Patent application number | Description | Published |
20080207742 | Therapeutic effects of bryostatins, bryologs, and other related substances on head trauma-induced memory impairment and brain injury - The invention provides for the use of protein kinase activators or boosters of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or other neurotrophic factors to treat head trauma. Specifically, the present invention provides methods of treating head trauma comprising the steps of identifying a subject having suffered a head trauma and administering to said subject an amount of a pharmaceutical composition comprising a protein kinase C(PKC) activator or 4-methylcatechol acetic acid (MCBA) and a pharmaceutically acceptable carrier effective to treat at least one symptom of head trauma. | 08-28-2008 |
20080221042 | Alzheimer's disease-specific alterations of the ERK1/ERK2 Phosphorylation ratio-Alzheimer's disease-specific molecular biomarkers (ADSMB) - The present invention relates to methods of diagnosing Alzheimer's Disease as well as to methods of confirming the presence or absence of Alzheimer's Disease in a subject. The present invention is also directed to methods of identifying a lead compound useful for the treatment of Alzheimer's Disease by contacting non-Alzheimer's cells with an amyloid beta peptide, stimulating the cells with a protein kinase C activator, contacting the cells with a test compound, and determining the value of an Alzheimer's Disease-specific molecular biomarker. The present invention is also directed to methods of diagnosing Alzheimer's Disease in a subject by detecting alterations in the ratio of specific phosphorylated MAP kinase proteins in cells after stimulation with a protein kinase C activator. The Alzheimer's Disease-specific molecular biomarkers disclosed herein are useful for the diagnosis of Alzheimer's Disease, monitoring the progression of Alzheimer's Disease in a subject and in screening methods for the identification of compounds for treating or preventing Alzheimer's Disease. The invention is also directed to kits containing reagents for the detection and diagnosis of the presence or absence of Alzheimer's Disease using the Alzheimer's Disease-specific molecular biomarkers disclosed herein. | 09-11-2008 |
20090029355 | Abnormalities of Phosphatase 2A (PP2A) for Diagnosis and Treatment of Alzheimer's Disease - This invention relates to methods of diagnosing Alzheimer's disease and methods of screening for compounds for the treatment or prevention of Alzheimer's disease. The methods are based upon newly discovered differences in protein phosphatase 2A (PP2A) function and related molecular events in Alzheimer's disease cells compared to control cells. In one embodiment, differences in basal PP2A gene expression in Alzheimer's cells are compared to controls. In another embodiment differences in PP2A protein and enzyme activity are compared in test and control cells. In another embodiment differences in response to substances that inhibit PP2A function are compared. Still another embodiment detects differences in the subcellular distribution of phosphorylated Erk1/2, a substrate of PP2A, in normal and Alzheimer's disease cells. The detection of Alzheimer's disease-specific differences in PP2A function and related events in peripheral tissues provides the basis for highly practical and efficient tests and diagnostic test kits for the early diagnosis of Alzheimer's disease, as well as providing a biochemical basis for identifying therapeutic targets for drug development. | 01-29-2009 |
20090029873 | Alzheimer's Disease-Specific Alterations of the Erk1/Erk2 Phosphorylation Ratio-Alzheimer's Disease-Specific Molecular Biomarkers (Adsmb) - The present invention relates to methods of diagnosing Alzheimer's Disease as well as to methods of confirming the presence or absence of Alzheimer's Disease in a subject. The present invention is also directed to methods of identifying a lead compound useful for the treatment of Alzheimer's Disease by contacting non-Alzheimer's cells with an amyloid beta peptide, stimulating the cells with a protein kinase C activator, contacting the cells with a test compound, and determining the value of an Alzheimer's Disease-specific molecular biomarker. The present invention is also directed to methods of diagnosing Alzheimer's Disease in a subject by detecting alterations in the ratio of specific phosphorylated MAP kinase proteins in cells after stimulation with a protein kinase C activator. The Alzheimer's Disease-specific molecular biomarkers disclosed herein are useful for the diagnosis of Alzheimer's Disease, monitoring the progression of Alzheimer's Disease in a subject and in screening methods for the identification of compounds for treating or preventing Alzheimer's Disease. The invention is also directed to kits containing reagents for the detection and diagnosis of the presence or absence of Alzheimer's Disease using the Alzheimer's Disease-specific molecular biomarkers disclosed herein. | 01-29-2009 |
20090030055 | PKC activation as a means for enhancing sAPPALPHA secretion and improving cognition using bryostatin type compounds - The present invention relates to compositions and methods to modulate α-secretase and/or to improve cognitive ability. The invention further relates the improved/enhanced cognitive ability in diseased individuals, particularly Alzheimer's Disease patients, and treatment thereof through increased sAPP production. Macrocyclic lactones (i.e. bryostatin class and neristatin class) are compounds preferred for use with the present composition. The present invention also provides methods for increasing the generation of non-amyloidogenic soluble APP comprising the activation of protein kinase C (PKC) by administering an effective amount of PKC activator(s). | 01-29-2009 |
20090036514 | Therapeutic effects of Bryostatins, Bryologs, and other related substances on Ischemia/stroke-induced memory impairment and brain injury - The invention provides for the use of protein kinase activators or boosters of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or other neurotrophic factors to treat stroke. Specifically, the present invention provides methods of treating stroke comprising the steps of identifying a subject having suffered a stroke and administering to said subject an amount of a pharmaceutical composition comprising a protein kinase C (PKC) activator or 4-methylcatechol acetic acid (MCBA) and a pharmaceutically acceptable carrier effective to treat at least one symptom of stroke. | 02-05-2009 |
20090041667 | Treatment of Depressive Disorders - The invention provides for the use of carbonic anhydrase activators; protein kinase C activators and FGF-18 to treat depressive disorders. The invention also relates to improved animal models and methods for screening and identifying compounds the treatment of depressive disorders. | 02-12-2009 |
20100021913 | Stimulus-Elicited Genomic Profile Markers of Alzheimer's Disease - The present invention relates to a method for diagnosing Alzheimer's Disease (AD) using PKC-elicited gene expression profiles PKC-activation elicits different genomic profiles in AD cells, as compared with control cells, which can he used to diagnose AD and individuals at risk for developing AD. | 01-28-2010 |
20100022645 | PKC-Activating Compounds for the Treatment of Neurodegenerative Diseases - The present invention relates to methods of activate an isoform of protein kinase C (PKC) for the treatment of neurological diseases including Alzheimer's disease and stroke using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids. The present invention also relates to methods of reducing neurodegeneration using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids. | 01-28-2010 |
20100278803 | Alzheimer's Disease Diagnosis Based on Mitogen-Activated Protein Kinase Phosphorylation - A method of diagnosing Alzheimer's disease in a patient comprises determining whether the phosphorylation level of an indicator protein in cells of the patient after stimulus with an activator compound is abnormally elevated as compared to a basal phosphorylation level, the indicator protein being e.g. Erk1/2 and the activator compound being e.g. bradykinin. | 11-04-2010 |
20100303792 | PROTEIN SYNTHESIS REQUIRED FOR LONG-TERM MEMORY IS INDUCED BY PKC ACTIVATION ON DAYS PRECEDING ASSOCIATIVE LEARNING - The present invention provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC. | 12-02-2010 |
20110136144 | FIBROBLAST GROWTH PATTERNS FOR DIAGNOSIS OF ALZHEIMER'S DISEASE - Methods of diagnosing Alzheimer's disease are provided. At least five methods of diagnostic measurements are presented: Method 1: Integrated score; Method 2: Average aggregate area per number of aggregates; Method 3: Cell migration analysis; Method 4; Fractal analysis; Method 5: Lacunarity Analysis. In certain embodiments, a sample of a subject's skin provides a network of fibroblasts that is imaged and a fractal dimension of the image is calculated. The fractal dimension can be compared to an aged-matched control (non-Alzheimer's) database to determine if the subject has Alzheimer's disease. The network of fibroblasts may be cultured in a matrix, for example in a protein mixture. | 06-09-2011 |
20110196028 | PCK ACTIVATION AS A MEANS FOR ENHANCING sAPPa SECRETION AND IMPROVING COGNITION USING BRYOSTATIN TYPE COMPOUNDS - This invention provides a method for isolating and identifying proteins participating in protein-protein interactions in a complex mixture. The method uses a chemically reactive supporting matrix to isolate proteins that in turn non-covalently bind other proteins. The supporting matrix is isolated, and the non-covalently bound proteins are subsequently released for analysis. Because the proteins are accessible to chemical manipulation at both the binding and release steps, identification of the non-covalently bound proteins yields information on specific classes of interacting proteins, such as calcium-dependent or substrate-dependent protein interactions. This permits selection of a subpopulation of proteins from a complex mixture on the basis of specified interaction criteria. The method has the advantage of screening the entire proteome simultaneously, unlike two-hybrid systems or phage display methods which can only detect proteins binding to a single bait protein at a time. The method is applicable to the study of protein-protein interactions in biopsy and autopsy specimens, to the study of protein-protein interactions in the presence of signaling molecules, pharmacological agents or toxins, and for comparison of diseased and normal tissues or cancerous and untransformed cells. | 08-11-2011 |
20110212474 | ABNORMAL ALTERATIONS OF PKC ISOZYMES PROCESSING IN ALZHEIMER'S DISEASE PERIPHERAL CELLS - The present invention provides a method for the diagnosis of AD from non-AD conditions by using a PKC Isozyme Index obtained by determining ratios of ratios of different PKC Isozymes in peripheral cells of a test subject in the absence and presence of a beta-amyloid peptide, and optionally, in the presence of a PKC activator. | 09-01-2011 |
20110245307 | Methods for Alzheimer's Disease Treatment and Cognitive Enhancement - The present invention relates to compositions comprising a combination of PKC activators and PKC inhibitors and methods to modulate α-secretase activity; improve or enhance cognitive ability; and/or reduce neurodegeneration in individuals suffering from diseases that impair cognitive ability, particularly Alzheimer's Disease. The invention also relates to methods for improving or enhancing cognitive ability. The present invention also provides methods for increasing the generation of non-amyloidogenic soluble APP (sAPP) comprising the activation of protein kinase C (PKC) in the brain and inhibiting PKC in peripheral tissues. Macrocyclic lactones (i.e. bryostatin class and neristatin class) are preferred PKC activators and Vitamin E is a preferred PKC inhibitor for use in the inventive composition. | 10-06-2011 |
20110288022 | TREATMENT OF DEPRESSIVE DISORDERS - The invention provides for the use of carbonic anhydrase activators; protein kinase C activators and FGF-18 to treat depressive disorders. The invention also relates to improved animal models and methods for screening and identifying compounds the treatment of depressive disorders. | 11-24-2011 |
20120020948 | DAG-TYPE AND INDIRECT PROTEIN KINASE C ACTIVATORS AND ANTICOAGULANT FOR THE TREATMENT OF STROKE - The present disclosure provides a method for treating stroke by administering an anticoagulant, e.g., recombinant tissue plasminogen activator (rTPA), and a protein kinase C (PKC) activator, wherein the PKC activator may be administered before, after, or at the same time as the rTPA. The methods disclosed herein may limit the size of infarction and/or reduce mortality, the disruption of the blood-brain barrier, and/or the hemorrhagic damage due to ischemic stroke compared with rTPA administration alone; and may also extend the therapeutic time window for administering rTPA after a stroke. Also disclosed are compositions and kits comprising rTPA and a PKC activator for treating stroke. | 01-26-2012 |
20120027687 | FATTY ACID PROTEIN KINASE C ACTIVATORS AND ANTICOAGULANT FOR THE TREATMENT OF STROKE - The present disclosure provides a method for treating stroke by administering an anticoagulant, e.g., recombinant tissue plasminogen activator (rTPA), and a protein kinase C(PKC) activator, wherein the PKC activator may be administered before, after, or at the same time as the rTPA. The methods disclosed herein may limit the size of infarction and/or reduce mortality, the disruption of the blood-brain barrier, and/or the hemorrhagic damage due to ischemic stroke compared with rTPA administration alone; and may also extend the therapeutic time window for administering rTPA after a stroke. Also disclosed are compositions and kits comprising rTPA and a PKC activator for treating stroke. | 02-02-2012 |
20120034205 | PKC ACTIVATORS AND ANTICOAGULANT IN REGIMEN FOR TREATING STROKE - The present disclosure provides a method for treating stroke by administering to a subject an anticoagulant, e.g., recombinant tissue plasminogen activator (rTPA), and a protein kinase C (PKC) activator followed by administration of at least one PKC activator for a duration of treatment. The methods disclosed herein may limit the size of infarction and/or reduce mortality, the disruption of the blood-brain barrier, and/or the hemorrhagic damage due to ischemic stroke compared with rTPA administration alone; and may also extend the therapeutic time window for administering rTPA after a stroke. Also disclosed are kits comprising rTPA and a PKC activator for treating stroke. | 02-09-2012 |
20120149768 | PKC-ACTIVATING COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES - The present invention relates to methods of activate an isoform of protein kinase C (PKC) for the treatment of neurological diseases including Alzheimer's disease and stroke using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids. The present invention also relates to methods of reducing neurodegeneration using cyclopropanated or epoxidized derivatives of mono- and polyunsaturated fatty acids. | 06-14-2012 |
20120289557 | Protein Synthesis Required for Long-Term Memory is Induced by PKC Activation on Days Preceding Associative Learning - The present invention provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC. | 11-15-2012 |
20130072550 | PKC ACTIVATION AS A MEANS FOR ENHANCING sAPPalpha SECRETION AND IMROVING COGNITION USING BRYOSTATIN TYPE COMPOUNDS - The present disclosure relates to methods of administering compounds for treating conditions associated with amyloid processing such as Alzheimer's Disease. Methods are disclosed comprising the step of administering a macrocyclic lactone, a benzolactam, a pyrrolidinone or a combination thereof to a subject in need in an amount effective to decrease soluble Aβ-40 or Aβ-42, or to lower total amyloid precursor protein (“APP”). Methods are also disclosed further comprising the step of identifying a subject with increased soluble Aβ-40 or Aβ-42 levels, or elevated APP levels compared to a control population. | 03-21-2013 |
20130165453 | THERAPEUTIC EFFECTS OF BRYOSTATINS, BRYOLOGS, AND OTHER RELATED SUBSTANCES ON ISCHEMIA/STROKE-INDUCED MEMORY IMPAIRMENT AND BRAIN INJURY - The invention provides for the use of protein kinase activators or boosters of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) or other neurotrophic factors to treat stroke. Specifically, the present invention provides methods of treating stroke comprising the steps of identifying a subject having suffered a stroke and administering to said subject an amount of a pharmaceutical composition comprising a protein kinase C (PKC) activator or 4-methylcatechol acetic acid (MCBA) and a pharmaceutically acceptable carrier effective to treat at least one symptom of stroke. | 06-27-2013 |
20130231384 | METHODS OF STIMULATING CELLULAR GROWTH, SYNAPTIC REMODELING AND CONSOLIDATION OF LONG-TERM MEMORY - The present invention provides methods of slowing or reversing the loss of memory and learning comprising the steps of contacting an effective amount of a PKC activator with a protein kinase C (PKC) in a subject identified with memory loss slowing or reversing memory loss. The present invention provides methods of stimulating cellular growth, neuronal growth, dendritic growth, dendritic spine formation, dendritic spine density, and the translocation of ELAV to proximal dendrites, and synaptic remodeling. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC. | 09-05-2013 |
20130273545 | Abnormalities of Phosphatase 2A (PP2A) for Diagnosis and Treatment of Alzheimer's Disease - This invention relates to methods of diagnosing Alzheimer's disease and methods of screening for compounds for the treatment or prevention of Alzheimer's disease. The methods are based upon newly discovered differences in protein phosphatase 2A (PP2A) function and related molecular events in Alzheimer's disease cells compared to control cells. In one embodiment, differences in basal PP2A gene expression in Alzheimer's cells are compared to controls. In another embodiment differences in PP2A protein and enzyme activity are compared in test and control cells. In another embodiment differences in response to substances that inhibit PP2A function are compared. Still another embodiment detects differences in the subcellular distribution of phosphorylated Erk1/2, a substrate of PP2A, in normal and Alzheimer's disease cells. The detection of Alzheimer's disease-specific differences in PP2A function and related events in peripheral tissues provides the basis for highly practical and efficient tests and diagnostic test kits for the early diagnosis of Alzheimer's disease, as well as providing a biochemical basis for identifying therapeutic targets for drug development. | 10-17-2013 |
20130281522 | METHODS FOR ALZHEIMER'S DISEASE TREATMENT AND COGNITIVE ENHANCEMENT - The present invention relates to compositions and methods to modulate α-secretase and/or to improve cognitive ability. The invention further relates the improved/enhanced cognitive ability in diseased individuals, particularly Alzheimer's Disease patients, and treatment thereof through increased sAPP production. Macrocyclic lactones (i.e. bryostatin class and neristatin class) are compounds preferred for use with the present composition. The present invention also provides methods for increasing the generation of non-amyloidogenic soluble APP comprising the activation of protein kinase C (PKC) by administering an effective amount of PKC activator(s). | 10-24-2013 |
20130331427 | METHODS OF STIMULATING CELLULAR GROWTH, SYNAPTIC, REMODELING AND CONSOLIDATION OF LONG-TERM MEMORY - The present invention provides methods of slowing or reversing the loss of memory and learning comprising the steps of contacting an effective amount of a PKC activator with a protein kinase C (PKC) in a subject identified with memory loss slowing or reversing memory loss. The present invention provides methods of stimulating cellular growth, neuronal growth, dendritic growth, dendritic spine formation, dendritic spine density, and the translocation of ELAV to proximal dendrites, and synaptic remodeling. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC. | 12-12-2013 |
20130331444 | TREATMENT OF COGNITIVE DISORDERS ASSOCIATED WITH ABNORMAL DENDRITIC SPINES USING PKC ACTIVATORS - The present disclosure provides methods of treating a cognitive disorder associated with abnormal dendritic spines, such as Fragile X Syndrome, Fragile X Associated Tremor/Ataxia Syndrome, autism, or mental retardation, using PKC activators. | 12-12-2013 |
20140031245 | ALZHEIMER'S DISEASE-SPECIFIC ALTERATIONS OF THE ERK1/ERK2 PHOSPHORYLATION RATIO-ALZHEIMER'S DISEASE-SPECIFIC MOLECULAR BIOMARKERS (ADSMB) - The present invention relates to methods of diagnosing Alzheimer's Disease as well as to methods of confirming the presence or absence of Alzheimer's Disease in a subject. The present invention is also directed to methods of identifying a lead compound useful for the treatment of Alzheimer's Disease by contacting non-Alzheimers cells with an amyloid beta peptide, stimulating the cells with a protein kinase C activator, contacting the cells with a test compound, and determining the value of an Alzheimer's Disease-specific molecular biomarker. The present invention is also directed to methods of diagnosing Alzheimer's Disease in a subject by detecting alterations in the ratio of specific phosphorylated MAP kinase proteins in cells after stimulation with a protein kinase C activator. The Alzheimer's Disease-specific molecular biomarkers disclosed herein are useful for the diagnosis of Alzheimer's Disease, monitoring the progression of Alzheimer's Disease in a subject and in screening methods for the identification of compounds for treating or preventing Alzheimer's Disease. The invention is also directed to kits containing reagents for the detection and diagnosis of the presence or absence of Alzheimer's Disease using the Alzheimer's Disease-specific molecular biomarkers disclosed herein. | 01-30-2014 |
20140038186 | ALZHEIMER'S DISEASE-SPECIFIC ALTERATIONS OF PROTEIN KINASE C EPSILON (PKC-EPSILON) PROTEIN LEVELS - The present invention relates to methods of diagnosing Alzheimer's Disease in a human patient by detecting alterations in the ratio of PKC epsilon protein levels in a human patient compared with PKC epsilon levels in a control subject. The Alzheimer's disease-specific molecular biomarkers disclosed herein are useful for the diagnosis of Alzheimer's disease and for screening methods for the identification of compounds for treating or preventing Alzheimer's disease. The present invention also provides methods for elevating PKC epsilon protein levels comprising the steps of contacting one or more human cells with an amount of a PKC activator effective to elevate PKC epsilon levels compared to an uncontacted human cell. | 02-06-2014 |
20140235496 | STIMULUS-ELICITED GENOMIC PROFILE MARKERS OF A NEURODEGENERATIVE CONDITION - The present disclosure is directed to methods of diagnosing a neurodegenerative condition, such as Alzheimer's disease, comprising contacting a cell sample from a subject with at least one stimulus, such as a protein and/or polysaccharide mixture, a protein kinase C activator, an Aβ oligomer, an agent, and combinations thereof; and detecting the expression of at least one gene in the cell sample. Methods may further comprise comparing the expression of the at least one gene in the cell sample to the expression of the same at least one gene in control cells; and determining whether the subject has the neurodegenerative condition (e.g., Alzheimer's disease), wherein a change in the expression of the at least one gene in the cell sample compared to the expression of the same at least one gene in the control cells indicates the subject has the neurodegenerative condition (e.g., Alzheimer's disease). | 08-21-2014 |
20140248648 | PHRIPHERAL DIAGNOSTIC METHODS FOR SCREENING ALZHEIMER'S DISEASE USING BETA AMYLOID AND INTERCELLULAR COMMUNICATION - The present disclosure relates to a peripheral diagnostic method for screening Alzheimer's disease in patients based on quantitatively measured complexity of skin-sampled fibroblast networks. | 09-04-2014 |
20140249176 | PROTEIN SYNTHESIS REQUIRED FOR LONG-TERM MEMORY IS INDUCED BY PKC ACTIVATION ON DAYS PRECEDING ASSOCIATIVE LEARNING - The present invention provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC. | 09-04-2014 |
20140315990 | PKC ACTIVATORS AND COMBINATIONS THEREOF - The present disclosure relates to PKC activators and combinations thereof. The disclosure further relates to compositions, kits, uses, and methods thereof. | 10-23-2014 |
20140323456 | ESTERS OF DCPLA AND METHODS OF TREATMENT USING THE SAME - The present disclosure relates to esters of 8-[2-(2-pentyl-cyclopropylmethyl)cyclopropyl]-octanoic acid (“DCPLA”). The disclosure further relates to compositions, kits, and methods for treatment using the esters. | 10-30-2014 |
20140329264 | FIBROBLAST GROWTH PATTERNS FOR DIAGNOSIS OF ALZHEIMER'S DISEASE - Methods of diagnosing Alzheimer's disease are provided. At least five methods of diagnostic measurements are presented: Method 1: Integrated score; Method 2: Average aggregate area per number of aggregates; Method 3: Cell migration analysis; Method 4: Fractal analysis; Method 5: Lacunarity Analysis. In certain embodiments, a sample of a subject's skin provides a network of fibroblasts that is imaged and a fractal dimension of the image is calculated. The fractal dimension can be compared to an aged-matched control (non-Alzheimer's) database to determine if the subject has Alzheimer's disease. The network of fibroblasts may be cultured in a matrix, for example in a protein mixture. | 11-06-2014 |