In certain aspects, the present invention provides compositions and methods for decreasing FSH levels in a patient. The patient may, for example, be diagnosed with an FSH-related disorder or desire to delay or inhibit germ cell maturation.
Protein replacement therapy for patients with hemophilia or other inherited protein deficiencies is often complicated by pathogenic antibody responses, including antibodies that neutralize the therapeutic protein or that predispose to potentially life-threatening anaphylactic reactions by formation of IgE. Using murine hemophilia B as a model, we have developed a prophylactic protocol against such responses that is non-invasive and does not include immune suppression or genetic manipulation of the patient's cells. Oral delivery of coagulation factor IX (F. IX) expressed in chloroplasts, bioencapsulated in plant cells, effectively blocked formation of inhibitory antibodies in protein replacement therapy. Inhibitor titers were mostly undetectable and up to 100-fold lower in treated mice when compared to controls. Moreover, this treatment eliminated fatal anaphylactic reactions that occurred after 4 to 6 exposures to intravenous F. IX protein. While only 20-25% of control animals survived after 6-8 F. IX doses, 90-95% of tolerized mice survived 12 injections without signs of allergy or anaphylaxis. This high-responder strain of hemophilia B mice represents the first hemophilic animal model to study anaphylactic reactions. The plant material was effective over a range of oral antigen doses (equivalent to 5-80 .mu.g recombinant F.IX/kg), and controlled inhibitor formation and anaphylaxis long-term, up to 7 months. Oral antigen administration caused a deviant immune response that suppressed formation of IgE and inhibitory antibodies. This cost-effective and efficient approach to oral delivery of protein antigens to the gut should be applicable to several genetic diseases that are prone to pathogenic antibody responses during treatment.
Provided herein is a transgenic animal whose genome comprises a first nucleic acid sequence encoding a fusion polypeptide, wherein the fusion polypeptide comprises a Cre recombinase and a mutated ligand binding domain of human estrogen receptor (CreER), wherein the first nucleic acid is operably linked to a chondrocyte-specific promoter and a second nucleic acid sequence encoding a .beta.-catenin polypeptide, wherein the second nucleic acid sequence comprises one or more loxP sequences. Also provided is a method of modifying a transgenic animal comprising administering tamoxifen to the transgenic animal. Also provided are methods of screening for an agent that reduces or prevents Cre-Negative Control one or more symptoms of osteoarthritis or intervertebral disc disease in a subject. Methods for identifying a subject with or at risk of developing osteoarthritis or intervertebral disc disease are also provided, as well as methods of treating or preventing osteoarthritis or intervertebral disc disease in a subject.
Disclosed are methods and compositions for an animal model of Parkinson's disease. In particular, disclosed is the use of antisense compounds to inhibit the expression of ALDH1A1 in the substantia nigra of an animal brain for the purpose of creating an animal that will displays the symptoms of a human with Parkinson's Disease, including various biochemical, histological, and behavioral characteristics. Also disclosed are methods for using the animal model for Parkinson's disease to test potential therapeutic agents for Parkinson's disease.
The present invention relates to the use of a Severe Combined T-B-Immune Deficient (SCID) mouse engrafted with human immunocompetent cells (Hu-SCID-mouse) as an animal model for the evaluation of the effectiveness of an HIV vaccine. Furthermore, the present invention relates to a method for the evaluation of an HIV vaccine, wherein a Hu-SCID-mouse of the invention is inoculated with the HIV vaccine and thereafter challenged with HI-virus. The invention also relates to novel HIV vaccine compositions, which can be evaluated using the animal model.
The invention relates to the use of fetal tissues to generate a tissue model in a non-human animal. The tissue model comprises target tissues allowed to progress through development in vivo in a non-human host in order to obtain tissues having a mature phenotype that can be used to assess toxicity and/or efficacy of an agent.
An animal model includes a photo-activatable fluorescent protein that can conditionally label the mitochondria throughout the animal or in selective animal cells and tissues, allowing for effective studying of the mitochondria and tracking of mitochondrial dynamics.
This invention relates generally to animal models of anxiety and depression. Specifically, this invention relates to an in vivo high utility, high-throughput model for screening anxiolytic/antidepressant drugs in fowl chicks with stress vulnerability. This new animal model utilizes an inexpensive avian model, measures spontaneous behaviors in very young animals, and is capable of detecting and/or differentiating a compound's anxiolytic and/or antidepressant effects. This new animal model is especially useful in detecting and/or differentiating a compound's anxiolytic and/or antidepressant effects in treatment-resistant subjects. Animal costs are less than 10% of rodent costs and the assay can be run in a high-throughput mode.
The present disclosure describes an animal model of central neuropathic pain relevant to spinal cord injury, as well as methods of using the model to screen for therapeutic agents and to test existing therapies.
The subject invention pertains to a non-human animal model of human cancer, methods of producing a non-human animal model of human cancer, methods of using a non-human animal model to propagate human cancer cells, methods of using a non-human animal model to study cancer, methods of using a non-human animal model to screen potential treatments for a subject's cancer, methods of using a non-human animal model for treating cancer in a subject (providing personalized therapy), methods of using a non-human animal model for identifying a biomarker of cancer treatment; and methods of using a non-human animal model for selecting cancer patients for a clinical trial.
The invention discloses methods for the generation of chimaeric human--non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.
The invention discloses methods for the generation of chimaeric human-non-human antibodies and chimaeric antibody chains, antibodies and antibody chains so produced, and derivatives thereof including fully humanised antibodies; compositions comprising said antibodies, antibody chains and derivatives, as well as cells, non-human mammals and vectors, suitable for use in said methods.
The present invention relates to the field of neurological disorders and more particularly to the field of neuropsychiatric disorders. The invention provides non-human, transgenic animal models for brain disorders such as schizophrenia, bipolar disorders, compulsive disorders, addictive disorders and the like. The animals also have applications in the field of GABA neuro-transmission and other disorders in which GABA-dependent gene regulation has a role.
The present invention relates to novel therapeutic antibodies directed against HER2 (ErbB2), as well as recombinant polyclonal anti-HER2 antibody compositions comprising at least two of said recombinant anti-HER2 antibodies, and use of the antibodies and antibody compositions for treatment of cancer.
Provided are antisense oligonucleotides and other agents that target and modulate IL-17 and/or IL-23 signaling activity in a cell, compositions that comprise the same, and methods of use thereof. Also provided are animal models for identifying agents that modulate 17 and/or IL-23 signaling activity.
This invention provides a method for identifying a small molecule as an antidepressant, a method for identifying a small molecule as an anxiolytic, and a method for identifying a small molecule as able to increase dendritic arborization, decrease expression of an immaturity marker, increase expression of a maturity marker, or enhance artificial cerebrospinal fluid-type long-term potentiation in central nervous system. This invention also provides a transgenic mouse model for SSRI-non-responders.
Methods, compositions, and assays are described which are useful in identifying point mutations, identifying cancer cells, and diagnosing cancer.
Systems and methods are providing for performing high-throughput, programmable, multiplexed assays of biological, chemical or biochemical systems. Preferably, a micro-pallet includes a small flat surface designed for single adherent cells to plate, a cell plating region designed to protect the cells, and shaping designed to enable or improve flow-through operation. The micro-pallet is preferably patterned in a readily identifiable manner and sized to accommodate a single cell to which it is comparable in size. Each cell thus has its own mobile surface. The cell can be transported from place to place and be directed into a system similar to a flow cytometer. Since, since the surface itself may be tagged (e.g., a bar code), multiple cells of different origin and history may be placed into the same experiment allowing multiplexed experiments to be performed.
The present techniques provide for the evaluation of cellular motion and/or cellular properties based on an analysis of motion. In an exemplary technique, images of one or more cells are acquired and motion data for the one or more cells is derived from the images. The motion data is decomposed to generate one or more motion components. The one or more motion components can be used to evaluate cellular properties and/or cellular motion properties.
Disclosed herein are methods for diagnosing or predicting B-cell rejection in a subject. In one example, for assessing transplant rejection, the method includes determining an antigen presenting index by comparing uptake of a donor antigen to uptake of a reference antigen in a biological sample obtained from the subject. In another example, for assessing GVHD, the method includes determining an antigen presenting index by comparing uptake of a recipient antigen to uptake of a reference antigen in a biological sample obtained from the subject.
The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-H' function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-H's bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. Compounds and methods are described herein.
Provided is a method and compositions for of treating an inflammatory or autoimmune disease in a subject comprising blocking the interaction between DR3 and TL1A. The interaction between DR3 and TL1A can be blocked by reducing expression of TL1A. The interaction between DR3 and TL1A can be blocked by administration of anti-DR3 antibodies. The interaction between DR3 and TL1A can be blocked by administration of anti-TL1A antibodies. In the methods of treating inflammatory or autoimmune disease, the inflammatory or autoimmune disease can be an autoimmune disease with a T cell component. In the methods of treating inflammatory or autoimmune disease, the inflammatory or autoimmune disease can be asthma, multiple sclerosis, rheumatoid arthritis, type 1 diabetes, graft versus host disease or inflammatory bowel disease (IBD).
The present invention relates to a transgenic animal mode system based on the development of transgenic mice bearing components of the human immune system. Specifically, the Invention relates to a Flk2 deficient Rag \".gamma.c\" transgenic mouse and the engraftment of said mouse with human hematopoietic stem cells. The present invention further presides methods for increasing the numbers of functionally competent human dendritic cells is and the hematopoietic targets cells that they interact with in said transgenic mouse through the administration of Flk2L. The transgenic animal model system of the invention may be used for testing human vaccine candidates, for screening potential Immune adjuvants and for developing novel therapeutics.
The present invention relates to a transgenic fertilized egg in which expression constructs, excluding human expression constructs, are introduced, including: (a) a nucleotide sequence encoding hypoxia-inducible factor 2.alpha. (HIF-2.alpha.); and (b) a transcription-regulating sequence which is operatively linked to the nucleotide sequence, as well as to a transgenic animal model for arthritis obtained therefrom. A transgenic mouse transformed with a recombinant expression vector of the present invention may be very useful as a therapeutic model for arthritis, which may be used in studies on the cartilage degeneration process. In addition, the transgenic mouse of the present invention may be applied to a method for screening arthritis therapeutics.
Versatile, efficient cell assays which can be prepared with use of nanolithography and can be used to test nanomaterials, pharmaceuticals, toxins, and the like. For example, a method comprising: depositing at least one first composition comprising at least one cell adhesion material on at least one substrate to form a pattern which forms an interior space on the substrate within the pattern, depositing in the interior space on the substrate at least one second composition, different from the first, comprising at least one material adapted to affect or potentially affect cell function. Tip-based deposition and direct-write methods can be used for deposition at nanoscale and sub-cellular resolutions. Nanoscopic and atomic force microscope tips can be used. Multiplexing can be carried out.
Cell culture media, concentrated media and feeds, methods of manufacturing cell culture media and feeds, and methods of culturing cells are provided. One or more small peptides, including dipeptides are added to the cell culture media to provide improved stability and improved conditions for culturing cells.
The present invention relates in a first aspect to a cell model containing chondrocytes whereby said chondrocytes contain a first heterologous nucleic acid sequence operably linked with a mb1 promoter sequence. In another aspect, the present invention relates to a cell model, in particular, to a transgenic animal model whose genome comprises a first heterologous nucleic acid sequence encoding a recombinase and/or restriction enzyme operably linked to a chondrocyte specific promoter, and a second heterologous nucleic acid sequence encoding a target peptide of interest wherein the second nucleic acid sequence further comprises recombination sequences or restriction site for the enzyme encoded by the first heterologous nucleic acid sequence. In addition, methods for screening foreign agent or methods for testing the efficacy and/or efficiency of an agent are provided. Said agents are tested for their ability to reduce or prevent or to allow treatment of diseases, disorders or conditions involving arthropathy and/or chondropathy, in particular, spinal malfunction.
The present invention relates to animal model systems comprising a chimera between an avian embryo and a mammalian organism. Specifically, chimeric model systems comprising normal, diseased or genetically transformed mammalian cells and tissues transplanted into avian embryos, and uses thereof for in vivo testing of drugs and therapeutic modalities are disclosed.
The invention provides methods of label-free detection of changes in cell populations and mixed cell populations.
The present invention provides a method for diagnosing and detecting diseases associated with colon. The present invention provides one or more proteins or fragments thereof, peptides or nucleic acid molecules differentially expressed in colon diseases (CCAT) and antibodies binds to CCAT. The present invention provides that CCAT is used as targets for screening agents that modulates the CCAT activities. Further the present invention provides methods for treating diseases associated with colon.
Serum-containing and serum-free immunoglobulin inhibitors of steroid hormone responsive cancer cell growth are disclosed, along with their methods of production. Also disclosed are defined cell culture media, assay protocols, and model systems using the inhibitors for demonstrating steroid hormone growth effects of natural and synthetic substances, and other cell culture applications. The disclosed compositions and methods employing the immunoglobulin inhibitors are also useful as reagents in research, and for the diagnosis, treatment and prevention of mucus epithelial cancers.
Disclosed herein is a non-human animal model of protein aggregation cardiomyopathy. Also disclosed are compo-sitions and methods of treating or preventing a condition in a subject caused or exacerbated by reductive stress. Also disclosed are compositions and methods of predicting, detecting, or monitoring reductive stress in a subject.
An antisense compound for use in treating myotonic dystrophy DM1 or DM2, a method of enhancing antisense targeting to heart and quadricep muscles, and a method for treating DM1 or DM2 in a mammalian subject are disclosed. The oligonucleotide has 8-30 bases, with at least 8 contiguous bases being complementary to the polyCUG or polyCCUG repeats in the 3'UTR region of dystrophia myotonica protein kinase (DMPK) mRNA in DM1 or DM2, respectively. Conjugated to the oligonucleotide is a cell-penetrating peptide having the sequence (RXRR(B/X)R).sub.2XB, where R is arginine; B is .beta.-alanine; and each X is --C(O)--(CH.sub.2).sub.n--NH--, where n is 4-6. The antisense compound is effective to selectively block the sequestration of muscleblind-like 1 protein (MBNL1) and/or CUGBP, in heart and quadricep muscle in a myotonic dystrophy animal model.
Provided are a diagnosis marker, a diagnosis method, and a therapeutic agent suitable for diagnosing and treating amyotrophic lateral sclerosis (ALS). Also provided are an animal model and a cell model suitable for developing a therapeutic agent and a treatment method for ALS. The diagnosis method for ALS includes: an isolation step in which a nucleic acid is isolated from a specimen taken from a subject; a detection step in which bases expressed in a human chromosome 10 optineurin (OPTN) gene region are detected from the isolated nucleic acid; and a determination step in which it is determined whether or not the detected bases are mutated.
The present invention relates to method of identifying whether or not an individual has Parkinson's disease (PD). In particular, the invention relates to a method for identifying whether or not an individual has PD in the pre-symptomatic phase of the disease or to distinguishing PD from another neurological disorder. The method of the invention comprises measuring the amount of soluble .alpha.-synuclein oligomers in a cerebrospinal fluid sample taken from an individual. The method optionally also comprises measuring the total amount of .alpha.-synuclein in the CSF sample, calculating the ratio of the amount of .alpha.-synuclein oligomers to the total amount of .alpha.-synuclein, and thereby determining whether or not the individual has PD. The method of the invention can be used in clinical trials to measure the effect of drugs in both PD animal models and human PD patients.
The invention relates to compounds having either agonist or antagonist activities for the neurotrophins NGF and BDNF and represented by monomeric or dimeric substituted dipeptides that are analogs of the exposed portions of loop 1 or loop 4 regions of these neurotrophins near or at a beta-turn of the respective loop. N-acylated substituents of these dipeptides are biostereoisomers of the amino acid residues preceding these dipeptide sequences in the neurotrophin primary structure. The dimeric structure is produced advantageously by using hexamethylenediamine to which dipeptides are attached via their carboxyl groups. The claimed compounds displayed neuroprotective and differentiation-inducing activities in cellular models and enhanced the amount of phosphorylated tyrosine kinase A and the heat shock proteins Hsp32 and Hsp70 in the concentration range of 10.sup.-9 to 10.sup.-5 M. They also displayed neuroprotective, anti-parkinsonian, anti-stroke, anti-ischemic, anti-depressant and anti-amnestic activities in animal models and were active in experimental models of Alzheimer's disease. These in vivo effects of the claimed compounds are displayed in the dose range of 0.01 to 10 mg/kg when administered intraperitoneally.
A drug composition for treating chronic liver diseases, consists of: Astragalus Astragalosides and Glycyrrhiza Acid by weight ratio of 3.about.6:1. By testing and validating with classic animal model, the results confirmed that the drug composition of the present invention can significantly reduce the collagen content of rat liver, and reduce liver fibrosis and liver injury, wherein the effect is better than the effect of each component alone. The drug composition of the two components or ingredients can improve the anti-hepatic fibrosis, effectively prevent liver fibrosis and promote the development of liver fibrosis reversal, and thus can be used for the treatment and prevention of various chronic hepatitis, liver fibrosis, cirrhosis and other illnesses.
A first embodiment is a dry eyed animal model method by peri or post-menopausal estrogen-treated rats have decreased tear production wherein the menopausal rat may be produced by ovariectomy Chronic estrogen exposure can decrease tear production in rats receiving a nine month course of estrogen versus placebo treatment after ovariectomy. The aged, chronically estrogen-treated female rats can provide a suitable model for the study of KCS and its treatment.
The presently described subject matter is based on the finding that inhibition of eotaxin-2 by polyclonal or monoclonal antibodies, has a significant protective effect in animal models of inflammatory diseases such as rheumatoid arthritis, experimental autoimmune encephalomyelitis (EAE), colitis, diabetes, and atherosclerosis. Thus, provided are pharmaceutical compositions including specific anti-eotaxin 2 antibodies for use alone or in combination with other therapeutic agents in the treatment of inflammatory, autoimmune and cardiovascular diseases. Also provided are specific anti-eotaxin-2 monoclonal antibodies, and methods of treatment utilizing such antibodies.
Disclosed are compositions and methods for treating Guillain-Barre syndrome (GBS) in a subject that involves neutralizing specific pathogenic anti-glycolipid antibodies in the circulation of the subject. This can involve administering to the subject a molecular mimic of a ganglioside that serves as a specific competitive inhibitor for anti-ganglioside antibodies in the circulation. Also disclosed is an animal model of GBS having anti-ganglioside antibodies in the circulation.
The present invention relates to the generation of vascularized human heart tissue from human primordial Islet1-positive (ISL1+) progenitors, and more particularly the generation of vascularized human heart tissue from human primordial Islet1+ cardiovascular stem cells which are positive for markers ISL1+/NKX2.5-/KDR-. One aspect of the invention relates to isolation of human ISL1+ primordial cells from human pluripotent cells, such as human ES cells or other human pluripotent stem cell sources, wherein the human ISL1+ primordial cells can differentiate into three different lineages; cardiomyocyte lineages, endothelial lineages and smooth muscle lineages. Another aspect relates to use and implantation of the human primordial ISL1+ progenitors into an animal model to generate human vascularized heart tissue, and more particularly, the production of an in vivo humanized model of vascular disease. One embodiment relates to the use of an in vivo humanized model of vascular disease as an assay, for example to assess drug toxicity and/or identify agents which increase and decrease coronary blood flow to the human vascularized heart tissue. Another embodiment relates to the therapeutic use of human primordial ISL1+ progenitors, for example, in one embodiment the invention provides methods for the treatment cardiovascular disorders and/or congenital heart disease in a subject comprising transplanting into subjects vascularized human heart tissue generated from human ISL1+ progenitors.
The present disclosure relates to methods for dedifferentiating and transdifferentiating recipient cells, preferably human somatic cells. These methods minimize the risk of undesired genome sequence alteration. These methods employ reprogramming factors, which may be used alone or in certain combinations with one another. These methods have application especially in the context of cell-based therapies, establishment of cell lines, and the production of genetically modified cells.
In this application is described the complete genomic sequence of avian parmyxovirus type 2, strains Yucaipa, England, Kenya and Bangor. The sequences are useful for production of recombinant infective virus, a virus vector, for vaccine development and for therapeutic compositions.
The present invention is a method of detecting abnormality of liver in a subject, comprising: (i) measuring expression level of genes consisting of survival and proliferation genes, oncogenes, tumor suppressor genes, one carbon metabolism genes and glycogen storage disease related genes, and (ii) determining expression level of genes are indicative of abnormality of liver function when expression level of the survival and proliferation genes and the oncogenes in sample are higher than in wild-type; and expression level of the tumor suppressor genes, the one carbon metabolism genes, and the glycogen storage disease related genes in sample is lower than in wild-type.
The present invention relates to use of the GPR30 gene for diagnosis and treatment of cardiovascular disorders, especially cardiomyopathy. The present invention also relates to a GPR30 deficient animal model, more specifically to a mouse in which the GPR30 gene is disrupted and which exhibits a cardiomyopathy, a tissue and a cell of the mouse and a process of producing the same. The present invention further relates to use of said knockout mouse as a model of cardiovascular diseases, especially cardiomyopathy, and a method of screening a compound useful for the prevention and/or treatment of cardiovascular diseases, especially cardiomyopathy, using the knockout mouse.
In the present invention cells are placed in a multiwell plate and grown. When the assay is to be performed, one uses gravity to wash away any unbound ligands rather than vacuum or centrifugation. The cells are then examined to detect the bound ligand. To perform the washing step(s) the plate is placed into a carrier plate having open wells in register with the wells of the filter plate or one may use a wicking device or an underdrain attached to the bottom of the filter plate. Sufficient wash liquid is added to allow for filtration by the effect of gravity to occur. Cells are retained within the wells at a rate of 4 times that of other rapid methods.
A nucleic acid construct comprising a genetic engineered heterogeneous nuclear ribonucleoprotein (hnRNP) A1 gene is provided. A transgenic mouse in which the expression of hnRNP A1 gene has been disrupted is also provided. The mouse is useful for studying the role of hnRNP A1 gene in normal and disease states of a neurodegenerative disease or a cancer for developing therapies to treat any of these diseases. Therefore, a method of screening a compound for potential use in prevention and/or treatment of neurodegenerative disease or cancer is further provided.
Provided is a transgenic animal model for testing immunogenicity and protective efficacy of human vaccines and the method for generating such a multitransgenic animal. Also disclosed are methods for screening compositions for human vaccine development. More specifically, a mouse model capable of expressing human leukocyte antigen DR4, and human costimulatory molecules (CD80) upon infusion of human HLA-matched hematopoietic stem cells, which can develop into a functional man immune system is provided.
The present invention relates to molecules, particularly polypeptides, more particularly immunoglobulins (e.g., antibodies), comprising a variant Fc region, wherein said variant Fc region comprises at least one amino acid modification relative to a wild-type Fc region, which variant Fc region binds Fc.gamma.RIIIA and/or Fc.gamma.RIIA with a greater affinity, relative to a comparable molecule comprising the wild-type Fc region. The molecules of the invention are particularly useful in preventing, treating, or ameliorating one or more symptoms associated with a disease, disorder, or infection. The molecules of the invention are particularly useful for the treatment or prevention of a disease or disorder where an enhanced efficacy of effector cell function (e.g., ADCC) mediated by Fc.gamma.R is desired, e.g., cancer, infectious disease, and in enhancing the therapeutic efficacy of therapeutic antibodies the effect of which is mediated by ADCC.
Techniques for combining electrochemical measurements of the brain or spinal cord by voltammetry together with a scan such as magnetic resonance imaging or spectroscopy, e.g. fMRI. The techniques use particular microelectrodes, such as carbon fibre or carbon paste electrodes which do not affect the magnetic resonance measurements. The techniques allow the correlation of voltammetry and magnetic resonance measurements which in turn allows one to be used for substitution of the other in appropriate circumstances and also allows the translation of results in animal models to the human model.
A label-free cell assay method including: culturing rigid cells in a buffer, the rigid cells having a diameter of about 3 to about 7 micrometers; depositing the rigid cells on the surface of a sensor system; and detecting the rigid cells with the sensor when exposed to two or more wavelengths of light having two or more penetration depths, as defined herein. Also disclosed are assay methods for contacting the rigid cells with a substance and determining the response of the contacted rigid cells to the substance, such as a drug candidate or modulator compound, as defined herein.
A method for dedifferentiating adipose tissue stromal cells (ATSC) is provided. When the ATSC is treated under hypoxia condition and with a 4-(3,4-Dihydroxy-phenyl)-derivative (DHP-derivative), expression of stemness genes, cellular growth-related genes and cellular mobility-related genes increase, and expression of histone and DNA methylation-related genes decrease so that cell proliferation increases and pluripotency for differentiating into adipocytes, osteocytes, myocytes, beta cells and cartilage cells is acquired. When the dedifferentiated ATSC is implanted into animal model with spinal cord injury and diabetic animal model,effects of nerve regeneration and increased blood surge level are confirmed. As a result, the method for dedifferentiating the ATSC can be effectively used in the stem cell research, tissue regeneration and development of cytotherapeutic medicines.
The disclosure provides a long-circulating, micellar hybrid nanoparticles (MHN) that contain MN, QD, and the anti-cancer drug doxorubicin (DOX) within a single polyethylene glycol (PEG)-phospholipid micelle and provide the first examples of simultaneous targeted drug delivery and dual-mode NIR-fluorescent and MR imaging of diseased tissue in vitro and in vivo.
An objective of the present invention is to provide non-human animal models of cancer pathology, which mimic the hierarchical organization, cancer progression process, or biological property of human cancer tissues, and uses thereof. To achieve the objective described above, first, the present inventors transplanted cells of NOG-established cancer lines into NOG mice and morphologically observed the resulting tissue organization. As a result, the non-human animal models were demonstrated to exhibit pathologies (the hierarchical organization, cancer progression process, or biological properties of the cancer cells) similar to that of human cancer. Specifically, the present inventors succeeded in preparing non-human animal models exhibiting pathologies more similar to a human cancer, and cell culture systems using NOG-established cancer cell lines where the in vitro cell morphology is more similar to that of human cancer.
Treatment of lymphangioleiomyomatosis with the MEK1/2 inhibitor CI-1040 delayed the development of primary tumors and blocked the estrogen-induced lung metastases in treated animals. Such treatment also reduced the number of circulating ELT3 cells and decreased their lung colonization after intravenous injection.
A method of creating a biotechnological product and an efficient and stable bio-luminescence vector which could be used for tracking Gram-negative bacteria when distributing inside animal body are provided. Through conjugation, this auto-luminescence vector can be easily transmitted from bacteria to bacteria among Gram-negative bacteria, and may facilitate bacteria to be luminescence-labeled for subsequently analyzing the dynamic change of bio-luminescent bacteria within animal body in vivo. This system includes a lacZ promoter-driven IuxABCDE, a high copy number of ColE1 replicon, and a high plasmid stability of the conjugative and broad host-ranged plasmid pSE34 from Salmonella enterica serovar Enteritidis Sal550. This resulting construct pSE-Lux1 can not only conjugatively transmit among bacteria with broad host range, but also stably maintain in bacteria to efficiently express the bio-luminescent IuxABCDE without supplementing the subtract for luciferases and the antibiotics for plasmid selection.
Compositions and methods for measuring adaptive immune receptor (T cell receptor and immunoglobulin) diversity are described, and find uses for assessing immunocompetence and other purposes. Means are provided for assessing the effects of diseases or conditions that compromise the immune system and of therapies aimed to reconstitute it. Lymphoid (B- and T-cell) adaptive immune receptor diversity is quantified by calculating the number of uniquely rearranged, CDR3-containing immunoglobulin (Ig) or T-cell receptor (TCR) variable region-encoding genes from sample cells such as blood cells.
The present invention relates generally to a method for the treatment and prophylaxis of inflammatory conditions. The present invention is predicated in part on the identification of cells of the monocyte/macrophage lineage being critical for inflammation and, in particular, chronic inflammation. In accordance with the present invention, it is proposed that the reduction in levels of monocyte/macrophage-type cells and/or a reduction in the production of inflammatory and pro-inflammatory mediators by these cells, especially locally, is effective in reducing inflammatory conditions. The present invention further provides animal models useful for screening for reducing levels of monocyte/macrophage-type cells and/or reducing the production of inflammatory and pro-inflammatory mediators of these cells.
The present invention relates to cryopreserved cell cultures, methods for cryopreserving cells and methods for conducting cellular assays on such cells. A cryopreserved cell culture of the invention comprises a container having at least a surface which is coated with poly-lysine and frozen cells supported on the surface.
The invention provides methods of culturing mammalian taste cells, including taste receptor cells. Cells are maintained for a duration of up to three months and longer while maintaining molecular and functional characteristics of mature taste cells. The cells are cultured on coated cell culture vessels and, from first replacement of medium onwards, the medium is replaced in intervals of at least 5 days. The invention further provides isolation and culturing methods of taste cells wherein the time that the cells are exposed to isolation solution and proteolytic enzymes is minimized and the cells are cultured in coated culture vessels with the medium replaced in intervals of at least 5 days from first replacement onwards. The invention further provides cultured taste cells, transfection and assay methods, and taste cell assay buffers with an osmolarity of about 300-320 and pH of about 7.0-7.3.
A system and method for GPCR signaling pathway analysis and elucidation using a biosensor, a live-cell, and a pathway active compound, as defined herein.
The invention relates to methods of obtaining compositions for generating multipotent hematopoietic stem progenitor cells comprising expansion of hematopoietic stem cells in the presence of HDACI and IDM. Methods of obtaining compositions enriched in hematopoietic megakaryocyte progenitor cells are also provided. Compositions enriched for stem cells and populations of cells obtained therefrom are also provided by the invention.
This application pertains to methods for the whole-cell analysis of gram-positive bacteria. The methods are capable of making a determination of whether or not a sample (e.g. a clinical sample) comprises one or more select gram-positive bacteria as well as, for example, whether or not none, some or all of said select gram-positive bacteria in said sample, or possibly other bacteria in said sample, possess a select trait or traits of interest. In some embodiments, the methods can be used to determine methicillin-resistant (the select trait) staphylococcus aureus (the select gram-positive bacteria), coagulase-negative staphylococci (another select gram-positive bacteria) and/or methicillin-sensitive staphylococcus aureus (MSSA) in said sample. The whole-cell analysis can be performed, for example, by in-situ hybridization (ISH), fluorescence in-situ hybridization (FISH), immunocytochemistry (ICC), or any combination of two or more of the foregoing.
Disclosed are new methods for pancreatic .beta.-cell regeneration and the methods for identifying adult pancreatic endocrine stem cells and the methods for identifying the existence of differentiation processes from adult pancreatic endocrine stem cells toward pancreatic .beta.-cell fate and a new animal model for pancreatic .beta.-cell regeneration. The present invention can be utilized in screening and development of new medicines and therapy protocols for diabetes.
The present invention provides methods of screening an agent for activity using teleosts. Methods of screening an agent for angiogenesis activity, toxic activity and an effect cell death activity in teleosts are provided. Methods of screening an agent for an activity in the brain or central nervous system in zebrafish are provided. The invention further provides high throughput methods of screening agents in multi-well plates.
The present invention relates to methods of increasing tyrosinase synthesis, expression, or activity in a cell comprising administering to the cell at least one non polar grape seed extract, for example, a nonpolar grape seed extract obtained using hexane as an extraction solvent. The nonpolar grape seed extract may be obtained by any extraction process including solvent sequential fractionation and supercritical fluid extraction.
The present invention relates to the use of vaccines with adjuvants comprising cationic liposomes where neutral lipids has been incorporated into the liposomes to change the gel-liquid phase transition and thereby modifying the IgG sub-type response and enhancing the CD8 response of the liposomal adjuvant. This technology can be used to increase the production of IgG2 antibodies. This sub-type of anti-bodies (IgG2 in mice corresponding to IgG3 in humans) have been shown to selectively engage Fc activatory receptors on the surface of innate immune cells leading to enhanced proinflammatory responses and thereby a more efficient immune response with higher levels of protection in animal models of e.g. malaria and Chlamydia. The use of adjuvants which selectively give rise to higher levels of IgG2 antibodies will improve the effect of vaccines e.g. against intracellular infections. Furthermore the technology can be used to induce a CD8 response which has been reported to improve the effect of vaccines against e.g. HPV, HIV, influenza and cancer.
An animal model has been developed where the animals can survive myocardial infarctions caused by diet-induced coronary atherosclerosis, and live with chronic heart failure. This animal model is a result of reduced activity of scavenger receptor class BI (SR-BI) and ApoE and the inducible activity of the Mx1-Cre gene. In a preferred embodiment, the model is a result of crossbreeding two transgenic mouse lines: a knockout of SR-BI (SRBI.sup.-/-) and an impaired ApoE expressor (Apoe.sup.h/h) to generate a strain referred to as Apoe.sup.h/hSRB1.sup.-/- mice, which is then crossbred to mice that carry the inducible Mx1-Cre transgene. The Apoe.sup.h/hSRB1.sup.-/- mouse model is genetically modified, enabling the offspring to rapidly and permanently lower their high blood cholesterol levels caused by dietary challenge. The ability to rapidly and permanently lower blood cholesterol levels in these mice stops and may cause the regression of occlusive coronary atherosclerosis restoring blood flow to the heart, allowing the mice to survive from myocardial infarction and live with chronic heart failure.
This disclosure provides an intracellular fragment of natriuretic peptide receptor A (NPRA), referred to herein as soluble natriuretic peptide receptor-related fragment (sNRF). It is shown herein that sNRF causes NP resistance. Based on these observations, methods of treating a cardiovascular disorder by inhibiting the activity of sNRF are disclosed. Assays are provided that use sNRF to screen agents for their ability to increase the biological activity of an NPR, for example agents that increase the sensitivity of NPR for NPs (such as atrial natriuretic peptide, ANP), or that decrease growth factor deleterious effects, or combinations thereof. Also provided are agents identified using the disclosed assays, and methods of using the agents, for example to treat or diagnose a cardiovascular disorder, such as heart failure.
The invention relates to compositions for use in animal models of neurodegenerative disease and methods therefor. More particularly, the invention relates to the use of neurotoxic sterol glycosides or neurotoxic glycolipids, or combinations thereof, in animal models of neurodegenerative disease. Neurotoxicity-modulating chromenols can also be used in these animal models in combination with the neurotoxic sterol glycosides or neurotoxic glycolipids, or combinations thereof.
The invention relates to the surprising find that low density lipoprotein receptor-deficient mice (LDLr-/-) mice when fed with high energy diets produce controllable and consistent diabetic complications, especially renal damage, similar to the human pathophysiology and biological response. The invention thus comprises a method for discovering a preventive or therapeutic regimen for the prevention or treatment of diabetic micro- or macrovascular complications, comprising the steps of: a. feeding LDLr-/- mice, which have not been treated with streptozotocin, with a high energy diet; b. before, during and/or after this diet treating the mice with the preventive or therapeutic regimen; c. checking whether any change in the micro- or macrovascular system of the animal occurs. Specifically in such a method renal damage is assessed. Also use of said mice fed with a high energy diet for studying the diabetic micro- and macrovascular complications is part of the invention.
The present invention relates to a non human animal model for increased retinal vascular permeability wherein said increased retinal vascular permeability is induced by inhibiting in Muller cells of said animal the expression of a gene encoding for Dp71 or a dystrophin associated protein (DAP). Furthermore, the present invention relates to methods and compositions for the treatment of a disease associated with an increased retinal vascular permeability in a subject in need thereof.
The present invention provides a non-human animal model of myocardial infarction, which can be created by a less invasive method, shows an extremely low mortality during and after surgical induction of myocardial infarction, ensures the blood reflow after necrosis of cardiac muscles caused by blocking blood flow, and therefore, is usable in topical therapy for myocardial infarction and studies on regenerative medicine. The present invention also provides a method for creating the non-human animal model comprising administering a temporary embolic agent to a branch blood vessel of a heart coronary artery to block blood flow in the branch blood vessel; and after a definite period of time after said vascular branch blockage, administering a temporary embolic agent to the target coronary artery which is intended to induce myocardial infarction to block blood flow in the target coronary artery.
The present invention provides a non-human mammalian animal model for type 2 diabetes, which spontaneously develops a pathological condition similar to human type 2 diabetes of a non-obese type popular for the Japanese people. The non-human mammalian animal model for type 2 diabetes according to the present invention is deficient in a function of Cdkal1 gene on the chromosome of the .beta. cell of the pancreas.
The present invention relates to the novel benzofuran derivatives, the preparation thereof and the composition comprising the same. The benzofuran derivatives of the present invention showed potent inhibiting activity of beta-amyloid aggregation and cell cytotoxicity resulting in stimulating the proliferation of neuronal cells as well as recovering activity of memory learning injury caused by neuronal cell injury using transformed animal modelwith beta-amyloid precursor gene, therefore the compounds can be useful in treating or preventing cognitive function disorder.
The present invention relates to novel benzotriazole derivatives, efficacious in animal models of CNS disorders and, as such, valuable candidates for the prevention or treatment of CNS (Central Nervous System) diseases or disorders. In other aspects the invention relates to pharmaceutical compositions comprising the benzotriazole derivatives of the invention and to the use of these compounds for therapeutic applications.
Provided herein is a method for detection of migratory and invasive cancer cells based on a number of marker nucleic acids differentially expressed in migratory/invasive cancer cells relative to nonmigratory/noninvasive cancer cells. Also disclosed are antisense oligonucleotides of the marker nucleic acids and uses thereof for suppressing cancer cell migration and invasion.
Oral formulations of G-2MePE including microemulsions, coarse emulsions, liquid crystals, tablets and encapsulated forms of G-2MePE have improved bioavailability than conventional aqueous formulations. In particular, microparticles, nanoparticles and microemulsions can exhibit great neuroprotective effects after oral administration. In a microemulsion formulation, G-2MePE can nearly completely inhibit cerebral infarction in an animal model of stroke even after the stroke had been initiated. Thus, improved oral formulations can be desirably used to treat a variety of neurodegenerative conditions with improved convenience and improved efficacy.
The present invention provides an assay for detection of oxidized glutathione (GSSG).
Provided herein is an animal having a persistent hypercoagulable state by implanting a cell, for example a tumor cell, in which the gene of human tissue factor is implanted to an experimental animal such as a mouse and then growing the cell, thereby persistently supplying human tissue factor to the experimental animal. Thisanimal model is useful for research and development of therapeutic agents for diseases having a persistent hypercoagulable state. Also provided are preventive or therapeutic agents for diseases having a persistent hypercoagulable state, a hypercoagulable state resulting from infections, venous thrombosis, arterial thrombosis, and diseases resulting from the hypertrophy of vascular media, the agent comprising an antibody against human tissue factor (human TF) as an active ingredient.
The present invention relates to novel quinolinone derivatives (I), efficacious in animal models of CNS disorders and, as such, valuable candidates for the prevention or treatment of CNS (Central Nervous System) diseases or disorders. In other aspects the invention relates to pharmaceutical compositions comprising the quinolinone derivatives of the invention and to the use of these compounds for therapeutic applications.
The invention encompasses a recombinant bacterium capable of eliciting an immune response against Streptococcus pneumoniae, a vaccine comprising the bacterium, and methods of using the bacterium.
The present invention is directed to small interfering RNA molecules (siRNA) targeted against nucleic acid sequence that encodes huntingtin or ataxin-1, and methods of using these siRNA molecules.
Use of an animal model of spontaneous metastasis bearing a tumor derived from a cell line RM72 (Accession No. NITE BP-1110) allows simultaneous evaluation of tumorigenesis and spontaneous cancer metastasis. Use of a screening method using the animal model of spontaneous metastasis allows the obtainment of a substance having an anticancer activity and/or an anti-metastatic activity. Use of another screening method for selecting a substance that increases the expression of RECK in a cancer cell allows the obtainment of a substance that can serve as an active ingredient in an anticancer drug.
Disclosed are methods for identifying individuals suffering from a CNS disorder (including Alzheimer's Disease, ALS, behavioral disorders, and the like) that could be treated with a CNS drug with greater therapeutic efficacy and lower side effects and the compounds useful for such treatment. Also disclosed are methods for predicting the efficacy of a drug candidate for the treatment of a CNS disorder. The technology is also applicable to drug discovery for evaluation in animal models of neurodegenerative diseases.
The invention relates to databases of T cell epitopes, especially helper T cell epitopes, for rapid interrogation of protein sequences for the presence of T cell epitopes. The invention includes full or partial databases and data structures of T cell epitopes including epitopes identified especially by ex vivo T cell assays with test peptides and includes T cell epitopes identified by extrapolation of data from test peptides. The present invention also includes high throughput methods for determining the T cell epitope activity of peptides for subsequent inclusion in databases and data structures including methods where subsets of T cell especially regulatory T cells are removed or inhibited from T cell assays in order to maximize the sensitivity of detection of T cell epitope activity.
The present invention provides transgenic, large non-human animal models of diseases and conditions, as well as methods of making and using such animal models in the identification and characterization of therapies for the diseases and conditions.
The present invention relates to a non-human transgenic animal whose genome comprises a stably integrated transgenic nucleotide sequence encoding Lysine-specific Demethylase 1 (LSD1) operably linked to a promoter. The invention further concerns methods for generating the non-human animal and its use as a cancer model.
Methods useful for effecting prophylaxis or treatment of amyloidosis, including AA Amyloidosis and AL amyloidosis, by administering peptides comprising neoepitopes, such as AA fragments from a C-terminal region of AA, and antibodies specific for neoepitopes of aggregated amyloid proteins, for example, antibodies specific for the C-terminal region of AA fibrils. Antibodies for inhibition of formation and/or increasing clearance of amyloid deposits in a patient thus effecting prophylaxis or treating amyloid disease.
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.
This invention relates to the use of ADNF III polypeptides in the treatment of mental diseases or disorders, including schizophrenia. Embodiments of the invention provide methods for treating mental disorders, including schizophrenia, in a subject by administering a NAP, an 8-amino-acid peptide derived from Activity Dependent Neurotrophic Factor (ADNF III), in an amount sufficient to reduce or eliminate symptoms. The ADNF III polypeptides include polypeptides, analogs, subsequences, and D-amino acid versions (either wholly D-amino acid peptides or mixed D- and L-amino acid peptides), and combinations thereof which contain the active core sites and provide neuroprotective and anti-schizophrenic functions.
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