and FIG. 23 is a schematic view similar to FIG. 22 after the preoperative image has been aligned with the intraoperative image. DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS This invention may be accomplished by a system and/or method that acquire (i) at least one reference image including one of a preoperative image of a surgical site with skeletal and articulating bones and a contralateral image on an opposite side of the patient from the surgical site, and (ii) at least one intraoperative image of the site after an implant has been affixed to the articulating bone. The reference and intraoperative images are received and at least one reference landmark point is generated on at least one anatomical feature on the articulating bone, such as on the greater trochanter of a femur, in the reference image and at least one intraoperative landmark point on that anatomical feature in the intraoperative image. At least the first center of rotation of the implant is estimated in at least one of the reference image and the intraoperative image, and the longitudinal axis of the articulating bone is identified in each of the reference image and intraoperative image. One or more differences between the orientation of the articulating bone in the reference image relative to the orientation of the articulating bone in the intraoperative image are utilized to analyze at least one of offset and length differential. Broadly, some techniques according to the present invention, referred to by the present inventors as “Image Overlay”, place one image over another image during analysis to generate a combined overlapped image. Previous approaches for the ‘Image Overlay’ technique made use of a pelvic reference line having two or more points to scale and align a preoperative image and an intraoperative image. The pelvic reference line having two or more points is also referred to as a “stationary base” as defined in U.S. patent application Ser. No. 14/630,300 filed 24 Feb. 2015, sometimes referred to herein as “parent application”, now US Publication No. 2015/0238271. Alternative approaches for ‘Image Overlay’ technique according to the present invention obviate the need for the pelvic reference line or other stationary base. In some constructions, these alternatives instead rely upon certain image acquisition techniques, certain image manipulation techniques, certain known imaging information, and/or direct user manipulation to create consistent scale and alignment between (i) at least one of a preoperative image and an inverted contralateral image and (ii) an intraoperative image. Additionally, any change in positioning of the femur in the two images, relative to the pelvis, would adversely affect calculations in previous approaches of this technique. Maintaining femoral position while performing hip arthroplasty can pose a significant and often unrealistic challenge to a surgeon that is focused on performing a surgical procedure. Various approaches for the ‘Image Overlay’ technique according to the present invention can correct for deviations in femoral positioning between preoperative and intraoperative images by mathematically correcting for any deviation in femoral position in at least one of the visual output and calculation output of offset and leg length. Presently preferred techniques, both with and without image overlay, are described in more detail below in relation to FIGS. 17-23. In general, accurate analysis of two images of a patient is directly related not only to how similar the two images are, but also how similarly the images are aligned with respect to scale and alignment, including rotation, and translation. Using conventional techniques, a user would have to manually adjust the images and/or retake multiple images to achieve this goal, something that would be difficult to do reliably and accurately. Utilizing two or more points as a stationary base according to the present invention in each image enables accurate analysis of the two images. Furthermore, the present Image Overlay technique can analyze how “similar” these images are to give the user feedback as to how accurate the results are, that is, to provide a confidence interval. To obtain useful information, the images (the “intraop” intra-operative image and a “preop” pre-operative image, for example) preferably are scaled similarly and rotated similarly, at least relative to each other. For some constructions of image analysis according to the present invention, preferably at least one stationary base and at least one anatomical landmark are selected, at least for scaling and alignment of the images. The term “stationary base”, also referred to herein as a “stable base”, means a collection of two or more points, which may be depicted as a line or other geometric shape, drawn on each of two or more images that includes at least one anatomical feature that is present in the two or more images of a region of a patient. For example, different images of a pelvic girdle PG of a patient, FIG. 1, typically show one or both obturator foramen OF and a central pubic symphysis PS, which the present inventors have recognized as suitable reference points or features for use as part of a stationary base according to the present invention. Other useful anatomical features, especially to serve as landmarks utilized according to the present invention, include femoral neck FN and lesser trochanter LT, shown on right femur FR, and femoral head FH and greater trochanter GT shown on left femur FL, for example. Femoral head FH engages the left acetabulum of the pelvic girdle PG. Also shown in FIG. 1 are ischial tuberosities IT at the bottom of the ischium, a “tear drop” TD relating to a bony ridge along the floor of the acetabular fossa, and the anterior superior iliac spine ASIS and the anterior inferior iliac spine AIIS of the ileum. In general, a longer stationary base is preferred over a shorter stationary base, because the longer base, especially if it is a line, will contain more pixels in images thereof and will increase accuracy of overlays and scaling according to the present invention. However, the further the stationary base is from the area of anatomical interest, the greater the risk of parallax-induced error. For example, if the area of interest is the hip joint, then the ideal stationary base will be near the hip. In some procedures involving hip surgery, for example, a stationary base line begins at the pubic symphysis PS, touches or intersects at least a portion of an obturator foramen OF, and extends to (i) the “tear drop” TD, or (ii) the anterior interior iliac spine AIIS. Of course, only two points are needed to define a line, so only two reliable anatomical features, or two locations on a single anatomical feature, are needed to establish a stationary base utilized according to the present invention. More complex, non-linear stationary bases may utilize additional identifiable points to establish such non-linear bases. Additionally, at least one identifiable anatomic “landmark”, “stationary point” or “error point”, or a set of landmarks stationary points or error points, is selected to be separate from the stationary base; the one or more landmarks, stationary points or error points are utilized in certain constructions to analyze the accuracy of the overlay process. This additional anatomic feature preferably is part of the stationary anatomy being anatomically compared. For example, the inferior portion of the ischial tuberosity IT can be identified as an additional stationary point or error point. This anatomic feature, in conjunction with the stationary base, will depict any differences or errors in pelvic anatomy or the overlay which will enable the physician to validate, or to have more confidence in, the output of the present system. As generally utilized herein: (i) a “stationary point” refers to a point on a relatively stationary bone such as on the pelvis; (ii) a “landmark point” is located on an articulating bone such as a femur; (iii) an “error point” is preferably on pelvis and spaced from other points; and (iv) a “fixed point” is located on an implant, such as the shoulder of a femoral stem prosthesis. The term “trial hip prosthetic” is utilized herein to designate an initial implant selected by a surgeon as a first medical device to insert at the surgical site, which is either the right side or the left side of a patient's hip in certain constructions. In some techniques, the trial prosthetic is selected based on initial digital templating similar to the procedure described the parent application. The term “digital representation” or “digital annotation” as utilized herein includes a digital line having at least two points, e.g. a line representing a longitudinal axis or a diameter of an implant or a bone, or a digital circle or other geometric shape which can be aligned with an implant or a bone intraoperatively and then placed in a corresponding location in a preoperative image, or visa versa. FIGS. 2-16 herein correspond to FIGS. 4B, 7-16, 52-54 and 70, respectively, in the parent application. FIG. 2 herein is a schematic diagram of system 141 according to the present invention illustrating how multiple types of user interfaces in mobile computing devices 143, 145, 147 and 149, as well as laptop 151 and personal computer 153, can be networked via a cloud 109 with a remote server 155 connected through web services. Data and/or software typically are located on the server 155 and/or storage media 157. Software to accomplish the techniques described herein is located on a single computing device in some constructions and, in other constructions such as system 141, FIG. 2, is distributed among a server 155 and one or more user interface devices which are preferably portable or mobile. In some techniques a digitized X-ray image of the hip region of a patient along a frontal or anterior-to-posterior viewing angle is utilized for a screen view on a display and, in other techniques, a digital photograph “secondary” image of a “primary” X-ray image of the hip region of a patient along a frontal or anterior-to-posterior viewing angle is utilized for the screen view. In one construction, the screen view is shown on a computer monitor and, in another construction, is shown on the screen or viewing region of a tablet or other mobile computing device. Flowchart G, FIG. 3, shows technique flow for both contralateral and ipsilateral analysis. This technique is commenced, step 340, and either contralateral or ipsilateral analysis is selected, step 342. For contralateral analysis, the contralateral hip image is captured, step 344, and the image is flipped, step 346. For ipsilateral analysis, the preoperative ipsilateral hip image is opened, step 348. For both types of analysis, Flowchart W is applied, step 350. Flowchart W, FIG. 4, after being activated by step 350, FIG. 3, guides a user to identify a femoral landmark such as the greater trochanter in step 370, FIG. 4, and then the femoral axis is identified, step 372, which corresponds to the longitudinal axis of the femur in that image. These steps are illustrated in FIGS. 5 and 6, below. A line is then drawn across the bony pelvis, step 374, as shown in FIG. 7. The technique proceeds to capturing an operative hip image, step 352, FIG. 3, and identifying an acetabular component, step 354, such as shown in FIG. 8 below. Acetabular components are also shown in and discussed relative to FIGS. 9 and 10 below. The image is scaled by entering the size of the acetabular component, step 356, and Flowchart W, FIG. 4, is then applied to the operative hip, step 358. The operative and comparative hip images are scaled by a stationary base generated by selecting at least two reference points on the bony pelvis, step 360, such as shown in FIG. 11. The scaled images are then overlaid in step 362 using the bony pelvis points, such as the overlaid lines 386 and 412 shown in FIG. 12. Differences in offset and leg length are calculated, step 364, and the technique is terminated, step 366. One currently preferred implementation of the JointPoint IntraOp™ Anterior system, which provides the basis for intraoperative analysis of the anterior approach to hip surgery, is illustrated in relation to FIGS. 9-22 in the parent application; FIGS. 9-16 are described herein as FIGS. 5-12. FIG. 5 herein is an image 376 of the right side of a patient's hip prior to an operation and showing a marker 378, bracketed by reference squares 377 and 379, placed by a user as guided by the system, or placed automatically via image recognition, on the greater trochanter as a landmark or reference point. FIG. 6 is an image 376′ similar to FIG. 5 showing a reference line 380, bracketed by reference squares 381, 382, 383 and 384, drawn on (i) the pre-operative, ipsilateral femur or (ii) the contra-lateral femur, to represent the longitudinal axis of the femur. FIG. 7 is an image 376″ similar to FIG. 6 with a line 386, defined by two end-points, which is drawn across the pelvic bone intersecting selected anatomical features. FIG. 8 is a schematic screen view of two images, the left-hand image 376′ representing a pre-operative view similar to FIG. 6 and the right-hand image 390 representing an intra-operative view with a circle 392 placed around the acetabular component 394 of an implant 398 to enable rescaling of that image. In some constructions, circle 392 is placed by an image recognition program and then manually adjusted by a user as desired. Reference square 398 designates implant 398 to the user. FIG. 9 is a schematic screen view similar to FIG. 8 indicating marking of the greater trochanter of the right-hand, intra-operative image 390′ as a femoral landmark 400, guided by reference squares 402 and 404. FIG. 10 is a schematic screen view similar to FIG. 9 with a reference line 406 drawn on the intra-operative femur in the right-hand view 390″, guided by reference squares 407, 408, 409 and 410. FIG. 11 is an image similar to FIGS. 7 and 10 with a line 386, 412 drawn across the obturator foremen in both pre- and intra-operative views 376″ and 390′″, respectively. Reference squares 413, 414, 415 and 416 guide the user while drawing reference line 412. FIG. 12 is an overlay image showing the right-hand, intra-operative, PostOp image 390′″ of FIG. 11 superimposed and aligned with the left-hand, pre-operative PreOp image 376″. In this construction, soft button icons for selectively changing PreOp image 376″ and/or PostOp image 390′″ are provided at the lower left-hand portion of the screen. Note that “PostOp” as utilized herein typically indicates post-insertion of a trial prosthesis during the surgical procedure, and is preferably intra-operative. The PostOp image can also be taken and analysis conducted after a “final” prosthesis is implanted. “PreOp” designates an image preferably taken before any surgical incision is made at the surgical site. In some situations, the image is taken at an earlier time, such as a prior visit to the medical facility and, in other situations, especially in emergency rooms and other critical care situations, the “PreOp” image is taken at the beginning of the surgical procedure. A ball marker BM, FIG. 5, is shown but not utilized for alignment because ball markers can move relative to the patient's anatomy. Further PreOp and PostOp icons are provided in certain screen views to adjust viewing features such as contrast and transparency. Preferably, at least one icon enables rotation in one construction and, in another construction, “swaps” the images so that the underlying image becomes the overlying image, as discussed in more detail below. Additional icons and reference elements are provided in some constructions, such as described in the parent application. One or more of these “virtual” items can be removed or added to a screen view by a user as desired by highlighting, touching or clicking the “soft keys” or “soft buttons” represented by the icons. In certain embodiments, one or more of the icons serves as a toggle to provide “on-off” activation or de-activation of that feature. Characters or other indicia can be utilized to designate image number and other identifying information. Other useful information can be shown such as Abduction Angle, Offset Changes and Leg Length Changes, as discussed in more detail below. Optional user adjustment can be made by touching movement control icon 527, FIG. 12, also referred to as a “rotation handle”. In certain constructions, image recognition capabilities provide “automatic”, system-generated matching and alignment, with a reduced need for user input. Currently utilized image recognition provides automatic detection of selected items including: the spherical ball marker frequently utilized in preoperative digital templating; the acetabular cup in digital templates and in trial prosthetics; and the Cobb Angle line, also referred to as abduction angle. In another construction, more than two points are generated for the stationary base for each image, such as illustrated in FIG. 13 for a preoperative image 1200 and a postoperative image 1201, and in FIG. 14 for a combined overlay image 1298 of the preoperative image 1200 and the postoperative image 1201 of FIG. 13. Similar locations on the pelvis in each image are selected to generate the points utilized to establish a stationary base for each image. In image 1200, for example, a first point 1202 is generated on an upper corner of the obturator foramen or at the pelvic tear drop, a second point 1204 is generated at the top or superior portion of the pubic symphysis, and a third point 1206 is generated at the lowest or inferior point on the ischial tuberosity. Lines 1208, 1210 and 1212 are drawn connecting those points to generate a visible stationary base triangle 1216 on image 1200. Also shown is a point 1214 on the greater trochanter. In postoperative image 1201, first and second points 1203 and 1205 correspond with first and second points 1202 and 1204 in image 1200. A third point 1207 is shown in image 1201 between reference squares 1209 and 1211 in the process of a user selecting the lowest point on the ischial tuberosity to correspond with third point 1206 in image 1200. The user is prompted by “Mark lowest point on Ischial Tuberosity” in the upper portion of image 1201. Also shown is a circle 1213 around the acetabular component and a point 1215 on the greater trochanter. Establishing at least three points is especially useful for determining rotational differences between images. Overlay image 1298, FIG. 14, shows the three points 1202, 1204 and 1206 of preop image 1200, forming the visible preop stationary base triangle 1216, which is positioned relative to the corresponding three points 1203, 1205 and 1207 of postop image 1201, forming a visible postop stationary base triangle 1311 overlaid relative to triangle 1216 in FIG. 14. A ‘best fit overlay’ can be created using these points by identifying the centroid of the polygon created by these point, and rotating the set of point relative to one another to minimize the summation of distance between each of the related points. In this construction, scaling of the two images may be performed by these same set of points or, alternatively, a separate set of two or more points may be utilized to scale the two images relative to each other. Clicking on a PreOp soft-button icon 1300 and a PostOp icon 1301 enable a user to alter positioning of images 1200 and 1201, respectively, within image 1298 in a toggle-switch-type manner to selectively activate or de-activate manipulation of the selected feature. One or more points of a stationary base may be shared with points establishing a scaling line. Preferably, at least one landmark is selected that is spaced from the stationary base points to increase accuracy of overlaying and/or comparing images. Also illustrated in FIG. 14 are “Offset and Leg Length Changes” with “Leg Length: −0.2 mm”, “Offset: 21.8 mm” and “Confidence Score: 8.1”. A confidence ratio that describes the quality of fit can be created by comparing the overlay area of the two triangles relative to the size of the overall polygon formed by the two triangles, including the non-overlapping areas of each triangle. Abduction angle and anteversion calculations are described in the parent application in relation to FIGS. 55-59. Alternative constructions may alternatively apply absolute scaling to the preoperative and intraoperative images directly in each image, and without the need for a stationary base. For example, each image may be scaled by a ball marker or other scaling device, known magnification ratios of a radiographic device, or direct measurements of anatomical points (such as a direct measurement, via callipers, of the extracted femoral head, which can be used to scale the preoperative image). Alternative constructions may also replace the ‘stationary base’ with various other techniques that could be used to scale and align the preoperative and intraoperative images relative to one another. One example of such a construction would involve overlaying two images and displaying them with some transparency so that they could both be viewed on top of one another. The user would then be prompted to rotate and change their sizing, so that the pelvic anatomy in the two images were overlaid as closely as possible. In some constructions, a guidance system is provided to adjust the viewing area of one image on a screen to track actions made by a user to another image on the screen, such as to focus or zoom in on selected landmarks in each image. This feature is also referred to as an automatic ‘centering’ function: as a user moves a cursor to ‘mark’ a feature on one image, such as placing a point for a landmark or a stationary base on an intraoperative image, the other image on the screen is centered by the system to focus on identical points of interest so that both images on the screen are focused on the same anatomical site. FIG. 15 is a schematic combined block diagram and flow chart of an identification guidance module 1400 utilized in one construction to assist a user to select landmarks when comparing a post- or intra-operative results image, box 1402, with a reference image, box 1404. The module is initiated with a Start 1401 and terminates with an End 1418. When a visual landmark is added to a post-operative image, box 1406, the module 1400 locates all landmarks “l” on the pre-operative reference image, box 1408, and calculates the visible area “v” within the pre-operative image in which to scale, such as by using Equation 1: v=[maxx(l)−minx(l), maxy(l)−miny(l)] EQ. 1 The identical landmark on the pre-operative image is located and its center-point “c” is determined, box 1410. The identical landmark on the pre-operative image is highlighted in one construction to increase its visual distinctiveness, box 1414. The pre-operative image is centered, box 1410, and scaled, box 1412, such as by utilizing the following Equations 2 and 3, respectively: Center=c−(v)(0.5) EQ. 2 Scale=i/v EQ. 3 The user manipulates one or more visual landmarks in the results image, box 1416, as desired and/or as appropriate. In some constructions, the user manually ends the guidance activities, box 1418 and, in other constructions, the system automatically discontinues the guidance algorithm. In certain constructions, image recognition capabilities provide “automatic”, system-generated matching and alignment, with a reduced need for user input. Currently utilized image recognition provides automatic detection of selected items including: the spherical ball marker frequently utilized in preoperative digital templating; the acetabular cup in digital templates and in trial prosthetics; and the Cobb Angle line, also referred to as abduction angle. FIG. 16 is an overlay image 2000 of a preoperative hip image 2001 and an intraoperative hip image 2003 having a trial implant 2002 in a hip with the acetabular component 2004 transacted by stationary base lines 2006 and 2007 extending between a first point 2008 on the obturator foramen OF and a second point 2010 on the anterior inferior iliac spine AIIS of the ileum. Also shown are two error analysis triangles 2020 (solid lines) and 2030 (dashed lines). Circles 2022 and 2032 in this construction represent a landmark point on the greater trochanter in images 2001 and 2003, respectively. Image 2000 is a representation of preoperative and intraoperative hip images 2001 and 2003 overlaid according to stationary base lines 2006 and 2007, respectively. Three identical pelvic points 2024, 2026, 2028 and 2034, 2036, 2038 in images 2001 and 2003, respectively, have been identified, with a system such as system 200, FIGS. 4C-4F in the parent application, generating triangles 2020 and 2030 for each image as represented by FIG. 16. The triangles 2020 and 2030 can be visually compared to analyze the error in the anatomic area containing the stationary bases which, in this case, is the pelvis. A numerical confidence score or other normalized numeric error analysis value may also be calculated and displayed in the system by calculating the distance between points, comparing them to the length of the triangle vectors, and then normalizing the data, possibly using a log or other such nonlinear algorithm. The visual display and/or numerical confidence score provides efficacy analysis in the construction. In other words, error analysis and correction is provided in some constructions for at least one image, such as providing a confidence score or other normalized numeric error analysis, and/or a visual representation of at least one error value or error factor, such as relative alignment of one or more geometric shapes, e.g. triangles, or symbols in two or more images. In some constructions of the various alternative systems and techniques according to the present invention, visual and/or audible user instructions are sequentially generated by the system to guide the user such as “Draw line along Pubic Symphysis”. Guidance for surgery utilizing other types of implants, and for other surgical procedures, including partial or total knee or shoulder replacements and foot surgery as well as wrist surgery, will occur to those skilled in the art after reading this disclosure. Also, other types of medical imaging using energy other than visible light, such as ultrasound, may be utilized according to the present invention instead of actual X-rays. Moreover, if a computer interface tool, such as a stylus or light pen, is provided to the user in a sterile condition, than the user can remain within a sterile field of surgery while operating a computing device programmed according to the present invention. The term “vector” is utilised herein with the standard meaning of an Euclidean vector having an initial point or “origin” and a terminal point, representing magnitude and direction between the origin and the terminal point. The system then positions an acetabular component template or representative digital annotation, such as a digital line or digital circle, in the preop image by replicating this vector. Hip- and femur-related constructions of the present system and method calculate intraoperative changes in offset and leg length using a reference image, also referred to as a “preop image”, and an intraoperative image, also referred to as a “postop image” or an “intraop image”. To accomplish this, one construction of the system requires two consistently scaled images that are overlaid and aligned according to the stationary anatomic region (such as the pelvis), the generation of at least one landmark point on the non-stationary, articulating anatomic region (such as the femur) in both images, a mechanism to identify the difference in femoral angle of the femur relative to the pelvis between the images, a mathematical correction module that adjusts for differences in the articulating femur in each image relative to the stationary pelvis and, finally, a calculation module that uses this input to calculate intraoperative changes in offset and leg length. As utilized herein, the term “femoral angle” refers to the orientation of the longitudinal axis of the femur relative to the pelvis; a “difference in femoral angle” is described in more detail below in relation to FIG. 21. The system may optionally include an error analysis module that identifies and analyses potential error in the system. As described in more detail below in relation to FIGS. 17-23, an ‘Image Overlay’ process according to the present invention begins in some constructions by acquiring (i) at least one of a preoperative ipsilateral or an inverted contralateral image (“preop image” or “reference image”), and (ii) an intraoperative image (“intraop image”). The system generates at least one landmark point on the non-stationary femur in both images (such as identification of a consistent point on the greater trochanter in both images), generally performed with user guidance. Optionally, the system will generate at least one error point on the pelvis in both images to provide error analysis. If the images have not been previously scaled and aligned, the system will scale and align them using one of a plurality of techniques. One of the images is then overlaid according to the pelvic anatomy in both images. In some constructions, the system identifies points that can be used to analyze possible error in the images relative to each other. The system additionally performs a series of steps to calculate any deviation in alignment of the non-stationary femur relative to the pelvic anatomy between the preop and intraop images. The system then creates an overlay of the preop and intraop image, taking into consideration and correcting for the effect of any difference in femoral angles between the two images as the system compares the relative position of the generated femoral landmark points. Finally, the system analyses the difference between the landmark points, including a correction for femoral alignment differences, and uses this data to calculate intraoperative change in offset and leg length. In one construction, the process begins in the flowchart OA in FIG. 17 by acquiring, step 3000, either a selected preoperative ipsilateral image, or a selected inverted contralateral image. Whichever image is selected is referred to herein as a “first, reference image” or “preop image”. The process continues with acquisition of the intraop hip image, step 3002. Image acquisition in steps 3000 and 3002 is performed by the Image Capture module 3030, also referred to as an Image Selection Module, of overlay analysis system 3028, FIG. 18. Acquisition of these images can be performed in a variety of ways, such as a direct connection to a c-arm fluoroscopy unit, file upload, or similar techniques. Implementations that operate on a mobile device such as an iPad, or other platforms that similarly integrate a camera device, may also acquire the images in steps 3000 and 3002 by prompting the user to take a picture of the images using the device camera. If an inverted contralateral image is used as a ‘preop’ image, the contralateral image may be acquired and then inverted within the software, or otherwise it may be flipped in another system and then input to image capture module 3030. Screen view 3050, FIG. 19, shows preoperative image 3052 and intraoperative image 3070, referred to by labels 3053 and 3071 as “PreOp” and PostOp” images, respectively. The method continues in step 3004, FIG. 17, with Landmark Identification Module 3034, FIG. 18, identifying at least one point on the femoral anatomy in both the preop and intraop images. Landmark Identification Module 3038 and Calculation Module 3040 can be considered as components of an Analysis Module 3037, shown in dashed lines. In a preferred construction, a point in each image will be placed on the greater trochanter, a particularly useful landmark point because it is easily identifiable and because the anatomy is relatively insensitive to deviations in image acquisition. Alternatively, the point may be placed on the lesser trochanter or another identifiable femoral landmark. However, consistent point placement on the lesser trochanter is more susceptible to error originating from deviations in image acquisition angle based on its 3-dimensional anatomy. In various constructions, the user is either prompted to identify the point on the femoral anatomy, or otherwise the system auto-identifies the point or set of points using image recognition or other technology and then allows the user to modify the point placement. FIG. 5, described above, is an image 376 of the right side of a patient's hip prior to an operation and showing a marker 378, bracketed by reference squares 377 and 379, placed by a user as guided by the system, or placed automatically via image recognition, on the greater trochanter as a landmark or reference point, such as indicated in Landmark Identification Module 3034, FIG. 18. Reference squares 377 and 379 enable the user to position the marker 378 on touch-screen devices, such as an iPad, without the user's fingers obscuring the position of the marker 378. In a similar manner, reference landmark point 3054 and intraoperative landmark point 3074, FIG. 19, are placed on the greater trochanter of the femur Fp in PreOp image 3052 and of femur Fi in PostOp image 3070, respectively. Also shown in PreOp image 3052 are a femoral axis line 3055 and a pelvic reference line 3056, tear drop point 3056, pubic symphysis point 3058, and ischial tuberosity point 3059. Further shown in PostOp image 3070, FIG. 19, are acetabular cup AC and femoral stem FS of an implant I, a femoral axis line 3075 and a pelvic reference line 3076, tear drop point 3076, pubic symphysis point 3078, and ischial tuberosity point 3079. A circle 3080 has been drawn around acetabular cup AC as described in more detail below. In step 3006, FIG. 17, the Landmark Identification Module 3034, FIG. 18 asks via User Interface UI, shown in phantom as box 3035, whether the user wants to include error analysis in the system output. If yes, Module 3034 prompts the user, in Step 3008, to identify a set of anatomic points on the stationary pelvis in both the preop and intraop images. While a minimum of only one point is required to provide error analysis in the system, the system preferably generates at least three points on the pelvis, such as points 3057, 3058 and 3059 in PreOp image 3052, FIG. 19, and points 3077, 3078 and 3079 in PostOp image 3070. The user positions each point on the pelvis in some constructions but, in preferred constructions, automated algorithms of a system according to the present invention initially place the points in appropriate positions on the pelvic anatomy. If pelvic reference lines, as described in more detail below, are used to align and scale the preop and intraop images, the points selected for error analysis should be independent of the points used to create the pelvic reference lines. Ideal points will also be identifiable, such as a discernible point on the pelvic teardrop, ischial tuberosity and pubic symphysis. In Step 3010, the Landmark Identification Module 3034, FIG. 18, identifies the approximate femoral center of rotation in the intraop image; this center of rotation information assists correction for deviations in femoral positioning between the preop and intraop images. In a preferred construction, Landmark Construction Module 3034 identifies this point by placing a digital circle so that it overlays the boundary of the acetabular component, as shown by digital circle 392 in FIG. 9 and by circle 3080 in FIG. 19. The system then identifies the midpoint of the circle, which approximates the center of rotation of the acetabular component and functions as the intraoperative femoral center of rotation. Various constructions will accomplish step 3010 in different ways. In a preferred construction, the system may auto-detect the location of the digital circle by using image recognition to auto-detect the acetabular component in the intraoperative image, and then allow the user, via User Interface UI, box 3035, to adjust the size and position of the digital circle using navigation handles connected to the circle, such as navigation handle 527, FIG. 12, and by navigation handle 3099, FIG. 20. In another construction, the user estimates the approximate center of rotation by drawing or positioning a circle around the femoral head in the preoperative image, and utilizing the center of that circle as an estimate of the center of rotation. As shown in FIG. 19, the PreOp image 3052 shows three error points 3057, 3058 and 3059 positioned on the base of the pelvic teardrop, the superior point on the pubic symphysis, and the inferior point on the ischial tuberosity, respectively. Similarly, points 3077, 3078 and 3079 are positioned on corresponding points in PostOp image 3070. These corresponding points will be used for error analysis in constructions that include error analysis as part of the system. Digital circle 3080 has been positioned around the acetabular cup AC of implant I, with a center-point represented by the crosshair 3081 that identifies the midpoint of the circle. This midpoint identifies the approximate femoral center of rotation after implant insertion. In Step 3012, FIG. 17, the system begins the process of analysing the difference in the femoral axis angles, relative to the pelvis, between the preop and intraop images. In a preferred construction, the system accomplishes this by generating digital lines to identify the longitudinal axis of the femurs in both images, such as femoral axis lines 3055 and 3075, FIG. 19, and calculating any angle difference between them as described in more detail below in relation to FIG. 21. Landmark Identification Module 3034, FIG. 18 guides the user to generate a line that identifies the longitudinal axis of the femur in both the preop and intraop images. First, the system generates a digital line in the preop image to identify the femoral axis, and the system provides the ability to adjust the line location so that it can identify the angle of the femur in the preop image. Then, the system generates a digital line in the intraop image to identify the femoral axis in the intraop image, again allowing for user adjustment. Preferred constructions of this system will attempt to auto-identify the femoral axis in this step using image recognition and known data, and place the digital lines accordingly. The system then provides the functionality for the user to further manipulate these lines. FIG. 6, described above, is an image 376′ similar to FIG. 5 showing a reference line 380, bracketed by reference squares 381, 382, 383 and 384, drawn on the preop image to represent the longitudinal axis of the femur. Reference lines 381, 382, 383 and 384 can be manipulated to reposition the femoral axis line. FIG. 10, described above, is a schematic screen view with a reference line 406 drawn on the intra-operative femur in the right-hand view 390″, guided by reference squares 407, 408, 409 and 410. Reference lines 407, 408, 409 and 410 can be manipulated to reposition the femoral axis line. FIG. 19 again shows the positioned digital lines 3055 and 3075, placed in Step 3012, FIG. 17, that identify the femoral axis in the PreOp and PostOp images 3052 and 3070. In step 3014, FIG. 17, the Image Capture Module 3030, FIG. 18 determines whether the preop and intraop images have been pre-scaled and aligned according to pelvic anatomy. Consistent scaling and alignment may be previously performed in this construction using a variety of approaches. For example, a software system residing on a digital fluoroscopy system may have been used to align and scale the images prior to image acquisition by this system. Alternatively, the images may already be scaled and aligned because the surgeon took images with the patient and radiographic system in identical position with a known magnification ratio. If the images have not been either scaled or aligned, the system can scale, or align, or scale and align the images in optional step 3016. Consistent scale and alignment in this step is accomplished by the optional Image Scaling and Alignment Module 3032, FIG. 18, shown in dashed lines, which may accomplish these operations in various ways. One method to accomplish consistent scaling and alignment is by using stationary bases (i.e. pelvic reference lines), along with identification and scaling of the acetabular cup in the intraop image, as visually illustrated in FIG. 11. In this approach, a line is drawn connecting two identical landmarks on the pelvis in both the preop and intraop images. Stationary base line 386 in FIG. 15 connects, in the preop image, a point on the anterior superior iliac spine to the inferior point on the pubic symphysis. Stationary base line 412 in FIG. 11 connects the identical two pelvic landmarks in the intraop image. The system can use these two lines to rotate the images so that the overlay lines are aligned at the same angle relative to the software screen. The images can additionally be scaled, relative to one another, by scaling one image relative to another so that the pixel distances between the stationary base lines in the two images are equivalent. Finally, absolute scaling of the images can be achieved by scaling at least one image according to an object of known dimension. FIG. 8 depicts the digital circle 392 that has been generated around acetabular component 394. The digital circle may be either generated using image recognition to identify the acetabular component, positioned by the user, or initially system-generated in an approximate location and then positioned by the user. The size of this component is known because the surgeon has placed it in the patient's femur. Therefore, the known size of the component, such as “50” mm, can be entered into the box following text “Size of Acetabular Component” located at the top of the intraop screen 390. The system uses this information to generate absolute scaling in the intraop image. Additionally, the preop image can be scaled in absolute measurements, according to this generated circle, once the preop image is scaled so that the pelvic reference lines in both images are of equivalent length in pixels. FIG. 19 depicts the pelvic reference lines 3056 and 3076 that have been generated on identical points on the preop and intraop images 3052 and 3070 of the pelvis, allowing the system to align and scale the images according to the input. Alternative constructions may apply absolute scaling to other objects of known size in either the preop or intraop image. For example, scaling can be applied according to the preop image by drawing a digital line across diameter of the femoral head in the preop image, and entering the size in absolute terms. This absolute measurement is known during surgery because the surgeon traditionally extracts the femoral head and measures its size, using calipers, during hip arthroplasty. The output of the scaling and alignment performed in step 3016, FIG. 17, is used to generate an overlay in step 3018, and therefore may be represented visually by depicting the updated scaling and alignment visually on the software screen, or otherwise may exclusively be calculated by the system to create the overlay in step 3018. In this construction of Step 3018, the Image Comparison Module 3036, FIG. 18 superimposes the preop and intraop images by aligning pelvic anatomy, with the images displayed with some transparency so that both can be visualized in the overlay, such as illustrated in FIG. 20. In a preferred construction the overlaid images will contain the identified femoral landmarks (generally placed on the greater trochanter) generated in step 3008 so that location differences between the two points can be visualized. The system will maintain the location of the generated greater trochanter points and the femoral axis lines, relative to the preop and intraop images, as the images are manipulated to create the image overlay. The Image Comparison Module 3036 can align the images according to pelvic anatomy in a variety of ways in this step. In a preferred construction, the system will have previously guided the user in identifying at least two consistent points on the pelvic anatomy in both images. The Image Comparison Module 3036 then superimposes the images so that the stationary base lines are positioned identically. In other words, the images are scaled, aligned and superimposed according to the stationary bases drawn across consistent points on the pelvis in each image. The Image Comparison Module will move and scale all digital annotations in tandem with the underlying image so that they remain affixed to the underlying image. This includes positioning of the femoral and pelvic landmark annotations, the identified center of rotation of the femur, pelvic reference lines, the femoral axis lines, and any other annotations used in various constructions. Alternative constructions obviate the need for the use of the pelvic reference lines. In one alternative construction, the system uses image recognition technique to auto-identify the pelvic anatomy and overlay the images based on the image recognition, then the user is presented with the option to manually manipulate the resulting overlay. In another alternative, the user will be guided to manually position the images so that the pelvic anatomy matches. The system in this method will provide the user with the ability to manipulate both the position of each of the images as well as adjust the magnification so that the pelvic anatomy can be superimposed on the overlay. Alternative systems will rely on hardware implementations and stationary cameras to obviate the need for a digital line, image recognition, or user manipulation whatsoever to create the overlay. In these instances, the external system may provide a known magnification ratio and the consistent patient positioning that would be required to create the image overlay without the use of pelvic reference lines or similar technique. Differences between the preop and intraop positioning of the femur, relative to the pelvis, creates a challenge in comparing the relative location of a femoral landmark such as a greater trochanter because a change in leg position alters the vector between the two femoral landmarks in the overlay. In Step 3020, FIG. 17, the Landmark Correction Module 3038, FIG. 18 calculates any existing difference between the preop and intraop femoral axis angles. The terms “femoral angle” and “femoral axis angle” refer to the orientation of the longitudinal axis of the femur. If, for example, the preop and intraop femoral axis lines generated in step 3012 vary by eight degrees, the difference calculated in step 3020 will be eight degrees. In Step 3022, FIG. 17, Landmark Correction Module 3038, FIG. 18 uses data gathered in previous steps to generate an additional “corrected” or “phantom” landmark point that accounts for differences in femoral position between the preop and intraop images. A corrected landmark point 3082 is shown in FIG. 20, positioned along circle 3083 from intraoperative landmark point 3074′, which is similar to corrected landmark point 3116, FIG. 21, along circle 3124 as described in more detail below. To generate the corrected landmark point, the module first calculates anglefemur, which is the angular difference between the longitudinal axes of the femur in the preoperative and intraoperative images, respectively, also referred to as the preop and intraop femoral axis lines in the overlay. This technique is shown schematically in FIG. 21 for angle α, arrow 3108, between longitudinal axis lines 3104 (“L1”) and 3106 (“L2”). The system incorporates this with the femoral or acetabular center of rotation 3102 (“R1”), (Xorigin, Yorigin) in the intraop image, previously identified in step 3010, FIG. 17, and the greater trochanter point 3110 (“p1”), (Xtroch, Ytroch) in the intraop image. The system uses the following formulas to calculate the corrected landmark “phantom” point 3116 (“p3”), (Xphantom, Yphantom) in Equations 4 and 5: Xphantom=(Xtroch−Xorigin)*cosine(anglefemur)−(Ytroch−Yorigin)*sine(anglefemur)+Xorigin EQ. 4: Yphantom=(Xtroch−Xorigin)*sine(anglefemur)+(Ytroch−Yorigin)*cosine(anglefemur)+Yorigin EQ. 5: A vector “v”, line 3118, is extended from the preoperative landmark point 3112 (“p2”) to corrected landmark point 3116. Right triangle “legs” 3120 and 3122 are utilized to estimate offset and leg length, respectively. Leg 3122 is generally parallel to preoperative femoral axis 3104 in this construction. The Acetabular circle 3100 (“c1”) assists in locating center of rotation 3102. Also shown in FIG. 21 are radius lines 3130 and 3132 which are also separated by angle α, arrow 3114. As mentioned above, FIG. 20 is an “overlay” screen view 3050′ of the intraop image 3070, FIG. 19, superimposed as PostOp image 3070′ on the preoperative image 3052 as PreOp image 3052′. The two stationary base lines 3056 and 3076 of FIG. 19 are aligned exactly one on top of the other, represented as a single stationary base line 3056′, 3076′. First error correction triangle 3084 is shown connecting intraoperative error point 3077′ on the pelvic teardrop, point 3078′ on the ischial tuberosity and point 3079′ on the pubic symphysis, and a similar error correction triangle 3085 connects points 3057′, 3058′ and 3059′, representing points 3057, 3058 and 3059 of preoperative image 3052, FIG. 19. Details window 3090 lists “Leg Length: −0.4 mm”, “Offset: −3.8 mm” and “Confidence Score: 5.4” as described in more detail below. Finally, in Step 3018, FIG. 17, the Calculation Module 3040, FIG. 18, calculates the change in leg length and offset by analysing the vector between the greater trochanter point in the preop image and the calculated phantom point in the intraop image, such as illustrated in FIG. 21. To calculate leg length, the system calculates the distance between these two points along the femoral axis identified from the preop image, as identified by line 3122 in FIG. 21. To calculate offset, the system calculates the distance between the two points along the axis that is perpendicular to the femoral axis from the preop image, as identified by line 3120. A specific example of these calculations is given in Details window 3090, FIG. 20. The “Confidence Score” listed in box 3090 relates to the two error triangles 3084 and 3085 as follows. The three points comprising each triangle enables the user to easily visualize any differences in pelvic anatomy in the overlay which may exist even after scaling and alignment. Although the stationary bases are completely matched one on top of the other, such as illustrated by single stationary base line 3056′, 3076′, the amount of deviation in the two error triangles 3084, 3085 can be visually inspected to appreciate potential error in the system, such as caused by one or more of parallax, differences in imaging vantage point of the three-dimensional skeletal anatomy, and/or by point placement within the system. As an additional, optional step to quantify the differences between the placement of the two error triangles, the system provides a weighted “confidence score”, ranging from 0.0 to 10.0 in this construction. In one implementation, the system finds the difference in an absolute scale between each of two corresponding points in the preop and postop images as overlaid. In some constructions, error in certain point pairs is assigned a weighting that is greater or lesser than for other error point pairs. As one example, identifying a consistent point on the ischial tuberosity may be difficult between images, so that particular point pair (labelled 3059′ and 3079′ in FIG. 20) can be weighted less, such as by “discounting” it by fifty percent. Finally, the weighted sum of numerical error among the error point pairs is converted to a single confidence score, such as “5.4” shown in display window 3090. The weighting is not necessarily linear. Further, a cut-off value can be provided beyond which the error is deemed to be too great to provide useful analysis; in one construction, the system then recommends that the user obtain an alternative intraoperative image to compare with the preoperative image, or with a contralateral image, to analyze according to the present invention. Alternative constructions of this system and method will use different methods to determine the deviation between femoral angles in the preop and intraop images. For example, in one construction, the femoral angle can be analysed by creating an image cut-out of one femur and superimposing it on top of the other at the original angle. The cut-out and underlying image may also be connected by the known femoral landmark, such as the greater trochanter, and be made to be immutable at that single landmark point. Then, at least one of the system and user may adjust the image cut-out so that the femoral bone precisely overlays the femoral bone in the superimposed image by pivoting about that landmark point. The system may accomplish this using image recognition or other automated algorithm that identifies the femoral bone or related femoral landmarks such as the greater trochanter landmark previously identified. Alternatively, the user may match the femoral bones by adjusting the superimposed image of the femur so that it matches the femur in the underlying image. The system may attempt to initially match the femoral bones and then provide the user the option to reposition the femur to improve the position. Finally, the system will calculate the deviation in angle between the two femurs by calculating the angle that the cut-out was adjusted, providing similar information In yet another construction, reference (preop) and intraop images are compared via a grid-type X-Y coordinate system without utilizing femoral angles, such as for preoperative images 3202, 3202′ and intraoperative images 3242, 3242′ in screen views 3200 and 3200′ illustrated in FIGS. 22-23, respectively. The reference and intraoperative images are not actually digitally overlaid one on top of the other in this construction; instead, preop image 3202, FIG. 22, is overlaid with, or otherwise associated with, a grid 3204 having a Y-axis 3205 and an X axis 3306 with units “100, 200, . . . 500” as shown, with the origin in the upper left-hand corner of grid 3204. In a similar manner, intraop image 3242 is associated with a grid 3244 having a Y-axis 3245 and an X axis 3346, preop image 3202′, FIG. 23, is associated with a grid 3204′ having a Y-axis 3205′ and an X axis 3306, and intraop image 3242′ is associated with a grid 3244′ having a Y-axis 3245′ and an X axis 3346′. Preop image 3202, FIG. 22, includes femur Fp with landmark point 3208 on the greater trochanter, and stationary base 3210 and error triangle 3212 on the pelvis. Intraop image 3242 includes femur Fi with implant I having femoral stem FS and acetabular cup AC. Intraoperative landmark point 3248 has been placed on the greater trochanter. Stationary base 3250 and error triangle 3253 have been placed on the pelvis. Preop image 3202′, FIG. 23, includes femur Fp′ with landmark point 3208′ on the greater trochanter, and stationary base 3210′ and error triangle 3212′ on the pelvis. Intraop image 3242′ includes femur Fi′ with implant I′ having femoral stem FS′ and acetabular cup AC′. Intraoperative landmark point 3248′ is on the greater trochanter. Stationary base 3250′ and error triangle 3253′ have been placed on the pelvis. After a user activates a “Proceed To Analysis” icon 3260, FIG. 22, the system aligns preop image 3202′, FIG. 23, with intraop image 3242′. In this example, preop image 3202′ has been “tilted” or rotated counter-clockwise relative to the initial position of preop image 3202 in FIG. 22 to represent alignment achieved using stationary base 3210′ and 3250′. After both preop image and 3202′ and 3242′ have been aligned relative to each other, then a difference in position of one of the landmark points is determined, such as the shift of preop landmark point 3208, FIG. 22 to the aligned position of preop landmark point 3208′, FIG. 23. In this example, intraoperative landmark point 3248′ is in the same grid location as intraoperative landmark point 3248, FIG. 22. A vector can then be calculated from intraop landmark point 3248′ to corrected point 3208′ using calculations similar to that described above in relation to FIG. 21. In this construction, a “Details” window 3270 graphically shows the change in position of initial preop landmark point 3208 to corrected landmark point 3208′. Other alternative constructions will change the order of various steps, including the generation of various digital landmarks. An additional alternative construction will identify an estimated center of rotation in the preop image instead of the intraop image, using a similar digital circle placed around the femoral head, or similar technique to annotate the estimate center of rotation. Although specific features of the present invention are shown in some drawings and not in others, this is for convenience only, as each feature may be combined with any or all of the other features in accordance with the invention. While there have been shown, described, and pointed out fundamental novel features of the invention as applied to one or more preferred embodiments thereof, it will be understood that various omissions, substitutions, and changes in the form and details of the devices illustrated, and in their operation, may be made by those skilled in the art without departing from the spirit and scope of the invention. For example, it is expressly intended that all combinations of those elements and/or steps that perform substantially the same function, in substantially the same way, to achieve the same results be within the scope of the invention. Substitutions of elements from one described embodiment to another are also fully intended and contemplated. It is also to be understood that the drawings are not necessarily drawn to scale, but that they are merely conceptual in nature. Other embodiments will occur to those skilled in the art and are within the scope of the present disclosure.",A61B612,A61B612,20160113,,20160512,77654.0
6,14909084,PENDING,HANDLING SEARCH QUERIES,"A system for providing advertisements with search results in response to a search query comprises a front end and an advertisement server. The front end is configured: to receive a search query; to send a first search request to a search server and sending a first advertisement request to an advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; to receive search results from the search server; and to send at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided. The advertisement server is configured: in response to receiving the first advertisement request, to search for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, to modify the score of at least one of the plural advertisement results; to rank the plural advertisement results according to their scores; to select one or more of the highest ranked plural advertisement results; and to send an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results. The front end is configured to provide the search results with the selected one or more highest ranked plural advertisement results.","1. A system for providing advertisements with search results in response to a search query, the system comprising a front end and an advertisement server, wherein: the front in is configured: to receive a search query; to open a first communication session with a load balancer, wherein the load balancer is configured to open a second communication session with an advertisement server, wherein the front end and the load balancer are configured to use a first session identifier in all messages sent within the first communication session after the first communication session has been established, and wherein the load balancer and the advertisement server are configured to use a second session identifier in all messages sent with the second communication session after the second communication session has been established; to send a first search request to a search server and send a first advertisement request to the advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; to receive search results from the search server; and to send at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server is configured: in response to receiving the first advertisement request, to search for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, to modify the score of at least one of the plural advertisement results; to rank the plural advertisement results according to their scores; to select one or more of the highest ranked plural advertisement results; and to send an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end is configured: to provide the search results with the selected one or more highest ranked plural advertisement results. 2. A system as claimed in claim 1, wherein the advertisement server is configured to respond to receiving the second advertisement request by performing an additional search for advertisements using information forming part of the second advertisement request. 3. A system as claimed in claim 1, wherein the advertisement server is configured to modify the score of at least one of the plural advertisement results by modifying a predicted click-through rate of at least one of the plural advertisement results. 4. A system as claimed in claim 3, wherein the advertisement server is configured to modify the score of at least one of the plural advertisement results by modifying the predicted click-through rate of at least one of the plural advertisement results depending on user interface elements that are indicated in the second advertisement request. 5. A system as claimed in claim 1, wherein the advertisement server configured to modify the score of at least one of the plural advertisement results by modifying a bid associated with of at least one of the plural advertisement results. 6. A system as claimed in claim 1, wherein the advertisement server is configured to modify the score of at least one of the plural advertisement results by modifying a relevance score associated with of at least one of the plural advertisement results. 7. A system as claimed in claim 6, wherein the advertisement server is configured to modify the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on content of the top one of multiple search results identified in the second advertisement request. 8. A system as claimed in claim 6, wherein the advertisement server is configured to modify the score of at least one of the plural advertisement results modifying the relevance score associated with of at least one of the plural advertisement results based on a location of the top one of multiple search results identified in the second advertisement request. 9. (canceled) 10. (canceled) 11. A system as claimed in claim 1, wherein the front end is configured to process the search results received from the search server and, for the at least some of the search results, to include some but not all of the information comprising the search results in the second advertisement request. 12. A system as claimed in claim 1, wherein the front end is configured to include in the second advertisement request one or more of: content type information; map information indicating a map area; information identifying the presence or absence of a knowledge card; and information specific to the user. 13. A system as claimed in claim 1, wherein the advertising server is configured to modify visual appearance characteristics of one or more advertisements based on content of the second advertisement request. 14. A method of providing advertisements with search results in response to a search query, the method comprising: a front end: receiving a search query; opening a first communication session with a load balancer, wherein the load balancer opens a second communication session with an advertisement server, wherein the front end and the load balancer using a first session identifier in all messages sent within a first communication session after the first communication session has been established, and wherein the load balancer and the advertisement server use a second session identifier in all messages sent with the second communication session after the second communication session has been established; sending a first search request to a search server and sending a first advertisement request to the advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; receiving search results from the search server; and sending at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server: in response to receiving the first advertisement request, searching for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, modifying the score of at least one of the plural advertisement results; ranking the plural advertisement results according to the their scores; selecting one or more of the highest ranked plural advertisement results; and sending an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end: providing the search results with the selected one or more highest ranked plural advertisement results. 15. A method as claimed in claim 14, comprising the advertisement server responding to receiving the second advertisement request by performing an additional search for advertisements using information forming part of the second advertisement request. 16. A method as claimed in claim 14, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying a predicted click-through rate of at least one of the plural advertisement results. 17. A method as claimed in claim 16, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying the predicted click-through rate of at least one of the plural advertisement results depending on user interface elements that are indicated in the second advertisement request. 18. A method as claimed in claim 14, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying a bid associated with of at least one of the plural advertisement results. 19. A method as claimed in claim 14, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying relevance score associated with of at least one of the plural advertisement results. 20. A method as claimed in claim 19, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on content of the top one of multiple search results identified in the second advertisement request. 21. A method as claimed in claim 19, comprising the advertisement server modifying the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on a location of the top one of multiple search results identified in the second advertisement request. 22. (canceled) 23. (canceled) 24. A method as claimed in claim 14, comprising the front end processing the search results received from the search server and, for the at least some of the search results, including some but not all of the information comprising the search results in the second advertisement request. 25. A method as claimed in claim 14, comprising the front end including in the second advertisement request one or more of: content type information; map information indicating a map area; information identifying the presence or absence of a knowledge card; and information specific to the user. 26. A method as claimed in claim 14, comprising the advertising server modifying visual appearance characteristics of one or more advertisement based on content of the second advertisement request. 27. A computer program comprising machine readable instructions that when executed control a system comprising a front end and an advertisement server to perform a method as claimed in claim 14.","<SOH> BACKGROUND TO THE INVENTION <EOH>Worldwideweb search services, such as those provided by Google, Inc. through google.com, have been used for a number of years and have been becoming increasingly sophisticated. It is common when providing search results to a user to provide also one or more advertisements. Advertisements are paid for by advertisers, who are normally charged by the provider of the search services on the basis of a number of impressions (the number of times that an advertisement is presented to users) or on the basis of click-through (the number of occasions on which users click on a link in an advertisement, thereby directing traffic to the advertiser's website). A webpage provided in response to a search query thus typically has two components. The first is a number of search results, which are discreet listings that have been selected by a search engine used by the search services provider to identify webpages that are anticipated to be of interest to the user that submitted the search query. The second component of the webpage is one or more advertisements, which are selected by an advertisement server operated by the search services provider and which have been selected as likely being of interest to the user, based on the search query. It would be desirable to take into account the search results provided by the search server when selecting advertisements for inclusion in the webpage. However, it has not heretofore been technically feasible to use the results provided by the search server in selecting advertisements without increasing the time between receiving a search query and providing the webpage of search results to an unacceptably long time. The present invention seeks to provide a solution to this problem.","<SOH> SUMMARY OF THE INVENTION <EOH>A first aspect of the invention provides a system for providing advertisements with search results in response to a search query, the system comprising a front end and an advertisement server, wherein: the front end is configured: to receive a search query; to send a first search request to a search server and sending a first advertisement request to an advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; to receive search results from the search server; and to send at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server is configured: in response to receiving the first advertisement request, to search for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, to modify the score of at least one of the plural advertisement results; to rank the plural advertisement results according to their scores; to select one or more of the highest ranked plural advertisement results; and to send an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end is configured: to provide the search results with the selected one or more highest ranked plural advertisement results. The advertisement server may be configured to respond to receiving the second advertisement request by performing an additional search for advertisements using information forming part of the second advertisement request. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a predicted click-through rate of at least one of the plural advertisement results. Here, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the predicted click-through rate of at least one of the plural advertisement results depending on user interface elements that are indicated in the second advertisement request. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a bid associated with of at least one of the plural advertisement results. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a relevance score associated with of at least one of the plural advertisement results. Here, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on content of the top one of multiple search results identified in the second advertisement request. Alternatively or additionally, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on a location of the top one of multiple search results identified in the second advertisement request. The front end may be configured to open a first communication session with a load balancer, and wherein the load balancer is configured to open a second communication session with the advertisement server. Here, the front end and the load balancer may be configured to use a first session identifier in all messages sent within the first communication session after the first communication session has been established, and wherein the load balancer and the advertisement server are configured to use a second session identifier in all messages sent with the second communication session after the second communication session has been established. The front end may be configured to process the search results received from the search server and, for the at least some of the search results, to include some but not all of the information comprising the search results in the second advertisement request. The front end may be configured to include in the second advertisement request one or more of: content type information; map information indicating a map area; information identifying the presence or absence of a knowledge card; and information specific to the user. The advertising server may be configured to modify visual appearance characteristics of one or more advertisements based on content of the second advertisement request. A second aspect of the invention provides a method of providing advertisements with search results in response to a search query, the method comprising: a front end: receiving a search query; sending a first search request to a search server and sending a first advertisement request to an advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; receiving search results from the search server; and sending at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server: in response to receiving the first advertisement request, searching for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, modifying the score of at least one of the plural advertisement results; ranking the plural advertisement results according to their scores; selecting one or more of the highest ranked plural advertisement results; and sending an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end: providing the search results with the selected one or more highest ranked plural advertisement results. The invention also provides a computer program comprising machine readable instructions that when executed control a system comprising a front end and an advertisement server to perform this method.","FIELD OF THE INVENTION This invention relates to handling search queries. In particular, it relates to providing advertisements with search results in response to a search query. BACKGROUND TO THE INVENTION Worldwideweb search services, such as those provided by Google, Inc. through google.com, have been used for a number of years and have been becoming increasingly sophisticated. It is common when providing search results to a user to provide also one or more advertisements. Advertisements are paid for by advertisers, who are normally charged by the provider of the search services on the basis of a number of impressions (the number of times that an advertisement is presented to users) or on the basis of click-through (the number of occasions on which users click on a link in an advertisement, thereby directing traffic to the advertiser's website). A webpage provided in response to a search query thus typically has two components. The first is a number of search results, which are discreet listings that have been selected by a search engine used by the search services provider to identify webpages that are anticipated to be of interest to the user that submitted the search query. The second component of the webpage is one or more advertisements, which are selected by an advertisement server operated by the search services provider and which have been selected as likely being of interest to the user, based on the search query. It would be desirable to take into account the search results provided by the search server when selecting advertisements for inclusion in the webpage. However, it has not heretofore been technically feasible to use the results provided by the search server in selecting advertisements without increasing the time between receiving a search query and providing the webpage of search results to an unacceptably long time. The present invention seeks to provide a solution to this problem. SUMMARY OF THE INVENTION A first aspect of the invention provides a system for providing advertisements with search results in response to a search query, the system comprising a front end and an advertisement server, wherein: the front end is configured: to receive a search query; to send a first search request to a search server and sending a first advertisement request to an advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; to receive search results from the search server; and to send at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server is configured: in response to receiving the first advertisement request, to search for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, to modify the score of at least one of the plural advertisement results; to rank the plural advertisement results according to their scores; to select one or more of the highest ranked plural advertisement results; and to send an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end is configured: to provide the search results with the selected one or more highest ranked plural advertisement results. The advertisement server may be configured to respond to receiving the second advertisement request by performing an additional search for advertisements using information forming part of the second advertisement request. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a predicted click-through rate of at least one of the plural advertisement results. Here, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the predicted click-through rate of at least one of the plural advertisement results depending on user interface elements that are indicated in the second advertisement request. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a bid associated with of at least one of the plural advertisement results. The advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying a relevance score associated with of at least one of the plural advertisement results. Here, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on content of the top one of multiple search results identified in the second advertisement request. Alternatively or additionally, the advertisement server may be configured to modify the score of at least one of the plural advertisement results by modifying the relevance score associated with of at least one of the plural advertisement results based on a location of the top one of multiple search results identified in the second advertisement request. The front end may be configured to open a first communication session with a load balancer, and wherein the load balancer is configured to open a second communication session with the advertisement server. Here, the front end and the load balancer may be configured to use a first session identifier in all messages sent within the first communication session after the first communication session has been established, and wherein the load balancer and the advertisement server are configured to use a second session identifier in all messages sent with the second communication session after the second communication session has been established. The front end may be configured to process the search results received from the search server and, for the at least some of the search results, to include some but not all of the information comprising the search results in the second advertisement request. The front end may be configured to include in the second advertisement request one or more of: content type information; map information indicating a map area; information identifying the presence or absence of a knowledge card; and information specific to the user. The advertising server may be configured to modify visual appearance characteristics of one or more advertisements based on content of the second advertisement request. A second aspect of the invention provides a method of providing advertisements with search results in response to a search query, the method comprising: a front end: receiving a search query; sending a first search request to a search server and sending a first advertisement request to an advertisement server, wherein the first search request includes the search query or information based on the search query, and wherein the first advertisement request includes the search query or information based on the search query and an indication that an advertisement response is not to be provided; receiving search results from the search server; and sending at least some of the search results to the advertisement server in a second advertisement request, wherein the second advertisement request includes an indication that an advertisement response is to be provided; the advertisement server: in response to receiving the first advertisement request, searching for advertisements related to the search query to produce plural advertisement results each with an associated score; in response to receiving the second advertisement request, modifying the score of at least one of the plural advertisement results; ranking the plural advertisement results according to their scores; selecting one or more of the highest ranked plural advertisement results; and sending an advertisement response to the front end, the advertisement response including the selected one or more highest ranked plural advertisement results; and the front end: providing the search results with the selected one or more highest ranked plural advertisement results. The invention also provides a computer program comprising machine readable instructions that when executed control a system comprising a front end and an advertisement server to perform this method. BRIEF DESCRIPTION OF THE DRAWINGS Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, in which: FIG. 1 is a schematic diagram illustrating a system operating according to aspects of the invention; FIG. 2 is a flow chart illustrating high level operation of the system of FIG. 1 according to aspects of the invention; FIG. 3 is a flow chart illustrating operation of a front end of the system of FIG. 1 according to aspects of the invention; FIG. 4 is a flow chart illustrating operation of an ads server of the system of FIG. 1 according to aspects of the invention; FIG. 5 is a messaging diagram illustrating the flow of messages between some components of the FIG. 1 system according to aspects of the invention; and FIG. 6 is a schematic diagram illustrating components within some components of the FIG. 1 system. DETAILED DESCRIPTION OF EMBODIMENTS Referring firstly to FIG. 1, a system 100 operating according to aspects of the invention will now be described. The system 100 includes three main components. These are a front end 101, a search server system 102 and an ads server system 103. The server system 102 is in bidirectional communication with the front end 101. The ads server system 103 is in bidirectional communication with the front end 101. In this example, there is no direct communication between the search server system 102 and the ads server system 103. The search server system 102 comprises multiple servers. These are illustrated schematically in FIG. 1 as first to fourth servers 102a . . . 102d. However, it will be appreciated that this is merely schematic and that the search server system may comprise between one and many hundreds of physical servers. Similarly, the ads server system 103 is shown in FIG. 1 as comprising four ads servers 103a . . . 103d. However, the ads server system 103 may comprise any number of physical servers between one and many hundreds of physical servers. A load balancer 104 is connected between the front end 101 and the ads server system 103. Operation of the load balancer 104 is described in some detail below. The ads server system 103 is bidirectionally connected to three subsystems. A first system is a retrieve subsystem 105. A second subsystem is a PCTR, or predicted click-through rate, subsystem 106. A third subsystem is a relevance score subsystem 107. Each of the servers 103a-103d of the ads server system 103 may include dedicated retrieve, PCTR and relevance score subsystems 105, 106, 107. Alternatively, multiple ones of the ads servers 103a to 103d may share common retrieve, PCTR and relevance score subsystems 105-107. The front end 101 is a system comprising a server or multiple servers. The front end 101 is the system that is accessed when a user accesses a home webpage of a search service provider, for instance google.com. At least some of the servers of the front end 101 are web servers. High level operation of the system of FIG. 1 will now be described with reference to FIG. 2. The operation of FIG. 2 starts at step 51. At step S2, the front end 101 receives a search query from a user. Typically, step S2 involves receiving an http request from a browser application being used by the user, the http request including a search query that is presented into a search form provided by the browser application as a result of HTML code provided by the front end 101. Various alternative ways in which the front end 101 may be provided with a search query from a user will be apparent to the skilled person. At step S3, the system runs search and ads (advertising) processing in parallel. This involves the search query being sent from the front end 101 to both the search server system 102 (as a search request) and the ads server system 103 (as a first advertisement request). The search request may be sent to the search server system 102 substantially simultaneously with the sending of the first advertisement request to the ads server system 103, or one may slightly follow the other. The first advertisement request sent to the ads server system 103 includes an instruction not to provide an advertisement response. At step S4, some of the search results provided by the search server system 102 are provided by the front end 101 to the ads server system 103 as a second advertisement request. The aspects of the search results provided by the search server system to the front end 101 that are selected by the front end 101 for sending to the ads server system 103 in the second advertisement request may be made in any suitable way, and some examples are described later in this specification. The second advertising request sent as part of step S4 includes an indication that an advertisement response is to be provided. At step S5, the ads server system 103 completes processing of the search query, using the original search query and using the part of the results of the search that were provided in step S4. The ads server system 103 then provides the resulting advertisement response to the front end 101. A webpage including the search results provided by the search service system 102 and the advertisements provided by the ads server system 103 is prepared by the front end and is provided to the user, who views the webpage using their browser application. This webpage can be called the search response. The operation ends at step S7. Very briefly, the process described with reference to FIG. 2 allows the advertisements provided in the search response webpage to the user to include advertisements that take into account the results of the processing of the search query by the search server system 102. Moreover, this is achieved relatively quickly. The relatively quick speed of provision is a result of the ads server 103 being able to partially process the search query in parallel with the search query being processed by the search server system 102. This is possible due to the contents of the advertisement requests, in particular the inclusion in the first advertisement request of an indication that an advertisement response is not to be provided and an inclusion in the second advertisement request that an advertisement response is to be provided, and because of the configuration of the front end 101 and the ads server system 103 to provide part-processing of the search query by the ads server 103 and to complete the processing using the results of the search performed by the search server system 102. Further details and additional advantages will be apparent from the following description, which is to be read in accordance with the accompanying figures. Detailed embodiments will now be described with reference to FIGS. 3, 4 and 5. FIG. 3 relates to steps performed by the front end 101 and FIG. 4 relates to steps performed by the ads server system 103. Referring firstly to FIG. 3, the operation begins at step S1. At step S2, the search query is received from the user. This step was described above with reference to FIG. 2. At step S3, the front end 101 sends a first search request to the search server system 102 in a message. The sending of the first search request is indicated at S1 in FIG. 1. The first search request may take any suitable form. For instance, it may include all of the text of the search query that was provided by the user and was received at step S2. Typically, the first search request does include all of the text of the search query received at step S2. The first search request may additionally include some context information. For instance, the context information may take the form of information relating to the user's current location, if this information is available. The context information may include information about content that is being displayed by a webpage in which the search query was entered by a user. For instance, if the search query was entered into a search text entry field provided in conjunction with content such as one or more maps or images or a third party website, the context information may include information identifying the related content. At step S4, a first advertisement request is sent by the front end 101 to the ads server system 103 in a message. The sending of the first advertisement request is indicated at A2 in FIG. 1. The first advertisement request can take the same form as the first search request that was sent at step S3. Alternatively, the first advertisement request may take a different form. For instance, the first advertisement request may include a subset of the information that was included in the first search request that was sent to the search server. The first advertisement request prepared by the front end 101 and sent at step S4 includes an indication that an advertisement response is not to be provided by the ads server 103. This may be provided in any suitable way. For instance, it may take the form of a flag, or more generally a predetermined value in a predetermined field. The indication may take the form of text, or it may simply be data. After sending the first search request to the search server 102 at step S3, the search server system 102 processes the first search request. This may be entirely conventional, and does not need to be explained here. The result of processing of the first search request by the search server system 102 is search results, that are sent in a search response message to the front end 101. This is indicated at S2 in FIG. 1. The search response message including the search results are received from the search server system at the front end 101 at step S5 of FIG. 3. The search results received at the front end 101 from the search server system 102 at step S5 include information falling into two categories, and possibly also information falling into a third category. Information falling into the first category is information that is presented in the search response webpage to the user. This information includes a URL, a text snippet and one or more site links. The URL is text that indicates the location/node on the worldwideweb to which the first site link points. The site link is a hyperlink to the URL that is indicated. The displayed text of the hyperlink typically is different to the URL, and for instance typically is descriptive. The text snippet is plain text that is derived from the webpage to which the particular search result relates. The text snippet typically includes between 10 and 20 words and about 100 or so characters, although this is merely an example. The text snippet is text derived from the webpage to which the particular search result relates and which has been determined by the search server system 102 as being particularly relevant to the search query. The second category of information is information that is not displayed to a user in the search page. This includes location information relating to the search result. The location information may for instance be an address, that is a street address or a PO box address, or latitude and longitude coordinates or such like. The information that is not displayed may additionally include entity information that is on the webpage to which the search result relates, for instance it may include categories that are relevant to the search result. The optional other category of information is other elements such as a knowledge card, a map, a video, and other search queries. The information described above is provided for each of plural search results. The number of search results that are included in the search results may be determined by the front end 101, for instance based on a preference setting of the user or based on some other information, or it may be determined by the search server system 102. A typical number of search results presented on a search response webpage is 10. The number of search results included in the search response typically is sufficient for a number of pages of search response webpage. For instance, 100 search results may be included in the search response. The search response may also include a full page replacement, where the search server system 102 has determined that the search query may have included a spelling mistake. A full page replacement includes search results for a spell-corrected version of the search query, and indicates both the spell-corrected search query and the uncorrected search query. Search results for the uncorrected search query typically are not provided in a search response including a full page replacement. At step S6, the front end 101 selects data from the search results received at step S5. The selection of data at step S6 involves selecting some of the data forming part of the search results received from the search server, and not selecting other data. This step may be performed in any suitable way. For instance, if a knowledge card is present in search results, the knowledge card is not selected at step S6. Text snippets are selected at step S6, although in some embodiments they are not selected. Site links are not selected at step S6. Furthermore, full location information is not selected at step S6. URLs from the search results are selected. At step S7, a second advertisement request is prepared using the data that was selected at step S6. The second advertisement request may includes some additional information. The second advertisement request may include information relating to the plural search results. For instance, if a knowledge card is present in the search response, the knowledge card is not selected at step S6. However, the front end 101 provides the second advertisement request with a flag indicating that a knowledge card is present in the search response. The flag may be of a Boolean representation. Furthermore, full location information is not selected at step S6. However, a flag indicating whether or not location information is present may be provided. A flag is provided for each search result, allowing determination of which search results have location information associated therewith. Also, information identifying the type of content present at the webpage linked to by the URL of a search result is included in the second advertisement request. The type of content may be indicated as for instance a video, a webpage, a news story or an image. The type of content is provided separately for each search result. Where the search response indicates that a map is to be provided in the search response webpage, the second advertisement request can include information identifying the map area, for instance by defining the rectangular border of the map. The second advertisement request can additionally include information identifying when search results are located within the map area. The second advertisement request includes data selected from each of the search results that were provided by the search server system 102 to the front end 101 at step S5. For instance, where ten search results were provided, the second advertisement request includes information relating to each of the ten separate search results, which may be quite different from one another, as well as the user-specific data. Additionally, the search query to which the search results relate, this being the search query that was received by the front end 101 at step S2, is included in the second advertisement request. The second advertisement request also includes an indication that an advertisement response is to be provided by the ads server system 103. This can be achieved in any suitable way. For instance, it may involve including a flag having an opposite value to the flag used in the first advertisement request that was sent at step S4. Following preparation of the second advertisement request, it is sent to the ads server system 103 at step S7 by the front end 101. This is illustrated at A2 in FIG. 1. Following step S7, the front end 101 waits for an advertisement response from the ads server system 103. The advertisement response is indicated at A3 in FIG. 1. When the advertisement response is received at step S8, the front end 101 continues with the operation of FIG. 3. In particular, at step S9 the front end 101 combines information from the search response received from the search server system 102 at step S5 with information from the advertisement response received from the ads server system 103 at step S8 into a search response webpage. The search response webpage is then provided at step S10 to the user, and is viewed by the user through their browser application. The operation ends at step S11. Operation of the ads server system 103 will now be described with reference to FIG. 4. Operation begins at step S1. At step S2, the ads server system 103 receives the first advertisement request. This is the first advertisement request that was sent by the front end 101 at step S4 of FIG. 3. At step S3, the ads server system 103 searches for advertisements using the information included in the first advertisement request. This step may be performed in a conventional way. The result of step S3 is a number of advertisements that may be of interest to the user. For instance, the result of step S3 may be some dozens of advertisements, some hundreds of advertisements or even around a thousand advertisements. At step S4, the advertisements are ranked. Ranking involves attributing a score to each of the advertisements and then ordering the advertisements according to their score. This may be performed conventionally. For instance, attributing a score to an advertisement may involve applying a function of three parameters, which can be represented as follows: Score=f(bid, PCTR, relevance) Here, the numerical value of the bid parameter is a value provided by an advertiser in advance, through their advertising account with the search service provider. The provision of a bid value for an advertisement is provided by the retrieve subsystem 105. The operation involves the ads server system 103 sending a request R1 for a bid for an advertisement to the retrieve subsystem 105. The retrieve subsystem 105 then calculates a bid value and sends it at R2 to the ads server system 103. The calculation of the bid value by the retrieve subsystem 105 may be performed in any suitable way, for instance conventionally. PCTR is predicted click-through rate, and has a numerical value. A PCTR for a given advertisement is calculated by the PCTR subsystem 106. The PCTR may be calculated in any suitable way. The procedure is that the ads server system 103 sends P1 a request for a PCTR for an advertisement to the PCTR subsystem 106. The PCTR subsystem 106 then calculates a PCTR value for the advertisement, which can be performed in any suitable way. The PCTR value for the advertisement then is returned to the ads server system 103 by P2 in FIG. 1. The numerical value of the relevance parameter is provided by the relevance score subsystem 107. This may be performed in any suitable way, for instance in a conventional manner. The procedure is that the ads server system 103 sends a relevance score RS1 request to the relevance score subsystem 107. The relevance score subsystem then calculates a relevance score for the advertisement and sends it at RS2 to the ads server system 103. After a score has been calculated for each of the advertisements, using the function of the three parameters, the advertisements are ranked at step S4. Step S4 may involve physically organising the data relating to the advertisements such that higher ranked advertisements are physically located in memory together. Alternatively, the ranking of advertisements at step S4 may merely involve deleting or marking for deletion advertisements which have a score that is so low that the advertisement does not qualify to be included in the ranked advertisements. At step S5, the ads server system 103 waits for a second advertisement request from the front end 101. The ads server system 103 knows to wait for the second advertisement request by virtue of the inclusion in the first advertisement request of the indication that an advertisement response is not to be provided. Once a second advertisement request is received from the front end 101, the operation continues to step S6. Step S6 is an optional step of performing further searching for advertisements. Step S6 is not a repeat of step S3; instead it is a significantly more focussed and shorter duration search. The further searching performed in step S6 may for instance be based on a small number of the highest search results included in the second advertisement request. For instance, the further searching performed at step S6 may be based on the top (first) one of the search results included in the second advertisement request. For instance, a search query of “highest mountain in the world” may produce from the search server system 102 a number of search results including a top (first) result relating to an online encyclopaedia entry for Mount Everest. The search query is included in the first advertisement request received at step S2 and the search result of “Mount Everest” is received in the second advertisement request at step S5. In this case, step S6 may involve performing further searching in respect of “Mount Everest”, resulting in one or more advertisements for organised tours or vacations to Mount Everest. Advertisements found during the further search in step S6 are scored using the formula given above and are included in the ranked advertisements from step S4. At step S7, the scores of advertisements, and thus potentially their ranking, is changed by the ads server system 103. As shown in FIG. 4, there are three aspects to this step. The first is modifying the PCTR at step S7.1. The second is modifying the relevance score at step S7.2. The third is modifying the bid at step S7.3. Changing the score/ranking of ads at step S7 may involve just one of the options of steps S7.1 to S7.3. Alternatively, it may involve two of the options of steps S7.1 to S7.3. For instance, it may involve modifying the PCTR and modifying the relevance score. Alternatively, step S7 may involve all three of the options of step S7.1 to S7.3. Step S7 is performed separately for each advertisement. The ads server system 103 may modify the value of PCTR for an advertisement at step S7.1 in one of a number of different ways. For instance, the PCTR of an advertisement is changed depending on the user interface elements that are indicated in the second advertisement request. For a given advertisement, the PCTR may be modified by the ads server system 103 depending on whether a map is indicated as being a user interface element that is present in the search results. As indicated above, the second advertisement request does not include any maps, but can include an indication of whether a map is to be provided. The PCTR may be modified upwards or downwards, that is it may be increased or decreased, depending on whether a map is to be provided with the search results. The particular algorithm for modifying the PCTR depending on whether or not a map is to be provided can take any suitable form. Similarly, the PCTR for an advertisement can be changed depending on whether the search response includes a knowledge card. As indicated above, the presence or absence of a knowledge card in the search response is indicated in the second advertisement request. Additionally, the PCTR for an advertisement may be modified by the ads server system 103 depending on the number of images that are present in the search results, as indicated in the second advertisement request. In the case of modifying the PCTR depending on whether there is a knowledge card in the search results and how many images are present in the search results may result in the PCTR being increased or decreased, depending on the choice of algorithm. Modifying the relevance score of an advertisement at step S7.2 can take any suitable form. For instance, for a search query relating to “car insurance”, the top search result may be an insurance provider such as “Example Car Insurance”. In this case, step S7.2 may modify the relevance score of advertisements that relate to “Example Car Insurance”, in particular by giving them a higher relevance score. Step S7.2 may or may not involve reducing the relevant score of advertisements that do not lead to “Example Car Insurance”. Modifying the relevance at step S7.2 may involve increasing the relevance score for advertisements that relate to a physical location that is relatively proximate to a location of the top search result. For instance, a top search result relating to a particular theatre in London may result in step S7.2 increasing the relevance score for advertisements relating to restaurants that are located geographically close to the physical location of the theatre. If the second advertisement request includes snippets for the search results, modifying the relevant score at step S7.2 may involve increasing the relevance score for advertisements that include a relatively large amount of text in common with the snippets of the top one or more search results. Modifying the bid for an advertisement at step S7.3 can be performed in one of a number of ways. For instance, advertisers may specify with the search services provider that their bids for their advertisements are modified depending on search results that are to be provided to the user in the search response webpage. For instance, an advertiser may specify that their bid for an advertisement is to be increased from value x to value y if the search results resulting from a search query include a particular advertiser, which may for instance be the bidding advertiser or may be a third party advertiser, for instance a competitor of the bidding advertiser. For instance, an advertisement for a flower delivery service may be specified by the advertiser to have a bid x associated therewith and for the bid to be modified to a value y if the search results for a search query include flower delivery services of a particular competitor to the bidding advertiser. It will be appreciated that modifying the PCTR at step S7.1, modifying relevance at step S7.2, and modifying bid at step S7.3 is performed for at least some of the advertisements that were ranked in step S4. As such, the score for at least some of the advertisements is changed by performance at step S7. Consequently, the ranking of the advertisements will be changed as a result of performance at step S7 in most, if not all, instances. It will be appreciated also that modifying the PCTR at step S7.1, modifying relevance at step S7.2, and modifying bid at step S7.3 is performed using information related to only some of the search results included in the search response. For instance, modifying the PCTR at step S7.1, modifying relevance at step S7.2, and modifying bid at step S7.3 is performed using information related to only three or five of the search results included in the search response. As is conventional, one or more highest rank advertisements are provided in the search response webpage to the user by the front end 101. As such, modifying the score of advertisements in step S7 can result in different advertisements being provided to the user. Advantageously, these advertisements have been selected taking into account not only the search query but also the search results, as provided by the search server system 102, that are to be provided alongside the advertisements in the webpage to the user. Thus, more information is taken into account in the provision of advertisements than is possible on prior art systems. Moreover, this is achieved with a relatively small additional delay since the searching for advertisements and much of the processing of the advertisements by the ads server system 103 is performed whilst the search server system 102 is searching for the relevant search results. There is some additional delay in the provision of the search response webpage to the user but the additional delay is relatively small, resulting only from step S7 and optionally steps S6 and S8, and is considered to be an acceptable additional delay considering the benefits. Following step S7, there is an optional step of changing the visual appearance of advertisements at step S8. The changing of the visual appearance of the advertisements takes into account the content of the second advertisement request received at step S5. For instance, if search results have site links, step S8 may involve displaying more site links for a given advertisement. Alternatively or additionally, if a number of top search results prominently feature location information, step S8 may involve changing the visual appearance of the advertisements that are to be provided in the search response webpage such that locations within the advertisements are shown more prominently. Step S8 may alternatively involve making a determination to show extensions of advertisements whereas otherwise they would not have been shown. These extensions can include map extensions or video extensions etc. Map extensions of advertisements can be determined to be shown at step S8 where for instance the top search results include a relatively high amount of location information. A decision to show video extensions may be made at step S8 where the top search results include a relatively high amount of video content. Alternatively, step S8 may involve determining to show extensions such as map extensions and video extensions more prominently than otherwise they would have been shown in the search results provided to the user. At step S9, the ads server system 103 prepares and sends an advertisement response to the front end 101. The advertisement response includes a number of advertisements. The number of advertisements is selected by the ads server system 103 depending on a number of factors, and this may be performed in a conventional manner. The content of the advertisement included in the advertisement response sent at step S9 may be conventional. The content of the advertisements may include text, URLs and site links. The content of the advertisements may also include other content such as video, map content etc. The advertisement response may also include information that allows the front end 101 to determine how to show the corresponding advertisements. In particular, the advertisement response may include information identifying what site links are to be displayed, what locations are to be displayed and in what format, and whether extensions are to be displayed and if so how they are to be displayed. The advertisement response may be the same as in conventional systems. However, there is a difference in that the selection of advertisements included in the advertisement response takes account of the search results provided by the search server system 102, in particular by changing the score and thus ranking of advertisements through implementation of step S7 of FIG. 4. The operation ends at step S10. As mentioned above, the ads server system 103 includes multiple servers 103a to 103d. There may be many tens or even hundreds of servers 103a to 103d within the ads server system 103. This poses a number of challenges with the two stage advertisement searching and ranking procedure that was described above with reference to FIG. 4. These challenges have been overcome using a new technique which will now be described with reference primarily to FIG. 5. Briefly, the load balancer 104 responds to receiving the first advertisement request A1 from the front end 101 by choosing one of the ads servers 103a to 103d. The load balancer 104a opens a communication session with the selected ads server 103a to 103d, to provide a connection between the load balancer 104a and the selected ads server 103a to 103d. The load balancer 104 also maintains a separate communication session between the front end 101 and the load balancer 104, to provide a separate connection between the front end 101 and the load balancer 104. Subsequently, the load balancer 104 manages communication between the front end 101 and the selected ads server 103a to 103d through these two separate connections. In detail, FIG. 5 shows the front end 101, the load balancer 104 and a particular ads server, in this case the first ads server 103a. FIG. 5 also shows messages that pass between the various components. It will be seen that the front end 101 does not communicate directly with the ads server 103a. Instead the front end 101 communicates with the load balancer 104, and the load balancer 104 communicates with the ads server 103a. The first message is an open message 5.1 that is sent from the front end 101 to the load balancer 104. This constitutes a request to open a connection or commence a communication session between the front end 101 and the load balancer 104. The front end 101 sends the open message 5.1 in response to receiving a search query from the user, but before sending the first advertisement request. In response to receiving the first open message 5.1 from the front end 104, the load balancer 104 selects an ads server, in this case the first ads server 103a, for handling the search and ranking of advertisements. The load balancer 104, after it has selected the ads server 103a, sends an open message 5.2 to the selected ads server 103a. In response to receiving the open message 5.2, the ads server 103a prepares and sends an establish message 5.3 to the load balancer 104. Upon receipt of the establish message 5.3 at the load balancer 104, a connection is established between the load balancer 104 and the ads server 103a. In response to receiving the establish message 5.3, the load balancer 104 sends an establish message 5.4 to the front end 101. After the establish message 5.4 has been received at the front end 101, a connection is established between the front end 101 and the load balancer 104. For each connection, a session is in place between the two relevant components. The session is identified by a session identifier, that is agreed by the parties involved in the session. The session identifier is included in headers of packets that are sent between the parties to the connection, so that the recipient party can ascertain that the packets are part of the relevant connection. This may be performed in any suitable way, and connection sessions are well known in the art. Using session identifiers in this way allows the presence of multiple simultaneous sessions between the parties, allowing the processing of many search queries in parallel. After the session has been established between the front end 101 and the load balancer 104, the front end 101 sends the first advertisement request message 5.5 to the load balancer 104. This is the first advertisement request message that was sent at step S4 of FIG. 3 and received at step S2 of FIG. 4. From the session identifier included in headers of the message 5.5, the load balancer 104 is able to determine the particular ads server 103a to which to forward the first advertisement request. The first advertisement request is forwarded as a forward message 5.6 from the load balancer 104 to the ads server 103a. Here, the payload of the message is the same as that of the first advertisement request, but the headers of the message are different because of the different connection. The first advertisement request message 5.5 and the forwarded message 5.6 include an indication that an advertisement response is not required. As such, the ads server 103a does not provide a response. Instead, the ads server 103a performs steps S1 to S5 of FIG. 4, and waits for the second advertisement request. The front end 101 sends the second advertisement request message 5.7 to the load balancer 104. The load balancer 104 in response forwards a message 5.8 including the payload of the second advertisement request message to the ads server 103a. As discussed above, the second advertisement request message 5.7 and the forwarding message 5.8 include an indication that an advertisement response is required. This is the trigger for the first ad server 103a to progress from step S5 onto step S7. Upon receipt of the forwarding message 5.8, the ads server 103a performs step S7 of FIG. 4, and optionally performs steps S6 and S8 as appropriate. The advertisement response is then prepared in the ads server 103a and is sent as an advertisement response message 5.9 to the load balancer 104. The load balancer 104 upon receiving the advertisement response message 5.9 forwards 5.10 the advertisement response message to the front end 101. The payload of the forwarded message 5.10 is the same as the payload of the advertisement response message 5.9 but the headers are different. After sending the advertisement response message 5.9, the ads server 103a knows that the connection with the load balancer 104 for this particular session is no longer required. Consequently, it sends a close message 5.11 to the load balancer 104a. In response to receiving the close message 5.11, the load balancer 104 sends a close message 5.12 to the front end 101. This requests closing of the connection between the load balancer 104 and the front end 101. In response to receiving the close message 5.12, the front end 101 sends a close message 5.13 to the load balancer 104. Once the close message 5.13 is received at the load balancer, the connection between the front end 101 and the load balancer 104 is closed, or put another way the session is terminated. The load balancer 104 closes the session with the first ad server 103a by sending a close message 5.14 to the first ad server 103a. Upon receiving the close message 5.14 at the first ad server 103a, the session between the load balancer 104 and the first ad server 103a is closed. The close message 5.14 may be sent from the load balancer 104 to the first ad server 103a in response to receiving the closed message 5.13 from the front end 101. Alternatively, it may be sent in response to receiving the close message 5.11 from the first ad server 103a. Each of the front end 101, the load balancer 104 and the first ad server 103a are configured to implement timeouts. When a message is not received with a predetermined period, set by a timeout value, it is determined that a problem has occurred and the connection is closed/the session is terminated. The termination of the session between the load balancer 104 and the first ad server 103a necessarily results in the load balancer 104 failing to provide one of the expected messages to the front end 101. As such, the front end 101 also experiences a timeout and closes the connection session between the front end 101 and the load balancer 104. The corresponding situation applies where the load balancer 104 does not receive a message from the front end 101 within a timeout period, resulting in termination also of the connection between the load balancer 104 and the ads server 103a. Similarly, the front end 101 is responsive to determining that a message has not been received from the load balancer 104 within a predetermined timeout period to close the connection between the front end 101 and the load balancer 104. A consequence of this is that the session between the load balancer 104 and the first ad server 103a is also terminated. The ads server 103a is configured in a corresponding manner to behave in a corresponding way. Using the scheme of FIG. 5, the front end 101 does not need to be aware of the identity of the first ad server 103a nor does it need to know its network address. Instead, the load balancer 104 conducts all needed communication with the first ad server 103a. All that the front end 101 needs to know is the session identifier relating to the communication session between the front end 101 and the load balancer 104. Similarly, the first ad server 103a does not need to know the identity of the front end 101, nor does it need to know its network address. All that the ads server 103a needs to know is the session identifier relating to the communication session between the ads server 103a and the load balancer 104. FIG. 6 illustrates schematically some internal components of the front end 101 and the ads server 103a. The other ads servers 103b to 103d are substantially the same as the first ads server 103a. The front end 101 includes at least one processor 101P, at least one volatile memory 101V and at least one non-volatile memory 101N. Each is connected to a bus 101B. Within the non-volatile memory 101N are stored an operating system OS and one or more software applications App. The non-volatile memory may be read only memory (ROM), such as for instance a hard disk drive, or flash memory, optical storage, tape storage etc. Other non-volatile memories may be included, and are illustrated schematically in the figure. The volatile memory 101V may be for instance random access memory (RAM), flash memory etc. Multiple volatile memories may be included, and are illustrated in FIG. 6. The processor 101P may for instance be a general purpose processor. It may be a single core device or a multiple core device. The processor 101P may be a central processing unit (CPU) or a general processing unit (GPU). Alternatively, it may be a more specialist unit, for instance a RISC processor or programmable hardware with embedded firmware. Multiple processors 101P may be included in the front end 101, and are illustrated as such in FIG. 6. The processor 101P may be termed processing means. Generally speaking, the processor 101P executes one or more applications App using the operating system OS, both of which are stored permanently or semi-permanently in the non-volatile memory 101N, using the volatile memory 101V temporarily to store software forming a whole or part of the operating system OS and the applications App and also temporarily to store data generated during execution of the software. The first ads server 103a is similarly constructed. In particular, the first ads server 103a includes at least one processor 101P, at least one volatile memory 101V and at least one non-volatile memory 101N. Each is connected to a bus 101B. Within the non-volatile memory 103N are stored an operating system OS and one or more software applications App. The non-volatile memory may be read only memory (ROM), such as for instance a hard disk drive, or flash memory, optical storage, tape storage etc. Other non-volatile memories may be included, and are illustrated schematically in the figure. The volatile memory 103V may be for instance random access memory (RAM), flash memory etc. Multiple volatile memories may be included, and are illustrated in FIG. 6. The processor 103P may for instance be a general purpose processor. It may be a single core device or a multiple core device. The processor 103P may be a central processing unit (CPU) or a general processing unit (GPU). Alternatively, it may be a more specialist unit, for instance a RISC processor or programmable hardware with embedded firmware. Multiple processors 103P may be included in the first ads server 103a, and are illustrated as such in FIG. 6. The processor 103P may be termed processing means. Generally speaking, the processor 103P executes one or more applications App using the operating system OS, both of which are stored permanently or semi-permanently in the non-volatile memory 103N, using the volatile memory 103V temporarily to store software forming a whole or part of the operating system OS and the applications App and also temporarily to store data generated during execution of the software. It will be appreciated that the above-described embodiments are not limiting on the scope of the invention, which is defined by the appended claims and their alternatives. Various alternative implementations will be envisaged by the skilled person, and all such alternatives are intended to be within the scope of the claims. For instance, although in the above it is the second advertisement request that includes an indication that a response is required, the invention is not limited to this. In other implementations, it is a third or subsequent request that includes the indication that a response is required. The second request may include further information that can be used in the search and/or ranking of candidate advertisements, in which case the modifying of the score of advertisements may be a two-stage process. Embodiments of the present invention may be implemented in software, hardware, application logic or a combination of software, hardware and application logic. The software, application logic and/or hardware may reside on memory, or any computer media. In an example embodiment, the application logic, software or an instruction set is maintained on any one of various conventional computer-readable media. In the context of this document, a “computer-readable medium” may be any media or means that can contain, store, communicate, propagate or transport the instructions for use by or in connection with an instruction execution system, apparatus, or device, such as a computer. A computer-readable medium may comprise a computer-readable storage medium that may be any tangible media or means that can contain or store the instructions for use by or in connection with an instruction execution system, apparatus, or device, such as a computer as defined previously. According to various embodiments of the previous aspect of the present invention, the computer program according to any of the above aspects, may be implemented in a computer program product comprising a tangible computer-readable medium bearing computer program code embodied therein which can be used with the processor for the implementation of the functions described above. Reference to “computer-readable storage medium”, “computer program product”, “tangibly embodied computer program” etc, or a “processor” or “processing circuit” etc. should be understood to encompass not only computers having differing architectures such as single/multi processor architectures and sequencers/parallel architectures, but also specialised circuits such as field programmable gate arrays FPGA, application specify circuits, and other devices. References to computer program, instructions, code etc. should be understood to express software for a programmable processor firmware such as the programmable content of a hardware device as instructions for a processor or configured or configuration settings for a fixed function device, gate array, programmable logic device, etc. If desired, the different functions discussed herein may be performed in a different order and/or concurrently with each other. Furthermore, if desired, one or more of the above-described functions may be optional or may be combined. Although various aspects of the invention are set out in the independent claims, other aspects of the invention comprise other combinations of features from the described embodiments and/or the dependent claims with the features of the independent claims, and not solely the combinations explicitly set out in the claims.",G06Q300246,G06Q3002,20160129,,20160616,61492.0
7,15001537,ACCEPTED,METHODS AND SYSTEMS FOR ADMISSION CONTROL IN D2D COMMUNICATION IN A WIRELESS BROADBAND NETWORK,"This disclosure relates generally to wireless communication systems, and more particularly to methods and systems for admission control in D2D communication in a wireless broadband network. In one embodiment, a method is disclosed for admission control in device-to-device communication in a wireless broadband network. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request.","1. A system for admission control in device-to-device communication in a wireless broadband network, comprising: a hardware processor; and a memory storing instructions executable by the hardware processor for: receiving, via the hardware processor, proximity-based device-to-device discovery requests; classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins; determining, via the hardware processor, priority levels for the bins; selecting, via the hardware processor, one of the bins as having a highest priority level; identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. 2. The system of claim 1, wherein the proximity-based device-to-device discovery requests are configured according to a 3GPP Long-Term Evolution standard. 3. The system of claim 1, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins is based on: a criticality of a device-to-device communication related to the at least one received proximity-based device-to-device discovery request, whether the device-to-device communication is broadcast or unicast in nature, or whether the device-to-device communication is real-time in nature. 4. The system of claim 1, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins further comprises: restricting, via the hardware processor, a number of proximity-based device-to-device discovery requests per bin based on a system capacity threshold per bin. 5. The system of claim 1, the memory further storing instructions for: triggering, via the hardware processor, the step of classifying the received proximity-based device-to-device discovery requests into bins based on a periodicity timer. 6. The system of claim 1, wherein determining, via the hardware processor, priority levels for the bins comprises; calculating, via the hardware processor, a composite hierarchical classification index for each bin based on a weight sum of: a number of proximity-based device-to-device discovery requests in the bin, a number of proximity-based device-to-device discovery requests dropped from the bin, and a system capacity threshold for the bin; and sorting, via the hardware processor, the bins by priority according to the calculated composite hierarchical classification index for each bin. 7. The system of claim 1, wherein generating, via the hardware processor, the proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request comprises: calculating, via the hardware processor, a validity timer value as a ratio of a default timer value of a bin corresponding to the identified proximity-based device-to-device discovery request to a system capacity threshold for the bin; and generating, via the hardware processor, the proximity-based device-to-device discovery response to include the validity timer value. 8. A method for admission control in device-to-device communication in a wireless broadband network, comprising: receiving, via a hardware processor, proximity-based device-to-device discovery requests; classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins; determining, via the hardware processor, priority levels for the bins; selecting, via the hardware processor, one of the bins as having a highest priority level; identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based de-vice-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. 9. The method of claim 8, wherein the proximity-based device-to-device discovery requests are configured according to a 3GPP Long-Term Evolution standard. 10. The method of claim 8, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins is based on: a criticality of a device-to-device communication related to the at least one received proximity-based device-to-device discovery request, whether the device-to-device communication is broadcast or unicast in nature, or whether the device-to-device communication is real-time in nature. 11. The method of claim 8, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins further comprises: restricting, via the hardware processor, a number of proximity-based device-to-device discovery requests per bin based on a system capacity threshold per bin. 12. The method of claim 8, further comprising: triggering, via the hardware processor, the step of classifying the received proximity-based device-to-device discovery requests into bins based on a periodicity timer. 13. The method of claim 8, wherein determining, via the hardware processor, priority levels for the bins comprises: calculating, via the hardware processor, a composite hierarchical classification index for each bin based on a weight sum of: a number of proximity-based device-to-device discovery requests in the bin, a number of proximity-based device-to-device discovery requests dropped from the bin, and a system capacity threshold for the bin; and sorting, via the hardware processor, the bins by priority according to the calculated composite hierarchical classification index for each bin. 14. The method of claim 8, wherein generating, via the hardware processor, the proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request comprises: calculating, via the hardware processor, a validity timer value as a ratio of a default timer value of a bin corresponding to the identified proximity-based device-to-device discovery request to a system capacity threshold for the bin; and generating, via the hardware processor, the proximity-based device-to-device discovery response to include the validity timer value. 15. A non-transitory computer-readable medium storing processor-executable instructions for admission control in device-to-device communication in a wireless broadband network, the instructions comprising instructions for: receiving, via a hardware processor, proximity-based device-to-device discovery requests; classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins; determining, via the hardware processor, priority levels for the bins; selecting, via the hardware processor, one of the bins as having a highest priority level; identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. 16. The medium of claim 15, wherein the proximity-based device-to-device discovery requests are configured according to a 3GPP Long-Term Evolution standard. 17. The medium of claim 15, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins is based on: a criticality of a device-to-device communication related to the at least one received proximity-based device-to-device discovery request, whether the device-to-device communication is broadcast or unicast in nature, or whether the device-to-device communication is real-time in nature. 18. The medium of claim 15, wherein classifying, via the hardware processor, at least one of the received proximity-based device-to-device discovery requests into one of the bins further comprises: restricting, via the hardware processor, a number of proximity-based device-to-device discovery requests per bin based on a system capacity threshold per bin. 19. The medium of claim 15, further storing instructions for: triggering, via the hardware processor, the step of classifying the received proximity-based device-to-device discovery requests into bins based on a periodicity timer. 20. The medium of claim 15, wherein determining, via the hardware processor, priority levels for the bins comprises: calculating, via the hardware processor, a composite hierarchical classification index for each bin based on a weight sum of: a number of proximity-based device-to-device discovery requests in the bin, a number of proximity-based device-to-device discovery requests dropped from the bin, and a system capacity threshold for the bin; and sorting, via the hardware processor, the bins by priority according to the calculated composite hierarchical classification index for each bin. 21. The medium of claim 15, wherein generating, via the hardware processor, the proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request comprises: calculating, via the hardware processor, a validity timer value as a ratio of a default timer value of a bin corresponding to the identified proximity-based device-to-device discovery request to a system capacity threshold for the bin; and generating, via the hardware processor, the proximity-based device-to-device discovery response to include the validity timer value.","<SOH> BACKGROUND <EOH>Device-to-device (“D2D”) communications have been considered one of the key techniques in the 3 rd Generation Partnership Project (3GPP) Long Term Evolution Advanced (LTE-A) standards, where it provides direct communication among pieces of user equipment (“UEs”) in close proximity. As per the 3GPP standard TS 23.303 Release 12, D2D communication among UEs is enabled by a Proximity Service (“ProSe”) function server. The inventors here have recognized several technical problems with such conventional systems, as explained below. In 3GPP standard TS 23.303 Release 12, there is no admission control mechanism for D2D communications among UEs. Since there is no admission control mechanism, the existing ProSe function server as provided in 3GPP standard TS 23.303 Release 12 gets overloaded when the number of devices and number of simultaneous D2D communication links increases in a network. This results in packet drop and decreases Quality of Service (“QoS”). In a scenario where several D2D discovery request messages from multiple UEs arrive at the ProSe function server, the signaling load at the ProSe function server increases. Also, if the ProSe function server fails to respond to received discovery request messages, then the D2D-enabled UEs cannot perform their communication, hence causing a loss of QoS. Currently, the ProSe function server honors discovery requests solely based on subscription information (entitlement) of each UE, which leads to the following limitations. First, the ProSe function server is not designed to handle multiple discovery requests at any instant. This means that the ProSe function server will honor a single discovery request at any instant, and refuse/drop the rest, thus not allowing many initiator UEs to start D2D communication. Second, the ProSe function server fails to differentiate among discovery requests from UEs with different levels of criticality. This may result in allowance of D2D communication to an incorrect/improper initiator UE and dropping of a more critical initiator UE out of the set of initiator UEs that had sent discovery requests simultaneously at any instant. However, for maintaining the QoS of initiator UEs in a network, it is desired for the ProSe function server to have the following capabilities. First, it it desired that the ProSe function server be capable of handling multiple discovery requests at any instant. Second, it is desired that the ProSe function server be capable of differentiating among discovery requests coming from initiator UEs with different levels of criticality, and ensuring that the most appropriate ones are allowed in order to maintain QoS.","<SOH> SUMMARY <EOH>Embodiments of the present disclosure present technological improvements as solutions to one or more of the above-mentioned technical problems recognized by the inventors in conventional systems. For example, in one embodiment, a system is disclosed for admission control in device-to-device communication in a wireless broadband network, comprising a hardware processor and a memory storing instructions executable by the hardware processor for performing a method. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. In another embodiment, a method is disclosed for admission control in device-to-device communication in a wireless broadband network. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. In yet another embodiment, a non-transitory computer-readable medium is disclosed storing processor-executable instructions for admission control in device-to-device communication in a wireless broadband network, the instructions comprising instructions for performing a method. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.","PRIORITY CLAIM This U.S. patent application claims priority under 35 U.S.C. §119 to India Application No. TBD, filed DATE. The entire contents of the aforementioned application are incorporated herein by reference. TECHNICAL FIELD This disclosure relates generally to wireless communication systems, and more particularly to methods and systems for admission control in D2D communication in a wireless broadband network. BACKGROUND Device-to-device (“D2D”) communications have been considered one of the key techniques in the 3rd Generation Partnership Project (3GPP) Long Term Evolution Advanced (LTE-A) standards, where it provides direct communication among pieces of user equipment (“UEs”) in close proximity. As per the 3GPP standard TS 23.303 Release 12, D2D communication among UEs is enabled by a Proximity Service (“ProSe”) function server. The inventors here have recognized several technical problems with such conventional systems, as explained below. In 3GPP standard TS 23.303 Release 12, there is no admission control mechanism for D2D communications among UEs. Since there is no admission control mechanism, the existing ProSe function server as provided in 3GPP standard TS 23.303 Release 12 gets overloaded when the number of devices and number of simultaneous D2D communication links increases in a network. This results in packet drop and decreases Quality of Service (“QoS”). In a scenario where several D2D discovery request messages from multiple UEs arrive at the ProSe function server, the signaling load at the ProSe function server increases. Also, if the ProSe function server fails to respond to received discovery request messages, then the D2D-enabled UEs cannot perform their communication, hence causing a loss of QoS. Currently, the ProSe function server honors discovery requests solely based on subscription information (entitlement) of each UE, which leads to the following limitations. First, the ProSe function server is not designed to handle multiple discovery requests at any instant. This means that the ProSe function server will honor a single discovery request at any instant, and refuse/drop the rest, thus not allowing many initiator UEs to start D2D communication. Second, the ProSe function server fails to differentiate among discovery requests from UEs with different levels of criticality. This may result in allowance of D2D communication to an incorrect/improper initiator UE and dropping of a more critical initiator UE out of the set of initiator UEs that had sent discovery requests simultaneously at any instant. However, for maintaining the QoS of initiator UEs in a network, it is desired for the ProSe function server to have the following capabilities. First, it it desired that the ProSe function server be capable of handling multiple discovery requests at any instant. Second, it is desired that the ProSe function server be capable of differentiating among discovery requests coming from initiator UEs with different levels of criticality, and ensuring that the most appropriate ones are allowed in order to maintain QoS. SUMMARY Embodiments of the present disclosure present technological improvements as solutions to one or more of the above-mentioned technical problems recognized by the inventors in conventional systems. For example, in one embodiment, a system is disclosed for admission control in device-to-device communication in a wireless broadband network, comprising a hardware processor and a memory storing instructions executable by the hardware processor for performing a method. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. In another embodiment, a method is disclosed for admission control in device-to-device communication in a wireless broadband network. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. In yet another embodiment, a non-transitory computer-readable medium is disclosed storing processor-executable instructions for admission control in device-to-device communication in a wireless broadband network, the instructions comprising instructions for performing a method. The method may comprise receiving, via the hardware processor, proximity-based device-to-device discovery requests; and classifying, via the hardware processor, the received proximity-based device-to-device discovery requests into bins. The method may further include determining, via the hardware processor, priority levels for the bins; and selecting, via the hardware processor, one of the bins as having a highest priority level. The method may also include identifying in a first-in-first-out manner, via the hardware processor, one of the proximity-based device-to-device discovery requests classified into the selected bin; and generating and providing, via the hardware processor, a proximity-based device-to-device discovery response to the identified proximity-based device-to-device discovery request. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated in and constitute a part of this disclosure, illustrate exemplary embodiments and, together with the description, serve to explain the disclosed principles. FIG. 1 is a block diagram illustrating aspects of a prior art wireless communication system. FIG. 2 is a block diagram illustrating aspects of a prior art proximity-based services (ProSe) function server. FIG. 3 is a flow diagram illustrating a prior art method for device-to-device (“D2D”) communication in using a ProSe service. FIG. 4 is a block diagram illustrating aspects of an improved wireless communication system according to some embodiments. FIG. 5 is a block diagram illustrating aspects of an improved proximity-based services (ProSe) function server according to some embodiments. FIG. 6 is a block diagram illustrating aspects of an admission control system for a ProSe function server according to sonic embodiments. FIG. 7 is a flow diagram illustrating a method for admission control in D2D communication in a wireless broadband network according to some embodiments. FIG. 8 is a flow diagram illustrating a method for classifying D2D discovery requests according to some embodiments. FIG. 9 is a flow diagram illustrating a method for differential processing of D2D discovery requests according to some embodiments. FIG. 10 is a block diagram of an exemplary computer system for implementing embodiments consistent with the present disclosure. DETAILED DESCRIPTION Exemplary embodiments are described with reference to the accompanying drawings. In the figures, the left-most digit(s) of a reference number identifies the figure in which the reference number first appears. Wherever convenient, the same reference numbers are used throughout the drawings to refer to the same or like parts. While examples and features of disclosed principles are described herein, modifications, adaptations, and other implementations are possible without departing from the spirit and scope of the disclosed embodiments. It is intended that the following detailed description be considered as exemplary only, with the true scope and spirit being indicated by the following claims. Embodiments of the present disclosure provide an improved ProSe function enabled with D2D admission control in a wireless broadband network that has the ability to process multiple DRs of different levels of criticality, at any instant, and ensure that the most appropriate ones are allowed in order to maintain QoS. Further, in some embodiments, the D2D admission control (D2DAC) mechanism is able to handle multiple discovery requests by classifying each discovery request in a composite hierarchical manner and buffering them. Pending discovery requests are not outright rejected. Instead, the ProSe function server is capable of maintaining a backlog of discovery requests that will considered for processing in a subsequent round of processing. Further, in some embodiments, the D2DAC can perform classification of received discovery requests in a composite hierarchical manner based on the criticality, D2D-communication-mode (e.g., 1-to-1, 1-to-many) and application-need (real-time/non-real-time). This classification may be represented in the form of a composite-hierarchical-classification-index (“CHCI”). Processing of the discovery requests may be performed by the D2DAC based on the CHCI values. FIG. 1 is a block diagram illustrating aspects of a prior art wireless communication system 100. In some embodiments, connected to the broader Internet 110 may be an evolved packet core (“EPC”) 120. One or more pieces of user equipment (UEs) 133, 134, 15, and 136 may be connected to the EPC 120 over a E-UTRAN network 130. A Macro Evolved NodeB station eNB1 132 may serve as a base station for LTE radio. The EPC 120 may be composed of four network elements: the Serving Gateway (Serving GW 123, 124), the public data network (“PDN”) Gateway (PDN GW 121), the MME (123, 124) and the Home Subscriber Server (“HSS”) 125. The gateways (Serving GW and PDN GW) deal with the user plane. They transport the IP data traffic between the User Equipment (UE) and the external networks. The Serving GW 123, 124 is the point of interconnect between the radio-side and the EPC. As its name indicates, this gateway serves the UE by routing the incoming and outgoing IP packets. The PDN GW 121 is the point of interconnect between the EPC and the external IP networks. These networks are called PDN (Packet Data Network), hence the name. The PDN GW 121 routes packets to and from the PDNs. The PDN GW 121 also performs various functions such as IP address/IP prefix allocation or policy control and charging. The MME (for Mobility Management Entity) 123, 124 deals with the control plane. It handles the signalling related to mobility and security for E-UTRAN access. The MME is responsible for the tracking and the paging of UE in idle-mode. It is the termination point of the Non-Access Stratum (NAS). The HSS 125 may be a database that contains user-related and subscriber-related information. It also may provide support functions in mobility management, call and session setup, user authentication and access authorization. The EPC is connected to the external networks, which can include the IP Multimedia Core Network Subsystem (IMS). Also, the wireless communication system 100 may include a Policy and Charging Rules Function (“PCRF”) 122, which may be a software node designated in real-time to determine policy rules in a multimedia network. As a policy tool, the PCRF 122 may plays a central role in next-generation networks. Unlike earlier policy engines that were added onto an existing network to enforce policy, the PCRF 122 is usually a software component that operates at the network core and accesses subscriber databases and other specialized functions, such as a charging system, in a centralized manner. A ProSe application server 126 and a ProSe function server 131 may provided proximity-based services for UEs. The ProSe application server 126 may support capabilities for storage and mapping of application and user identifiers. Specific application level signaling between the ProSe application server 126 and the ProSe application may be done over PC1. The ProSe application server 126 may interact with the ProSe function server 131 over the PC2 reference point. The ProSe function server 131 may perform a logical function that is used for network related actions required for ProSe. It may consist of three main sub-functions that perform different roles depending on the ProSe feature, as explained below with reference to FIG. 2. FIG. 2 is a block diagram illustrating aspects of a prior art proximity-based services (ProSe) function server 131. In some embodiments, a ProSe function server 131 may include hardware 240 (see, e.g., FIG. 10 for a description of exemplary hardware and software components), an IP transport layer 230 for transport of packets through an Internet Protocol, and an interface layer 220 (e.g., PC3, PC4a, PC4b, PC6, PC7). Further, the ProSe function server 131 may include a ProSe functional layer 210, which may include a direct provisioning module 212, a direct discovery name management module 214, and a EPC level discovery module 216. The direct provisioning module 212 may be used to provision a UE with necessary parameters in order to use ProSe direct discovery and ProSe direct communication. The UEs may be provisioned with public land mobile network (“PLMN”)-specific parameters allowing them to use ProSe in a specific PLMN. This can include information such as a list of PLMNs in which a Use can perform direct discovery and parameters needed for direct communication when the UE is out of network coverage. Direct discovery name management module 214 may be used for open ProSe direct discovery to allocate and process the mapping of ProSe application IDs and ProSe application codes. It may use ProSe-related subscriber data stored in a Home Subscriber Server (“HSS”) for authorization of each discovery request. It may also provide the UE with necessary security data to protect discovery messages exchanged over the air interface. EPC level discovery module 216 may be used to provide network-assisted discovery using location information to UEs. FIG. 3 is a flow diagram illustrating a prior art method 300 for device-to-device (“D2D”) communication in using a ProSe service. In some embodiments, a UE 310 may utilize a ProSe application ID configuration 320 to generate a D2D discovery request 330, e.g., including the ProSe application ID, UE identity, an application IP, and an “ANNOUNCE” command. A ProSe function server 312 may receive the discovery request, and may initiate a discovery authorization sequence with Home Subscriber Server (“HSS”) 314 for authorization of each discovery request. Based on the authorization sequence, the ProSe function sever 312 may generate a discovery response message 350, including a ProSe application code and a validity timer, for UE 310. Based on the discovery response message 350, UE 310 a=may engage in radio resource allocation 360 for D2D communication. FIG. 4 is a block diagram illustrating aspects of an improved wireless communication system 400 according to some embodiments. In some embodiments, system 400 may have similar components 110-136 as described above with regard to the prior art system of FIG. 1. System 400, however, may further include an improved ProSe function server 431 including a new module named “D2D Admission Control (D2DAC).” A description of the D2DAC may proceed with reference to FIG. 5. FIG. 5 is a block diagram illustrating aspects of an improved proximity-based services (ProSe) function server 431 according to some embodiments. As shown in FIG. 5, the ProSe function server 431 may include similar components 210-240 as described above with respect to the prior art system 131 of FIG. 2. In addition, however, the ProSe function server may include a (D2DAC) admission control module 518. D2DAC 518 may interface with a craft-person via a command-line interface for receiving configuration details during startup of the system. Once D2DAC 518 receives the configuration details, those details may be stored into the D2DAC 518's persistent-memory. During the steady state of the ProSe system, D2DAC 518 may predominantly interact with Interface Layer 220 for performing admission control by analyzing discovery request messages. The system architecture of an exemplary embodiment of the proposed “D2D Admission Control” module is shown in FIG. 6. FIG. 6 is a block diagram illustrating aspects of an admission control system 600 for a ProSe function server according to some embodiments. In some embodiments, a D2DAC module 630 may be responsible for performing admission control of D2D UEs by analyzing each of the discovery request messages received from the interface layer 620. A configuration module 632 may be responsible for storing the environment and configuration parameters required by all other modules of the D2DAC. The D2DAC may obtain its configuration parameters from the craft-person via the command line interface 610 and store the configuration parameters in its own local data structures. Examples of configuration parameters sored include those described below. In some embodiments, each D2D discovery request message may be categorized into one or more application category bins. A system capacity threshold may be defined per application category bin (SCthreshold), which may be a threshold value received from command line interface 610 during system initialization. This value may be used to restrict the number of D2D devices requesting for discovery announcement per application category bin. The system capacity threshold may be used by decision module 638. For example, if there are if there are five bins defined, then five different system capacity threshold values may be obtained, as shown below: SCthreshold(1), SCthreshold(2), SCthreshold(3), SCthreshold(4), SCthreshold(5) A periodicity timer value may be defined (Tthreshold), which may be a periodic timer received from command line interface 610 during system initialization. This value may be used to trigger the initiation of calculations related to each of the application category bins. The periodicity timer value may be used by decision module 638. For example, if there are five application category bins defined, then a single periodicity timer value may be obtained. (Tthreshold(1)). In some embodiments, a classification module 636 may be responsible for classification of received discovery requests in a composite hierarchical manner. The classification module 636 may dynamically classify the packets coming from interface layer 620 based on the criticality, D2D-communication-mode (e.g., 1-to-1, 1-to-many) and application-need (e.g., real-time/non-real-time). This classification may be represented in the form of a composite-hierarchical-classification-index (CHCI), calculated by a parameter calculation module 634. The parameter calculation module 634 may also calculate a validity timer for a selected request message, to facilitate the admission control system 600 to respond back to the UE with a discovery response message. In some embodiments, a decision module 638 may dynamically select the application category bin from which the D2D request message is selected for processing. The decision module 638 may use the parameter calculation module 634 to calculate the composite-hierarchical-classification-index (CHCI) for each application category bin. After determining the CHCI values, the application category bin with the highest CHCI may be selected, from which the request is selected to be honored. FIG. 7 is a flow diagram illustrating a method 700 for admission control in D2D communication in a wireless broadband network according to some embodiments. In some embodiments, at step 710, a ProSe function server 431 may receive one or more D2D discovery request messages from one or more UEs (e.g., UE2 134). The ProSe functional server 431 may invoke an admissions control module 518 within a ProSe functional layer 210. The admissions control module 518 may include an D2D admission control module 630, which includes a classification module 636. At step 720, classification module 636 may classify the discovery requests into one or more application category bins, as explained with reference to FIG. 8. FIG. 8 is a flow diagram illustrating a method 800 for classifying D2D discovery requests according to some embodiments. In some embodiments, a classification module 636 may extract an application code and UE identity from a discovery request. The classification module 636 may then check whether the UE with UE identity is subscribed for D2D direct discovery. If not, then the discovery request may be dropped. Further, the classification module 636 may then check whether the application represented by the application ID is authorized for direct discovery. If not, then the discovery request may be dropped. In some embodiments, at step 805, classification module 636 may determine whether a received discovery request is considered mission critical (e.g., related to an emergency or high-priority situation). If so, classification module 636 may classify the discovery request into an application category 1 bin 810. If the classification module 636 determines that the received discovery request is not considered mission critical, the classification module 636 may, at step 815, determine whether the received discovery request is for broadcast (e.g., 1-to-many) or unicast (e.g., 1-to-1) communication. If the discovery request is for broadcast communication, at step 820, the classification module 636 may determine whether the communication type is real-time or not. If the communication type is real-time, the classification module 636 may classify the received discovery request into an application category 2 bin 825; otherwise, the classification module 636 may classify the received discovery request into an application category 3 bin 830. If the discovery request is for unicast communication, at step 835, the classification module 636 may determine whether the communication type is real-time or not. If the communication type is real-time, the classification module 636 may classify the received discovery request into an application category 4 bin 840; otherwise, the classification module 636 may classify the received discovery request into an application category 5 bin 845. Returning to FIG. 7, at step 730, a parameter calculation module 634 to calculate a composite-hierarchical-classification-index (CHCI) for each application category bin, as explained with reference to FIG. 9. Further, at step 740, a decision module 638 may perform differential processing of the received discovery requests, as also explained with reference to FIG. 9. FIG. 9 is a flow diagram illustrating a method 900 for differential processing of D2D discovery requests according to some embodiments. At step 910, decision module 638 may determine whether the application category 1 bin is empty. If it is not empty, at step 920, decision module 638 may select application category 1 bin, and select a discovery request message from application category 1 bin for processing. For example, decision module 638 may employ a first-in-first-out (“FIFO”) principle in selecting a discovery request message from the application category 1 bin for processing (see step 960). If the application category 1 bin is empty, at step 930, decision module 638 may invoke parameter calculation module 634 to calculate a composite-hierarchical-classification-index (CHCI) for each non-empty application category bin (e.g., application category 2-5 bins). For example, parameter calculation module 634 may calculate the CHCI value for each non-empty application category bin at every periodicity timer (Tthreshold), using parameters like: (1) number of pending requests in the bin; (2) number of direct discovery requests dropped from the bin; and (3) system capacity threshold for each of the application category bins. For example, parameter calculation module 634 may calculate the CHCI value for each non-empty application category bin as a weighted sum of the above parameters. At step 940, decision module 638 may sort the application category bins in descending order of their associated CHCI values. At step 950, decision module 638 may select the application category bin with the highest CHCI value. At step 960, decision module 638 may select a discovery request message for processing from the bin selected in step 920 or step 950. For example, decision module 638 may employ a first-in-first-out (“FIFO”) principle in selecting a discovery request message from the selected application category bin for processing (see step 960). Returning to FIG. 7, at step 750, D2D admission control module 630 may generate and provide a discovery response to the selected discovery request(s) in e.g., accordance with the 3GPP Release 12 standard. Accordingly, in some embodiments, some advantages obtained may be as follows: Multiple DR Processing: In sonic embodiments, the D2D Admission Control (D2DAC) mechanism may be able to handle multiple discovery requests by classifying each discovery request in a composite hierarchical manner and buffering the discovery requests. Pending discovery requests may not be outright rejected. A backlog of discovery requests may be maintained that may be considered for processing in a subsequent cycle. Differential Handling Based on Classification: In some embodiments, the D2DAC may perform classification of received discovery requests in a composite hierarchical manner based on the criticality, D2D-communication-mode (1-to-1, 1-to-many) and application-need (real-time/non-real-time). This classification may be represented in the form of composite-hierarchical-classification-index (CHCI). Processing of the discovery requests may be performed by the D2DAC based on CHCI for effective differential handling of DR in D2D communication. Computer System FIG. 10 is a block diagram of an exemplary computer system for implementing embodiments consistent with the present disclosure. Variations of computer system 1001 may be used for implementing the devices and systems disclosed herein. Computer system 1001 may comprise a central processing unit (“CPU” or “processor”) 1002. Processor 1002 may comprise at least one data processor for executing program components for executing user- or system-generated requests. A user may include a person a person using a device such as those included in this disclosure, or such a device itself. The processor may include specialized processing units such as integrated system (bus) controllers, memory management control units, floating point units, graphics processing units, digital signal processing units, etc. The processor may include a microprocessor, such as AMD Athlon, Duron or Opteron, ARM's application, embedded or secure processors. IBM PowerPC, Intel's Core, Itanium, Xeon, Celeron or other line of processors, etc. The processor 1002 may be implemented using mainframe, distributed processor, multi-core, parallel, grid, or other architectures. Some embodiments may utilize embedded technologies like application-specific integrated circuits (ASICs), digital signal processors (DSPs), Field Programmable Gate Arrays (FPGAs), etc. Processor 1002 may be disposed in communication with one or more input/output (I/O) devices via I/O interface 1003. The I/O interface 1003 may employ communication protocols/methods such as, without limitation, audio, analog, digital, monoaural, RCA, stereo, IEEE-1394, serial bus, universal serial bus (USB), infrared, PS/2, BNC, coaxial, component, composite, digital visual interface (DVI), high-definition multimedia interface (HDMI), RF antennas, S-Video, VGA, IEEE 802.11 a/b/g/n/x, Bluetooth, cellular (e.g., code-division multiple access (CDMA), high-speed packet access (HSPA+), global system for mobile communications (GSM), long-term evolution (LTE), WiMax, or the like), etc. Using the I/O interface 1003, the computer system 1001 may communicate with one or more I/O devices. For example, the input device 1004 may be an antenna, keyboard, mouse, joystick, (infrared) remote control, camera, card reader, fax machine, dongle, biometric reader, microphone, touch screen, touchpad, trackball, sensor (e.g., accelerometer, light sensor, GPS, gyroscope, proximity sensor, or the like), stylus, scanner, storage device, transceiver, video device/source, visors, etc. Output device 1005 may be a printer, fax machine, video display (e.g., cathode ray tube (CRT), liquid crystal. display (LCD), light-emitting diode (LED), plasma, or the like), audio speaker, etc. In some embodiments, a transceiver 1006 may be disposed in connection with the processor 1002. The transceiver may facilitate various types of wireless transmission or reception. For example, the transceiver may include an antenna operatively connected to a transceiver chip (e.g., Texas Instruments WiLink WL1283, Broadcom BCM47501UB8, Infineon Technologies X-Gold 618-PMB9800, or the like), providing IEEE 802.11a/b/g/n, Bluetooth, FM, global positioning system (GPS), 2G/3G HSDPA/HSUPA communications, etc. In some embodiments, the processor 1002 may be disposed in communication with a communication network 1008 via a network interface 1007. The network interface 1007 may communicate with the communication network 1008. The network interface may employ connection protocols including, without limitation, direct connect, Ethernet (e.g., twisted pair 10/100/1000 Base T), transmission control protocol/internet protocol (TCP/IP), token ring, IEEE 802.11a/b/g/n/x, etc. The communication network 1008 may include, without limitation, a direct interconnection, local area network (LAN), wide area network (WAN), wireless network (e.g., using Wireless Application Protocol), the Internet, etc. Using the network interface 1007 and the communication network 1008, the computer system 1001 may communicate with devices 1010, 1011, and 1012. These devices may include, without limitation, personal computer(s), server(s), fax machines, printers, scanners, various mobile devices such as cellular telephones, smartphones (e.g., Apple iPhone, Blackberry, Android-based phones, etc.), tablet computers, eBook readers (Amazon Kindle, Nook, etc.), laptop computers, notebooks, gaming consoles (Microsoft Xbox, Nintendo DS, Sony PlayStation, etc.), or the like. In some embodiments, the computer system 1001 may itself embody one or more of these devices. In some embodiments, the processor 1002 may be disposed in communication with one or more memory devices (e.g., RAM 1013, ROM 1014, etc,) via a storage interface 1012. The storage interface may connect to memory devices including, without limitation, memory drives, removable disc drives, etc., employing connection protocols such as serial advanced technology attachment (BATA), integrated drive electronics (IDE), IEEE-1394, universal serial bus (USE), fiber channel, small computer systems interface (SCSI), etc. The memory drives may further include a drum, magnetic disc drive, magneto-optical drive, optical drive, redundant array of independent discs (RAID), solid-state memory devices, solid-state drives, etc. Variations of memory devices may be used for implementing, for example, the databases disclosed herein. The memory devices may store a collection of program or database components, including, without limitation, an operating system 1016, user interface application 1017, web browser 1018, mail server 1019, mail client 1020, user/application data 1021 (e.g., any data variables or data records discussed in this disclosure), etc. The operating system 1016 may facilitate resource management and operation of the computer system 1001. Examples of operating systems include, without limitation, Apple Macintosh OS X, Unix, Unix-like system distributions (e.g., Berkeley Software Distribution (BSD), FreeBSD, NetBSD, OpenBSD, etc.), Linux distributions (e.g., Red Hat, Ubuntu, Kubuntu, etc.), IBM OS/2, Microsoft Windows (XP, Vista/7/8, etc.), Apple iOS, Google Android, Blackberry OS, or the like. User interface 1017 may facilitate display, execution, interaction, manipulation, or operation of program components through textual or graphical facilities. For example, user interfaces may provide computer interaction interface elements on a display system operatively connected to the computer system 1001, such as cursors, icons, check boxes, menus, scrollers, windows, widgets, etc. Graphical user interfaces (GUIs) may be employed, including, without limitation, Apple Macintosh operating systems' Aqua, IBM OS/2, Microsoft Windows (e.g., Aero, Metro, etc,), Unix X-Windows, web interface libraries (e.g., ActiveX, Java, JavaScript, AJAX, HTML, Adobe Flash, etc.), or the like. In some embodiments, the computer system 1001 may implement a web browser 1018 stored program component. The web browser may be a hypertext viewing application, such as Microsoft Internet Explorer, Google Chrome, Mozilla Firefox, Apple Safari, etc. Secure web browsing may be provided using HTTPS (secure hypertext transport protocol), secure sockets layer (SSL), Transport Layer Security (TLS), etc. Web browsers may utilize facilities such as AJAX, DHTML, Adobe Flash, JavaScript, Java, application programming interfaces (APIs), etc. In some embodiments, the computer system 1001 may implement a mail server 1019 stored program component. The mail server may be an Internet mail server such as Microsoft Exchange, or the like, The mail server may utilize facilities such as ASP, ActiveX, ANSI C++/C#, Microsoft .NET, CGI scripts, Java, JavaScript, PERL, PHP, Python, WebObjects, etc. The mail server may utilize communication protocols such as internet message access protocol (IMAP), messaging application programming interface (MAPI), Microsoft Exchange, post office protocol (POP), simple mail transfer protocol (SMTP), or the like. In some embodiments, the computer system 1001 may implement a mail client 1020 stored program component. The mail client may be a mail viewing application, such as Apple Mail, Microsoft Entourage, Microsoft Outlook, Mozilla Thunderbird, etc. In some embodiments, computer system 1001 may store user/application data 1021, such as the data, variables, records, etc. as described in this disclosure. Such databases may be implemented as fault-tolerant, relational, scalable, secure databases such as Oracle or Sybase. Alternatively, such databases may be implemented using standardized data structures, such as an array, hash, linked list, struct, structured text file (e.g., XML), table, or as object-oriented databases (e.g., using ObjectStore, Poet, Zope, etc.), Such databases may be consolidated or distributed, sometimes among the various computer systems discussed above in this disclosure. It is to be understood that the structure and operation of any computer or database component may be combined, consolidated, or distributed in any working combination. The specification has described methods and systems for admission control in D2D communication in a wireless broadband network. The illustrated steps are set out to explain the exemplary embodiments shown, and it should be anticipated that ongoing technological development will change the manner in which particular functions are performed. These examples are presented herein for purposes of illustration, and not limitation. Further, the boundaries of the functional building blocks have been arbitrarily defined herein for the convenience of the description. Alternative boundaries can be defined so long as the specified functions and relationships thereof are appropriately performed. Alternatives (including equivalents, extensions, variations, deviations, etc., of those described herein) will be apparent to persons skilled in the relevant art(s) based on the teachings contained herein. Such alternatives fall within the scope and spirit of the disclosed embodiments. Also, the words “comprising,” “having,” “containing,” and “including,” and other similar forms are intended to be equivalent in meaning and be open ended in that an item or items following any one of these words is not meant to be an exhaustive listing of such item or items, or meant to be limited to only the listed item or items. It must also be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Furthermore, one or more computer-readable storage media may be utilized in implementing embodiments consistent with the present disclosure. A computer-readable storage medium refers to any type of physical memory on which information or data readable by a processor may be stored. Thus, a computer-readable storage medium may store instructions for execution by one or more processors, including instructions for causing the processor(s) to perform steps or stages consistent with the embodiments described herein. The term “computer-readable medium” should be understood to include tangible items and exclude carrier waves and transient signals, i.e., be non-transitory. Examples include random access memory (RAM), read-only memory (ROM), volatile memory, nonvolatile memory, hard drives, CD ROMs, DVDs, flash drives, disks, and any other known physical storage media. It is intended that the disclosure and examples be considered as exemplary only, with a true scope and spirit of disclosed embodiments being indicated by the following claims.",H04W76023,H04W7602,20160120,20180703,20170601,78485.0
8,14992360,ACCEPTED,Natural Oil Derivatives Including Primary Amine Functional Groups,"A compound has Structure I: where R1 and R2 independently are C2-C12 alkyl groups, X1 is a C4-C28 alkyl or alkenyl group, and R3 is H or is a bis(aminoalkyl)amide group having Structure II: where R4 and R5 independently are C2-C12 alkyl groups. The compound may be a reaction product of a metathesized natural oil and a bis(aminoalkyl)amine.","1-25. (canceled) 26. A polymer, which comprises constitutional units formed from a reaction mixture comprising: (a) a monomer having two or more epoxy groups; and (b) a compound according to Structure I: wherein: R1 and R2 independently are C2-C12 alkyl groups; X1 is a C4-C28 alkyl group or a C4-C28 alkenyl group; and R3 is a hydrogen atom or a bis(aminoalkyl)amide group according to Structure II: wherein R4 and R5 independently are C2-C12 alkyl groups. 27. The polymer of claim 26, wherein R1, R2, R4, and R5 independently are C2-C6 alkyl groups. 28. The polymer of claim 26, wherein X1 is a C10-C16 alkyl group or a C10-C16 alkenyl group. 29. The polymer of claim 28, wherein R3 is a hydrogen atom and R1 and R2 are C2 alkyl groups. 30. The polymer of claim 28, wherein R3 is a bis(aminoalkyl)amide group according to Structure II and R1, R2, R4, and R5 are C2 alkyl groups. 31. The polymer of claim 30, wherein R1, R2, R4, and R5 are —CH2—CH2—. 32. The polymer of claim 26, wherein the monomer having two or more epoxy groups is bisphenol A diglycidyl ether, bisphenol F diglycidyl ether, tetraglycidyl diamine-diphenyl-methane, or a multi-glycidyl ether of phenol formaldehyde novolac polymers. 33. The polymer of claim 32, wherein the monomer having two or more epoxy groups is bisphenol A diglycidyl ether. 34. The polymer of claim 32, wherein the monomer having two or more epoxy groups is bisphenol F diglycidyl ether.","<SOH> BACKGROUND <EOH>Compounds having multiple primary amine functional groups are used in a wide variety of applications. Polymeric materials such as polyamides, epoxy polymers, polyureas and other polymers can be formed by condensation reactions of amine-functionalized monomers such as diamines, triamines or tetramines with monomers having other functional groups. Polyamides typically are formed by reaction of a diamine monomer such as ethylenediamine or hexamethylenediamine, with a diacid monomer such as adipic acid or with a diacid chloride monomer such as sebacoyl chloride or terephthaloyl chloride. Epoxy polymers typically are formed by reaction of amine-functionalized monomers such as ethylenediamine, triethylenetriamine, diethylenetriamine, hexamethylenetetramine, tetraethylenepentamine, or amine-terminated polymers or prepolymers with monomers having two or more epoxy groups, such as diglycidyl ethers of bisphenol A or bisphenol F, tetraglycidyl diaminediphenylmethane, or multi-glycidyl ethers of phenol formaldehyde novolac polymers. Polyureas typically are formed by reaction of a diamine or triamine monomer with a diisocyanate monomer. Compounds having multiple primary amine functional groups also are used to form dendritic molecules. Dendritic molecules may be used as solubility enhancers, as catalyst supports, as immunoassay components, and as precursors for advanced materials. Species of the poly(amido amine) (PAMAM) class of dendrimers typically are formed by alternating reaction of ethylenediamine and methyl acrylate. Examples of PAMAM dendrimers include but are not limited to [NH 2 (CH 2 ) 2 NH 2 ]: (G=0);dendri PAMAM(NH 2 ) 4 and its associated higher generation molecules. The physical and chemical properties of polymers and of dendritic molecules are affected by the chemical structures of the building blocks used to prepare the polymers and/or dendritic molecules. Alteration of the chemical structure, size and/or concentration of these building blocks can allow for modification of the properties of the polymer or dendritic molecule. It is desirable to expand the chemical structures present in compounds having multiple primary amine functional groups, so as to expand the useful properties that can be provided by polymers or dendritic molecules formed from the compounds. With regard to polymers, for example, properties such as flexibility, toughness, etc. can be increased by incorporating chemical groups that lower the modulus or that can absorb energy, respectively. This expansion of chemical structures may be accomplished through post-polymerization processing, such as reaction with other reagents or blending with other polymers. It is especially desirable, however, to expand the chemical structures by introducing new chemical structures in the monomeric building blocks from which the polymer is formed. With regard to dendritic molecules, properties such as solubility, chemical reactivity, density, etc. can be changed by incorporating branches having different chain lengths and substitution points. One potential approach to altering the chemical structure of compounds having multiple primary amine functional groups is to form the compounds from renewable feedstocks. Renewable feedstocks, such as fatty acids or fatty esters derived from natural oils, have opened new possibilities for the development of a variety of industrially useful substances, including specialty chemicals and intermediates. For example, renewable feedstocks can be used to prepare compounds having combinations of properties that were not available with conventional petroleum feedstocks. In another example, renewable feedstocks can be used to prepare compounds more efficiently, without requiring undesirable reagents or solvents, and/or with decreased amounts of waste or side products. It would be desirable to provide compounds having multiple primary amine functional groups that include previously unavailable chemical structures. Preferably such compounds can be used as substitutes for conventional amine-functionalized compounds, while providing an increase in the renewable content of the final product formed using the compounds. Preferably such compounds can provide useful combinations of properties that are difficult to obtain using compounds formed from conventional petroleum feedstocks.","<SOH> SUMMARY <EOH>The scope of the present invention is defined solely by the appended claims, and is not affected to any degree by the statements within this summary. In one aspect, a compound is provided that has Structure I: where R 1 and R 2 independently are C 2 -C 12 alkyl groups, X 1 is a C 4 -C 28 alkyl or alkenyl group, and R 3 is H or is a bis(aminoalkyl)amide group having Structure II: where R 4 and R 5 independently are C 2 -C 12 alkyl groups. In another aspect, an (aminoalkyl)amide composition is provided that includes the reaction product of a metathesized natural oil and a bis(aminoalkyl)amine. In another aspect, a method of making an (aminoalkyl)amide composition is provided that includes forming a reaction mixture including a metathesized natural oil and a bis(aminoalkyl)amine, and forming a product mixture including an (aminoalkyl)amide formed from the metathesized natural oil and the bis(aminoalkyl)amine.","REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 61/779,358 entitled “Natural Oil Derivatives Including Primary Amine Functional Groups” filed Mar. 13, 2013, which is incorporated by reference in its entirety. BACKGROUND Compounds having multiple primary amine functional groups are used in a wide variety of applications. Polymeric materials such as polyamides, epoxy polymers, polyureas and other polymers can be formed by condensation reactions of amine-functionalized monomers such as diamines, triamines or tetramines with monomers having other functional groups. Polyamides typically are formed by reaction of a diamine monomer such as ethylenediamine or hexamethylenediamine, with a diacid monomer such as adipic acid or with a diacid chloride monomer such as sebacoyl chloride or terephthaloyl chloride. Epoxy polymers typically are formed by reaction of amine-functionalized monomers such as ethylenediamine, triethylenetriamine, diethylenetriamine, hexamethylenetetramine, tetraethylenepentamine, or amine-terminated polymers or prepolymers with monomers having two or more epoxy groups, such as diglycidyl ethers of bisphenol A or bisphenol F, tetraglycidyl diaminediphenylmethane, or multi-glycidyl ethers of phenol formaldehyde novolac polymers. Polyureas typically are formed by reaction of a diamine or triamine monomer with a diisocyanate monomer. Compounds having multiple primary amine functional groups also are used to form dendritic molecules. Dendritic molecules may be used as solubility enhancers, as catalyst supports, as immunoassay components, and as precursors for advanced materials. Species of the poly(amido amine) (PAMAM) class of dendrimers typically are formed by alternating reaction of ethylenediamine and methyl acrylate. Examples of PAMAM dendrimers include but are not limited to [NH2(CH2)2NH2]: (G=0);dendri PAMAM(NH2)4 and its associated higher generation molecules. The physical and chemical properties of polymers and of dendritic molecules are affected by the chemical structures of the building blocks used to prepare the polymers and/or dendritic molecules. Alteration of the chemical structure, size and/or concentration of these building blocks can allow for modification of the properties of the polymer or dendritic molecule. It is desirable to expand the chemical structures present in compounds having multiple primary amine functional groups, so as to expand the useful properties that can be provided by polymers or dendritic molecules formed from the compounds. With regard to polymers, for example, properties such as flexibility, toughness, etc. can be increased by incorporating chemical groups that lower the modulus or that can absorb energy, respectively. This expansion of chemical structures may be accomplished through post-polymerization processing, such as reaction with other reagents or blending with other polymers. It is especially desirable, however, to expand the chemical structures by introducing new chemical structures in the monomeric building blocks from which the polymer is formed. With regard to dendritic molecules, properties such as solubility, chemical reactivity, density, etc. can be changed by incorporating branches having different chain lengths and substitution points. One potential approach to altering the chemical structure of compounds having multiple primary amine functional groups is to form the compounds from renewable feedstocks. Renewable feedstocks, such as fatty acids or fatty esters derived from natural oils, have opened new possibilities for the development of a variety of industrially useful substances, including specialty chemicals and intermediates. For example, renewable feedstocks can be used to prepare compounds having combinations of properties that were not available with conventional petroleum feedstocks. In another example, renewable feedstocks can be used to prepare compounds more efficiently, without requiring undesirable reagents or solvents, and/or with decreased amounts of waste or side products. It would be desirable to provide compounds having multiple primary amine functional groups that include previously unavailable chemical structures. Preferably such compounds can be used as substitutes for conventional amine-functionalized compounds, while providing an increase in the renewable content of the final product formed using the compounds. Preferably such compounds can provide useful combinations of properties that are difficult to obtain using compounds formed from conventional petroleum feedstocks. SUMMARY The scope of the present invention is defined solely by the appended claims, and is not affected to any degree by the statements within this summary. In one aspect, a compound is provided that has Structure I: where R1 and R2 independently are C2-C12 alkyl groups, X1 is a C4-C28 alkyl or alkenyl group, and R3 is H or is a bis(aminoalkyl)amide group having Structure II: where R4 and R5 independently are C2-C12 alkyl groups. In another aspect, an (aminoalkyl)amide composition is provided that includes the reaction product of a metathesized natural oil and a bis(aminoalkyl)amine. In another aspect, a method of making an (aminoalkyl)amide composition is provided that includes forming a reaction mixture including a metathesized natural oil and a bis(aminoalkyl)amine, and forming a product mixture including an (aminoalkyl)amide formed from the metathesized natural oil and the bis(aminoalkyl)amine. BRIEF DESCRIPTION OF THE DRAWINGS The invention can be better understood with reference to the following drawings and description. The components in the figures are not necessarily to scale and are not intended to accurately represent molecules or their interactions, emphasis instead being placed upon illustrating the principles of the invention. Moreover, in the figures, like referenced numerals designate corresponding parts throughout the different views. FIG. 1 depicts a reaction scheme for a metathesis reaction of a natural oil. FIG. 2 depicts a method of making an (aminoalkyl)amide. FIG. 3 depicts a representative reaction scheme for a method of forming an (aminoalkyl)amide. DETAILED DESCRIPTION To provide a clear and more consistent understanding of the specification and claims of this application, the following definitions are provided. The terms “reaction” and “chemical reaction” refer to the conversion of a substance into a product, irrespective of reagents or mechanisms involved. The term “reaction product” refers to a substance produced from a chemical reaction of one or more reactant substances. The term “alkyl group” refers to a group formed by removing a hydrogen from a carbon of an alkane, where an alkane is an acyclic or cyclic compound consisting entirely of hydrogen atoms and saturated carbon atoms. The term “alkenyl group” refers to a group formed by removing a hydrogen from a carbon of an alkene, where an alkene is an acyclic or cyclic compound consisting entirely of hydrogen atoms and carbon atoms, and including at least one carbon-carbon double bond. A compound containing an alkenyl group is conventionally referred to as an “unsaturated compound”. The term “functional group” refers to a group that includes one or a plurality of atoms other than hydrogen and sp3 carbon atoms. Examples of functional groups include but are not limited to hydroxyl (—OH), protected hydroxyl, ether (—C—O—C—), ketone (>C═O), ester (—C(═O)O—C—), carboxylic acid (—C(═O)OH), cyano (—C≡N), amido (—C(═O)NH—C—), isocyanate (—N═C═O), urethane (—O—C(═O)—NH—), urea (—NH—C(=O)—NH—), protected amino, thiol(—SH), sulfone, sulfoxide, phosphine, phosphite, phosphate, halide(—X), and the like. The terms “amine”, “amine group” and “amino group” refer to a group formed by removing a hydrogen from ammonia (NH3), from the nitrogen of a primary amine compound (RNH2) or from the nitrogen of a secondary amine compound (R′R″NH), where R, R′ and R″ are organic groups. A primary amino group may be represented by the structural formula —NH2, and a secondary amino group may be represented by the structural formula —NRH. The terms “amide”, “amide group” and “amido group” refer to a group formed by removing a hydrogen from a carbon atom and/or removing one or both hydrogens from the nitrogen of an organic amide (R—C(═O)—NH2) compound, where R is an organic group. A primary amide group may be represented by the structural formula —C(═O)—NH2, a secondary amide group may be represented by the structural formula —C(═O)—NH—R′, and a tertiary amide group may be represented by the structural formula —C(═O)—NR′R″, where R′ and R″ are organic groups. The term “(aminoalkyl)amide” refers to a compound that includes a least one alkyl and/or alkenyl group, at least one amide group, and at least one aminoalkyl group bonded to the amide nitrogen through a C—N bond. The term “metathesis catalyst” refers to any catalyst or catalyst system configured to catalyze a metathesis reaction. The terms “metathesize” and “metathesizing” refer to a chemical reaction involving a single type of olefin or a plurality of different types of olefin, which is conducted in the presence of a metathesis catalyst, and which results in the formation of at least one new olefin product. The phrase “metathesis reaction” encompasses cross-metathesis (a.k.a. co-metathesis), self-metathesis, ring-opening metathesis (ROM), ring-opening metathesis polymerizations (ROMP), ring-closing metathesis (RCM), and acyclic diene metathesis (ADMET), and the like, and combinations thereof. The terms “natural oils,” “natural feedstocks,” or “natural oil feedstocks” mean oils derived from plants or animal sources. The term “natural oil” includes natural oil derivatives, unless otherwise indicated. Examples of natural oils include but are not limited to vegetable oils, algal oils, animal fats, tall oils, derivatives of these oils, combinations of any of these oils, and the like. Examples of vegetable oils include but are not limited to canola oil, rapeseed oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil, linseed oil, palm kernel oil, tung oil, jatropha oil, mustard oil, camelina oil, pennycress oil, castor oil, and the like, and combinations thereof. Examples of animal fats include but are not limited to lard, tallow, poultry fat, yellow grease, fish oil, and the like, and combinations thereof. Tall oils are by-products of wood pulp manufacture. A natural oil may be refined, bleached, and/or deodorized. The term “natural oil derivatives” refers to compounds or mixtures of compounds derived from one or more natural oils using any one or combination of methods known in the art. Such methods include but are not limited to saponification, transesterification, esterification, hydrogenation (partial or full), isomerization, oxidation, reduction, and the like, and combinations thereof. Examples of natural oil derivatives include but are not limited to gums, phospholipids, soapstock, acidulated soapstock, distillate or distillate sludge, fatty acids and fatty acid alkyl esters such as 2-ethylhexyl ester, hydroxy-substituted variations thereof of the natural oil, and the like, and combinations thereof. For example, the natural oil derivative may be a fatty acid methyl ester (FAME) derived from the glyceride of the natural oil. The term “metathesized natural oil” refers to the metathesis reaction product of a natural oil in the presence of a metathesis catalyst, where the metathesis product includes a new olefinic compound. A metathesized natural oil may include a reaction product of two triglycerides in a natural feedstock (self-metathesis) in the presence of a metathesis catalyst, where each triglyceride has an unsaturated carbon-carbon double bond, and where the reaction product includes a “natural oil oligomer” having a new mixture of olefins and esters that may include one or more of metathesis monomers, metathesis dimers, metathesis trimers, metathesis tetramers, metathesis pentamers, and higher order metathesis oligomers (e.g., metathesis hexamers). A metathesized natural oil may include a reaction product of a natural oil that includes more than one source of natural oil (e.g., a mixture of soybean oil and palm oil). A metathesized natural oil may include a reaction product of a natural oil that includes a mixture of natural oils and natural oil derivatives. A metathesized natural oil may include a cross-metathesis reaction product of a natural oil with another substance having a carbon-carbon double bond, such as an olefin or ethylene. Compounds having a plurality of primary amine functional groups may be formed from a renewable feedstock, such as a renewable feedstock formed through metathesis reactions of natural oils and/or their fatty acid or fatty ester derivatives. When compounds containing a carbon-carbon double bond undergo metathesis reactions in the presence of a metathesis catalyst, some or all of the original carbon-carbon double bonds are broken, and new carbon-carbon double bonds are formed. The products of such metathesis reactions include carbon-carbon double bonds in different locations, which can provide unsaturated organic compounds having useful chemical structures. Renewable feedstocks for compounds having a plurality of primary amine functional groups may include unsaturated compounds having an internal carbon-carbon double bond. Compounds having a plurality of primary amine functional groups may be used as monomers in polymerization reactions. The use of a monomer containing a metathesized natural oil derivative can provide additional options for providing polymeric materials having useful combinations of properties, including but not limited to mechanical properties, crosslink density, and post-polymerization reactivity. The compounds having a plurality of primary amine functional groups also may be used as intermediates for preparing larger compounds through the reaction of one or more of the plurality of primary amine functional groups with another substance. The use of a monomer and/or an intermediate containing a metathesized natural oil derivative may provide certain advantages over commercial monomers and intermediates, including but not limited to simpler and/or more cost-effective production, reduced variability, improved sourcing, and increased biorenewability. A compound having a plurality of primary amine functional groups may be an (aminoalkyl)amide represented by Structure I: where R1 and R2 independently are C2-C12 alkyl groups, X1 is a C4-C28 alkyl or alkenyl group, and R3 is selected from the group consisting of H and a N,N-bis(aminoalkyl)amide group represented by Structure II: where R4 and R5 independently are C2-C10 alkyl groups. Preferably R1, R2, R4 and R5 independently are C2-C10 alkyl groups, C2-C8 alkyl groups, C2-C6 alkyl groups or C2-C4 alkyl groups. In one example, R1, R2, R4 and R5 are the same, and are a C2-C10 alkyl group, a C2-C8 alkyl group, a C2-C6 alkyl group, or a C2-C4 alkyl group. Preferably X1 is a C8-C22 alkyl or alkenyl group, or a C10-C16 alkyl or alkenyl group. X1 may be derived from a natural oil, and preferably is derived from a metathesized natural oil. In one example, R1 and R2 are C2 alkyl groups, and R3 is H. A compound having a plurality of primary amine functional groups according to this example may be a bis(aminoethyl)amide represented by Structure III: where X2 is a C4-C28 alkyl or alkenyl group. Preferably X2 is a C8-C22 alkyl or alkenyl group, or a C10-C16 alkyl or alkenyl group. X2 may be derived from a natural oil, and preferably is derived from a metathesized natural oil. In another example, R1 and R2 are C2 alkyl groups, R3 is the bis(aminoalkyl)amide group represented by Structure (II), and R4 and R5 are C2 alkyl groups. A compound having a plurality of primary amine functional groups according to this example may be a tetra(aminoethyl)diamide represented by Structure IV: where X3 is a C4-C28 alkenyl group. Preferably X3 is a C8-C22 alkyl or alkenyl group, or a C10-C16 alkyl or alkenyl group. X3 may be derived from a natural oil, and preferably is derived from a metathesized natural oil. Preferably the compound having a plurality of primary amine functional groups is derived from a natural oil. More preferably the compound having a plurality of primary amine functional groups is derived from a metathesized natural oil. Preferably the compound having a plurality of primary amine functional groups is the reaction product of a metathesized natural oil and a bis(aminoalkyl)amine. In one example, the reaction product of a metathesized natural oil and a bis(aminoalkyl)amine may be represented by Structure I, III or IV, above. The metathesized natural oil used to form the compound having a plurality of primary amine functional groups may be the product of a metathesis reaction of a natural oil in the presence of a metathesis catalyst. The metathesis catalyst in this reaction may include any catalyst or catalyst system that catalyzes a metathesis reaction. Any known metathesis catalyst may be used, alone or in combination with one or more additional catalysts. Examples of metathesis catalysts and process conditions are described in paragraphs [0069]-[0155] of US 2011/0160472, incorporated by reference herein in its entirety, except that in the event of any inconsistent disclosure or definition from the present specification, the disclosure or definition herein shall be deemed to prevail. A number of the metathesis catalysts described in US 2011/0160472 are presently available from Materia, Inc. (Pasadena, Calif.). In some embodiments, the metathesis catalyst includes a transition metal. In some embodiments, the metathesis catalyst includes ruthenium. In some embodiments, the metathesis catalyst includes rhenium. In some embodiments, the metathesis catalyst includes tantalum. In some embodiments, the metathesis catalyst includes nickel. In some embodiments, the metathesis catalyst includes tungsten. In some embodiments, the metathesis catalyst includes molybdenum. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a material selected from the group consisting of a ruthenium vinylidene complex, a ruthenium alkylidene complex, a ruthenium methylidene complex, a ruthenium benzylidene complex, and combinations thereof, and/or an entity derived from any such complex or combination of such complexes. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex including at least one phosphine ligand and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex including at least one tricyclohexylphosphine ligand and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex including at least two tricyclohexylphosphine ligands [e.g., (PCy3)2Cl2Ru═CH—CH═C(CH3)2, etc.] and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex including at least one imidazolidine ligand and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a ruthenium carbene complex including an isopropyloxy group attached to a benzene ring and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a Grubbs-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a first-generation Grubbs-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a second-generation Grubbs-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a first-generation Hoveda-Grubbs-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a second-generation Hoveda-Grubbs-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes one or a plurality of the ruthenium carbene metathesis catalysts sold by Materia, Inc. of Pasadena, Calif. and/or one or more entities derived from such catalysts. Representative metathesis catalysts from Materia, Inc. for use in accordance with the present teachings include but are not limited to those sold under the following product numbers as well as combinations thereof: product no. C823 (CAS no. 172222-30-9), product no. C848 (CAS no. 246047-72-3), product no. C601 (CAS no. 203714-71-0), product no. C627 (CAS no. 301224-40-8), product no. C571 (CAS no. 927429-61-6), product no. C598 (CAS no. 802912-44-3), product no. C793 (CAS no. 927429-60-5), product no. C801 (CAS no. 194659-03-9), product no. C827 (CAS no. 253688-91-4), product no. C884 (CAS no. 900169-53-1), product no. C833 (CAS no. 1020085-61-3), product no. C859 (CAS no. 832146-68-6), product no. C711 (CAS no. 635679-24-2), product no. C933 (CAS no. 373640-75-6). In some embodiments, the metathesis catalyst includes a molybdenum and/or tungsten carbene complex and/or an entity derived from such a complex. In some embodiments, the metathesis catalyst includes a Schrock-type olefin metathesis catalyst and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a high-oxidation-state alkylidene complex of molybdenum and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes a high-oxidation-state alkylidene complex of tungsten and/or an entity derived therefrom. In some embodiments, the metathesis catalyst includes molybdenum (VI). In some embodiments, the metathesis catalyst includes tungsten (VI). In some embodiments, the metathesis catalyst includes a molybdenum- and/or a tungsten-containing alkylidene complex of a type described in one or more of (a) Angew. Chem. Int. Ed. Engl., 2003, 42, 4592-4633; (b) Chem. Rev., 2002, 102, 145-179; and/or (c) Chem. Rev., 2009, 109, 3211-3226, each of which is incorporated by reference herein in its entirety, except that in the event of any inconsistent disclosure or definition from the present specification, the disclosure or definition herein shall be deemed to prevail. Metathesis is a catalytic reaction that involves the interchange of alkylidene units among compounds containing one or more double bonds (i.e., olefinic compounds) via the formation and cleavage of the carbon-carbon double bonds. The metathesis reaction of a natural oil containing unsaturated polyol esters can produce oligomers of the unsaturated polyol esters. The resulting oligomers typically contain a mixture of olefins and esters that may include one or more of metathesis monomers, metathesis dimers, metathesis trimers, metathesis tetramers, metathesis pentamers, and higher order metathesis oligomers (e.g., metathesis hexamers, etc.). FIG. 1 depicts chemical structures and reaction schemes related to a metathesis reaction 100 of a natural oil 110, producing metathesis dimer 120, metathesis trimer 130 and higher order metathesis oligomers (not pictured). A metathesis dimer refers to a compound formed when two unsaturated polyol ester molecules are covalently bonded to one another by a metathesis reaction. The molecular weight of the metathesis dimer typically is greater than the molecular weight of the individual unsaturated polyol ester molecules from which the dimer is formed. A metathesis trimer refers to a compound formed when three unsaturated polyol ester molecules are covalently bonded together by metathesis reactions. A metathesis trimer may be formed by the cross-metathesis of a metathesis dimer with an unsaturated polyol ester. A metathesis tetramer refers to a compound formed when four unsaturated polyol ester molecules are covalently bonded together by metathesis reactions. A metathesis tetramer may be formed by the cross-metathesis of a metathesis trimer with an unsaturated polyol ester. Metathesis tetramers may also be formed, for example, by the cross-metathesis of two metathesis dimers. Higher order metathesis oligomers (such as metathesis pentamers, metathesis hexamers, and the like) also may be formed. The metathesized natural oil may be derived from natural oils such as vegetable oil, algal oil, animal fat, tall oil, derivatives of these oils, or mixtures thereof. Examples of vegetable oils include but are not limited to canola oil, rapeseed oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil, linseed oil, palm kernel oil, tung oil, jatropha oil, mustard oil, camelina oil, pennycress oil, castor oil, and the like, and combinations thereof. Examples of animal fats include but are not limited to lard, tallow, poultry fat, yellow grease, fish oil, and the like, and combinations thereof. Examples of natural oil derivatives include but are not limited to metathesis oligomers, gums, phospholipids, soapstock, acidulated soapstock, distillate or distillate sludge, fatty acids and fatty acid alkyl ester such as 2-ethylhexyl ester, hydroxyl-substituted variations of the natural oil, and the like, and combinations thereof. For example, the natural oil derivative may be a fatty acid methyl ester (FAME) derived from the glyceride of the natural oil. The natural oil may include canola or soybean oil, such as refined, bleached and deodorized soybean oil (i.e., RBD soybean oil). Soybean oil typically includes about 95 percent by weight (wt %) or greater (e.g., 99 wt % or greater) triglycerides of fatty acids. Major fatty acids in the polyol esters of soybean oil include but are not limited to saturated fatty acids such as palmitic acid (hexadecanoic acid) and stearic acid (octadecanoic acid), and unsaturated fatty acids such as oleic acid (9-octadecenoic acid), linoleic acid (9,12-octadecadienoic acid), and linolenic acid (9,12,15-octadecatrienoic acid). The metathesized natural oil may be a metathesized vegetable oil, a metathesized algal oil, a metathesized animal fat, a metathesized tall oil, a metathesized derivatives of these oils, or a mixture thereof. For example, a metathesized vegetable oil may include metathesized canola oil, metathesized rapeseed oil, metathesized coconut oil, metathesized corn oil, metathesized cottonseed oil, metathesized olive oil, metathesized palm oil, metathesized peanut oil, metathesized safflower oil, metathesized sesame oil, metathesized soybean oil, metathesized sunflower oil, metathesized linseed oil, metathesized palm kernel oil, metathesized tung oil, metathesized jatropha oil, metathesized mustard oil, metathesized camelina oil, metathesized pennycress oil, metathesized castor oil, metathesized derivatives of these oils, or mixtures thereof. In another example, the metathesized natural oil may include a metathesized animal fat, such as metathesized lard, metathesized tallow, metathesized poultry fat, metathesized fish oil, metathesized derivatives of these oils, or mixtures thereof. FIG. 2 depicts a method 200 of making an (aminoalkyl)amide composition. The method 200 includes forming 201 a reaction mixture 210 containing a metathesized natural oil 212 and a bis(aminoalkyl)amine 214; forming 202 a product mixture 220 containing an (aminoalkyl)amide 222 formed from the metathesized natural oil 212 and the bis(aminoalkyl)amine 214; and optionally isolating 203 an (aminoalkyl)amide 222 from the product mixture 220. The metathesized natural oil 212 may be a metathesized vegetable oil, a metathesized algal oil, a metathesized animal fat, a metathesized tall oil, a metathesized derivatives of these oils, or a mixture thereof, as described above. Preferably the metathesized natural oil 212 includes metathesized soybean oil (MSBO). The bis(aminoalkyl)amine 214 may be any secondary amine that includes two aminoalkyl groups bonded to the secondary amine nitrogen through C—N bonds. The bis(aminoalkyl)amine 214 may be represented by Structure V: where R1 and R2 are as described above regarding Structure I. The two aminoalkyl groups (—R1—NH2 and —R2—NH2) may be the same, or they may be different. The primary amine group may be at any of a number of positions within the aminoalkyl group. Preferably at least one of the aminoalkyl groups is a ω-aminoalkyl group, in which the primary amine group is at the end of the aminoalkyl group opposite that of the C—N bond to the secondary amine nitrogen. Examples of bis(aminoalkyl)amines include bis(2-aminopropyl)amine and N-2-aminopropyl-N-aminoethylamine. Examples of bis(ω-aminoalkyl)amines include but are not limited to diethylenetriamine. Preferably the bis(aminoalkyl)amine 214 includes diethylene triamine. In some embodiments, the amount of bis(aminoalkyl)amine 214 present in the reaction mixture may be between about 0.1 percent by weight (wt %) and about 30 wt % of the metathesized natural oil in the reaction mixture. The amount of bis(aminoalkyl)amine in the reaction mixture also may be expressed in terms of the ratio of equivalents of secondary amine in the bis(aminoalkyl)amine to ester equivalents in the metathesized natural oil (A:E ratio). For example, in some embodiments, the A:E ratio may be between about 1:100 and about 10:1, or between about 1:10 and about 5:1. In another example, the A:E ratio may be about 1:3, about 2:3, about 1:2, or about 1:1. The reaction mixture 210 may include one or more other substances, such as a solvent, a base and/or a catalyst, in addition to the metathesized natural oil 212 and the bis(aminoalkyl)amine 214. The metathesized natural oil 212, bis(aminoalkyl)amine 214 and optional other substances may be combined simultaneously or in any order. In some embodiments, a base may be present in the reaction mixture to increase the rate of reaction between the bis(aminoalkyl)amine and the metathesized natural oil. Examples of bases include but are not limited to sodium carbonate, lithium carbonate, sodium methoxide, potassium hydroxide, sodium hydride, potassium butoxide, potassium carbonate, or mixtures of these. The base may be added to the reaction mixture 210 neat or as a mixture with a solvent such as water, alcohol, or another organic solvent. In some embodiments, the amount of base in the reaction mixture may be between about 0.1 wt % and about 10 wt % of the metathesized natural oil in the reaction mixture, or between about 1 wt % and about 15 wt % of the metathesized natural oil. In some embodiments, the amount of base in the reaction mixture may be between about 1 wt % and about 10 wt % of the metathesized natural oil, between about 0.1 wt % and about 1.0 wt % of the metathesized natural oil, or between about 0.01 wt % and about 0.1 wt % of the metathesized natural oil. The forming 202 a product mixture 220 containing an (aminoalkyl)amide 222 may include heating the reaction mixture 210. In some embodiments, the rate of reaction between the bis(aminoalkyl)amine 214 and the metathesized natural oil 212 may be increased by heating the reaction mixture, with or without a base, to at least about 100° C., at least about 120° C., at least about 140° C., at least about 160° C., or between about 100° C. and about 200° C. In some embodiments, the reaction may be carried out at an elevated temperature of between about 30 and about 200° C., between about 80 and about 150° C., or between about 100 and about 125° C. In some embodiments, the reaction mixture may be maintained at the elevated temperature for a time sufficient to form an (aminoalkyl)amide 222, such as between about 1 and about 24 hours, or between about 4 and about 24 hours. For example, the reaction mixture may be maintained at the elevated temperature for about 1 hour, about 2 hours, about 4 hours, or about 6 hours. In some embodiments, the reaction may be carried out in an inert atmosphere, such as a nitrogen atmosphere or a noble gas atmosphere. In some embodiments, the reaction may be carried out in an ambient atmosphere. The optionally isolating 203 an (aminoalkyl)amide 222 from the product mixture 220 may include removing volatile substances under vacuum. For example, the product mixture may be placed under a vacuum for between about 30 minutes and about 1 hour. Volatile substances may include but are not limited to water, solvent, unreacted bis(aminoalkyl)amine, and/or glycerol. The (aminoalkyl)amide 222 reaction product may have one chemical structure, or the reaction product may be a mixture of compounds having different chemical structures. For example, the (aminoalkyl)amide 222 reaction product may include a mixture of compounds represented by Structure I. For a reaction product that includes a mixture of compounds having different chemical structures, individual compounds may be isolated from the reaction product, or the reaction product may be used as a mixture. FIG. 3 depicts chemical structures and a reaction scheme for an example of a method 300 of making an (aminoalkyl)amide composition. The method 300 includes forming a reaction mixture 310 containing metathesized soybean oil (MSBO) 312 as the metathesized natural oil and diethylenetriamine 314 as the bis(aminoalkyl)amine. The reaction mixture 310 also may include one or more other substances, such as a solvent, a base and/or a catalyst. Method 300 further includes forming 302 a product mixture 320 containing (aminoethyl)amide species, such as 322 and/or 324. In species 322 and 324, w, x, y and z independently are integers from 0 to 18, such that the total number of carbon atoms between the amido groups is from 6 to 28, and the partially dashed double line indicates that species may or may not include one or more carbon-carbon double bonds. The forming 302 may include heating the reaction mixture as described above, including maintaining the reaction mixture at a temperature of from about 30° C. to about 200° C. for a time sufficient to form (aminoalkyl)amide species. The tetra(aminoethyl)diamide species 322 and bis(aminoethyl)amide species 324 are exemplary, as the product mixture 320 may include a number of different species of (aminoethyl)amides consistent with Structure I. Structural variables between the species include but are not limited to the presence and number of carbon-carbon double bonds, the number of carbon atoms in the organic group bonded to the (aminoethyl)amide group(s), and branching. Method 300 further may include isolating an (aminoethyl)amide species. As noted above, isolating one or both of the (aminoethyl)amide species may include removing volatile substances under vacuum, where the volatile substances may include but are not limited to water, solvent, unreacted diethylenetriamine 314, and/or glycerol. The optional isolating may provide a mixture of (aminoalkyl)amide species, or it may provide a single (aminoalkyl)amide species. A compound having a plurality of primary amine functional groups, such as the reaction product of a metathesized natural oil and a bis(aminoalkyl) amine and/or a compound represented by Structure I above, may be used in a polymerization reaction. A monofunctional monomer, such as a monomer having Structure I in which —R3 is H, may be used as a chain extender in a polymer. A difunctional monomer, such as a monomer having Structure I in which —R3 is a bis(aminoalkyl) amide group, may be used as a crosslinker in a polymer. A mixture of monofunctional and difunctional monomers may be used to provide both chain extension and crosslinking features to a polymer. In one example, the compound having a plurality of primary amine functional groups may be reacted with monomers having two or more epoxy groups to form an epoxy polymer. Examples of monomers having two or more epoxy groups include but are not limited to diglycidyl ethers of bisphenol A or bisphenol F, tetraglycidyl diamine-diphenylmethane, and multi-glycidyl ethers of phenol formaldehyde novolac polymers. The compound having a plurality of primary amine functional groups may account for all of the amine-functionalized monomer in the polymerization reaction, or one or more other amine-functionalized monomers, such as such as ethylene diamine, triethylenetriamine, diethylenetriamine, hexamethylenetetramine, tetraethylenepentamine or amine-terminated polymers or prepolymers, may be present in the polymerization. In another example, the compound having a plurality of primary amine functional groups may be reacted with a diacid monomer or a diacid chloride monomer to form a polyamide. Examples of diacid monomers include but are not limited to adipic acid. Examples of diacid chloride monomers include but are not limited to sebacoyl chloride and terephthaloyl chloride. The compound having a plurality of primary amine functional groups may account for all of the amine-functionalized monomer in the polymerization reaction, or one or more other amine-functionalized monomers, such as such as ethylenediamine or hexamethylenediamine, may be present in the polymerization. A compound having a plurality of primary amine functional groups, such as the reaction product of a metathesized natural oil and a bis(aminoalkyl) amine and/or a compound represented by Structure I above, may be used to form a dendritic molecule. In one example, the compound having a plurality of primary amine functional groups may be used as a substitute for some or all of the ethylenediamine typically used in the synthesis of PAMAM dendrimers. In another example, the compound having a plurality of primary amine functional groups may be used as the core in the divergent synthesis of a dendrimer. Reaction of the compound with methyl acrylate, followed by reaction with ethylenediamine, may provide a dendrimer analogous to the PAMAM system, but with a core that is more flexible and less sterically hindered. The following examples and representative procedures illustrate features in accordance with the present teachings, and are provided solely by way of illustration. They are not intended to limit the scope of the appended claims or their equivalents, and numerous variations can be made to the following examples that lie within the scope of these claims. EXAMPLES Example 1 Formation of (Aminoalkyl)amide Compounds An (aminoalkyl)amide compound was formed by reacting a metathesized natural oil and a bis(aminoalkyl)amine. Diethylenetriamine (DETA) (106.18 grams (g)) and sodium methoxide (1.11 g) were combined in a flask equipped with a condenser, and the mixture was heated to 115° C. and stirred. To this mixture, metathesized soybean oil (MSBO; 250 g) was added dropwise. Table 1 lists the reactants present in the reaction mixture. The saponification value (SAP) of MSBO was determined using the standard AOCS (American Oil Chemists' Society) procedure. The average molecular weight between ester groups in the MSBO was approximately 56,100 /SAP=56,100/210=267.2 Daltons. TABLE 1 Reactants used to form (aminoalkyl)amide compounds MSBO Diethylenetriamine Sodium methoxide molecular 210* 103.17 g/mol 54.02 g/mol weight mass 250 g 106.18 g 1.11 g moles 0.9357 1.0292 0.0206 equivalents 1 1.1 0.022 *saponification value The mixture was maintained at 115° C. for 2 hours after the MSBO addition was complete. The mixture was allowed to cool, and was then dissolved in diethyl ether, washed with a saturated sodium chloride solution, and dried. The ether was removed from the product by rotary evaporation to provide a mixture of monomers having at least two primary amine functional groups and containing a group derived from the MSBO. Characterization of the product by Fourier Transform Infrared Spectroscopy (FTIR) was consistent with full conversion of the ester groups of the MSBO to N,N-bis(aminoethyl)amide groups. While neither desiring to be bound by any particular theory nor intending to limit in any measure the scope of the appended claims or their equivalents, it is presently believed that the product may be represented by Structures III and/or IV, above. Example 2 Formation of Epoxy Thermoset A polymer was formed by reacting bisphenol A diglycidyl ether with a compound having a plurality of primary amine functional groups. The (aminoalkyl)amide compound of Example 1 and bisphenol A diglycidyl ether were combined, resulting in a hard epoxy polymer product. The foregoing detailed description and accompanying drawings have been provided by way of explanation and illustration, and are not intended to limit the scope of the appended claims. Many variations in the presently preferred embodiments illustrated herein will be apparent to one of ordinary skill in the art, and remain within the scope of the appended claims and their equivalents. It is to be understood that the elements and features recited in the appended claims may be combined in different ways to produce new claims that likewise fall within the scope of the present invention. Thus, whereas the dependent claims appended below depend from only a single independent or dependent claim, it is to be understood that these dependent claims can, alternatively, be made to depend in the alternative from any preceding claim—whether independent or dependent and that such new combinations are to be understood as forming a part of the present specification.",C08G5954,C08G5954,20160111,20170404,20160714,86027.0
9,14994130,ACCEPTED,FLUX CONCENTRATOR FOR IRONLESS MOTOR,"In one possible embodiment, a magnet array for a motor is provided which has an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array, the array further includes flux concentrators located at poles on the reinforcing side of the array.","1. A magnet array for a motor comprising an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array, wherein the magnets are arranged such that the magnetic moments of adjacent magnets are oriented in directions separated by about 45 degrees, and such that a magnet within the array comprises a magnetic moment oriented generally perpendicular to the reinforcing side of the array, and comprising an ironless winding adjacent to the array comprising conductor bundles having a generally rectangular cross-section arranged such that a long side of the generally rectangular cross-section is transverse to a direction of magnetic field lines of the magnet having the generally perpendicular magnetic moment. 2. The magnet array of claim 1, further comprising flux concentrators located on the reinforcing side of the array at magnets having the generally perpendicular magnetic moment. 3. The magnet array of claim 2, wherein the flux concentrators comprise a magnetic material having a higher flux density than the magnets. 4. The magnet array of claim 3, wherein the flux concentrators comprise iron. 5. The magnet array of claim 1, wherein the flux concentrators comprise iron. 6. A motor comprising: a) an inner rotor and an outer rotor; b) a stator comprising an ironless winding between the inner rotor and the outer rotor; c) the inner rotor and the outer rotor each comprising an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on a side of the array facing the stator and substantially canceling on a side of the array opposite the stator, wherein the magnets of the arrays of the inner and outer rotors are arranged such that the magnetic moments of adjacent magnets are oriented in directions separated by about 45 degrees, and such that a magnet within the array comprises a magnetic moment oriented generally perpendicular to the stator side of the array, and d) wherein the ironless winding comprises conductor bundles comprising a generally rectangular cross-section arranged such that a long side of the generally rectangular cross-section is transverse to a direction of magnetic field lines of the generally perpendicular magnetic moments of inner and outer arrays. 7. The motor of claim 6, wherein the inner and outer rotors are secured together separated by a gap, and wherein the magnetic moments of the magnets in the arrays are aligned to reinforce magnetic fields across the gap. 8. The motor of claim 7, further comprising flux concentrators located on the reinforcing side of the array at magnets having the generally perpendicular magnetic moment. 9. The motor of claim 8, wherein the flux concentrators comprise a magnetic material having a higher flux density than the magnets. 10. The motor of claim 9, wherein the flux concentrators comprise iron. 11. The motor of claim 8, wherein the flux concentrators comprise iron. 12. A motor comprising: a) an inner rotor and an outer rotor with an ironless stator winding therebetween; b) the inner and outer rotors each comprise flux concentrators and permanent magnets, the inner rotor and the outer rotor each comprising an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on a side of the array facing the stator and substantially canceling on a side of the array opposite the stator, wherein the magnets of the arrays of the inner and outer rotors are arranged such that the magnetic moments of adjacent magnets are oriented in directions separated by about 45 degrees, and such that a magnet within the array comprises a magnetic moment oriented generally perpendicular to the stator side of the array; c) wherein the permanent magnets each comprise a pole surface, the flux concentrators of the inner and outer rotors being located at a pole surface of the magnet having the generally perpendicular magnetic magnet within the array so as to mutually reinforce flux across the winding; and d) wherein the ironless stator winding comprises conductor bundles comprising a generally rectangular cross-section arranged such that a long side of the generally rectangular cross-section is transverse to a direction of magnetic field lines of the generally perpendicular magnetic moments of inner and outer arrays. 13. The motor of claim 12, wherein the winding comprises turns each having a width, and wherein the flux concentrators of the inner and outer rotors have a width that is substantially a same width as a single winding turn. 14. The motor of claim 13, wherein the flux concentrators comprise a magnetic material having a higher flux density than the magnets. 15. The motor of claim 13, wherein the flux concentrators comprise iron. 16. The motor of claim 12, wherein the flux concentrators of the inner and outer rotors have a width, the permanent magnets of the inner and outer rotors have a width, and the winding comprises turns each having a width such that a non-fringing density of magnetic field lines across the winding has substantially a same width as the width of a single winding turn. 17. The motor of claim 16, wherein the winding comprises turns each having a width, and wherein the flux concentrators of the inner and outer rotors have a width that is substantially a same width as a single winding turn. 18. The motor of claim 17, wherein the flux concentrators comprise a magnetic material having a higher flux density than the magnets. 19. The motor of claim 18, wherein the flux concentrators comprise iron. 20. The motor of claim 12, wherein the flux concentrators comprise iron.","<SOH> BACKGROUND <EOH>Electric motors for vehicles need to have high efficiency to conserve power. Furthermore, in unmanned or manned vehicles, light weight and compact electric motors are also desirable. Thus, ironless motors are often used which can provide the benefit of no iron losses due to changing flux direction. Ironless motors, however, suffer from poor field strength in the gap. Motors are normally rated for the peak power and efficiency of the motor. In some applications, high part load efficiency is desired, which is high efficiency when machine is loaded at a partial load, i.e. 15% or some other percent. What is needed is a higher efficiency compact motor.","<SOH> SUMMARY <EOH>In one possible embodiment, a magnet array for a motor is provided which has an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array, the array further includes flux concentrators located at poles on the reinforcing side of the array. In another possible embodiment, a magnet array is provided for a motor having an array of permanent magnets arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array. In this embodiment, the magnets are arranged such that the magnetic moments of adjacent magnets are oriented in directions separated by about 45 degrees, and such that a magnet within the array comprises a magnetic moment oriented generally perpendicular to the reinforcing side of the array. The embodiments may be combined and other embodiments are possible.","CROSS REFERENCE TO RELATED APPLICATIONS The present application is a divisional of U.S. patent application Ser. No. 12/565,718, filed Sep. 23, 2009, by Hibbs et al., entitled FLUX CONCENTRATOR FOR IRONLESS MOTORS, herein incorporated by reference in its entirety, which claims the benefit of the following applications which are herein incorporated by reference in their entireties: U.S. Provisional Application No. 61/194,056, filed Sep. 23, 2008, by Bart Dean Hibbs, entitled FLUX CONCENTRATOR FOR IRONLESS MOTORS; and U.S. Provisional Application No. 61/194,099, filed Sep. 23, 2008, by Daboussi et al., entitled PROPELLER DRIVE UNIT FOR HALE UAV. The present application is also related to the following applications, which are hereby incorporated by reference in their entireties: U.S. Non-provisional application Ser. No. 12/565,705, filed Sep. 23, 2009, entitled COMPRESSED MOTOR WINDING, by Rippel et al., U.S. Pat. No. 9,035,526, Issued May 19, 2015; U.S. Non-provisional Application No. 12/565,715, filed Sep. 23, 2009, entitled MOTOR AIR FLOW COOLING, by Sheppard et al., U.S. Pat. No. 8,604,652, Issued Dec. 10, 2013; and U.S. Non-provisional application Ser. No. 12/565,710, filed Sep. 23, 2009, entitled STATOR WINDING HEAT SINK CONFIGURATION, by Daboussi et al., U.S. Pat. No. 8,723,378, Issued May 13, 2014. BACKGROUND Electric motors for vehicles need to have high efficiency to conserve power. Furthermore, in unmanned or manned vehicles, light weight and compact electric motors are also desirable. Thus, ironless motors are often used which can provide the benefit of no iron losses due to changing flux direction. Ironless motors, however, suffer from poor field strength in the gap. Motors are normally rated for the peak power and efficiency of the motor. In some applications, high part load efficiency is desired, which is high efficiency when machine is loaded at a partial load, i.e. 15% or some other percent. What is needed is a higher efficiency compact motor. SUMMARY In one possible embodiment, a magnet array for a motor is provided which has an array of permanent magnets being arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array, the array further includes flux concentrators located at poles on the reinforcing side of the array. In another possible embodiment, a magnet array is provided for a motor having an array of permanent magnets arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array. In this embodiment, the magnets are arranged such that the magnetic moments of adjacent magnets are oriented in directions separated by about 45 degrees, and such that a magnet within the array comprises a magnetic moment oriented generally perpendicular to the reinforcing side of the array. The embodiments may be combined and other embodiments are possible. BRIEF DESCRIPTION OF THE DRAWINGS The features and advantages of the present invention will be better understood with regard to the following description, appended claims, and accompanying drawings where: FIG. 1 shows a simplified exploded perspective view of an example motor. FIG. 2 shows a simplified cross sectional side view of the motor of FIG. 1 along its longitudinal axis. FIG. 3 shows a simplified cut away front view of a portion of a possible embodiment of a permanent magnet motor. FIG. 4 shows a simplified cut away front view of a portion of a possible another embodiment of a permanent magnet motor. FIGS. 5A & B are a simplified cut away front views illustrating a B field in a permanent magnet motor without and with flux concentrators, respectively. DESCRIPTION FIG. 1 shows a simplified exploded perspective view of an example motor 10 along axis 22. A stator 40 is secured to a housing 60. Inner rotor 50 and outer rotor 30 are secured to each other and surround the stator 40. An optional propeller hub 75, into which propeller blades 70 are mounted, is secured to the inner rotor 50. The propeller hub 75 rotatably mounts on the spindle 65 with bearings 16 and 18. The bearings 16 and 18 are retained by retainers 20 and 14 and cover 12. FIG. 2 shows a simplified cross-sectional side view of the motor 10 of FIG. 1 along its longitudinal axis 22. The stator 40 is located between magnets 35 and 55 of the inner and outer rotors 50 and 30, respectively. The propeller hub 75 is bonded to the inner rotor 50 which is rotatably mounted on the spindle 65. The spindle 65 may be fabricated of carbon fiber or other suitable material. FIG. 3 shows a simplified cut away front view of a portion 300 of a possible embodiment of a permanent magnet motor. In FIG. 3, a stator 340 having a winding 345 is located between inner and outer magnet assemblies 355 and 335 of inner and outer rotors 350 and 330. The inner and outer magnet assemblies 355 and 335 have magnets 355a-g and 335a-g arranged with the permanent magnetic fields oriented as indicated by arrows within the magnets 355a-g and 335a-g. The magnetic orientations 357a-g of magnets 355a-g, or the magnetic orientations 337a-g of magnets 335a-g, are similar to those in a Halbach array. In a Halbach array, permanent magnets are arranged such that flux from the permanent magnets reinforce on one side of the array and substantially cancel on an opposite side of the array. Distinguished from a Halbach array, however, various embodiments have flux concentrators 335x-z and 355x-z, provided in the inner and outer magnet assemblies 355 and 335. The flux concentrators 335x-z and 355x-z increase the flux density B onto the area of the winding 345. The force and therefore the torque resulting from the flux density B is calculated from this formula F=B×I×L, where I is the current in the wire and L is the length of the wire in the B field. Thus, increasing the B field density on each Litz wire 345a, increases the force F on the in the wire 340a. Increasing the flux concentration on the same wire, at the same length and current, results in higher force on the wire 340a to improve efficiency. Without the flux concentrators 335x-z and 355x-z fringing can occur which reduces the flux density in the wire 345a. FIG. 5A is a simplified cut away front view illustrating how the B field 542 in the gap 545b fringes without the flux concentrators, resulting in less flux density in the conductor 545b. With flux concentrators 535x and 555x as shown in FIG. 5B, however, the B field 548 has higher density in the wire 545b. Referring to FIG. 3, the flux concentrators 355x-z and 335x-z are located within the inner and outer magnet assemblies 355 and 335 in opposing positions across the gap 349. They are located in positions where the magnetic fields 346, 347, and 348 reinforce, and in positions where the magnetic fields 346, 347, and 348 cancel, on opposing surfaces 335s and 355s of the gap 349. The flux concentrators 355x-z are located between the gap 349 and respective back magnets 355b, 355d, and 355f. Similarly, the flux concentrators 335x-z are located between the gap 349 and respective back magnets 355b, 355d, and 355f. The flux concentrators 355x-z and 335x-z may be made of iron, or other magnetic material. The iron material form poles that collect and concentrate the flux from the magnets. Field strength is limited in readily available permanent magnets to about 1 Tesla. Iron on the other hand, can support 2 Teslas. By using poles along with magnets to force flux across the gap 349, a greater fields 346, 347, and 348, in the gap 349 may be possible. Motor torque is proportional to the field, so as at a fixed torque, doubling the field cuts the I2R losses by ¼. As used herein, ironless motor means no iron in the winding. The flux concentrators are not limited to iron and may be made of other magnetic materials and high magnetic moment materials. Although shown as one half the thickness of the corresponding back magnets 335b, 335d, and 335f, the flux concentrators 335x, 335y, and 335z may be larger, or smaller than the back magnet, depending on the materials used and the strength of the magnets. Furthermore, the respective widths of the between magnets 335a, 335c, 335d, and 335g, and the flux concentrator and/or the back magnets 335b, 335d, 335f, may be different and need not be equal. The spacing and orientations/periodicity of the magnets with respect to the number and spacing of windings in the rotor should be matched, so that the fields in the gap generate additive currents in the stator windings. FIG. 4 shows a simplified cut away front view of a portion 500 of a possible another embodiment of a permanent magnet motor. In this embodiment, the orientation of the magnetic moments of successive permanent magnets in the outer rotor array 535 are each rotated 45 degrees or π/4 radians, with respect to an adjacent magnet. Similarly, the orientation of the magnetic moments of successive permanent magnets in the inner rotor array 355 are each rotated 45 degrees with respect to an adjacent magnet. The outer magnets 535 are oriented such that they reinforce at −90 degrees at magnet 535d and cancel at 90 degrees at magnet 535h at the gap surface 535s in the outer array 535, and the inner magnets 555 are oriented such that they reinforce at 90 degrees at magnet 555h and cancel at −90 degrees at magnet 555d at the gap surface 555s. An advantage of orienting the magnets with 45 degrees of separation, and including 90 degree orientation with respect to the stator winding 545, as shown in FIG. 4, is that it provides a higher back EMF than a 60, 30, −30, −60 degree orientations. In some embodiments the embodiment of FIG. 4 provided about a 10% higher back EMF than a 60, 30, −30, −60 degree orientations. Embodiments and implementation of the present invention are not limited to the motor embodiments shown in FIGS. 3 and 4. The magnet arrays described herein may be applied to various axial or radial motors, or to other Halbach array/cylinder/sphere devices, or the like, including wigglers, and are not limited to use in dual rotor motors. As used herein, array is intended to cover cylinders, spheres, or the like, utilizing the array structure. Furthermore, embodiments and implementations are not limited to aircraft motors, but may also be employed in automobiles, machinery, instruments, space, or other applications. It is worthy to note that any reference to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment may be included in an embodiment, if desired. The appearances of the phrase “in one embodiment” in various places in the specification are not necessarily all referring to the same embodiment. The illustrations and examples provided herein are for explanatory purposes and are not intended to limit the scope of the appended claims. This disclosure is to be considered an exemplification of the principles of the invention and is not intended to limit the spirit and scope of the invention and/or claims of the embodiment illustrated. Those skilled in the art will make modifications to the invention for particular applications of the invention. The discussion included in this patent is intended to serve as a basic description. The reader should be aware that the specific discussion may not explicitly describe all embodiments possible and alternatives are implicit. Also, this discussion may not fully explain the generic nature of the invention and may not explicitly show how each feature or element can actually be representative or equivalent elements. Again, these are implicitly included in this disclosure. Where the invention is described in device-oriented terminology, each element of the device implicitly performs a function. It should also be understood that a variety of changes may be made without departing from the essence of the invention. Such changes are also implicitly included in the description. These changes still fall within the scope of this invention. Further, each of the various elements of the invention and claims may also be achieved in a variety of manners. This disclosure should be understood to encompass each such variation, be it a variation of any apparatus embodiment, a method embodiment, or even merely a variation of any element of these. Particularly, it should be understood that as the disclosure relates to elements of the invention, the words for each element may be expressed by equivalent apparatus terms even if only the function or result is the same. Such equivalent, broader, or even more generic terms should be considered to be encompassed in the description of each element or action. Such terms can be substituted where desired to make explicit the implicitly broad coverage to which this invention is entitled. It should be understood that all actions may be expressed as a means for taking that action or as an element which causes that action. Similarly, each physical element disclosed should be understood to encompass a disclosure of the action which that physical element facilitates. Such changes and alternative terms are to be understood to be explicitly included in the description. Having described this invention in connection with a number of embodiments, modification will now certainly suggest itself to those skilled in the art. The example embodiments herein are not intended to be limiting, various configurations and combinations of features are possible. As such, the invention is not limited to the disclosed embodiments, except as required by the appended claims.",H02K12706,H02K127,20160112,20180410,20160721,68952.0