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2. Synthesis and Pro-Apoptotic Effects of Nitrovinylanthracenes and Related Compounds in Chronic Lymphocytic Leukaemia (CLL) and Burkitt’s Lymphoma (BL)

Author

Byrne, Andrew J., primary, Bright, Sandra A., additional, McKeown, James. P., additional, Bergin, Adam, additional, Twamley, Brendan, additional, McElligott, Anthony M., additional, Noorani, Sara, additional, Kandwal, Shubhangi, additional, Fayne, Darren, additional, O’Boyle, Niamh M., additional, Williams, D. Clive, additional, and Meegan, Mary J., additional

Published
2023
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4. Data from The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Author

McElligott, Anthony M., primary, Maginn, Elaina N., primary, Greene, Lisa M., primary, McGuckin, Siobhan, primary, Hayat, Amjad, primary, Browne, Paul V., primary, Butini, Stefania, primary, Campiani, Giuseppe, primary, Catherwood, Mark A., primary, Vandenberghe, Elisabeth, primary, Williams, D. Clive, primary, Zisterer, Daniela M., primary, and Lawler, Mark, primary

Published
2023
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5. Supplementary Figure 1 from The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Author

McElligott, Anthony M., primary, Maginn, Elaina N., primary, Greene, Lisa M., primary, McGuckin, Siobhan, primary, Hayat, Amjad, primary, Browne, Paul V., primary, Butini, Stefania, primary, Campiani, Giuseppe, primary, Catherwood, Mark A., primary, Vandenberghe, Elisabeth, primary, Williams, D. Clive, primary, Zisterer, Daniela M., primary, and Lawler, Mark, primary

Published
2023
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6. Supplementary Figure Legend from The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Author

McElligott, Anthony M., primary, Maginn, Elaina N., primary, Greene, Lisa M., primary, McGuckin, Siobhan, primary, Hayat, Amjad, primary, Browne, Paul V., primary, Butini, Stefania, primary, Campiani, Giuseppe, primary, Catherwood, Mark A., primary, Vandenberghe, Elisabeth, primary, Williams, D. Clive, primary, Zisterer, Daniela M., primary, and Lawler, Mark, primary

Published
2023
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7. Low CD49d expression in newly diagnosed chronic lymphocytic leukaemia may be associated with high‐risk features and reduced treatment‐free‐intervals

Author

Elizabeth, Smyth, primary, Aidan, Kelly, additional, David, O' Brien, additional, Deirdre, Waldron, additional, Sarah, Brophy, additional, Emer, Atkinson, additional, Kanthi, Perera, additional, Crotty, Gerard M., additional, Aileen, Walsh, additional, Michelle, Connolly, additional, Ruth, Clifford, additional, Hilary, O'Leary, additional, Ashique, Khan, additional, Bacon, Christopher L., additional, Emily, Smyth, additional, McElligott, Anthony M., additional, Fiona, Quinn, additional, Elisabeth, Vandenberghe, additional, and Carmel, Waldron, additional

Published
2022
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8. A novel aryl-guanidinium derivative, VP79s, targets the signal transducer and activator of transcription 3 signaling pathway, downregulates myeloid cell leukaemia-1 and exhibits preclinical activity against multiple myeloma

Author

Amet, Rebecca, primary, Previtali, Viola, additional, Mihigo, Helene B., additional, Sheridan, Emily, additional, Brophy, Sarah, additional, Hante, Nadhim Kamil, additional, Santos-Martinez, Maria Jose, additional, Hayden, Patrick J., additional, Browne, Paul V., additional, Rozas, Isabel, additional, McElligott, Anthony M., additional, and Zisterer, Daniela M., additional

Published
2022
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10. Epidemiology of chronic lymphocytic leukaemia in an Irish subpopulation with total case ascertainment: an additional tool for health economic planning

Author

Waldron, Carmel, primary, O’Brien, David, additional, Brophy, Sarah, additional, Perera, Kanthi, additional, Crotty, Gerard M., additional, Dunlea, Eoghan, additional, Walsh, Aileen, additional, Connolly, Michelle, additional, Clifford, Ruth, additional, O’Leary, Hilary, additional, Khan, Ashique, additional, Lee, Greg, additional, Atkinson, Emer, additional, Le, Giao, additional, Gillett, Alexander, additional, Bacon, Christopher L., additional, McElligott, Anthony M., additional, Quinn, Fiona, additional, and Vandenberghe, Elisabeth, additional

Published
2021
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16. Epidemiology of chronic lymphocytic leukaemia in an Irish subpopulation with total case ascertainment: an additional tool for health economic planning.

Author

Waldron, Carmel, O'Brien, David, Brophy, Sarah, Perera, Kanthi, Crotty, Gerard M., Dunlea, Eoghan, Walsh, Aileen, Connolly, Michelle, Clifford, Ruth, O'Leary, Hilary, Khan, Ashique, Lee, Greg, Atkinson, Emer, Le, Giao, Gillett, Alexander, Bacon, Christopher L., McElligott, Anthony M., Quinn, Fiona, and Vandenberghe, Elisabeth

Subjects
CHRONIC leukemia, LYMPHOCYTIC leukemia, CENTRAL economic planning, EPIDEMIOLOGY
Abstract

Keywords: chronic lymphocytic leukaemia; TP53; epidemiology; incidence; targeted therapies EN chronic lymphocytic leukaemia TP53 epidemiology incidence targeted therapies e47 e49 3 02/28/22 20220301 NES 220301 Chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL) is the commonest B-cell malignancy affecting Caucasians, with a variable national incidence depending on the ethnic composition and age profile of the population.1 The National Cancer Registry of Ireland (NCRI) quotes a Republic of Ireland (ROI) CLL incidence of 6-1/100 000, which appeared lower than our clinical experience indicated.2 Establishing accurate CLL incidence figures and numbers of patients requiring therapy would improve health service provision planning. Written consent was unavailable for 27 (18-2%) patients because of non-CLL associated ill health/death (11/27), cognitive impairment (2 of 27), patient wishes (7 of 27) and unknown (7 of 27). The "gold standard" of systematic disease data collection requires a national healthcare system and unique patient numbering system; however, complete CLL case ascertainment in a defined subpopulation with immunophenotyping as the diagnostic criteria has allowed us to establish accurate data that can be used by healthcare economists. [Extracted from the article]

Published
2022
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25. BRAF V600E-Negative Hairy Cell Leukaemia

Author

Langabeer, Stephen E., O'Brien, David, McElligott, Anthony M., Lavin, Michelle, and Browne, Paul V.

Subjects
Article Subject
Abstract

Since the initial report of the BRAF V600E mutation in hairy cell leukemia, numerous investigators have demonstrated the presence of this activating mutation in nearly all cases of this disease. A case of hairy cell leukemia is documented with a classical clinical, morphological, immunophenotypic, and cytochemical profile in which the BRAF V600E was not detected. The diagnostic and therapeutic implications are discussed.

Published
2013
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27. The microtubule targeting agent PBOX-15 inhibits integrin-mediated cell adhesion and induces apoptosis in acute lymphoblastic leukaemia cells

Author

LYSAGHT, JOANNE, primary, VERMA, NAVIN K., additional, MAGINN, ELAINA N., additional, RYAN, JACQUELINE M., additional, CAMPIANI, GIUSEPPE, additional, ZISTERER, DANIELA M., additional, WILLIAMS, D. CLIVE, additional, BROWNE, PAUL V., additional, LAWLER, MARK P., additional, and McELLIGOTT, ANTHONY M., additional

Published
2012
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29. Microtubule-targeting-compound PBOX-15 radiosensitizes cancer cells in vitro

Author

Forde, James C., primary, Maginn, Elaina N., additional, McNamara, Gillian, additional, Martin, Lynn M., additional, Campiani, Guiseppe, additional, Williams, D. Clive, additional, Zisterer, Daniela, additional, McElligott, Anthony M., additional, Lawler, Mark, additional, Lynch, Thomas H., additional, Hollywood, Donal, additional, and Marignol, Laure, additional

Published
2011
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30. PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells

Author

Maginn, E N, primary, Browne, P V, additional, Hayden, P, additional, Vandenberghe, E, additional, MacDonagh, B, additional, Evans, P, additional, Goodyer, M, additional, Tewari, P, additional, Campiani, G, additional, Butini, S, additional, Williams, D C, additional, Zisterer, D M, additional, Lawler, M P, additional, and McElligott, A M, additional

Published
2010
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31. The Vascular Targeting Agent Combretastatin-A4 and a Novelcis-Restricted β-Lactam Analogue, CA-432, Induce Apoptosis in Human Chronic Myeloid Leukemia Cells and Ex Vivo Patient Samples Including Those Displaying Multidrug Resistance

Author

Greene, Lisa M., primary, Nathwani, Seema M., additional, Bright, Sandra A., additional, Fayne, Darren, additional, Croke, Aisling, additional, Gagliardi, Maria, additional, McElligott, Anthony M., additional, O'Connor, Lisa, additional, Carr, Miriam, additional, Keely, Niall O., additional, O'Boyle, Niamh M., additional, Carroll, Peig, additional, Sarkadi, Balazs, additional, Conneally, Eibhlin, additional, Lloyd, David G., additional, Lawler, Mark, additional, Meegan, Mary J., additional, and Zisterer, Daniela M., additional

Published
2010
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32. Novel pyrrolo-1,5-benzoxazepine compounds display significant activity against resistant chronic myeloid leukaemia cells in vitro, in ex vivo patient samples and in vivo

Author

Bright, S A, primary, McElligott, A M, additional, O'Connell, J W, additional, O'Connor, L, additional, Carroll, P, additional, Campiani, G, additional, Deininger, M W, additional, Conneally, E, additional, Lawler, M, additional, Williams, D C, additional, and Zisterer, D M, additional

Published
2010
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33. The Novel Tubulin-Targeting Agent Pyrrolo-1,5-Benzoxazepine-15 Induces Apoptosis in Poor Prognostic Subgroups of Chronic Lymphocytic Leukemia

Author

McElligott, Anthony M., primary, Maginn, Elaina N., additional, Greene, Lisa M., additional, McGuckin, Siobhan, additional, Hayat, Amjad, additional, Browne, Paul V., additional, Butini, Stefania, additional, Campiani, Giuseppe, additional, Catherwood, Mark A., additional, Vandenberghe, Elisabeth, additional, Williams, D. Clive, additional, Zisterer, Daniela M., additional, and Lawler, Mark, additional

Published
2009
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34. Poster 133

Author

Jo Hodges, Nancy, primary, McElligott, Jacinta M., additional, and Dolezal, Jeanette M., additional

Published
2005
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42. PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells.

Author

Maginn, E. N., Browne, P. V., Hayden, P., Vandenberghe, E., MacDonagh, B., Evans, P., Goodyer, M., Tewari, P., Campiani, G., Butini, S., Williams, D. C., Zisterer, D. M., Lawler, M. P., and McElligott, A. M.

Subjects
MULTIPLE myeloma, APOPTOSIS, CYTOCHROME c, MITOCHONDRIAL membranes, CYTOMETRY, DEATH receptors, AZEPINES, BIOCHEMISTRY, RESEARCH, HETEROCYCLIC compounds, MICROSCOPY, RESEARCH methodology, CELL receptors, MEDICAL cooperation, EVALUATION research, PHENOMENOLOGY, COMPARATIVE studies, CELL lines, CARRIER proteins, CYTOPLASM
Abstract

Background: In recent years, much progress has been made in the treatment of multiple myeloma. However, a major limitation of existing chemotherapeutic drugs is the eventual emergence of resistance; hence, the development of novel agents with new mechanisms of action is pertinent. Here, we describe the activity and mechanism of action of pyrrolo-1,5-benzoxazepine-15 (PBOX-15), a novel microtubule-targeting agent, in multiple myeloma cells.Methods: The anti-myeloma activity of PBOX-15 was assessed using NCI-H929, KMS11, RPMI8226, and U266 cell lines, and primary myeloma cells. Cell cycle distribution, apoptosis, cytochrome c release, and mitochondrial inner membrane depolarisation were analysed by flow cytometry; gene expression analysis was carried out using TaqMan Low Density Arrays; and expression of caspase-8 and Bcl-2 family of proteins was assessed by western blot analysis.Results: Pyrrolo-1,5-benzoxazepine-15 induced apoptosis in ex vivo myeloma cells and in myeloma cell lines. Death receptor genes were upregulated in both NCI-H929 and U266 cell lines, which displayed the highest and lowest apoptotic responses, respectively, following treatment with PBOX-15. The largest increase was detected for the death receptor 5 (DR5) gene, and cotreatment of both cell lines with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the DR5 ligand, potentiated the apoptotic response. In NCI-H929 cells, PBOX-15-induced apoptosis was shown to be caspase-8 dependent, with independent activation of extrinsic and intrinsic apoptotic pathways. A caspase-8-dependent decrease in expression of Bim(EL) preceded downregulation of other Bcl-2 proteins (Bid, Bcl-2, Mcl-1) in PBOX-15-treated NCI-H929 cells.Conclusion: PBOX-15 induces apoptosis and potentiates TRAIL-induced cell death in multiple myeloma cells. Thus, PBOX-15 represents a promising agent, with a distinct mechanism of action, for the treatment of this malignancy. [ABSTRACT FROM AUTHOR]

Published
2011
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43. The vascular targeting agent combretastatin-A4 and a novel cis-Restricted {beta}-Lactam Analogue, CA-432, induce apoptosis in human chronic myeloid leukemia cells and ex vivo patient samples including those displaying multidrug resistance.

Author

Greene, Lisa M, Nathwani, Seema M, Bright, Sandra A, Fayne, Darren, Croke, Aisling, Gagliardi, Maria, McElligott, Anthony M, O'Connor, Lisa, Carr, Miriam, Keely, Niall O, O'Boyle, Niamh M, Carroll, Peig, Sarkadi, Balazs, Conneally, Eibhlin, Lloyd, David G, Lawler, Mark, Meegan, Mary J, and Zisterer, Daniela M

Abstract

Combretastatin-A4 (CA-4) is a natural derivative of the African willow tree Combretum caffrum. CA-4 is one of the most potent antimitotic components of natural origin, but it is, however, intrinsically unstable. A novel series of CA-4 analogs incorporating a 3,4-diaryl-2-azetidinone (β-lactam) ring were designed and synthesized with the objective to prevent cis -trans isomerization and improve the intrinsic stability without altering the biological activity of CA-4. Evaluation of selected β-lactam CA-4 analogs demonstrated potent antitubulin, antiproliferative, and antimitotic effects in human leukemia cells. A lead β-lactam analog, CA-432, displayed comparable antiproliferative activities with CA-4. CA-432 induced rapid apoptosis in HL-60 acute myeloid leukemia cells, which was accompanied by depolymerization of the microtubular network, poly(ADP-ribose) polymerase cleavage, caspase-3 activation, and Bcl-2 cleavage. A prolonged G(2)M cell cycle arrest accompanied by a sustained phosphorylation of mitotic spindle checkpoint protein, BubR1, and the antiapoptotic proteins Bcl-2 and Bcl-x(L) preceded apoptotic events in K562 chronic myeloid leukemia (CML) cells. Molecular docking studies in conjunction with comprehensive cell line data rule out CA-4 and β-lactam derivatives as P-glycoprotein substrates. Furthermore, both CA-4 and CA-432 induced significantly more apoptosis compared with imatinib mesylate in ex vivo samples from patients with CML, including those positive for the T315I mutation displaying resistance to imatinib mesylate and dasatinib. In summary, synthetic intrinsically stable analogs of CA-4 that display significant clinical potential as antileukemic agents have been designed and synthesized.

Published
2010
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47. Characterisation of Naive Immunological Profile of Umbilical Cord Blood: The Role of Mucosal-Associated Invariant T Cells and Functional Defects of T Cells and Natural Killer Cells

Author

McElligott, Anthony M, Breen, Eamon P, Cleary, Ruth, Brophy, Sarah, McCarthy, Fiona, Heffernan, Emma, O'Mahony, Vincent, Gardiner, Nicola, Doherty, Derek G, Byrne, Bridgette, Browne, Paul V, and Flynn, Catherine M

Abstract

Patients undergoing allogeneic haematopoietic stem cell (HSC) transplantation are susceptible to infection and reactivation of viruses, such as cytomegalovirus, due to impairment of the T cell compartment following intensive immunosuppressive therapy. There is a growing interest in evaluating cell-mediated immunity to improve the management of these infections. Over the last two decades, umbilical cord blood (UCB) has emerged as an alternative source of cellular products for the treatment of a range of haematological disorders. UCB HSCs have a number of distinguishing characteristics which differentiate them from adult HSCs, including increased proliferation and increased in vitrocolony forming capacity. The use of UCB as HSC grafts for allogeneic stem cell transplant has a number of advantages, including immediate availability and reduced risk of graft-versus-host disease despite donor-recipient HLA disparity. However, the limited number of HSCs present in a single UCB collection and incomplete immune reconstitution because of delayed HSC engraftment has restricted the use of cord blood in stem cell transplantation. In addition, UCB transplantation is associated with lack of transferred adoptive immunity, resulting in transplant related morbidity and mortality due to infectious complications. While the human neonatal immune system is considered to be immature compared with its adult counterpart, the role of the innate immune cells in the immunological naïvety is not fully understood.

Published
2017
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48. Selected nitrostyrene compounds demonstrate potent activity in chronic lymphocytic leukaemia cells, including those with poor prognostic markers.

Author

Bright SA, Byrne AJ, Vandenberghe E, Browne PV, Mcelligott AM, Meegan MJ, and Williams DC

Subjects
Aged, Antineoplastic Combined Chemotherapy Protocols chemistry, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Line, Tumor, Cell Survival drug effects, Drug Screening Assays, Antitumor, Drug Synergism, Female, Humans, Inhibitory Concentration 50, Leukemia, Lymphocytic, Chronic, B-Cell blood, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell mortality, Leukocytes, Mononuclear, Male, Middle Aged, Nitro Compounds chemistry, Nitro Compounds therapeutic use, Primary Cell Culture, Prognosis, Purines pharmacology, Purines therapeutic use, Quinazolinones pharmacology, Quinazolinones therapeutic use, Structure-Activity Relationship, Styrenes chemistry, Styrenes therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Nitro Compounds pharmacology, Styrenes pharmacology
Abstract

The nitrostyrene scaffold was previously identified as a lead target structure for the development of effective compounds targeting Burkitt's lymphoma. The present study aimed to develop these compounds further in haematological malignancies, including chronic lymphocytic leukaemia (CLL). Cellular viability, flow cytometry and lactate dehydrogenase assays, amongst others, were used to examine the effects of nitrostyrene compounds on CLL cells, including a cell line representing disease with poor prognosis (HG‑3) and in ex vivo CLL patient samples (n=14). The results demonstrated that two representative nitrostyrene compounds potently induced apoptosis in CLL cells. The pro‑apoptotic effects of the compounds were found to be reactive oxygen species and caspase‑dependent, and had minimal effects on the viability of normal donor peripheral blood mononuclear cells. Nitrostyrene compounds exhibited synergistic augmentation of apoptosis when combined with the phosphatidylinositol 3‑kinase inhibitor idelalisib and demonstrated potent toxicity in ex vivo CLL cells, including those co‑cultured with bone marrow stromal cells, making them more resistant to apoptosis (n=8). These compounds also demonstrated activity in samples from patients with poor prognostic indicators; unmutated immunoglobulin heavy chain genes, expression of CD38 and deletions in chromosomes 17p and 11q. These results suggest that this class of pharmaceutically active compounds offer potential in the treatment of CLL.

Published
2019
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49. Selective detection of UCP 3 expression in skeletal muscle: effect of thyroid status and temperature acclimation.

Author

Cunningham O, McElligott AM, Carroll AM, Breen E, Reguenga C, Oliveira ME, Azevedo JE, and Porter RK

Subjects
Adipose Tissue, Brown chemistry, Animals, COS Cells, Ion Channels, Mitochondrial Proteins, Peroxisomes chemistry, Rats, Uncoupling Protein 3, Acclimatization physiology, Carrier Proteins analysis, Muscle, Skeletal chemistry, Thyroid Hormones pharmacology
Abstract

A novel peptide antibody to UCP 3 is characterized which is sensitive and discriminatory for UCP 3 over UCP 2, UCP 1 and other mitochondrial transporters. The peptide antibody detects UCP 3 expression in E. coli, COS cells and yeast expression systems. The peptide antibody detects a single approximately 33 kDa protein band in mitochondria from isolated rat skeletal muscle, mouse and rat brown adipose tissue, and in whole muscle groups (soleus and extensor digitorum longus) from mice. No 33 kDa band is detectable in isolated mitochondria from liver, heart, brain, kidney and lungs of rats, or gastrocnemius mitochondria from UCP 3 knock-out mice. From our data, we conclude that the peptide antibody is detecting UCP 3 in skeletal muscle, skeletal muscle mitochondria and brown adipose tissue mitochondria. It is also noteworthy that the peptide antibody can detect human, mouse and rat forms of UCP 3. Using the UCP 3 peptide antibody, we confirm and quantify the increased (2.8-fold) UCP 3 expression observed in skeletal muscle mitochondria isolated from 48-h-starved rats. We show that UCP 3 expression is increased (1.6-fold) in skeletal muscle of rats acclimated over 8 weeks to 8 degrees C and that UCP 3 expression is decreased (1.4-fold) in rats acclimated to 30 degrees C. Furthermore, UCP 3 expression is increased (2.3-fold) in skeletal muscle from hyperthyroid rats compared to euthyroid controls. In addition, we show that UCP 3 expression is only coincident with the mitochondrial fraction of skeletal muscle homogenates and not peroxisomal, nuclear or cytosolic and microsomal fractions.

Published
2003
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50. Tissue inhibitor of metalloproteinase expression. A target for gene therapy in renal cell carcinoma.

Author

McElligott AM, Baker AH, and McGlynn H

Subjects
Adenoviridae, Carcinoma, Renal Cell pathology, Humans, Kidney Neoplasms pathology, Neoplasm Invasiveness, Recombinant Proteins biosynthesis, Tissue Inhibitor of Metalloproteinase-1 biosynthesis, Tissue Inhibitor of Metalloproteinase-2 biosynthesis, Transfection, Tumor Cells, Cultured, Carcinoma, Renal Cell therapy, Genetic Therapy methods, Kidney Neoplasms therapy, Tissue Inhibitor of Metalloproteinase-1 genetics, Tissue Inhibitor of Metalloproteinase-2 genetics
Published
1998

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