Publications
54 results found
Mintz P, Sætrom P, Reebye V, et al., 2016, MicroRNA-181a* targets Nanog in a subpopulation of CD34+ cells isolated from peripheral blood, Molecular Therapy - Nucleic Acids, Vol: 1, ISSN: 2162-2531
Exploiting the properties of stem cells by microRNA (miRNA) profiling offers an attractive approach to identify new regulators of stem cell fate. Although numerous miRNA have been screened from hematopoietic stem cells (HSC), the targets corresponding to many of these miRNA have not yet been fully elucidated. By miRNA profiling in a subpopulation of CD34+ cells isolated from peripheral blood, we have identified eight clusters of miRNA that were differentially expressed. Further analysis of one of the clusters by bioinformatics revealed that a miRNA, miR-181a*, which is highly expressed in the adherent CD34+ cells, affects the expression levels of Nanog, a stem cell surrogate marker. We show specifically by reporter assay and mutational analysis that miR-181a* targets a seedless 3′ compensatory site in the 3′UTR of Nanog and affects gene expression. We demonstrate that inhibiting miR-181a* upregulates the Nanog expression level, in addition to an increase in alkaline phosphatase activity. Our studies suggest that miR-181a* may be important in controlling the expression level of Nanog in a subpopulation of CD34+ cells.
Blakey D, Reebye V, Voutila J, et al., 2016, Small activating RNA to CEBPA as a novel therapeutic approach to treat patients with liver cancer, 28th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, Publisher: Elsevier, Pages: S149-S149, ISSN: 0959-8049
Yoon S, Huang K-W, Reebye V, et al., 2016, Targeted Delivery of C/EBPα -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth <i>In Vivo</i> (vol 24, pg 1106, 2016), MOLECULAR THERAPY, Vol: 24, Pages: 2131-2132, ISSN: 1525-0016
Reebye V, Huang K-W, Czysz K, et al., 2016, Hepatocellular Nuclear Factor 4 alpha (HNF-4 alpha) activation by saRNA rescues dyslipidemia and promotes favorable metabolic profile in a high fat diet (HFD) fed rat model., 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: Wiley, Pages: 794A-794A, ISSN: 1527-3350
Reebye V, Voutila J, Blakey D, et al., 2016, The clinical candidate MTL-CEBPA leads to significant reduction in ascites and improvement in overall survival in a CCl4-induced acute liver failure model., 67th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: Wiley, Pages: 1045A-1046A, ISSN: 0270-9139
Yoon S, Huang KW, Reebye V, et al., 2016, Targeted delivery of C/EBPα -saRNA by pancreatic ductal adenocarcinoma-specific RNA aptamers inhibits tumor growth in vivo, Molecular Therapy, Vol: 24, Pages: 1106-1116, ISSN: 1525-0024
The 5-year survival rate for pancreatic ductal adenocarcinoma (PDAC) remains dismal despite current chemotherapeutic agents and inhibitors of molecular targets. As the incidence of PDAC constantly increases, more effective multidrug approaches must be made. Here, we report a novel method of delivering antitumorigenic therapy in PDAC by upregulating the transcriptional factor CCAAT/enhancer-binding protein-α (C/EBPα), recognized for its antiproliferative effects. Small activating RNA (saRNA) duplexes designed to increase C/EBPα expression were linked onto PDAC-specific 2′-Fluropyrimidine RNA aptamers (2′F-RNA) - P19 and P1 for construction of a cell type–specific delivery vehicle. Both P19- and P1-C/EBPα-saRNA conjugates increased expression of C/EBPα and significantly suppressed cell proliferation. Tail vein injection of the saRNA/aptamer conjugates in PANC-1 and in gemcitabine-resistant AsPC-1 mouse-xenografts led to reduced tumor size with no observed toxicity. To exploit the specificity of the P19/P1 aptamers for PDAC cells, we also assessed if conjugation with Cy3 would allow it to be used as a diagnostic tool on archival human pancreatic duodenectomy tissue sections. Scoring pattern from 72 patients suggested a positive correlation between high fluorescent signal in the high mortality patient groups. We propose a novel aptamer-based strategy for delivery of targeted molecular therapy in advanced PDAC where current modalities fail.
Reebye V, Voutila J, Huang K-W, et al., 2015, Systemic administration of a novel development candidate, MTL-CEBPA, up-regulates the liver-enriched transcription factor C/EBP-α and reverses CCl4-induced liver failure in vivo, The 66th Annual Meeting of the American Association for the Study of Liver Diseases, Publisher: Wiley, Pages: 269A-270A, ISSN: 1527-3350
Mintz PJ, Huang K-W, Reebye V, et al., 2014, Exploiting human CD34(+) stem cell-conditioned medium for tissue repair, Molecular Therapy, Vol: 22, Pages: 149-159, ISSN: 1525-0016
Despite the progress in our understanding of genes essential for stem cell regulation and development, little is known about the factors secreted by stem cells and their effect on tissue regeneration. In particular, the factors secreted by human CD34+ cells remain to be elucidated. We have approached this challenge by performing a cytokine/growth factor microarray analysis of secreted soluble factors in medium conditioned by adherent human CD34+ cells. Thirty-two abundantly secreted factors have been identified, all of which are associated with cell proliferation, survival, tissue repair, and wound healing. The cultured CD34+ cells expressed known stem cell genes such as Nanog, Oct4, Sox2, c-kit, and HoxB4. The conditioned medium containing the secreted factors prevented cell death in liver cells exposed to liver toxin in vitro via inhibition of the caspase-3 signaling pathway. More importantly, in vivo studies using animal models of liver damage demonstrated that injection of the conditioned medium could repair damaged liver tissue (significant reduction in the necroinflammatory activity), as well as enable the animals to survive. Thus, we demonstrate that medium conditioned by human CD34+ cells has the potential for therapeutic repair of damaged tissue in vivo.
Reebye V, Saetrom P, Mintz PJ, et al., 2014, A Novel RNA Oligonucleotide Improves Liver Function and Inhibits Liver Carcinogenesis In Vivo, HEPATOLOGY, Vol: 59, Pages: 216-227, ISSN: 0270-9139
Huang KW, Reebye V, Mintz PJ, et al., 2013, Short activating RNA (saRNA) targeting C/EBPA significantly inhibits cell proliferation of undifferentiated cancer cells., MOLECULAR CANCER THERAPEUTICS, Vol: 12, ISSN: 1535-7163
Reebye V, 2013, A novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo., 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Reebye V, Cano LQ, Lavery DN, et al., 2012, Role of the HSP90-Associated Cochaperone p23 in Enhancing Activity of the Androgen Receptor and Significance for Prostate Cancer, MOLECULAR ENDOCRINOLOGY, Vol: 26, Pages: 1694-1706, ISSN: 0888-8809
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- Citations: 27
Thwaites JW, Reebye V, Mintz P, et al., 2012, Cellular replacement and regenerative medicine therapies in ischemic stroke., Regen Med., Vol: 7
Thwaites JW, Reebye V, Mintz P, et al., 2012, Cellular replacement and regenerative medicine therapies in ischemic stroke, REGENERATIVE MEDICINE, Vol: 7, Pages: 387-395, ISSN: 1746-0751
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- Citations: 19
Reebye V, Frilling A, Hajitou A, et al., 2012, A perspective on non-catalytic Src homology (SH) adaptor signalling proteins, CELLULAR SIGNALLING, Vol: 24, Pages: 388-392, ISSN: 0898-6568
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- Citations: 13
Reebye V, Levicar N, Habib N, 2011, Stem Cell Therapy for Patients with Chronic Liver Disease, Stem Cells in Clinic and Research, Pages: 501-512, ISBN: 978-953-307-797-0
Adult stem cells are a population of immature cells that have the capability of self renewalto provide the human body with a constant source of cells for maintaining healthy tissues orreplacing those that are damaged. Our present day scientific developments alongsideclinical experiences have collectively consolidated our understanding of the signals thatmediate stem cell lineage commitment and differentiation. From this, the concept of usingadult stem cells to repopulate chronically diseased organs is now a feasible option forregenerative medicine.Whilst the use of human embryonic stem cells in the clinical setting has beenoverwhelmingly marred by its oncogenic potential as well as ethical concerns, the rate ofprogress in understanding the complex developmental plasticity of adult stem cells, inparticular those derived from the bone marrow, has successfully allowed their use fortranslational research with unattached ethical issues. The pioneering use of bone marrowstem cells in the 1960s as a viable treatment option for leukaemia, myeloma and lymphomahas come a long way since then. Today we are able to use these stem cells to give rise tobone and cartilage (1) and to repair both cardiac and liver function (2, 3). Since a detailedreview for each of these exciting developments is too broad for this chapter, we will mainlyfocus on the use of bone marrow derived stem cell for the treatment of chronic liver disease.
Reebye V, Frilling A, Habib NA, et al., 2011, Intracellular adaptor molecules and AR signalling in the tumour microenvironment, CELLULAR SIGNALLING, Vol: 23, Pages: 1017-1021, ISSN: 0898-6568
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- Citations: 14
Reebye V, Bevan CL, Nohadani M, et al., 2010, Interaction between AR signalling and CRKL bypasses casodex inhibition in prostate cancer, CELLULAR SIGNALLING, Vol: 22, Pages: 1874-1881, ISSN: 0898-6568
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- Citations: 4
O'Kane PD, Reebye V, Ji Y, et al., 2008, Aspirin and clopidogrel treatment impair nitric oxide biosynthesis by platelets., Journal of Molecular Cell Cardiology, Vol: 45, Pages: 223-229
Aspirin and clopidogrel are used therapeutically for their anti-platelet effects. We examined the effects of aspirin and clopidogrel on basal and beta-adrenoceptor (beta-AR)-mediated platelet nitric oxide (NO) synthesis in healthy subjects and patients with coronary heart disease (CHD). Healthy subjects (n=19) were randomized in a double-blind cross-over manner to receive aspirin or clopidogrel, each at 75 mg daily, for 14 days. Patients (n=17) of similar age with CHD, taking aspirin, were randomized double-blind to either continue on aspirin 75 mg daily or to receive clopidogrel 75 mg daily for 14 days. NO synthase (NOS) activity was measured from l-[(3)H]arginine to l-[(3)H]citrulline conversion, and cGMP was determined by radioimmunoassay, in platelets basally and following incubation with isoproterenol or albuterol (each at 10(-5) mol/L). In healthy subjects, aspirin did not affect basal NOS activity or cGMP in platelets, but suppressed the normal increase in both by isoproterenol and albuterol. Clopidogrel suppressed platelet NOS activity and cGMP both basally and in response to beta-AR agonists. In platelets from CHD patients, clopidogrel suppressed basal and beta-AR-stimulated NOS activity and cGMP as compared with aspirin. Platelet NOS activity and cGMP were lower in CHD subjects pre-randomization compared with healthy subjects both pre-randomization and post-aspirin. We conclude that chronic aspirin treatment suppresses beta-AR-stimulated but not basal platelet NO synthesis, as previously described, whereas chronic clopidogrel treatment suppresses both, with resultant functional consequences. Moreover, CHD may itself be associated with decreased platelet NO biosynthesis.
Ji Y, Ferracci G, Warley A, et al., 2007, β-Actin regulates platelet nitric oxide synthase 3 activity through interaction with heat shock protein 90, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 104, Pages: 8839-8844, ISSN: 0027-8424
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- Citations: 35
Gamble SC, Chotai D, Odontiadis M, et al., 2007, Prohibitin, a protein downregulated by androgens, represses androgen receptor activity, ONCOGENE, Vol: 26, Pages: 1757-1768, ISSN: 0950-9232
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- Citations: 62
Ji Y, Ferracci G, Warley A, et al., 2007, beta-Actin regulates platelet nitric oxide synthase 3 activity thrug interaction with heat shock protein 90, PNAS.USA, Vol: 104, Pages: 8839-8844
Cytoskeletal proteins are crucial in maintaining cellular structure and, in certain cell types, also play an essential role in motility and shape change. Nitric oxide (NO) is an important paracrine mediator of vascular and platelet function and is produced in the vasculature by the enzyme NO synthase type 3 (NOS-3). Here, we demonstrate in human platelets that the polymerization state of beta-actin crucially regulates the activation state of NOS-3, and hence NO formation, through altering its binding of heat shock protein 90 (Hsp90). We found that NOS-3 binds to the globular, but not the filamentous, form of beta-actin, and the affinity of NOS-3 for globular beta-actin is, in turn, increased by Hsp90. Formation of this ternary complex among NOS-3, globular beta-actin, and Hsp90, in turn, results in an increase in both NOS activity and cyclic guanosine-3',5'-monophosphate, an index of bioactive NO, as well as an increased rate of Hsp90 degradation, thus limiting the duration for which NOS-3 remains activated. These observations suggest that beta-actin plays a critical role in regulating NO formation and signaling in platelets.
Powell SM, Brooke GN, Whitaker HC, et al., 2006, Mechanisms of androgen receptor repression in prostate cancer, BIOCHEMICAL SOCIETY TRANSACTIONS, Vol: 34, Pages: 1124-1127, ISSN: 0300-5127
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- Citations: 14
O'Kane PD, Queen LR, Ji Y, et al., 2003, Aspirin modifies nitric oxide synthase activity in platelets: effects of acute versus chronic aspirin treatment., Cardiovasc Res, Vol: 59, Pages: 152-159
OBJECTIVE: We examined the effects of aspirin on basal and beta-adrenoceptor (beta-AR)-mediated nitric oxide synthase (NOS) activity in normal platelets. METHODS: NOS activity was determined from the conversion of L-[3H]arginine to L-[3H]citrulline, both basally and following beta-AR stimulation, in platelets from healthy human subjects following both short- and long-term aspirin administration. RESULTS: Basal L-[3H]citrulline increased following aspirin 800 mg administered intravenously in vivo, from 0.31+/-0.12 to 0.76+/-0.14 pmol/10(8) platelets (P<0.01). Isoproterenol at 1 micromol/l increased platelet NOS activity before but not following intravenous aspirin. After short-term in vitro treatment with aspirin 10 micromol/l, 400 micromol/l or 4 mmol/l, basal platelet L-[3H]citrulline increased similarly, an effect not seen with indomethacin 100 micromol/l or ibuprofen 10 micromol/l. Platelet NOS activity was not increased by albuterol 1 micromol/l, in the presence of indomethacin, ibuprofen or aspirin in vitro. By contrast, oral aspirin 75 mg daily for 14 days did not affect basal platelet NOS activity, but abolished beta-adrenergic NOS activation. CONCLUSIONS: Aspirin activates basal platelet NOS acutely, but not chronically, through a mechanism independent of cyclooxygenase (COX) inhibition. By contrast, both short- and long-term aspirin treatment inhibit platelet beta-adrenergic NOS activation by a COX-dependent mechanism. This indicates that aspirin exerts divergent effects on basal and beta-AR-stimulated platelet NOS activity, which are likely to be of clinical relevance.
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