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Showing papers by "Kettering University published in 2003"


Journal ArticleDOI
TL;DR: A role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development is suggested.
Abstract: To address the biological function of RNA interference (RNAi)-related pathways in mammals, we disrupted the gene Dicer1 in mice. Loss of Dicer1 lead to lethality early in development, with Dicer1-null embryos depleted of stem cells. Coupled with our inability to generate viable Dicer1-null embryonic stem (ES) cells, this suggests a role for Dicer, and, by implication, the RNAi machinery, in maintaining the stem cell population during early mouse development.

1,966 citations


Journal ArticleDOI
06 Nov 2003-Nature
TL;DR: Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of hedgehog signalling.
Abstract: Intraflagellar transport (IFT) proteins were first identified as essential factors for the growth and maintenance of flagella in the single-celled alga Chlamydomonas reinhardtii. In a screen for embryonic patterning mutations induced by ethylnitrosourea, here we identify two mouse mutants, wimple (wim) and flexo (fxo), that lack ventral neural cell types and show other phenotypes characteristic of defects in Sonic hedgehog signalling. Both mutations disrupt IFT proteins: the wim mutation is an allele of the previously uncharacterized mouse homologue of IFT172; and fxo is a new hypomorphic allele of polaris, the mouse homologue of IFT88. Genetic analysis shows that Wim, Polaris and the IFT motor protein Kif3a are required for Hedgehog signalling at a step downstream of Patched1 (the Hedgehog receptor) and upstream of direct targets of Hedgehog signalling. Our data show that IFT machinery has an essential and vertebrate-specific role in Hedgehog signal transduction.

1,345 citations


Journal ArticleDOI
TL;DR: A set of coculture conditions is provided that allows rapid and efficient derivation of most central nervous system phenotypes and transplantation of ES and ntES cell–derived dopaminergic neurons corrected the phenotype of a mouse model of Parkinson disease, demonstrating an in vivo application of therapeutic cloning in neural disease.
Abstract: Existing protocols for the neural differentiation of mouse embryonic stem (ES) cells require extended in vitro culture, yield variable differentiation results or are limited to the generation of selected neural subtypes. Here we provide a set of coculture conditions that allows rapid and efficient derivation of most central nervous system phenotypes. The fate of both fertilization- and nuclear transfer-derived ES (ntES) cells was directed selectively into neural stem cells, astrocytes, oligodendrocytes or neurons. Specific differentiation into gamma-aminobutyric acid (GABA), dopamine, serotonin or motor neurons was achieved by defining conditions to induce forebrain, midbrain, hindbrain and spinal cord identity. Neuronal function of ES cell-derived dopaminergic neurons was shown in vitro by electron microscopy, measurement of neurotransmitter release and intracellular recording. Furthermore, transplantation of ES and ntES cell-derived dopaminergic neurons corrected the phenotype of a mouse model of Parkinson disease, demonstrating an in vivo application of therapeutic cloning in neural disease.

692 citations


Journal ArticleDOI
TL;DR: This Review focuses on the comparison of the different strategies to assemble the bicyclo[3.2.1]octane core, to introduce the bridgehead quaternary C20 to form the pyrrolidine moiety, to construct the oxindole residue, and to close the tetrahydropyran ring en route to gelsemine.
Abstract: Gelsemine and 21-oxogelsemine have been synthesized through several routes. This Review focuses on the comparison of the different strategies to assemble the bicyclo[3.2.1]octane core, to introduce the bridgehead quaternary C20 to form the pyrrolidine moiety, to construct the oxindole residue, and to close the tetrahydropyran ring en route to gelsemine.

529 citations


Journal ArticleDOI
TL;DR: These trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process.
Abstract: trials showed unequivocally that human fetal dopaminergicneurons can survive and function for more than 10 years inthe striatum of patients with PD and show no signs of beingaffected by the ongoing disease process. These studies have also provided a clear indication that grafted fetaldopaminergic neurons can be therapeutically effective. On thebasis of the limited, but encouraging, observations in theseearly open-label trials,

353 citations


Journal ArticleDOI
TL;DR: It was decided to form a subcommittee to coordinate the naming of alleles of the genes encoding the killer-cell immunoglobulin-like receptors (KIRs) and a request has been made by the International Union of Immunological Societies to provide a standardized nomenclature for the expressed protein products of the KIR genes.

329 citations


Patent
28 May 2003
TL;DR: Chimeric T cell receptors (TCR) as mentioned in this paper are provided that combine, in a single chimeric species, the intracellular domain of CD3 ζ-chain, a signaling region from a costimulatory protein such as CD28, and a binding element that specifically interacts with a selected target.
Abstract: Chimeric T cell receptors (TCR) are provided that combine, in a single chimeric species, the intracellular domain of CD3 ζ-chain, a signaling region from a costimulatory protein such as CD28, and a binding element that specifically interacts with a selected target. When expressed, for example in T-lymphocytes from the individual to be treated for a condition associated with the selected target, a T cell immune response is stimulated in the individual to the target cells. The chimeric TCR's are able to provide both the activation and the co-stimulation signals from a single molecule to more effectively direct T-lymphocyte cytotoxicity against the selected target and T-lymphocyte proliferation.

259 citations


Journal ArticleDOI
TL;DR: The use of Cpl-1, the lytic enzyme of a pneumococcal bacteriophage, as an intravenous therapy for pneumococCal bacteremia in a mouse model and is also very effective as a topical nasal treatment against colonization by S. pneumoniae.
Abstract: Streptococcus pneumoniae is becoming increasingly antibiotic resistant worldwide, and thus new antimicrobials are badly needed. We report the use of Cpl-1, the lytic enzyme of a pneumococcal bacteriophage, as an intravenous therapy for pneumococcal bacteremia in a mouse model. A 2,000-μg dose of Cpl-1 reduced pneumococcal titers from a median of log10 4.70 CFU/ml to undetectable levels (

257 citations


Journal ArticleDOI
TL;DR: Data reveal a unique requirement for Tcf3 repressor function in restricting induction of the anterior-posterior axis during early mouse development.
Abstract: The roles of Lef/Tcf proteins in determining cell fate characteristics have been described in many contexts during vertebrate embryogenesis, organ and tissue homeostasis, and cancer formation. Although much of the accumulated work on these proteins involves their ability to transactivate target genes when stimulated by beta-catenin, Lef/Tcf proteins can repress target genes in the absence of stabilized beta-catenin. By ablating Tcf3 function, we have uncovered an important requirement for a repressor function of Lef/Tcf proteins during early mouse development. Tcf3-/- embryos proceed through gastrulation to form mesoderm, but they develop expanded and often duplicated axial mesoderm structures, including nodes and notochords. These duplications are preceded by ectopic expression of Foxa2, an axial mesoderm gene involved in node specification, with a concomitant reduction in Lefty2, a marker for lateral mesoderm. By contrast, expression of a beta-catenin-dependent, Lef/Tcf reporter (TOPGal), is not ectopically activated but is faithfully maintained in the primitive streak. Taken together, these data reveal a unique requirement for Tcf3 repressor function in restricting induction of the anterior-posterior axis.

248 citations


Journal ArticleDOI
TL;DR: Structural plasticity combined with remodeling of CTD primary structure by kinases and phosphatases provides a versatile mechanism by which the CTD can recruit structurally dissimilar proteins during transcription.

223 citations


Journal ArticleDOI
TL;DR: Results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.
Abstract: Oncogenic Kit mutations are found in somatic gastrointestinal (GI) stromal tumors (GISTs) and mastocytosis. A mouse model for the study of constitutive activation of Kit in oncogenesis has been produced by a knock-in strategy introducing a Kit exon 11-activating mutation into the mouse genome based on a mutation found in a case of human familial GIST syndrome. Heterozygous mutant KitV558Delta/+ mice develop symptoms of disease and eventually die from pathology in the GI tract. Patchy hyperplasia of Kit-positive cells is evident within the myenteric plexus of the entire GI tract. Neoplastic lesions indistinguishable from human GISTs were observed in the cecum of the mutant mice with high penetrance. In addition, mast cell numbers in the dorsal skin were increased. Therefore KitV558Delta/+ mice reproduce human familial GISTs, and they may be used as a model for the study of the role and mechanisms of Kit in neoplasia. Importantly, these results demonstrate that constitutive Kit signaling is critical and sufficient for induction of GIST and hyperplasia of interstitial cells of Cajal.

Journal ArticleDOI
TL;DR: The results are consistent with the notion that a single species of activator, Gal4, separately contacts, and thereby directly recruits, SAGA and Mediator.

Journal ArticleDOI
TL;DR: Genetic loss-of-function analysis in the mouse has provided important insights into the functions of several genes that direct neural cell fate, and scientists are beginning to define how the organization and connectivity of these neurons is established.
Abstract: The organized arrangement of neurons in the mature spinal cord arises from a pattern of cell types that is established in the embryonic neural tube. Initial research on the molecular mechanisms that underlie this cellular diversity focused on the specification of ventral cell types, but recently more has been learned about cell-type specification in the dorsal neural tube. Genetic loss-of-function analysis in the mouse has provided important insights into the functions of several genes that direct neural cell fate, and we are beginning to define how the organization and connectivity of these neurons is established.

Patent
22 Aug 2003
TL;DR: In this paper, the authors provide convergent processes for preparing epothilone A and B, desoxyepothilones B and C, and analogues thereof for the treatment of cancer and cancer which has developed a multidrug resistant phenotype.
Abstract: The present invention provides convergent processes for preparing epothilone A and B, desoxyepothilones A and B, and analogues thereof. Also provided are analogues related to epothilone A and B and intermediates useful for preparing same. The present invention further provides novel compositions based on analogues of the epothilones and methods for the treatment of cancer and cancer which has developed a multidrug-resistant phenotype.

Journal ArticleDOI
TL;DR: It is demonstrated here that Wg can synergize with DFz2 and function cooperatively with LRP to activate the β-catenin/Armadillo signaling pathway, and the results are consistent with the proposal that Wnt/Wg signals through the aminoterminal domains of its dual receptors, activating target genes through Dishevelled.
Abstract: Wnt/Wingless (Wg) signals are transduced by seven-transmembrane Frizzleds (Fzs) and the single-transmembrane LDL-receptor-related proteins 5 or 6 (LRP5/6) or Arrow. The aminotermini of LRP and Fz were reported to associate only in the presence of Wnt, implying that Wnt ligands form a trimeric complex with two different receptors. However, it was recently reported that LRPs activate the Wnt/β-catenin pathway by binding to Axin in a Dishevelled – independent manner, while Fzs transduce Wnt signals through Dishevelled to stabilize β-catenin. Thus, it is possible that Wnt proteins form separate complexes with Fzs and LRPs, transducing Wnt signals separately, but converging downstream in the Wnt/β-catenin pathway. The question then arises whether both receptors are absolutely required to transduce Wnt signals. We have established a sensitive luciferase reporter assay in Drosophila S2 cells to determine the level of Wg – stimulated signaling. We demonstrate here that Wg can synergize with DFz2 and function cooperatively with LRP to activate the β-catenin/Armadillo signaling pathway. Double-strand RNA interference that disrupts the synthesis of either receptor type dramatically impairs Wg signaling activity. Importantly, the pronounced synergistic effect of adding Wg and DFz2 is dependent on Arrow and Dishevelled. The synergy requires the cysteine-rich extracellular domain of DFz2, but not its carboxyterminus. Finally, mammalian LRP6 and its activated forms, which lack most of the extracellular domain of the protein, can activate the Wg signaling pathway and cooperate with Wg and DFz2 in S2 cells. We also show that the aminoterminus of LRP/Arr is required for the synergy between Wg and DFz2. Our study indicates that Wg signal transduction in S2 cells depends on the function of both LRPs and DFz2, and the results are consistent with the proposal that Wnt/Wg signals through the aminoterminal domains of its dual receptors, activating target genes through Dishevelled.

Journal ArticleDOI
TL;DR: It is shown that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity and the autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Srcfamily kinases from cell surface receptors.
Abstract: The activities of the related Abl and Arg nonreceptor tyrosine kinases are kept under tight control in cells, but exposure to several different stimuli results in a two- to fivefold stimulation of kinase activity. Following the breakdown of inhibitory intramolecular interactions, Abl activation requires phosphorylation on several tyrosine residues, including a tyrosine in its activation loop. These activating phosphorylations have been proposed to occur either through autophosphorylation by Abl in trans or through phosphorylation of Abl by the Src nonreceptor tyrosine kinase. We show here that these two pathways mediate phosphorylation at distinct sites in Abl and Arg and have additive effects on Abl and Arg kinase activation. Abl and Arg autophosphorylate at several sites outside the activation loop, leading to 5.2- and 6.2-fold increases in kinase activity, respectively. We also find that the Src family kinase Hck phosphorylates the Abl and Arg activation loops, leading to an additional twofold stimulation of kinase activity. The autoactivation pathway may allow Abl family kinases to integrate or amplify cues relayed by Src family kinases from cell surface receptors.

Journal ArticleDOI
TL;DR: It is demonstrated that Nurr1 induces dopaminergic features in naïve CNS precursors in vitro, and additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursor for cell therapy in Parkinson's disease.
Abstract: In vitro expanded CNS precursors could provide a renewable source of dopamine (DA) neurons for cell therapy in Parkinson's disease. Functional DA neurons have been derived previously from early midbrain precursors. Here we demonstrate the ability of Nurr1, a nuclear orphan receptor essential for midbrain DA neuron development in vivo, to induce dopaminergic differentiation in naive CNS precursors in vitro. Independent of gestational age or brain region of origin, Nurr1-induced precursors expressed dopaminergic markers and exhibited depolarization-evoked DA release in vitro. However, these cells were less mature and secreted lower levels of DA than those derived from mesencephalic precursors. Transplantation of Nurr1-induced DA neuron precursors resulted in limited survival and in vivo differentiation. No behavioral improvement in apomorphine-induced rotation scores was observed. These results demonstrate that Nurr1 induces dopaminergic features in naive CNS precursors in vitro. However, additional factors will be required to achieve in vivo function and to unravel the full potential of neural precursors for cell therapy in Parkinson's disease.

Patent
09 Jul 2003
TL;DR: In this paper, the authors presented methods of treating cancers, chemoprevention, selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors.
Abstract: The present invention provides methods of treating cancers, chemoprevention, selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and/or inhibiting histone deacetylase (HDAC) by administration of pharmaceutical compositions comprising potent HDAC inhibitors. The oral bioavailability of the active compounds in the pharmaceutical compositions of the present invention is surprisingly high. Moreover, the pharmaceutical compositions unexpectedly give rise to high, therapeutically effective blood levels of the active compounds over an extended period of time. The present invention further provides a safe, daily dosing regimen of these pharmaceutical compositions, which is easy to follow, and which results in a therapeutically effective amount of the HDAC inhibitors in vivo.

Journal ArticleDOI
TL;DR: During discussion at the WHO Nomenclature Committee for Factors of the HLA System meeting in Victoria, Canada in May 2002, it was decided to form a subcommittee to co-ordinate the naming of alleles of the genes encoding the killer-cell immunoglobulin-like receptors (KIR).
Abstract: During discussion at the WHO Nomenclature Committee for Factors of the HLA System meeting in Victoria, Canada in May 2002, it was decided to form a subcommittee to coordinate the naming of alleles of the genes encoding the killer-cell immunoglobulin-like receptors (KIRs) (Marsh et al., 2002). These genes are encoded on chromosome 19 (19q13.4) and have varying degrees of polymorphism. The receptors encoded by the KIR genes are expressed by natural killer (NK) cells and a subset of T cells, and some of them have been shown to have specificity for determinants of HLA class I molecules. The extracellular ligand-binding part of KIR consists of two or three immunoglobulin (Ig)-like domains. The discussions which took place in Victoria are further to earlier discussions on KIR nomenclature at the NK Polymorphism meeting (27-29 July 2001) in Cambridge, UK. In addition, a request has been made by the International Union of Immunological Societies (IUIS) to provide a standardized nomenclature for the expressed protein products of the KIR genes.

Journal ArticleDOI
TL;DR: In this article, aufsatz werden die zentralen Elemente der unterschiedlichen Synthesestrategien zusammengefasst und die Ansatze zum Aufbau des Bicyclo.
Abstract: Die Totalsynthese von Gelsemin und 21-Oxogelsemin ist auf mehreren Wegen moglich. In diesem Aufsatz werden die zentralen Elemente der unterschiedlichen Synthesestrategien zusammengefasst und die Ansatze zum Aufbau des Bicyclo[3.2.1]octan-Kerns, zur Einfuhrung des quartaren Bruckenkopf-Kohlenstoffatoms C20 bei der Bildung der Pyrrolidineinheit, zum Aufbau des Oxindol-Rests und zum Ringschluss des Tetrahydropyranrings diskutiert.

Journal ArticleDOI
15 Dec 2003-Blood
TL;DR: The ability of the leukemia-associated AML1-ETO fusion protein to establish a reproducible technique that allows for the long-term ex vivo expansion of human HSCs and maintains self-renewal and multipotential differentiation is reported.

Journal ArticleDOI
TL;DR: Vertebrate developmental genetics is now flourishing, with forward and reverse genetics in both zebrafish and the mouse providing new dimensions to the authors' understanding of development.
Abstract: The past decade has seen the development of powerful techniques to dissect the molecular processes that regulate development. New tools have been used to reveal the basis of cell polarity, morphogen gradients and regulation of signaling in developing animals. Cell biology and developmental biology have become closely intertwined, and many genes that had been thought of as regulators of general cell biological (housekeeping) functions have been shown to act as specific developmental regulators. Vertebrate developmental genetics is now flourishing, with forward and reverse genetics in both zebrafish and the mouse providing new dimensions to our understanding of development.

Journal ArticleDOI
19 Sep 2003-Cell
TL;DR: It is demonstrated that proteoglycans are required during mouse gastrulation specifically to promote Fgf signaling, and signaling by the growth factors Nodal and Wnt3 appears to be normal in lzme embryos.

Journal ArticleDOI
TL;DR: H-L(3)MBT is a transcriptional repressor and that its activity is largely dependent on the presence of a region containing the three MBT repeats, and the ability of TEL to repress TEL-responsive promoters is enhanced by the absence of H-L (3) MBT, suggesting that histone deacetylase-independent transcriptional repression by TEL depends on the recruitment of PcG proteins.

Journal ArticleDOI
01 Jul 2003-Leukemia
TL;DR: It is proposed that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later.
Abstract: The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

Book ChapterDOI
06 Jan 2003
TL;DR: In this paper, a Spalart-Allmaras-based Detached-Eddy Simulation (DES) of the Ahmed reference car model with 25° and 35° slant angles using unstructured grids and the solver Cobalt is presented.
Abstract: This paper presents a Spalart-Allmaras based Detached-Eddy Simulation (DES) of the Ahmed reference car model with 25° and 35° slant angles using unstructured grids and the solverCobalt. Comparisons are made to experimental laser doppler velocity measurements as well as total and surface pressure integrated drag. The Reynolds number based on body length was 2.78 ×106, making the boundary layers approaching the slant fully turbulent. The flow over the base slant in the experiments is attached at 25° and separated at 35°. This causes a large drop in the drag with the increased slant angle as the vortices on the side of the slant are weakened due to the separation. These cases stress turbulence models due to the need to accurately predict the boundary layer separation over the slant as well as predict the pressures in the massively separated base region accurately. The DES results are compared to the experiments as well as the Spalart-Allmaras RANS model. DES is seen to predict separation at 25◦ slant angle, in contrast to the experiments. Drag is relatively close to the experiments, but the distribution of drag is more on the rear than on the slant due to the separation. At the 35 ° slant angle, DES is in good agreement to the experimental drag, with the correct distribution, while RANS over-predicts the drag.

Journal ArticleDOI
TL;DR: Lame's formulas for the eigenvalues and eigenfunctions of the Laplacian with Dirichlet boundary conditions on an equilateral triangle are derived using direct elementary mathematical techniques and shown to form a complete orthonormal system.
Abstract: Lame's formulas for the eigenvalues and eigenfunctions of the Laplacian with Dirichlet boundary conditions on an equilateral triangle are derived using direct elementary mathematical techniques. They are shown to form a complete orthonormal system. Various properties of the spectrum and nodal lines are explored. Implications for related geometries are considered.

Journal ArticleDOI
TL;DR: Gas adsorption measurements: Sorption isotherms were measured at 298 K on an FMS-BG (BEL inc.) automatic gravimetric adsorbate measurement system with Rubotherm magnet coupling balance incorporated in a SUS steel pressure chamber.
Abstract: procedure. Elemental analysis (%) calcd for C13H8NO4Cu: C 51.06, H 2.62, N 4.58; found C 50.62, H 2.45, N 4.60. Gas adsorption measurements: Sorption isotherms were measured at 298 K on an FMS-BG (BEL inc.) automatic gravimetric adsorption measurement system with Rubotherm magnet coupling balance incorporated in a SUS steel pressure chamber. A known weight (200±300 mg) of the as-synthesized sample was placed in the aluminum sample cell in the chamber, and the sample was dried under high vacuum at 373 K for 5 h to remove the host water molecules. The adsorbate was dosed into the chamber, and the change in weight was monitored. After correction for buoyancy, the absorbed amount was determined.

Journal ArticleDOI
TL;DR: A model whereby Spt5-induced arrest of early elongation ensures a temporal window for recruitment of the capping enzymes, which in turn attract Cdk9 to alleviate the arrest is suggested, which may avoid wasteful rounds of transcription of uncapped pre-mRNAs.

Patent
14 Feb 2003
TL;DR: In this paper, a method for treating and/or preventing thioredoxin (TRX)-mediated diseases and conditions, by administering to a subject in need of such treatment a therapeutically effective amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof, was proposed.
Abstract: The present invention provides a novel method for treating and/or preventing thioredoxin (TRX)-mediated diseases and conditions, by administering to a subject in need of such treatment a therapeutically effective amount of a histone deacetylase (HDAC) inhibitor or a pharmaceutically acceptable salt or hydrate thereof. The HDAC inhibitor can alter the expression of a thioredoxin-binding-protein (e.g. TBP-2), which in turn can lead to an altered TRX/thioredoxin-binding-protein cellular binding interaction, resulting in an increase or decrease in the level or activity of cellular TRX, for example the expression level or reducing activity of TRX. Thus the present invention relates to the use of HDAC inhibitors in a method of preventing and/or treating a wide variety of thioredoxin (TRX)-mediated diseases and conditions, such as inflammatory diseases, allergic diseases, autoimmune diseases, diseases associated with oxidative stress or diseases characterized by cellular hyperproliferation.