Abstract: There are provided vanadium compositions for use in the treatment of hypertension, obesity and diabetes, in particular improved oral compositions comprising oxovanadium (IV) chelates of monoprotic, bidentate oxygen, oxygen and oxygen, nitrogen coordinating ligands especially kojic acid, maltol and ethyl maltol.

Abstract: Plasmodium is shown to have an inhibition sensitive sphingomyelin synthase activity necessary for ring and early trophozoite maturation. Inhibitors can therefore be used to treat malarial infection which can differentiate between inhibition sensitive Plasmodium sphingomyelin synthase and mammalian synthase. Inhibitors of interest include 1-phenyl-3-morpholino-2-acylated-aminopropanol-1.

Abstract: A mutated form of human P-glycoprotein (mdr1.DELTA.F335/336) is identified, consisting of a single or double codon deletion (Phe335 and/or 336) in the TM region of P-gp. The mdr1.DELTA.F335/336 encoded P-glycoprotein is characterized by an altered spectrum of cross-reactivity to cytotoxins and resistance to modulation by cyclosporins, with a loss of the capacity to bind or transport cyclosporine, PSC 833, and vinblastine. These data demonstrate that cyclosporine, PSC 833, vinblastine, Rh-123, and dactinomycin share at least one binding domain on, which plays an important role in the interaction of P-gp with modulators. The nucleic acid compositions encoding mdr1.DELTA.F335/336 find use in gene therapy to transfer modulator-resistant multidrug resistance into transfected cells; to produce the encoded protein for functional mapping studies, and in studying associated physiological pathways.

Abstract: This invention encompasses a method for inhibiting vascular cellular activity of cells associated with vascular lesion formation in mammals which involves administering an effective dosage of at least one antisense sequence to at least one gene expressing a cyclin or a cyclin dependent kinase which inhibits the expression of the gene. More particularly, the invention involves administering antisense sequences which inhibit the expression of cyclin A, B1, B2, C, D1, D2, D3, E or cyclin X (p46) cyclin X and cyclin dependent kinase cdc2, cdk2, cdk4 or cdk5. It is preferable to use two antisense sequences each from a different cyclin or cyclin dependent kinase. The cyclin or cyclin kinase depending kinase dosage is preferable administered in combination with proliferating cell nuclear antigen (PCNA). Antisense methods and compositions direct to inhibiting the expression of growth factors such as TGF-.beta..sub.1, TGF, bFGF, PDGF are also contemplated by the present invention.

Abstract: A transgenic, non-human animal is provided which overexpresses a gene responsible for the accumulation of monocytes and leukocytes. The animal is preferably a mammal and more preferably a mouse, rat or guinea pig. The transgenic animal is created by artificially inserting a transgene into a fertilized egg of the animal which egg is then inserted within a pseudo pregnant female where it is allowed to grow. The transgene preferably expresses human Monocyte Chemoattractant Protein-1 (MCP-1) and more preferably overexpresses MCP-1 in type II pulmonary epithelial cells. The invention includes DNA constructs and vectors containing the constructs with a particularly preferred vector being SPC-MCP-1. The plasmid SPC-MCP-1 includes a promoter operatively linked to a human MCP-1 coding sequence. The transgenic animal provides a useful animal model for testing drugs for their efficacy with respect to the treatment of diseases and conditions which result in an acceptable high accumulation of monocytes and/or lymphocytes.

Abstract: TSG101 is a tumor susceptibility gene whose homozygous functional knock out in fibroblasts leads to transformation and the ability of these cells to form metastatic tumors in nude mice. The cellular transformation that results from inactivation of TSG101 is reversible by restoration of TSG101 function. Decreased expression of TSG101 is associated with the occurrence of certain human cancers, including breast carcinomas. The TSG101 nucleic acid compositions find use in identifying homologous or related proteins and the DNA sequences encoding such proteins; in producing compositions that modulate the expression or function of the protein; and in studying associated physiological pathways. In addition, modulation of the gene activity in vivo is used for prophylactic and therapeutic purposes, such as treatment of cancer, identification of cell type based on expression, and the like.

Abstract: Neointimal cells are shown to express high levels of an anti-apoptotic gene, bcl-x, while the medial cells of the vessel itself express only low levels. The difference in gene expression exploited to provide for selective deletion of the neointimal cells. Apoptosis is induced by administering anti-sense bcl-x oligonucleotides to the affected vessel. Apoptosis is desirable as a treatment because it does not induce inflammation, further tissue injury or reactive hyperplasia. A significant reduction in lesion size is seen after treatment.

Abstract: The gene responsible for the autosomal recessive mouse obesity mutation tub was identified by positional cloning. The homologous human gene is also provided. The genes are used to produce tubby protein; in screening for compositions that modulate the expression or function of the tubby protein; and in studying associated physiological pathways. The DNA is further used as a diagnostic for genetic predisposition to obesity, retinal degeneration or cochlear degeneration. The mutation responsible for the tub phenotype is a G to T transversion that abolishes a donor splice site in the 3' coding region and results in a larger transcript containing the unspliced intron. A second, prematurely truncated transcript arises from the introduction of a premature polyadenylation site in the unspliced intron.

Abstract: The gene responsible for the autosomal recessive mouse obesity mutation tub was identified by positional cloning. The homologous human gene is also provided. The genes are used to produce tubby protein; in screening for compositions that modulate the expression or function of the tubby protein; and in studying associated physiological pathways. The DNA is further used as a diagnostic for genetic predisposition to obesity, retinal degeneration or cochlear degeneration. The mutation responsible for the tub phenotype is a G to T transversion that abolishes a donor splice site in the 3' coding region and results in a larger transcript containing the unspliced intron. A second, prematurely truncated transcript arises from the introduction of a premature polyadenylation site in the unspliced intron.

Abstract: A mutation in the human sonic hedgehog gene is associated with tumorigenesis. A variety of human tumors, including basal cell carcinomas, breast carcinomas, medulloblastomas, etc., have a somatic mutation that results in an amino acid substitution at position 133 ?*his133 SHH!, or in a mutation at position 114. Such mutated genes and fragments thereof, encoded protein, and antibodies specific for the mutated protein are useful in characterizing the phenotype of associated tumors. The mutant protein is useful in drug screening for compositions that antagonize or otherwise modulate HH activity or expression. The encoded protein is also used as a therapeutic, to modulate cell proliferation and differentiation, and treatment of pathological conditions associated with decreased hedgehog signaling.

Abstract: Human hematopoietic stem cells are provided by separation of the stem cells from dedicated cells. The stem cells may than be maintained by regeneration in an appropriate growth medium. Means are provided for assaying for the stem cells as to their capability for producing members of each of the hematopoietic lineages.

Abstract: The use of individual or combinations of cytokines, particularly IL-3, GM-CSF, and c-kit ligand are employed for long-term hematopoiesis in serum free culture in the absence of stromal cells. The cultures can be used for evaluating compounds and their effect on hematopoiesis, particularly as to lifetime and nature of differentiation. In addition, the expanded cells may be used for engraftment in a mammalian host or enhancement of particular cell lineages in a mammalian host. The subject systems may be used with any mammalian hemopoietic cells, but finds particular application with primates, more particularly humans.

Abstract: Methods and compositions are provided for the modulation of monocyte binding to endothelial cells, particularly during inflammatory episodes. Compositions are provided which bind to one or both of the monocyte surface membrane protein or the endothelial surface membrane protein which are complementary or result in the adhesion of the monocyte to the endothelial cell. The subject compositions can be used in diagnosis or therapy.