1. A method of selecting subjects suffering or being predisposed to suffering from a proliferative disease (neoplasm) in non-neuroendocrine tissues for treatment with a Ret inhibitor and selecting those subjects displaying Ret expression andor activity for said treatment, comprising the steps of:
providing a sample from a patient suffering or being predisposed to suffering from said disease;
detecting any Ret expression andor activity in said sample; and
selecting those patients for treatment with a Ret inhibitor whose sample displays Ret expression andor activity.
2. The method according to claim 1 further comprising the step of comparing Ret expression andor activity with a control sample in order to detect an increase or decrease in Ret expression andor activity in the sample.
3. The method according to claim 2 wherein the patient is selected whose sample displays an increased level of Ret expression andor activity, in comparison to the control sample.
4. The method according to claim 3 wherein the detection of Ret expression andor activity is carried out by immunological, histochemical, immunocytochemical, immunohistochemical, microscopy andor geneproteinphosphoprotein expression techniques.
5. The method according to claim 4 wherein the detection of Ret expression andor activity is carried out using an antibody specific for Ret protein or phosphorylated Ret protein.
6. The method according to claim 5 wherein the antibody is labelled.
7. The method according to claim 6 wherein the patient to be tested is undergoing another form of therapy, such as chemotherapy andor radiotherapy.
8. The method according to claim 7 wherein the sample is a sample of tumour tissue or tissue suspected of comprising tumour cells or cells predisposed to becoming tumour cells.
9. The method according to claim 8 wherein the sample is a sample of breast tissue.
10. Use of a Ret inhibitor in the manufacture of a medicament for treating a proliferative disease of non-neuroendocrine origin, characterised by displaying Ret expression andor activity.
11. A method of treating a proliferative disease of non-neuroendocrine origin characterized by Ret expression andor activity, in a subject in need thereof, comprising administering to said subject a Ret inhibitor in an amount effective to reduce andor inhibit undesirable cell proliferation.
12. The method according to claim 10 wherein the Ret inhibitor is a small Ret binding molecule; an RNAi or siRNA molecule designed to inhibit Ret expression; an antibody capable of specifically binding to Ret or its phosphorylated form and interfering with Ret activity andor association or binding to other proteins; neutralizing aptamers against Ret; or a peptide fragment or peptide mimetic capable of disrupting or competitively inhibiting Ret function.
13. The method according to claim 12 wherein the Ret inhibitor is a molecule according to formula VIA as disclosed in WO2006034833.
14. The method according to claim 13 wherein the Ret inhibitor is 6-1-4-(4-methyl-1-piperazinyl)methyl-3-(trifluoromethyl)phenylaminocarbonyl-1H-indol-5-yloxy-4-pyrimidinylacetamide.
15. The method according to claim 14 wherein the non-neuroendocrine disorder is a benign or malignant proliferative disease, e.g. a cancer, e.g. tumours andor metastasis (where ever located), e.g. brain and other central nervous system tumours (e.g. tumours of the meninges, brain, spinal cord, cranial nerves and other parts of central nervous system, e.g. glioblastomas); head andor neck cancer; breast tumours; circulatory system tumours (e.g. heart, mediastinum and pleura, and other intrathoracic organs, vascular tumours and tumour-associated vascular tissue); excretory system tumours (e.g. kidney, renal pelvis, ureter, bladder, other and unspecified urinary organs); gastrointestinal tract tumours (e.g. oesophagus, stomach, small intestine, colon, colorectal, rectosigmoid junction, rectum, anus and anal canal), tumours involving the liver and intrahepatic bile ducts, gall bladder, other and unspecified parts of biliary tract, other and digestive organs); head and neck; oral cavity (lip, tongue, gum, floor of mouth, palate, and other parts of mouth, parotid gland, and other parts of the salivary glands, tonsil, oropharynx, nasopharynx, pyriform sinus, hypopharynx, and other sites in the lip, oral cavity and pharynx); reproductive system tumours (e.g. vulva, vagina, Cervix uteri, Corpus uteri, uterus, ovary, and other sites associated with female genital organs, placenta, penis, testis, and other sites associated with male genital organs); respiratory tract tumours (e.g. nasal cavity and middle ear, accessory sinuses, larynx, trachea, bronchus and lung, e.g. small cell lung cancer or non-small cell lung cancer); skeletal system tumours (e.g. bone and articular cartilage of limbs, bone articular cartilage and other sites); skin tumours (e.g. malignant melanoma of the skin, non-melanoma skin cancer, basal cell carcinoma of skin, squamous cell carcinoma of skin, mesothelioma. Kaposi’s sarcoma); and tumours involving other tissues including peripheral nerves and autonomic nervous system, connective and soft tissue, retroperitoneum and peritoneum, eye and adnexa, thyroid, adrenal gland and other endocrine glands and related structures, secondary and unspecified malignant neoplasm of lymph nodes, secondary malignant neoplasm of respiratory and digestive systems and secondary malignant neoplasm of other sites, tumours of blood and lymphatic system (e.g. Hodgkin’s disease, Non-Hodgkin’s lymphoma, Burkitt’s lymphoma, AIDS-related lymphomas, malignant immunoproliferative diseases, multiple myeloma and malignant plasma cell neoplasms, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell type, leukemia of unspecified cell type, other and unspecified malignant neoplasms of lymphoid, haematopoietic and related tissues, for example diffuse large cell lymphoma. T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cancer includes e.g. acute or chronic myeloid leukaemia.
16. The method according to claim 15 wherein the non-neuroendocrine disorder is breast cancer.
17. An imaging agent for detecting Ret expression comprising an antibody specific for Ret linked to a detectable label.
18. An immunotoxin for use in destroying andor reducing non-neuroendocrine cancer cells expressing Ret comprising an antibody conjugated to a toxin molecule.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A functional electrical stimulation system for controlling the movement of a portion of a body of a subject comprising:
a measuring device having at least one sensor that is mountable to the torso of the subject and which outputs signals representative of the angle of said subject’s torso relative to a predetermined spatial reference plane;
a controller that receives and processes the signals output by the measuring device and outputs control signals; and
a stimulator that receives the control signals and is adapted to provide electrical stimulation to said one or both legs in response to the angle of the subject’s torso determined by the measuring device;
wherein, on detecting twisting movements of the torso and that the subject is at least substantially horizontal, the controller outputs control signals that cause the stimulator to output a sequence of stimulation impulses that serve to roll the subject over.
2. The function electrical stimulation system of claim 1 wherein the controller is programmed to output signals to the stimulator to cause roll over of the subject at predetermined times.
3. The functional electrical stimulation system of claim 2 wherein the controller is programmed to output signals causing roll over of the subject at least 2 times in an 8 hour period.