US 8383124B2
· Zheng
· 2013
[cited by examiner]
US 9119824B2
· Dudakov
· 2015
[cited by examiner]
US 20230263800A1
· Dudakov
· 2023
[cited by examiner]
WO WO2008154098A2
· 2008
[cited by applicant]
WO WO2017143070A1
· 2017
[cited by applicant]
Lin Y, Zheng Y. Approaches of targeting Rho GTPases in cancer drug discovery. Expert Opin Drug Discov. 2015;10(9):991-1010. doi: 10.1517/17460441.2015.1058775. Epub Jun. 18, 2015. (Year: 2015).
[cited by examiner]
Onesto et al., “Characterization of EHT 1864, a Novel Small Molecule Inhibitor of Rac Family Small GTPases”, Methods of Enzymology, vol. 439, 2008 (Year: 2008).
[cited by examiner]
Gomez et al., “The GTPase Rac-1 Controls cell fate in the Thymus by diverting thymocyctes from Positive to Negative selection”, Immunity, vol. 15, Nov. 2001 (Year: 2001).
[cited by examiner]
Dedakov et al., “Interleukin-22 drives endogenous thymic regeneration in mice”, Science, Apr. 6, 2012 (Year: 2012).
[cited by examiner]
Ventevogel and Semproski, “Thymic Rejuenation and Age”, Curr Opin Immunol. Aug. 2013 (Year: 2013).
[cited by examiner]
Chaundry et al., “Thymus: The Next (Re)Generation”, Immunol Rev., May 2016 (Year: 2016).
[cited by examiner]
Jiang et al., “IL-22_CD4_ T-cells in patient with active systemic lupus erythematosus”, Exp. Biol. Med, Feb. 2013 (Year: 2013).
[cited by examiner]
Zhao et al., “A soy diet accelerates renal damage in autoimmune MRL/Mp-lpr/lpr mice”, International Immunopharmacology, Apr. 18, 2005 (Year: 2005).
[cited by examiner]
Bonnin et al., Secretion-mediated STAT3 activation promotes self-renewal of glioma stem-like cells during hypoxia. Oncogene 37, 1107-1118, Nov. 20, 2017 (Year: 2017).
[cited by examiner]
Xin et al., “Study on the relationship between DHA promoting NGF-induced PC12 differentiation and BMPs pathway”, Sep. 30, 2014, National Natural Science Foundation of China (Year: 2014).
[cited by examiner]
Wertheimer et al., “Endothelial Cells promote Endogenous thymic regeneration after Injury Via BMP4 signaling”, Blood, Dec. 6, 2014 (Year: 2014).
[cited by examiner]
Yoou et al., “Acteoside attenuates TSLP-induced mast cell proliferation via down-regulating MDM2”, International Immunopharmacology, May 2015 (Year: 2015).
[cited by examiner]
Abreu et al., “Eicosatetraenoic Acid Enhances the effects of mesenchymal stromal cell therapy in Experimental Allergic Asthma”, Front. Immunol. May 23, 2018 (Year: 2018).
[cited by examiner]
Deepthi et al., “Synthesis, DNA-binding, and cytotoxic studies on three copper(II) complexes of unsymmetrical analogues of curcumin”, Journal of Coordination Chemistry, May 4, 2016 (Year: 2016).
[cited by examiner]
Ahn, et al., “MicroRNA transcriptome in the newborn mouse ovaries determined by massive parallel sequencing,” Mol. Hum. Reprod., vol. 16, No. 7, 2010, pp. 463-471.
[cited by applicant]
Allshire, “RNAi and Heterochromatin—a Hushed-Up Affair,” Science, vol. 297, 2002, pp. 1818-1819.
[cited by applicant]
Anastasiadis, et al., “Inhibition of RhoA by p120 catenin,” Nat. Cell. Bio., vol. 2, 2000, pp. 637-644.
[cited by applicant]
Belinsky, et al., “Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced damage,” Cancer Res., vol. 67, No. 1, 2007, pp. 262-268.
[cited by applicant]
Bennett, et al., “Evaluation of Cyclosporine-Treated Mice as Hosts for Growing and Testing the Chemosensitivity of First-Transplant-Generation Human Tumor Xenografts Implanted Under the Kidney Capsule,” J. Natl. Cancer …
[cited by applicant]
Bernstein, et al., “Role for a bidentate ribonuclease in the initiation step of RNA interference,” Nature, vol. 409, 2001, pp. 363-366.
[cited by applicant]
Boehm & Bleul, “Thymus-homing precursors and the thymic microenvironment,” Trends in Immunology, vol. 27, No. 10, 2006, pp. 477-484.
[cited by applicant]
Brown, et al., “The Rac and Rho hall of fame: a decade of hypertrophic signaling hits,” Circ. Res., vol. 98, 2006, pp. 730-742.
[cited by applicant]
Canning, et al., “Inflammatory Signaling by NOD-RIPK2 Is Inhibited by Clinically Relevant Type II Kinase Inhibitors,” Chem. Biol., vol. 22, 2015, pp. 1174-1184.
[cited by applicant]
Chiang, et al, “Mammilian microRNAs: experimental evaluation of novel and previously annotated genes,” Genes and Development, vol. 24, 2010, pp. 992-1009.
[cited by applicant]
Chinn & Markert, “Induction of tolerance to parental parathyroid grafts using allogeneic thymus tissue in patients with DiGeorge anomaly,” J. Allergy Clin. Immunol., vol. 127, No. 6, 2011, pp. 1351-1355.
[cited by applicant]
Datta & Sarvetnick, “Lymphocyte proliferation in immune-mediated diseases,” Trends in Immunology, vol. 30, No. 9, 2009, pp. 430-438.
[cited by applicant]
Del Peso, et al., “Rho proteins induce mestatic properties in vivo,” Oncogene, vol. 15, 1997, pp. 3047-3057.
[cited by applicant]
Deng, et al., “Design and synthesis of small molecule RhoA inhibitors: a new promising therapy for cardiovascular diseases?,” J. Med. Chem., vol. 54, No. 13, 2011, pp. 4508-4522.
[cited by applicant]
Desire, et al., “RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases ABeta production in vitro and in vivo,” vol. 280, No. 45, 2005, pp. 37516-37525.
[cited by applicant]
Dixit, et al., “Ghrelin promotes thymopoiesis during aging,” J. Clin. Invest., vol. 117, No. 10, 2007, pp. 2778-2790.
[cited by applicant]
Dudakov, et al., “Interleukin-22 drives endogenous thymic regeneration in mice,” Science, vol. 336, No. 6077, 2012, 11 pages.
[cited by applicant]
Dunon & Imhof, “Mechanisms of Thymus Homing,” Blood, vol. 81, No. 1, 1993, pp. 1-8.
[cited by applicant]
Elbashir, et al., “Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells,” Nature, vol. 411, No. 6836, 2001, pp. 494-498.
[cited by applicant]
Elbashir, et al., “RNA interference is mediated by 21- and 22-nucleotide RNAs,” Genes Dev., vol. 15, 2001. pp. 188-200.
[cited by applicant]
Eriksson, et al., “Small GTP-binding protein Rac is an essential mediator of vascular endothelial growth factor-induced endothelial fenestrations and vascular permeability,” Circulation, vol. 107, No. 11, 2003, pp. 1532…
[cited by applicant]
Eysteinsdottir, et al., “The influence of partial or total thymectomy during open heart surgery in infants on the immune function later in life,” Clin. Exp. Immunol, vol. 136, No. 2, 2004, pp. 349-355.
[cited by applicant]
Fire, et al., “Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans,” Nature, vol. 391, 1998, pp. 806-811.
[cited by applicant]
Florian, et al., “Cdc42 activity regulates hematopoietic stem cell aging and rejuvenation,” Cell Stem Cell., vol. 10, No. 5, 2012, pp. 520-530.
[cited by applicant]
Fritz & Kaina, “Rho GTPases: promising cellular targets for novel anticancer drugs,” Current Cancer Drug Targets, vol. 6, No. 1, 2006, 14 pages.
[cited by applicant]
Fritz, et al., “Rho GTPases are over-expressed in human tumors,” Int. J. Cancer, vol. 81, No. 5, 1999, pp. 682-687.
[cited by applicant]
Fryer & Field, “Rho, Rac, Pak and angiogenesis: old roles and newly identified responsibilities in endothelial cells,” Cancer Letters, vol. 229, No. 1, 2005, pp. 13-23.
[cited by applicant]
Gagnerault, et al., “Autoimmunity during thymectomy-induced lymphopenia: role of thymus ablation and initial effector T cell activation timing in nonobese diabetic mice,” J. Imunnol., vol. 183, No. 8, 2009, pp. 4913-492…
[cited by applicant]
Gao, et al., “Rational design and characterization of a Rac GTPase-specific small molecule inihibitor,” PNAS, vol. 101, No. 20, 2004, pp. 7618-7623.
[cited by applicant]
Geenen, et al., “Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology,” J. Endocrinol, vol. 176, 2003, pp. 305-311.
[cited by applicant]
Goya, et al., “In vivo effects of growth hormone on thymus function in aging mice,” Brain Behav. Immun., vol. 6, No. 4, 1992, pp. 341-354.
[cited by applicant]
Giffith, et al., “Persistent degenerative changes in thymic organ function revealed by an inducible model of organ regrowth,” Aging Cell., vol. 11, No. 1, 2012, pp. 169-177.
[cited by applicant]
Haeusler, et al., “Purification and biochemical properties of Rac1, 2, 3 and the splice variant Rac1b,” Methods in Enzymology, vol. 406, 2006, pp. 1-11.
[cited by applicant]
Hall, “Rho GTPases and the actin cytoskeleton,” Science, vol. 279, No. 5350, 1998, pp. 509-514.
[cited by applicant]
Hall, et al., “Establishment and maintenance of a heterochromatin domain,” Science, vol. 297, No. 5590, 2002, pp. 2232-2237.
[cited by applicant]
Hammond, et al., “An RNA-directed nuclease mediates post-transcriptional gene silencing in
[cited by applicant]
Heng, et al., “Getting back at nature: understanding thymic development and overcoming its atrophy,” Curr. Opin. Pharmacol, vol. 10, No. 4, 2010, pp. 425-433.
[cited by applicant]
Hong, et al., “Characterization of a Cdc42 protein inhibitor and its use as a molecular probe,” J. Biol. Chem., vol. 288, No. 12, 2013, pp. 8531-8543.
[cited by applicant]
Hutvagner, et al., “A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA,” Science, vol. 293, No. 5531, 2001, pp. 834-838.
[cited by applicant]
Ishikawa, et al., “Comparative antitumor activity of 5-fluorouracil and 5′-deoxy-5-fluorouridine in combination with radiation therapy in mice bearing colon 26 adenocarcinoma,” Jpn. J. Cancer Res., vol. 80, No. 6, 1989,…
[cited by applicant]
Jakopin, “Nucleotide-binding oligomerization domain (NOD) inhibitors: a rational approach toward inhibition of NOD signaling pathway,” J. Med. Chem. vol. 57, No. 16, 2014, pp. 6897-6918.
[cited by applicant]
Jenuwein, “An RNA-guided pathway for the epigenome,” Science, vol. 297, No. 5590, 2002, pp. 2215-2218.
[cited by applicant]
Johnson, et al., “Subchronic oral toxicity and metabolite profiling of the p53 stabilizing agent, CP-31398, in rats and dogs,” Toxicology, vol. 289, No. 2-3, 2011, pp. 141-150.
[cited by applicant]
Jones & Jackson, “Ras-GRF Activates Ha-Ras, but Not N Ras or K-Ras 4B, Protein in Vivo,” J. Biol. Chem., vol. 273, No. 3, 1998, pp. 1782-1787.
[cited by applicant]
Kaminitz, et al., “Immunosuppressive therapy exacerbates autoimmunity in NOD mice and diminishes the protective activity of regulatory T cells,” J. Autoimmun., vol. 35, No. 2, 2010, pp. 145-152.
[cited by applicant]
Kapetanovic, et al., “Murine oncogenicity and pharmacokinetics studies of 9-cis-UAB30, an RXR agonist, for breast cancer chemoprevention,” Int. J. Toxicol., vol. 29, No. 2, 2010, pp. 157-164.
[cited by applicant]
Khosravi-Far, et al., “Increasing Complexity of Ras Signal Transduction: Involvement of Rho Family Proteins,” Adv. Cancer Res., vol. 72, 1998, pp. 57-107.
[cited by applicant]
King, et al., “Homeostatic expansion of T cells during immune insufficiency generates autoimmunity,” Cell, vol. 117, 2004, pp. 265-277.
[cited by applicant]
Knaus, et al., “Structural Requirements for PAK Activation by Rac GTPases,” J. Biol. Chem., vol. 273, No. 34, pp. 21512-21518.
[cited by applicant]
Lagos-Quintana, et al., “Identification of tissue-specific microRNAs from mouse,” Curr. Biol., vol. 12, No. 9, 2002, pp. 735-739.
[cited by applicant]
Invitation to Pay Fees Dated Mar. 27, 2019 for International Application No. PCT/US2019/013349, 2 Pages.
[cited by applicant]
Search Report and Written Opinion Dated May 23, 2019 for International Application No. PCT/US19/13349, 15 pages.
[cited by applicant]
Landgraf, et al., “A Mammalian microRNA Expression Atlas Based on Small RNA Library Sequencing,” Cell, vol. 129, No. 7, 2007, pp. 1401-1414.
[cited by applicant]
Lee, et al., “A four-week repeated study of intravenous toxicity of recombinant human interleukin-2 in Sprague-Dawley rats,” Regul. Toxicol. Pharmacol., vol. 64, No. 2, 2012, pp. 253-262.
[cited by applicant]
Lord-Fontaine, et al., “Local Inhibition of Rho Signaling by Cell-Permeable Recombinant Protein BA-210 Prevents Secondary Damage and Promotes Functional Recovery following Acute Spinal Cord Injury,” J. Neurotrauma, vol.…
[cited by applicant]
Lynch, et al., “Thymic involution and immune reconstitution,” Trends Immunol., vol. 30, No. 7, 2009, pp. 366-373.
[cited by applicant]
Ma, et al., “Development of Second-Generation Small-Molecule RhoA Inhibitors with Enhanced Water Solubility, Tissue Potency, and Significant in vivo Efficacy,” ChemMedChem., vol. 10, No. 1, 2015, pp. 193-206.
[cited by applicant]
Manlulu, et al., “Video-assisted thoracic surgery thymectomy for nonthymomatous myasthenia gravis,” Chest, vol. 128, No. 5, 2005, pp. 3454-3460.
[cited by applicant]
Marinkovic, et al., “Inhibition of GTPase Rac1 in endothelium by 6-mercaptopurine results in immunosuppression in nonimmune cells: new target for an old drug,” J. Immunol., vol. 192, No. 9, 2014, pp. 4370-4378.
[cited by applicant]
Markert, et al., “Transplantation of thymus tissue in complete DiGeorge syndrome,” N. Engl. J. Med., 1999, vol. 341, No. 16, 1999, pp. 1180-1189.
[cited by applicant]
Markert, et al, “Postnatal thymus transplantation with immunosuppression as treatment for DiGeorge syndrome,” Blood, vol. 104, No. 8, 2004, pp. 2574-281.
[cited by applicant]
Markert, et al., “Review of 54 patients with complete DiGeorge anomaly enrolled in protocols for thymus transplantation: outcome of 44 consecutive transplants,” Blood, vol. 109, No. 10, 2007, pp. 4539-4547.
[cited by applicant]
Markert, et al., “Thymus transplantation,” Clin. Immunol., vol. 135, No. 2, 2010, pp. 236-246.
[cited by applicant]
Min, et al., “Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of again,” Blood, vol. 509, No. 6, 2007, pp. 2529-2537.
[cited by applicant]
Molkentin & Dorn, “Cytoplasmic signaling pathways that regulate cardiac hypertrophy,” Annu. Rev. Pyhsiol., vol. 63, 2001, pp. 391-426.
[cited by applicant]
Montalvo-Ortiz, et al., “Characterization of EHop-016, novel small molecule inhibitor of Rac GTPase,” J. Biol. Chem., vol. 287, No. 16, 2012, pp. 13228-13238.
[cited by applicant]
Pogribny, et al., “Fractionated low-dose radiation exposure leads to accumulation of DNA damage and profound alterations in DNA and histone methylation in the murine thymus,” Mol. Cancer. Res., vol. 3, No. 10, 2005, pp.…
[cited by applicant]
Poy, et al., “A pancreatic islet-specific microRNA regulates insulin secretion,” Nature, vol. 432, No. 7014, 2004, pp. 226-230.
[cited by applicant]
Rebillard, et al., “Acid sphingomyelinase deficiency protects from cisplatin-inducedgastrointestinal damage,” Oncogene, vol. 27, No. 51, 2008, pp. 6590-6595.
[cited by applicant]
Rickard, et al., “Identification of benzimidazole diamides as selective inhibitors of the nucleotide-binding oligomerization domain 2 (NOD2) signaling pathway,” PloS One, vol. 8, No. 8, 2013, pp. 69619.
[cited by applicant]
Ridley, “The GTP-binding protein Rho,” Int. J. Biochem. Cell. Biol., vol. 29, No. 11, 1997, pp. 1225-1229.
[cited by applicant]
Sahai, et al., “RHO-GTPases and cancer,” Nat. Rev. Cancer, vol. 2, 2002, pp. 133-142.
[cited by applicant]
Schuurman, et al., “Chemicals trophic for the thymus: risk for immunodeficiency and autoimmunity,” Int. J. Immunopharmacol., vol. 14, No. 3, 1992, pp. 369-375.
[cited by applicant]
Seandel, et al., “Generation of a functional durable vascular niche by the adenoviral E40RF1 gene,” PNAS, vol. 105, No. 49, 2008, pp. 19288-19293.
[cited by applicant]
Seok, et al., “Isoflavone Attenuates Vascular Contraction through Inhibition of the RhoA/Rho-Kinase Signaling Pathway,” J. Pharmacol. Exp. Ther., vol. 326, No. 3, 2008, pp. 991-998.
[cited by applicant]
Shang, et al., “Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases,” Chem Biol., vol. 19, No. 6, 2012, pp. 699-710.
[cited by applicant]
Soga, et al., “Rho family GTPases regulate VEGF-stimulated endothelial cell motility,” Exp. Cell Res., vol. 269, No. 1, 2001, pp. 73-87.
[cited by applicant]
Su, et al., “Evaluation of the efficacy, toxicity and safety of vinorelbine incorporated in a lipid emulsion,” Int. J. Pharm., vol. 411, No. 1-2, 2011, pp. 188-196.
[cited by applicant]
Surviladze, et al., “Identification of a Small GTPase Inhibitor using a High-Throughput Flow Cytometry Bead-Based Multiplex Assay,” J. Biomol., vol. 15, No. 1, 2010, pp. 10-20.
[cited by applicant]
Tulinska, et al., “Immunotoxicity of ethyl-4-isothiocyanatobutanoate in male Wistar rats,” vol. 145, No. 2-3, 2000, pp. 217-225.
[cited by applicant]
Volpe, et al., “Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi,” Science, vol. 297, No. 5588, 2002, pp. 1833-1837.
[cited by applicant]
Wianny & Zernicka-Goetz “Specific interference with gene function by double-stranded RNA in early mouse development,” Nat. Cell. Biol., vol. 2, No. 2, 2000, pp. 70-75.
[cited by applicant]
Zlotoff & Bhandoola, “Hematopoietic progenitor migration to the adult thymus,” Annals of the New York Academy of Sciences, vol. 1217, 2011, pp. 122-138.
[cited by applicant]
Zou, et al., “Defective positive selection results in T cell lymphopenia and increased autoimmune diabetes in ADAP-deficient BDC2.5-C57BL/6 mice,” Eur. J. Immunol., vol. 38, No. 4, 2008, pp. 986-994.
[cited by applicant]
Zusman, et al., “T cell kinetics and apoptosis in immune organs and mammary tumors of rats treated with cyclophosphamide and soluble tumor-associated antigens,” In Vivo, vol. 16, No. 6, 2002, pp. 567-576.
[cited by applicant]
Zvelebil, et al., “Flavopiridol Hoechst AG,” IDrugs., vol. 1, No. 2, 1998, pp. 241-246.
[cited by applicant]