100 results on '"Mary R. Cahill"'
Search Results
2. All-Trans-Retinoic Acid Combined With Valproic Acid Can Promote Differentiation in Myeloid Leukemia Cells by an Autophagy Dependent Mechanism
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Dalyia N. Benjamin, Tracey R. O’Donovan, Kristian B. Laursen, Nina Orfali, Mary R. Cahill, Nigel P. Mongan, Lorraine J. Gudas, and Sharon L. McKenna
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APL ,AML ,ATRA ,valproic acid ,autophagy ,differentiation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Application of differentiation therapy to other AML subtypes would be a major treatment advance. Recent studies have indicated that autophagy plays a key role in the differentiation of ATRA-responsive APL cells. In this study, we have investigated whether differentiation could be enhanced in ATRA resistant cells by promoting autophagy induction with valproic acid (VPA). ATRA sensitive (NB4) and resistant leukemia cells (NB4R and THP-1) were co-treated with ATRA and valproic acid, followed by assessment of autophagy and differentiation. The combination of VPA and ATRA induced autophagic flux and promoted differentiation in ATRA-sensitive and -resistant cell lines. shRNA knockdown of ATG7 and TFEB autophagy regulators impaired both autophagy and differentiation, demonstrating the importance of autophagy in the combination treatment. These data suggest that ATRA combined with valproic acid can promote differentiation in myeloid leukemia cells by mechanism involving autophagy.
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- 2022
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3. Inhibition of UBE2L6 attenuates ISGylation and impedes ATRA‐induced differentiation of leukemic cells
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Nina Orfali, Deborah Shan‐Krauer, Tracey R. O’Donovan, Nigel P. Mongan, Lorraine J. Gudas, Mary R. Cahill, Mario P. Tschan, and Sharon L. McKenna
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AML ,APL ,ATRA ,differentiation ,ISG15 ,UBE2L6 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Ubiquitin/ISG15‐conjugating enzyme E2L6 (UBE2L6) is a critical enzyme in ISGylation, a post‐translational protein modification that conjugates the ubiquitin‐like modifier, interferon‐stimulated gene 15 (ISG15), to target substrates. Previous gene expression studies in acute promyelocytic leukemia (APL) cells showed that all‐trans‐retinoic acid (ATRA) altered the expression of many genes, including UBE2L6 (200‐fold) and other members of the ISGylation pathway. Through gene expression analyses in a cohort of 98 acute myeloid leukemia (AML) patient samples and in primary neutrophils from healthy donors, we found that UBE2L6 gene expression is reduced in primary AML cells compared with normal mature granulocytes. To assess whether UBE2L6 expression is important for leukemic cell differentiation—two cell line models were employed: the human APL cell line NB4 and its ATRA‐resistant NB4R counterpart, as well as the ATRA‐sensitive human AML HL60 cells along with their ATRA‐resistant subclone—HL60R. ATRA strongly induced UBE2L6 in NB4 APL cells and in ATRA‐sensitive HL60 AML cells, but not in the ATRA‐resistant NB4R and HL60R cells. Furthermore, short hairpin (sh)RNA‐mediated UBE2L6 depletion in NB4 cells impeded ATRA‐mediated differentiation, suggesting a functional role for UBE2L6 in leukemic cell differentiation. In addition, ATRA induced ISG15 gene expression in NB4 APL cells, leading to increased levels of both free ISG15 protein and ISG15 conjugates. UBE2L6 depletion attenuated ATRA‐induced ISG15 conjugation. Knockdown of ISG15 in NB4 APL cells inhibited ISGylation and also attenuated ATRA‐induced differentiation. In summary, we demonstrate the functional importance of UBE2L6 in ATRA‐induced neutrophil differentiation of APL cells and propose that this may be mediated by its catalytic role in ISGylation.
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- 2020
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4. Co-Formulation of Amphiphilic Cationic and Anionic Cyclodextrins Forming Nanoparticles for siRNA Delivery in the Treatment of Acute Myeloid Leukaemia
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Ayse Kont, Monique C. P. Mendonça, Michael F. Cronin, Mary R. Cahill, and Caitriona M. O’Driscoll
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modified cyclodextrins ,nanomaterials ,nucleic acids ,non-viral gene delivery ,acute myeloid leukaemia (AML) ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Non-viral delivery of therapeutic nucleic acids (NA), including siRNA, has potential in the treatment of diseases with high unmet clinical needs such as acute myeloid leukaemia (AML). While cationic biomaterials are frequently used to complex the nucleic acids into nanoparticles, attenuation of charge density is desirable to decrease in vivo toxicity. Here, an anionic amphiphilic CD was synthesised and the structure was confirmed by Fourier-transform infrared spectroscopy (FT-IR), Nuclear Magnetic Resonance (NMR), and high-resolution mass spectrometry (HRMS). A cationic amphiphilic cyclodextrin (CD) was initially used to complex the siRNA and then co-formulated with the anionic amphiphilic CD. Characterisation of the co-formulated NPs indicated a significant reduction in charge from 34 ± 7 mV to 24 ± 6 mV (p < 0.05) and polydispersity index 0.46 ± 0.1 to 0.16 ± 0.04 (p < 0.05), compared to the cationic CD NPs. Size was similar, 161–164 nm, for both formulations. FACS and confocal microscopy, using AML cells (HL-60), indicated a similar level of cellular uptake (60% after 6 h) followed by endosomal escape. The nano co-formulation significantly reduced the charge while maintaining gene silencing (21%). Results indicate that blending of anionic and cationic amphiphilic CDs can produce bespoke NPs with optimised physicochemical properties and potential for enhanced in vivo performance in cancer treatment.
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- 2022
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5. The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia
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Leanne R. O’Sullivan, Mary R. Cahill, and Paul W. Young
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actin cytoskeleton ,actinin ,actinin-1 ,actinin-4 ,ACTN1 ,platelets ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)—accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.
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- 2021
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6. The Impact of Expanded Access Programs for Systemic Anticancer Therapy in an Irish Cancer Centre
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Timothy K Cronin, Cian Ronayne, Niamh O’Donovan, Eimear McGuinness, Katie Cooke, Maeve Dennehy, Colum Dennehy, Derek G Power, Mary R Cahill, Dearbhaile C Collins, Roisin M Connolly, Richard M Bambury, Vitaliy Mykytiv, Michaela J Higgins, Sinéad A Noonan, and Seamus O'Reilly
- Abstract
Purpose Expanded access programs (EAPs) allow patients with cancer who have unmet clinical needs to obtain access to pre-authorisation treatments. There is no standardised process or registry for implementing these programs nationally and real world data on their impact is lacking. We evaluated their prevalence and impact in a cancer centre.Methods Data relating to adult cancer patients treated via EAPs from 2011 to 2021 in three Cork university hospitals was collated. Descriptive statistics were employed to get an overview of the impact these programs currently have on cancer care provision.Results We identified 193 patients who accessed EAPs during the study period, availing of 33 separate drugs for a total of 50 different cancer indications. The prevalence of EAP usage was shown to have been trending upwards in recent years with a total of 189 programs being accessed throughout the period. Drugs provided were from a number of different anti-cancer drug classes, particularly targeted therapies (n = 18) and immune checkpoint inhibitors (n = 17). Cancers from a wide range of both solid and liquid tumour types were identified as having been treated with EAP drugs and patients treated were from across a broad spectrum of ages (26–82, SD:11.99).Conclusion EAPs have an increasing role in access to novel cancer therapies in our community and by extension nationally. Equity of EAP access would be facilitated by a national registry of available agents which we have now established. Assessment of their benefits and toxicities would be enhanced by the requirement for a real world data base as a condition of EAP approval.
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- 2023
7. Platelet hyperactivation and hyporesponsiveness at diagnosis in multiple myeloma persists during treatment initiation
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Vitaliy Mykytiv, Mary R. Cahill, Paul Young, Leanne R O'Sullivan, Oonagh Gilligan, and Gerardene Meade-Murphy
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Blood Platelets ,Hyperactivation ,business.industry ,Immunology ,Humans ,Medicine ,Platelet ,Hematology ,Platelet activation ,Multiple Myeloma ,business ,medicine.disease ,Multiple myeloma - Published
- 2021
8. Functional impairment of erythropoiesis in Congenital Dyserythropoietic Anaemia type I arises at the progenitor level
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Caroline Scott, Kerol Bartolovic, Sally‐Ann Clark, Dominic Waithe, Quentin A. Hill, Steven Okoli, Raffaele Renella, Kate Ryan, Mary R. Cahill, Douglas R. Higgs, Noémi B. A. Roy, Veronica Buckle, Irene Roberts, and Christian Babbs
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Humans ,Erythropoiesis ,Hematology ,Anemia, Dyserythropoietic, Congenital - Published
- 2022
9. Phase 2 studies of lenalidomide, subcutaneous bortezomib, and dexamethasone as induction therapy in patients with newly diagnosed multiple myeloma
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Peter O'Gorman, Jacob P. Laubach, Michael E. O'Dwyer, Janusz Krawczyk, Andrew J. Yee, Oonagh Gilligan, Mary R. Cahill, Jacalyn Rosenblatt, John Quinn, Philip T. Murphy, Heidi DiPietro, Meegahage Ratnakanthi Perera, Gerard M. Crotty, Kristen Cummings, Patrick J. Hayden, Paul Browne, Alexandra Savell, Hilary M. O'Leary, Denis O'Keeffe, Kelly Masone, Brian J. Hennessy, Thomas Guerrero Garcia, Kathleen Scott, Khalid Saeed, Giada Bianchi, Paul Dowling, Ciara Tierney, and Paul G. Richardson
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Bortezomib ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Hematology ,Induction Chemotherapy ,Prospective Studies ,Middle Aged ,Multiple Myeloma ,Lenalidomide ,Dexamethasone - Abstract
There are limited prospective data on lenalidomide, subcutaneous bortezomib, and dexamethasone (RsqVd) in transplant-eligible/transplant-ineligible patients with newly diagnosed multiple myeloma. Reliable biomarkers for efficacy and toxicity are required to better tailor therapy. Two parallel studies were conducted by Cancer Trials Ireland (CTI; NCT02219178) and the Dana-Farber Cancer Institute (DFCI; NCT02441686). Patients received four 21-day cycles of RsqVd and could then receive either another 4 cycles of RsqVd or undergo autologous stem cell transplant. Postinduction/posttransplant, patients received lenalidomide maintenance, with bortezomib included for high-risk patients. The primary endpoint was overall response rate (ORR) after 4 cycles of RsqVd. Eighty-eight patients were enrolled and 84 treated across the two studies; median age was 64.7 (CTI study) and 60.0 years (DFCI study), and 59% and 57% had stage II-III disease. Pooled ORR after 4 cycles in evaluable patients was 93.5%, including 48.1% complete or very good partial responses (CTI study: 91.9%, 59.5%; DFCI study: 95.0%, 37.5%), and in the all-treated population was 85.7% (44.0%). Patients received a median of 4 (CTI study) and 8 (DFCI study) RsqVd cycles; 60% and 31% of patients (CTI study) and 33% and 51% of patients (DFCI study) underwent transplant or received further RsqVd induction, respectively. The most common toxicity was peripheral neuropathy (pooled: 68%, 7% grade 3-4; CTI study: 57%, 7%; DFCI study: 79%, 7%). Proteomics analyses indicated elevated kallikrein-6 in good versus poor responders, decreased midkine in good responders, and elevated macrophage inflammatory protein 1-alpha in patients who stopped treatment from neurotoxicity, suggesting predictive biomarkers warranting further investigation.
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- 2022
10. All
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Dalyia N, Benjamin, Tracey R, O'Donovan, Kristian B, Laursen, Nina, Orfali, Mary R, Cahill, Nigel P, Mongan, Lorraine J, Gudas, and Sharon L, McKenna
- Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with an overall survival of 30%. One form of AML, acute promyelocytic leukemia (APL) has become more than 90% curable with differentiation therapy, consisting of all
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- 2022
11. Polycythemia vera emerging eighteen years after acute myeloid leukemia diagnosis
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Derick W. O’Flynn, Stephen E. Langabeer, and Mary R. Cahill
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Oncology ,medicine.medical_specialty ,Polycythemia vera ,business.industry ,Internal medicine ,medicine ,Myeloid leukemia ,Hematology ,medicine.disease ,business ,Letters to the Editor - Published
- 2021
12. The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia
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Paul Young, Leanne R O'Sullivan, and Mary R. Cahill
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Blood Platelets ,Integrins ,actin cytoskeleton ,Platelet maturation ,QH301-705.5 ,Actinin ,macromolecular substances ,Review ,Biology ,ACTN1 ,Catalysis ,congenital macrothrombocytopenia ,Inorganic Chemistry ,Platelet Adhesiveness ,megakaryocytes ,macrothrombocytopenia ,Humans ,Platelet ,Platelet activation ,Physical and Theoretical Chemistry ,Biology (General) ,Molecular Biology ,QD1-999 ,Spectroscopy ,Actin ,CMTP ,actinin ,actinin-1 ,Organic Chemistry ,General Medicine ,Actin cytoskeleton ,Thrombocytopenia ,Computer Science Applications ,Cell biology ,actinin-4 ,Actinin, alpha 1 ,Chemistry ,Mutation ,platelets ,Function (biology) - Abstract
The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)—accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.
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- 2021
13. CyBorD-DARA is potent initial induction for MM and enhances ADCP: initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study
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Elizabeth Lenihan, Michael O'Dwyer, I. Parker, Aideen E. Ryan, A. Hernando, Philip Murphy, G. Hirakata, G. Gannon, Kevin Lynch, Serika D. Naicker, J. Walsh, Janusz Krawczyk, Alessandro Natoni, Robert Henderson, Vitaliy Mykytiv, Tara Kenny, Mary R. Cahill, Cian McEllistrim, E. Kinsella, and John Quinn
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Adult ,Male ,medicine.medical_specialty ,Neutropenia ,Antineoplastic Agents, Hormonal ,CyBorD-DARA ,Cyclophosphamide ,Clinical Trials and Observations ,Injections, Subcutaneous ,Infections ,Transplantation, Autologous ,Gastroenterology ,Dexamethasone ,Bortezomib ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Multiple myeloma (MM) ,Antineoplastic Agents, Alkylating ,Aged ,Very Good Partial Response ,Daratumumab (DARA) ,Intention-to-treat analysis ,business.industry ,Incidence ,Hematopoietic Stem Cell Transplantation ,Antibodies, Monoclonal ,Autologous stem cell transplantation (ASCT) ,Hematology ,Middle Aged ,medicine.disease ,Minimal residual disease ,Transplantation ,Treatment Outcome ,Female ,Multiple Myeloma ,business ,Ireland ,Proteasome Inhibitors ,medicine.drug - Abstract
CyBorD DARA as induction is well tolerated and induces deep responses when used in conjunction with ASCT for MM.Mechanism of action studies indicate that CyBorD DARA enhances macrophage activation, which may play a role in its clinical efficacy. Daratumumab (DARA) has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM). We conducted a phase 1b study to assess the safety and preliminary efficacy, as well as potential mechanisms of action, of DARA (16 mg/kg) in combination with a weekly schedule of subcutaneous bortezomib (1.3-1.5 mg/m2), cyclophosphamide (150-300 mg/m2), and dexamethasone (40 mg) (CyBorD DARA) as initial induction before autologous stem cell transplantation (ASCT). Eligible patients were ≤70 years of age with untreated MM requiring treatment and who lacked significant comorbidities. A total of 18 patients were enrolled. Their median age was 56 years (range, 32-66 years), and all patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively; 28% of patients had high-risk genetic features. There was no dose-limiting toxicity, and the incidence of grade 3 or 4 infection or neutropenia was
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- 2019
14. A multicenter report on the natural history of myelodysplastic syndromes in very old patients (aged over 85 years)
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Desmond O'Neill, Philip Murphy, Clodagh Keohane, Patrick Hogan, Su Wai Maung, Melanie Strickland, Ronan Desmond, Daniel H. Ryan, Elizabeth O'Connell, Mohammad Khan, Peter McCarthy, John Quinn, Vitaliy Mykytiv, Mary R. Cahill, John McHugh, Laura S McDonald, Eileen Kelleher, and Helen Enright
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Male ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Treatment outcome ,Mild cytopenia ,03 medical and health sciences ,Disease susceptibility ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Aged, 80 and over ,Ineffective Hematopoiesis ,Old patients ,business.industry ,Myelodysplastic syndromes ,Disease Management ,Myeloid leukemia ,Hematology ,Prognosis ,medicine.disease ,Natural history ,Treatment Outcome ,Oncology ,Myelodysplastic Syndromes ,030220 oncology & carcinogenesis ,Female ,Disease Susceptibility ,business ,030215 immunology - Abstract
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and risk of evolution to acute myeloid leukemia (AML) [1]. Presentation varies from mild cytopenia to profound symptom...
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- 2019
15. Cybord-Dara in Newly Diagnosed Transplant-Eligible Multiple Myeloma: Follow up Results from the 16Bcni-001/Ctrial-IE 16-02 Study Show High Rates of MRD Negativity at End of Treatment
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Cian McEllistrim, Kevin Lynch, Michael O'Dwyer, Marc Nolan, Elizabeth Lenihan, Andres Hernando, John Quinn, Aideen E. Ryan, Alessandro Natoni, Mary R. Cahill, Janusz Krawczyk, Dawn Swan, Philip Murphy, Imelda Parker, Vitaliy Mykytiv, Robert Henderson, Eva Szegezdi, and Serika D. Naicker
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Oncology ,High rate ,medicine.medical_specialty ,MRD Negativity ,business.industry ,Immunology ,Follow up results ,Cell Biology ,Hematology ,Newly diagnosed ,Dara ,medicine.disease ,Biochemistry ,Internal medicine ,medicine ,business ,Multiple myeloma - Abstract
The anti-CD38 monoclonal antibody Daratumumab has shown impressive activity in combination with other agents for the treatment of multiple myeloma (MM), improving progression free survival and overall survival in several phase 3 studies. We conducted a phase 1b study of intravenous Daratumumab (16 mg/kg) with weekly subcutaneous bortezomib (1.3-1.5 mg/m 2 ), cyclophosphamide (150-300 mg/m 2), and dexamethasone (40 mg) (CyBorD-DARA) as induction before autologous stem cell transplantation (ASCT), followed by CyBorD-DARA consolidation (2 cycles) and monthly DARA +/- bortezomib (in high-risk disease) maintenance for 24 months. We hypothesized that the addition of cyclophosphamide could lead to enhanced antibody dependent cellular phagocytosis (ADCP). This trial was registered at www.clinicaltrials.gov as NCT02955810. We previously reported the initial results of this study. 1. In addition to a favourable safety profile we observed promising anti-MM activity with 10 of 13 patients (77%) in whom assessment was possible achieving measurable residual disease (MRD) negativity at a sensitivity of 10 -5 by next generation sequencing (NGS) after ASCT. We now report the results at EOT, with a focus on MRD. Eligible patients were ≤70 years of age with untreated transplant-eligible MM. 18 patients were enrolled. Median age was 56.5 years (range, 32-66 years), 61% were male and 94% of patients had Eastern Cooperative Oncology Group performance status ≤1. The International Staging System stages were I, II, and III in 78%, 17%, and 6% of patients, respectively. 29% of patients had high-risk genetic features by fluorescent in situ hybridisation (FISH) or gene expression profiling, including 17p deletion in 12% and t(4;14) and t(14;16) in 6% each. On an ITT basis, the rates of very good partial remission or better (≥VGPR) after ASCT, consolidation and at end of treatment (EOT) (after completion of 24 months of DARA) were 94%, 94% and 81% respectively, and rates of complete response or better (≥CR) were 50%, 63% and 63% respectively. Measurable residual disease (MRD) assessment was possible in 13 patients after induction, ASCT and consolidation, and 10 at EOT. Sustained MRD negativity (ie. MRD negativity after ASCT, consolidation and at EOT) to a level of 10 -5 by NGS was achieved in 33% (ITT). Of 13 patients who remained on study at EOT in VGPR or better, 54% were MRD negative (MRD was unavailable in 23%). 7 patients were MRD negative after both ASCT and consolidation. Of these patients, all evaluable at EOT(6/7) remained MRD negative, with 1 patient unable to undergo MRD assessment due to the COVID-19 pandemic, but remaining in CR. Nausea and diarrhoea occurred in 89% of patients, but were mostly grade 1-2 (Grade ≥3 nausea 17%; diarrhoea 6%). Neutropenia occurred in 44% (Grade ≥3 17%), anaemia in 39% (Grade ≥3 22%), and thrombocytopenia in 33% (Grade ≥3 22%). The rate of neutropenic sepsis was 11%. Infusion-related reactions occurred in 50% (Grade ≥3 6%) and peripheral neuropathy occurred in 33% (Grade ≥3 0%) The most commonly reported serious adverse event (SAE) was sepsis in 22%. One patient developed abnormal liver function tests leading to discontinuation from the trial. CyBorD-DARA induction, consolidation and DARA-maintenance is an effective and well-tolerated IMiD free regimen in transplant-eligible patients with MM. MRD negativity at a level of > 10 -5 after ASCT and consolidation may be predictive of sustained MRD negativity at EOT. References: Naicker SD, et al. Cyclophosphamide alters the tumor cell secretome to potentiate the anti-myeloma activity of daratumumab through augmentation of macrophage-mediated antibody dependent cellular phagocytosis. Oncoimmunology. 2021 Jan 25;10(1):1859263. doi: 10.1080/2162402X.2020.1859263. PMID: 33552684; PMCID: PMC7849715. O'Dwyer M, et al. CyBorD-DARA is potent initial induction for MM and enhances ADCP: initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study. Blood Adv. 2019 Jun 25;3(12):1815-1825. doi: 10.1182/bloodadvances.2019000010. PMID: 31201169; PMCID: PMC6595251. Disclosures O'Dwyer: ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Bristol Myers Squibb: Research Funding. Quinn: Takeda: Honoraria. Szegezdi: ONK Therapeutics: Research Funding.
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- 2021
16. Validation of phlebotomy performance metrics developed as part of a proficiency-based progression initiative to mitigate wrong blood in tube
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Sarah Griffin, Anthony G. Gallagher, Noirin O’Herlihy, Mary R. Cahill, Robert Gaffney, and Patrick Henn
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medicine.medical_specialty ,Medical Errors ,business.industry ,Construct validity ,Reproducibility of Results ,General Medicine ,030204 cardiovascular system & hematology ,Phlebotomy ,Wrong blood in tube ,03 medical and health sciences ,Benchmarking ,0302 clinical medicine ,Benchmark (surveying) ,medicine ,Humans ,Medical physics ,030212 general & internal medicine ,Metric (unit) ,Clinical Competence ,business ,Performance metric ,Reliability (statistics) ,Working environment - Abstract
Aims The purpose of this study was to (1) characterise the procedure of phlebotomy, deconstruct it into its constituent parts and develop a performance metric for the purpose of training healthcare professionals in a large teaching hospital and to (2) evaluate the construct validity of the phlebotomy metric and establish a proficiency benchmark. Method By engaging with a multidisciplinary team with a wide range of experience of preanalytical errors in phlebotomy and observing video recordings of the procedure performed in the actual working environment, we defined a performance metric. This was brought to a modified Delphi meeting, where consensus was reached by an expert panel. To demonstrate construct validity, we used the metric to objectively assess the performance of novices and expert practitioners. Results A phlebotomy metric consisting of 11 phases and 77 steps was developed. The mean inter-rater reliability was 0.91 (min 0.83, max 0.95). The expert group completed more steps of the procedure (72 vs 69), made fewer errors (19 vs 13, p=0.014) and fewer critical errors (1 Vs 4, p=0.002) than the novice group. Conclusions The metrics demonstrated construct validity and the proficiency benchmark was established with a minimum observation of 69 steps, with no critical errors and no more than 13 errors in total.
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- 2020
17. Inhibition of UBE2L6 attenuates ISGylation and impedes ATRA-induced differentiation of leukemic cells
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Sharon L. McKenna, Deborah Shan-Krauer, Mario P. Tschan, Nina Orfali, Mary R. Cahill, Tracey R. O’Donovan, Lorraine J. Gudas, and Nigel P. Mongan
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0301 basic medicine ,Acute promyelocytic leukemia ,Cancer Research ,ISG15 ,HL60 ,Neutrophils ,Cellular differentiation ,Cell ,Tretinoin ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Leukemia, Promyelocytic, Acute ,AML ,Neutrophil differentiation ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,ATRA ,neoplasms ,Research Articles ,Gene knockdown ,Gene Expression Regulation, Leukemic ,organic chemicals ,UBE2L6 ,Cell Differentiation ,General Medicine ,differentiation ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,biological factors ,APL ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,Cell culture ,030220 oncology & carcinogenesis ,Gene Knockdown Techniques ,Ubiquitin-Conjugating Enzymes ,Cancer research ,Molecular Medicine ,570 Life sciences ,biology ,Protein Processing, Post-Translational ,Research Article - Abstract
Ubiquitin/ISG15‐conjugating enzyme E2L6 (UBE2L6) is a critical enzyme in ISGylation, a post‐translational protein modification that conjugates the ubiquitin‐like modifier, interferon‐stimulated gene 15 (ISG15), to target substrates. Previous gene expression studies in acute promyelocytic leukemia (APL) cells showed that all‐trans‐retinoic acid (ATRA) altered the expression of many genes, including UBE2L6 (200‐fold) and other members of the ISGylation pathway. Through gene expression analyses in a cohort of 98 acute myeloid leukemia (AML) patient samples and in primary neutrophils from healthy donors, we found that UBE2L6 gene expression is reduced in primary AML cells compared with normal mature granulocytes. To assess whether UBE2L6 expression is important for leukemic cell differentiation—two cell line models were employed: the human APL cell line NB4 and its ATRA‐resistant NB4R counterpart, as well as the ATRA‐sensitive human AML HL60 cells along with their ATRA‐resistant subclone—HL60R. ATRA strongly induced UBE2L6 in NB4 APL cells and in ATRA‐sensitive HL60 AML cells, but not in the ATRA‐resistant NB4R and HL60R cells. Furthermore, short hairpin (sh)RNA‐mediated UBE2L6 depletion in NB4 cells impeded ATRA‐mediated differentiation, suggesting a functional role for UBE2L6 in leukemic cell differentiation. In addition, ATRA induced ISG15 gene expression in NB4 APL cells, leading to increased levels of both free ISG15 protein and ISG15 conjugates. UBE2L6 depletion attenuated ATRA‐induced ISG15 conjugation. Knockdown of ISG15 in NB4 APL cells inhibited ISGylation and also attenuated ATRA‐induced differentiation. In summary, we demonstrate the functional importance of UBE2L6 in ATRA‐induced neutrophil differentiation of APL cells and propose that this may be mediated by its catalytic role in ISGylation., Knockdown of UBE2L6 or ISG15 in NB4 APL cells inhibits ISGylation of protein targets and attenuates ATRA‐induced differentiation.
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- 2020
18. Theranostic drug test incorporating the bone‐marrow microenvironment can predict the clinical response of acute myeloid leukaemia to chemotherapy
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Andrea Tirincsi, Eva Szegezdi, Dimitrios I. Zeugolis, Janusz Krawczyk, John Quinn, Mary R. Cahill, Sukhraj Pal Singh Dhami, and Denis V. Baev
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medicine.medical_treatment ,Antineoplastic Agents ,Drug resistance ,Theranostic Nanomedicine ,03 medical and health sciences ,0302 clinical medicine ,Bone Marrow ,Cell Line, Tumor ,Tumor Microenvironment ,medicine ,Humans ,Drug test ,030304 developmental biology ,0303 health sciences ,Chemotherapy ,medicine.diagnostic_test ,business.industry ,Hematology ,Coculture Techniques ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Myeloid leukaemia ,business - Published
- 2020
19. Platelet hyperactivation in multiple myeloma is also evident in patients with premalignant monoclonal gammopathy of undetermined significance
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Leanne R O'Sullivan, Gerardene Meade-Murphy, Oonagh Gilligan, Paul Young, Vitaliy Mykytiv, and Mary R. Cahill
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Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Gastroenterology ,Monoclonal Gammopathy of Undetermined Significance ,03 medical and health sciences ,0302 clinical medicine ,Thrombin ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Platelet ,Platelet activation ,Multiple myeloma ,Aged ,Aged, 80 and over ,Hyperactivation ,CD63 ,business.industry ,Fibrinogen ,Thrombosis ,Hematology ,Middle Aged ,medicine.disease ,Platelet Activation ,030220 oncology & carcinogenesis ,Smouldering myeloma ,Female ,business ,Multiple Myeloma ,Monoclonal gammopathy of undetermined significance ,030215 immunology ,medicine.drug - Abstract
Thrombotic events are common in patients with multiple myeloma (MM), smouldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS). Previous studies have indicated platelet hyperactivation as a feature of thrombotic risk in MM, but there is a dearth of data in MGUS. In the present study, multiparameter analysis of platelet activation and responsiveness was investigated by flow cytometry in patients with MGUS, SM/MM and healthy controls (HCs). The median platelet surface CD63 levels, annexin V and PAC-1 antibody (specific for activated integrin αIIbβ3) binding were significantly elevated in patients with MGUS versus the HCs. These markers were also elevated in SM/MM, but not significantly. In all, 74% of MGUS and 38% of SM/MM patients had one or more elevated marker of platelet activation, compared to 19% of the HCs. Marker-specific hyporesponsiveness of platelets to agonist [adenosine diphosphate (ADP), thrombin receptor-activating peptide 6] stimulation in vitro was observed, with significantly reduced surface levels of P-selectin in response to ADP in patients with MGUS. Platelet-leucocyte aggregates were not altered in patients, while platelet-associated immunoglobulins were elevated in a subset of patients. Overall, we found that platelet hyperactivation is prevalent in both MGUS and SM/MM patients and is potentially related to hyporesponsiveness. These observations suggest that further investigation of the predictive and prognostic value of platelet hyperactivation in such patients is warranted.
- Published
- 2020
20. All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)
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Sharon L. McKenna, David M. Nanus, Lorraine J. Gudas, Nigel P. Mongan, Dalyia Benjamin, Tracey R. O’Donovan, Nina Orfali, and Mary R. Cahill
- Subjects
Acute promyelocytic leukemia ,Myeloid ,Oncogene Proteins, Fusion ,Biopsy ,Cellular differentiation ,Retinoic acid ,Antineoplastic Agents ,Tretinoin ,Transcription factor EB ,Biology ,chemistry.chemical_compound ,Sequestosome 1 ,Leukemia, Promyelocytic, Acute ,Bone Marrow ,Cell Line, Tumor ,Autophagy ,medicine ,Humans ,RNA, Small Interfering ,education ,neoplasms ,education.field_of_study ,Acute myeloid leukemia ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors ,Gene Expression Regulation, Leukemic ,Cell Differentiation ,Hematology ,General Medicine ,medicine.disease ,Hematopoiesis ,Cell biology ,Haematopoiesis ,medicine.anatomical_structure ,chemistry ,Gene Knockdown Techniques ,Differentiation ,TFEB ,RNA Interference ,Retinoid ,Signal Transduction - Abstract
© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation. Therapeutic concentrations of all-trans-retinoic acid (ATRA) can restore retinoid-induced transcription and promote degradation of the PML-RARα protein. Autophagy is a catabolic pathway that utilizes lysosomal machinery to degrade intracellular material and facilitate cellular re-modeling. Recent studies have identified autophagy as an integral component of ATRA-induced myeloid differentiation. Methods: As the molecular communication between retinoid signaling and the autophagy pathway is not defined, we performed RNA sequencing of NB4 APL cells treated with ATRA and examined autophagy-related transcripts. Results: ATRA altered the expression of >80 known autophagy-related transcripts, including the key transcriptional regulator of autophagy and lysosomal biogenesis, TFEB (11.5-fold increase). Induction of TFEB and its transcriptional target, sequestosome 1 (SQSTM1, p62), is reduced in ATRA-resistant NB4R cells compared to NB4 cells. TFEB knockdown in NB4 cells alters the expression of transcriptional targets of TFEB and reduces CD11b transcript levels in response to ATRA. Conclusions: We show for the first time that TFEB plays an important role in ATRA-induced autophagy during myeloid differentiation and that autophagy induction potentiates leukemic cell differentiation (Note: this study includes data obtained from NCT00195156, https://clinicaltrials.gov/show/NCT00195156).
- Published
- 2020
21. The potential for clinical translation of antibody-targeted nanoparticles in the treatment of acute myeloid leukaemia
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Jianfeng Guo, Mary R. Cahill, Caitriona M. O'Driscoll, Sharon L. McKenna, Yao Sun, Limei Wang, Zhongcheng Cong, and Xue Luan
- Subjects
0301 basic medicine ,Immunoconjugates ,Pharmaceutical Science ,Antineoplastic Agents ,Malignancy ,Translational Research, Biomedical ,03 medical and health sciences ,Drug Delivery Systems ,Targeted nanoparticles ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,neoplasms ,Drug Carriers ,biology ,business.industry ,Antibodies, Monoclonal ,Treatment options ,Translation (biology) ,medicine.disease ,Leukemia, Myeloid, Acute ,Haematopoiesis ,030104 developmental biology ,biology.protein ,Cancer research ,Nanoparticles ,Antibody ,Myeloid leukaemia ,business - Abstract
Acute myeloid leukaemia (AML) is a heterogeneous haematopoietic malignancy. Currently, treatment options offer a 5 year survival of60%. In elderly patients, where the incidence is highest, the survival is much lower. Current standard treatments have significant toxicity and are least well tolerated in older adults, where the need is greatest. Therefore, alternatives are required. Monoclonal antibodies (mAbs), due to the specific targeting to cell surface proteins (i.e. antigens), represent a promising strategy for drug delivery to malignant cells. This concept favours the therapeutic ratio simultaneously by reducing toxicity and increasing efficacy. Although delivery of chemotherapeutics, genes and imaging agents using multifunctional nanoparticles has been substantially explored in treating solid cancers, less information on this approach is available in the case of AML. This review describes the development of antibody-targeted nanoparticulate drug delivery systems, and discusses the barriers to clinical translation in the treatment of AML.
- Published
- 2018
22. Proficiency-based progression intern training to reduce critical blood sampling errors including ‘wrong blood in tube’
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Noirin O' Herlihy, Sarah Griffin, Robert Gaffney, Patrick Henn, Ali S Khashan, Mary Ring, Anthony Gallagher, and Mary R Cahill
- Abstract
Background: Blood sampling errors including ‘wrong blood in tube’ (WBIT) may have adverse effects on clinical outcomes. WBIT errors occur when the blood sample in the tube is not that of the patient identified on the label. This study aims to determine the effect of proficiency-based progression (PBP) training in phlebotomy on the rate of blood sampling errors (including WBIT). Methods: A non-randomised controlled trial compared the blood sampling error rate of 43 historical controls who had not undergone PBP training in 2016 to 44 PBP trained interventional groups in 2017. In 2018, the PBP training programme was implemented and the blood sampling error rate of 46 interns was compared to the 43 historical controls in 2016. Data analysis was performed using logistic regression analysis adjusting for sample timing. Results: In 2016, 43 interns had a total blood sample error rate of 2.4%, compared to 44 interns in 2017, who had error rate of 1.2% (adjusted OR=0.50, 95% CI 0.36-0.70; Conclusions: The study demonstrates that PBP training in phlebotomy has the potential to reduce blood sampling errors. Trial registration number: NCT03577561
- Published
- 2021
23. Examining the Usefulness of the Charlson Comorbidity Index to Predict Early Mortality in Patients with Acute Myeloid Leukaemia
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Ruth Clifford, Philip Murphy, Conan Donnelly, Michael O'Dwyer, Nina Orfali, Paul Browne, Mohamed Bakri Mohamed, Ezzat El Hassadi, Vitaliy Mykytiv, Mary R. Cahill, Rose McMorrow, Seán R. Millar, Janusz Krawczyk, Oonagh Gilligan, Eamonn O'Leary, Eva Szegezdi, John Quinn, Paul M Walsh, and Peter O'Gorman
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,Charlson comorbidity index ,Immunology ,medicine ,In patient ,Cell Biology ,Hematology ,Myeloid leukaemia ,business ,Biochemistry - Abstract
Background and aims: Acute myeloid leukaemia (AML) is a relatively rare haematological malignancy which is the most common acute leukaemia in adults. Patients with AML often have a substantial comorbidity burden. Consequently, different scores are used in clinical practice to predict outcomes in patients with multiple comorbidities. The Charlson Comorbidity Index (CCI), calculated based on 19 different medical conditions, weighs the comorbidities to measure a patient's burden of disease. Previous publications have suggested that the CCI may be useful in determining survival in AML patients. However, the CCI is not in routine use in Ireland for assessing patients with AML. In this study we examined the usefulness of the CCI to predict early mortality in AML patients, drawing on data from the Extended Blood Cancer Registration (EBCR) in Ireland. Methods: The EBCR was undertaken by National Cancer Registry Ireland registrars trained by consultant haematologists and deployed in national centres. Data collection began in 2017 and continued to 2019; 141 AML patients underwent extended data registration. Comorbidities were identified by ICD-9 codes and chart review. Kaplan Meier curves and Cox regression analyses were used to determine the usefulness of the CCI to predict early mortality in AML patients. Results: Of the 141 AML patients, 82% were between 50 and 70 years of age and 84 had died by 31/12/2019 (median survival time = 289.0 days). The median survival time for patients in the lowest tertile of the CCI was 498.5 days, compared to 246.0 and 116.5 days for subjects in tertiles 2 and 3, respectively (Figure 1. Log rank P-value Conclusions: Although results demonstrate a strong relationship between the CCI and early mortality in AML patients, our findings suggest that the CCI provides little or no additional prognostic information beyond that which is obtained from age at AML diagnosis alone. This study highlights the importance of validating risk assessment tools in order to determine their potential usefulness in a clinical setting and emphasise the importance of weighing in the treatment decision making paradigm. The Blood Cancer Network Ireland (BCNI) thank the Science Foundation of Ireland (SFI) and the Irish Cancer Society (ICS) for funding (2015-2021). We also thank our colleagues in the National Cancer Registry Ireland for assistance, advice and guidance. Figure 1 Figure 1. Disclosures Quinn: Takeda: Honoraria. O'Dwyer: Bristol Myers Squibb: Research Funding; Janssen: Consultancy; ONK Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Szegezdi: ONK Therapeutics: Research Funding.
- Published
- 2021
24. Proficiency-based progression intern training to reduce critical blood sampling errors including ‘wrong blood in tube’
- Author
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Robert Gaffney, Mary Ring, Ali S. Khashan, Anthony G. Gallagher, Patrick Henn, Mary R. Cahill, Noirin O' Herlihy, and Sarah Griffin
- Subjects
030213 general clinical medicine ,Total blood ,medicine.medical_specialty ,business.industry ,Sampling error ,030204 cardiovascular system & hematology ,Phlebotomy ,Logistic regression ,Wrong blood in tube ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Emergency medicine ,Medicine ,Adverse effect ,business ,Blood sampling - Abstract
Background: Blood sampling errors including ‘wrong blood in tube’ (WBIT) may have adverse effects on clinical outcomes. WBIT errors occur when the blood sample in the tube is not that of the patient identified on the label. This study aims to determine the effect of proficiency-based progression (PBP) training in phlebotomy on the rate of blood sampling errors (including WBIT). Methods: A non-randomised controlled trial compared the blood sampling error rate of 43 historical controls who had not undergone PBP training in 2016 to 44 PBP trained interventional groups in 2017. In 2018, the PBP training programme was implemented and the blood sampling error rate of 46 interns was compared to the 43 historical controls in 2016. Data analysis was performed using logistic regression analysis adjusting for sample timing. Results: In 2016, 43 interns had a total blood sample error rate of 2.4%, compared to 44 interns in 2017, who had error rate of 1.2% (adjusted OR=0.50, 95% CI 0.36-0.70; Conclusions: The study demonstrates that PBP training in phlebotomy has the potential to reduce blood sampling errors. Trial registration number: NCT03577561
- Published
- 2021
25. Risk adjusted therapy in chronic lymphocytic leukemia: a phase II cancer trials Ireland (CTRIAL-IE [ICORG 07-01]) study of fludarabine, cyclophosphamide, and rituximab therapy evaluating response adapted, abbreviated frontline therapy with FCR in non-del(17p) CLL
- Author
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Mary R. Cahill, Kathleen Scott, Johanna Kelly, Hilary O'Leary, Michael O'Dwyer, Fiona Quinn, Andrew Hodgson, Elisabeth Vandenberghe, Niamh Appleby, Gerard Crotty, Brian Hennessy, Liam Smyth, Helen Enright, Imelda Parker, Maeve Leahy, Amjad Hayat, and David O'Brien
- Subjects
Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Cyclophosphamide ,Chronic lymphocytic leukemia ,DNA Mutational Analysis ,Immunophenotyping ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,In Situ Hybridization, Fluorescence ,Survival analysis ,Aged ,Neoplasm Staging ,Chromosome Aberrations ,business.industry ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Survival Analysis ,Minimal residual disease ,Surgery ,Fludarabine ,body regions ,Treatment Outcome ,030220 oncology & carcinogenesis ,Female ,Rituximab ,IGHV@ ,business ,Vidarabine ,Chromosomes, Human, Pair 17 ,030215 immunology ,medicine.drug - Abstract
Minimal residual disease negative complete response (MRD-negative CR) provides an early marker for time to treatment failure (TTF) in CLL treated with fludarabine, cyclophosphamide, and rituximab (FCR). MRD was assessed after four FCR cycles (FCR4); MRD-negative CR patients discontinued treatment. Fifty-two patients (35M; 17F) were enrolled. Eighteen (18/52; 34.6%) patients reached MRD-negative CR after FCR4 and 29/52 (55.8%) were MRD-negative CR at end of treatment (EOT). Median TTF was 71.1 months (95% CI 61.3-84.1 months), with median overall survival not reached. Mutated immunoglobulin heavy chain gene rearrangements (IGHV) were associated with early MRD-negative remissions, translating into prolonged TTF. Unmutated-IGHV, mutated-SF3B1 and mutated-NOTCH1 were associated with shortened TTF. No TTF difference was observed between patients in MRD-negative CR after four versus six cycles (82.2 versus 85.3 months, p = .6306). Abbreviated FCR therapy is effective for patients achieving early MRD-negative remissions. Interim MRD assessment assists in personalizing therapy and reducing chemotherapy-associated toxicity.
- Published
- 2017
26. Physician and practice characteristics associated with immunoglobulin test ordering
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Anthony P. Fitzgerald, Mary R. Cahill, Colin P Bradley, Sharon L Cadogan, and John Browne
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Male ,medicine.medical_specialty ,Attitude of Health Personnel ,Cross-sectional study ,Immunoglobulins ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,General Practitioners ,Surveys and Questionnaires ,medicine ,Humans ,030212 general & internal medicine ,Poisson regression ,Practice Patterns, Physicians' ,Retrospective Studies ,Primary Health Care ,Diagnostic Tests, Routine ,business.industry ,030503 health policy & services ,Retrospective cohort study ,Confidence interval ,Multilevel regression ,Test (assessment) ,Cross-Sectional Studies ,Family medicine ,symbols ,Female ,Immunoglobulin test ,0305 other medical science ,Family Practice ,business ,Ireland ,Test ordering - Abstract
Background Primary care test requests for serum immunoglobulins are rising rapidly, with concerns that many requests may be unnecessary. Evidence suggests some characteristics of general practitioners (GPs) and practices are associated with higher test ordering. Objective To identify the physician and practice characteristics associated with immunoglobulin test ordering. Methods Retrospective, cross-sectional study using routine laboratory data on primary care serum immunoglobulin requests. Data were linked with GP patient list size data. The primary outcome measure was the count of test requests per GP. Predictor variables were physician gender, years experience, practice region and type (number of GPs), GP patient list size and composition. Mixed-effects multilevel regression models were used to calculate incidence rate ratios (IRRs) with 95% confidence intervals (CIs) for the associations between physician and practice characteristics and GP requesting. Sensitivity analysis was performed by limiting the model to the more than 70 years age category. Results In total, 5990 immunoglobulin tests were ordered by 481 GPs in the South of Ireland during 2013. The number of tests ordered by individual GPs varied from one to 377. In the final fully adjusted Poisson regression analysis, female gender (IRR: 1.81; 95% CI: 1.45-2.26) and less experience (IRR: 2.27; 95% CI: 1.47-3.51) were associated with higher requesting (P < 0.001). None of the practice factors were associated with test ordering. Sensitivity analysis on the 70 years or more age category found similar results. Conclusion Further research is required to explore the potential reasons for higher requesting among GPs with fewer years of experience and also among female GPs.
- Published
- 2017
27. P76 Secular trends and costs of management of acute myeloid leukaemia: evidence from population-based cancer registration data
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R McMorrow, AO Ceilleachair, C Donnelly, and Mary R. Cahill
- Subjects
Chemotherapy ,Pediatrics ,medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,medicine.medical_treatment ,Cancer registration ,Disease ,Confidence interval ,Secular variation ,Transplantation ,Medicine ,Myeloid leukaemia ,business - Abstract
Background Acute myeloid leukaemia (AML) is an aggressive blood cancer that, left untreated, proves fatal within a short period. Though numbers diagnosed annually are relatively small, treatment costs from induction therapy through to clinical remission potentially are in excess of €200,000. We present, for the first time, using cancer registration data, evidence on trends in the incidence of AML for Ireland, together with an assessment of the costs of manging the disease. Methods Cancer registration data on individuals aged 20 years and older diagnosed with AML (ICD-10 C92.0) 1994–2013 were extracted from a population register. EASR and crude incidence rates were calculated with 95% confidence intervals by five-year age bands. Cases were assigned to one of four treatment pathways on the basis of patient characteristics. These were an intensive chemotherapy pathway, a pathway with bone marrow transplantation, a low intensity chemotherapy pathway and a best supportive care pathway. Resource use for each pathway was determined using clinical guidelines, the published literature and expert opinion. Costs were adjusted to 2016 prices. Results There were 1,675 cases of adult AML between 1993 and 2013 with 733 (44%) in women and 942 in men (56%). There was a statistically significant annual percentage change of 2.45% in the incidence of AML in men while incidence in women also increased significantly by 1.21% per year…The costs associated with intensive chemotherapy management were €89,750 per case while the costs for transplantation, low-intensity chemotherapy and best supportive care were €145,220, €11,790 and €12,745 respectively. The annual cost of managing AML in Ireland between 2010 and 2015 was on average €12.8 million. Conclusion The rising incidence of AML, together with improving survival means that more patients will be treated, achieve clinical remission and also require management for relapse. As novel treatments for this complex condition transition into practice, the costs of managing the disease will also rise. While routinely-collected cancer registration data can help to quantify this cost, better information on treatment patterns and recurrence will be necessary to accurately project and model the burden of this disease into the future.
- Published
- 2019
28. Educational intervention to optimise serum immunoglobulin test use in Irish primary care: an interrupted time series with segmented regression analysis
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Colin P Bradley, Anthony P. Fitzgerald, Sharon L Cadogan, Mary R. Cahill, and John Browne
- Subjects
Adult ,Male ,medicine.medical_specialty ,General Practice ,Immunoglobulins ,Primary care ,Interrupted Time Series Analysis ,03 medical and health sciences ,0302 clinical medicine ,Irish ,Intervention (counseling) ,Medicine ,Humans ,030212 general & internal medicine ,Segmented regression ,Practice Patterns, Physicians' ,Aged ,Hematologic Tests ,Primary Health Care ,business.industry ,030503 health policy & services ,Patient Selection ,Research ,Guideline ,Middle Aged ,language.human_language ,Confidence interval ,Test (assessment) ,Family medicine ,language ,Regression Analysis ,Female ,0305 other medical science ,Family Practice ,business ,Ireland - Abstract
BackgroundImplementation science experts recommend that theory-based strategies, developed in collaboration with healthcare professionals, have greater chance of success.AimThis study evaluated the impact of a theory-based strategy for optimising the use of serum immunoglobulin testing in primary care.Design and settingAn interrupted time series with segmented regression analysis in the Cork–Kerry region, Ireland. An intervention was devised comprising a guideline and educational messages-based strategy targeting previously identified GP concerns relevant to testing for serum immunoglobulins.MethodInterrupted time series with segmented regression analysis was conducted to evaluate the intervention, using routine laboratory data from January 2012 to October 2016. Data were organised into fortnightly segments (96 time points pre-intervention and 26 post-intervention) and analysed using incidence rate ratios with their corresponding 95% confidence intervals.ResultsIn the most parsimonious model, the change in trend before and after the introduction of the intervention was statistically significant. In the 1-year period following the implementation of the strategy, test orders were falling at a rate of 0.42% per fortnight (PConclusionThe authors’ tailored guideline combined with educational messages reduced serum immunoglobulin test ordering in primary care over a 1-year period. Given the rarity of the conditions for which the test is utilised and the fact that the researchers had only population-level data, further investigation is required to examine the clinical implications of this change in test-ordering patterns.
- Published
- 2019
29. Lentiviral-Mediated shRNA Approaches: Applications in Cellular Differentiation and Autophagy
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Nina Orfali, Tracey R. O’Donovan, Sharon L. McKenna, Dalyia Benjamin, Mary R. Cahill, Corinne L. Woodcock, Jennie N. Jeyapalan, Lorraine J. Gudas, and Nigel P. Mongan
- Subjects
0301 basic medicine ,Acute promyelocytic leukemia ,Cellular differentiation ,Autophagy ,Myeloid leukemia ,Biology ,medicine.disease ,Cell biology ,Small hairpin RNA ,03 medical and health sciences ,Leukemia ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Differentiation therapy ,030220 oncology & carcinogenesis ,medicine ,Bone marrow - Abstract
Acute myeloid leukemia (AML) is characterized by the accumulation of immature white blood cell precursors in the bone marrow and peripheral circulation. In essence, leukemic cells fail to differentiate and are stalled at a particular step of hematopoietic maturation and are unable to complete their development into functional blood cells with a finite life cycle. They are thus said to possess a "differentiation block." Pharmacological override of this block is one attractive avenue of therapy, termed "differentiation therapy." The most successful example of this therapeutic strategy is the use of the physiologic retinoid all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). In this chapter, we will outline the methods used to characterize the mechanisms mobilized by retinoid signaling and will use the activation of a key regulator of autophagy, ATG7, as an example of the functional characterization of a retinoid regulated gene during differentiation. We will discuss how lentiviral delivery of shRNA constructs into cultured APL cells, such as NB4, can be used to functionally deplete key proteins. We will also describe how the effect of protein knockdown on ATRA-induced differentiation and autophagy can be assessed using quantitative PCR, Western blotting, and flow cytometry.
- Published
- 2019
30. Cybord-Dara Is a Highly Effective Upfront Treatment for Newly Diagnosed Multiple Myeloma. Initial Efficacy Results of the 16-Bcni-001/Ctrial-IE (ICORG) 16-02 Study
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Mary R. Cahill, Emma Kinsella, Alessandro Natoni, Elizabeth Lenihan, John Quinn, Andres Hernando, Jessica Walsh, Imelda Parker, Grainne Gannon, Vitaliy Mykytiv, Grace Hirakata, Philip Murphy, Tara Kenny, Robert Henderson, and Michael O'Dwyer
- Subjects
Oncology ,medicine.medical_specialty ,Intention-to-treat analysis ,business.industry ,medicine.medical_treatment ,Immunology ,Daratumumab ,Cell Biology ,Hematology ,Neutropenia ,medicine.disease ,Biochemistry ,Minimal residual disease ,Transplantation ,Regimen ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,business ,Neoadjuvant therapy - Abstract
Introduction : Daratumumab (DARA), a human IgG1k monoclonal antibody with single activity in multiple myeloma (MM) shows strong synergy in combination with other anti-MM agents, including immunomodulatory drug (IMiDs) and proteasome inhibitors (PI). This has led to the exploration of DARA in combination with front line regimens. Triplets including a PI and an IMiD are considered an ideal backbone with which to combine DARA prior to Autologous Stem Cell Transplantation (ASCT). However, based on the ability of Cyclophosphamide (Cy) to enhance DARA mediated antibody dependent cellular phagocytosis, we hypothesized that CyBorD may provide an alternative option (Naicker, ASH 2017). We are currently exploring the preliminary safety and efficacy of CyBorD and DARA as part of an ongoing phase 1b study in newly diagnosed MM (NDMM) pts eligible for ASCT. Last year we reported on the safety of this combination with an absence of dose limiting toxicity (DLT) with weekly subcutaneous (SQ) Bortezomib (Bor) 1.5mg/m2, Cy 300mg/m2 and DARA 16mg/kg (McEllistrim, ASH 2017). We now report on the efficacy of this regimen as pre-transplant induction, including the rate of CR post ASCT. Methods : Pts received 4 cycles of induction therapy with weekly CyBorD and DARA 16mg/kg weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Following induction therapy, pts proceeded to stem cell mobilization and ASCT followed by 2 cycles of consolidation therapy with weekly CyBorD plus DARA 16mg/kg on days 1 and 15. Following completion of consolidation therapy, all pts receive DARA maintenance every 28-days for 2 yrs or until progression, unacceptable toxicity or withdrawal of consent. Pts with high-risk features receive Bor on days 1 and 15 during maintenance phase. The primary endpoints were the incidence of DLT within the first cycle of combination at each dose level and CR rate post ASCT. Secondary endpoints included: safety, CR rate at the end of induction, consolidation and maintenance, best overall response, minimal residual disease (MRD) negative rate, progression-free survival, clinical benefit rate and overall survival. Responses were investigator-assessed as per IMWG criteria. This trial is registered at www.clinicaltrials.gov as NCT02955810. Results : Eighteen pts were enrolled between Nov 2016 and Dec 2017 and received at least 1 dose of treatment. Baseline characteristics were: median age = 56 y (range 32-66); M (61%), F (39%), ISS stage I, II, III in 78%, 17% and 6% of pts, respectively. 28% patients were identified with high risk genetic features [17p deletion and/or t(4;14) by FISH and/or SKY92 (SkylineDx)]. Three patients discontinued therapy early (primary refractory, persistent liver toxicity, death, respectively). Overall, treatment was well tolerated. The most common grade (gr) 3/4 hematologic treatment emergent adverse events (TEAE) were lymphopenia (44%), neutropenia (11%) and anemia (11%). The most common gr 3/4 non-hematologic TEAE were diarrhea (11%) and infection (61%). One patient died from gr 5 diffuse alveolar damage 7 weeks post ASCT. A single patient developed gr 3 liver toxicity. DARA-associated infusion reactions were ≤ gr 2 (11%). On an intent to treat (ITT) basis 94% achieved ≥ very good partial response (VGPR) with ≥ complete response (CR) in 44% pts (Figure). Among the sixteen patients completing 4 cycles of induction ORR was 100%, ≥ VGPR (69%), ≥ CR (13%). Informative NGS data (Adaptive Biotech) are available on 11/16 patients post induction, of whom 100% are MRD negative post induction at a level of ≥ 10e4. Following the induction phase 15/16 patients readily mobilized sufficient CD34 positive progenitors and proceeded to ASCT, one patient failed repeated mobilization. One patient died prior to post ASCT response assessment and data on the last patient is pending. Thus 13/15 patients are currently evaluable for response post ASCT. Responses deepened post ASCT with 100% achieving ≥ VGPR and 62% achieving ≥ CR. Based on EBMT criteria the CR/nCR rate post ASCT was 92%. Post ASCT PET-CT scans were consistent with complete metabolic response in all 13 patients. Updated results, including MRD status post ASCT will be presented at the meeting. Conclusions: CyBorD-DARA is a highly active, well tolerated induction therapy for NDMM patients undergoing ASCT. These data support the further development of this combination as a convenient, cost effective alternative to PI-IMiD-DARA based combinations. Disclosures Quinn: Janssen: Honoraria. O'Dwyer:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Glycomimetics: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding.
- Published
- 2018
31. RNA interference for multiple myeloma therapy: targeting signal transduction pathways
- Author
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Mary R. Cahill, Jianfeng Guo, Michael O'Dwyer, Sharon L. McKenna, and Caitriona M. O'Driscoll
- Subjects
0301 basic medicine ,Cell Survival ,Clinical Biochemistry ,Down-Regulation ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Cell Movement ,RNA interference ,Drug Discovery ,microRNA ,Tumor Microenvironment ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Multiple myeloma ,Pharmacology ,Tumor microenvironment ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Disease Progression ,Cancer research ,Molecular Medicine ,RNA Interference ,Bone marrow ,Signal transduction ,Multiple Myeloma ,Signal Transduction - Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by infiltration of malignant plasma cells in the bone marrow (BM) and end-organ damage to the bone, BM, kidney and immune system. Although current treatments have improved the treatment of MM, it still remains an incurable disease. RNA interference (RNAi) effectors such as microRNAs and small interference RNAs have shown potential to selectively downregulate genes implicated in the pathology of a range of diseases. Signaling pathways that facilitate growth, survival and migration of MM cells, provide resistance to conventional therapies, and therefore, target these signaling pathways will prove promising for MM treatment.This review focuses on signaling pathways associated with the development of myeloma cells and how interaction of these cells with the tumor microenvironment impacts disease progression. Together these elements provide potential therapeutic targets for RNAi in the future.Recent advances in oncogenomic studies have revealed the molecular pathogenesis of MM, thus providing new therapeutic targets for RNAi therapy. Pre-clinical evidence suggests that non-viral delivery technology offers the potential to translate this concept into the next generation of RNAi-based therapeutics for MM.
- Published
- 2015
32. Antibody-Targeted Cyclodextrin-Based Nanoparticles for siRNA Delivery in the Treatment of Acute Myeloid Leukemia: Physicochemical Characteristics, in Vitro Mechanistic Studies, and ex Vivo Patient Derived Therapeutic Efficacy
- Author
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Caitriona M. O'Driscoll, Jianfeng Guo, Thomas G. Cotter, Eileen G. Russell, Sharon L. McKenna, Raphael Darcy, and Mary R. Cahill
- Subjects
0301 basic medicine ,Small interfering RNA ,Pharmaceutical Science ,Down-Regulation ,Apoptosis ,Biology ,Antibodies ,03 medical and health sciences ,Antigen ,RNA interference ,hemic and lymphatic diseases ,Cell Line, Tumor ,Drug Discovery ,medicine ,Humans ,RNA, Small Interfering ,Acute leukemia ,Cyclodextrins ,Cytarabine ,Myeloid leukemia ,Cell Differentiation ,medicine.disease ,Receptors, Interleukin-3 ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,Immunology ,Cancer research ,Neoplastic Stem Cells ,Molecular Medicine ,Nanoparticles ,Interleukin-3 receptor ,Stem cell ,K562 Cells ,Transcription Factors - Abstract
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults and is associated with high relapse rates. It is known that leukemia stem cells (LSCs), a very small subpopulation of the total number of leukemic cells, maintain the leukemia phenotype (∼80-90% of AML remain the same as at first diagnosis), display chemotherapy resistance, and contribute to disease regeneration. Therefore, targeting LSCs could control the relapse of AML. Small interfering RNA (siRNA), an effector of the RNA interference (RNAi) pathway, can selectively downregulate any gene implicated in the pathology of disease, presenting great potential for treatment of AML. In this study an antibody targeted cyclodextrin-based nanoparticle (NP) (CD.DSPE-PEG-Fab) was developed for siRNA delivery specifically to AML LSCs. The targeted CD.siRNA.DSPE-PEG-Fab formulation, where Fab specifically targets the IL-3 receptor α-chain (IL-3Rα, also known as CD123, a cell surface antigen for human AML LSCs), achieved antigen-mediated cellular uptake in KG1 cells (an AML leukemia stem and progenitor cell line). Efficient delivery of bromodomain-containing protein 4 (BRD4) siRNA using the targeted formulation resulted in downregulation of the corresponding mRNA and protein in KG1 cells and in ex vivo primary AML patient derived samples. The resulting silencing of BRD4 induced myeloid differentiation and triggered leukemia apoptosis. In addition, a synergistic therapeutic effect was detected when administered in combination with the chemotherapeutic, cytarabine (Ara-C). These results indicate the clinical potential of the antibody-tagged cyclodextrin NP for targeted delivery of therapeutic siRNA in the treatment of AML.
- Published
- 2017
33. Retinoid receptor signaling and autophagy in acute promyelocytic leukemia
- Author
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Lorraine J. Gudas, Nigel P. Mongan, Sharon L. McKenna, Nina Orfali, and Mary R. Cahill
- Subjects
Acute promyelocytic leukemia ,Cell signaling ,Receptors, Retinoic Acid ,medicine.drug_class ,Cellular differentiation ,Retinoid receptor ,Retinoid X receptor ,Biology ,Article ,Retinoids ,Leukemia, Promyelocytic, Acute ,immune system diseases ,Differentiation therapy ,Autophagy ,medicine ,Animals ,Humans ,Retinoid ,neoplasms ,Cell Differentiation ,Cell Biology ,medicine.disease ,Hematopoiesis ,Cancer research ,Signal Transduction - Abstract
Retinoids are a family of signaling molecules derived from Vitamin A with well established roles in cellular differentiation. Physiologically active retinoids mediate transcriptional effects on cells through interactions with retinoic acid (RARs) and retinoid-X (RXR) receptors. Chromosomal translocations involving the RARα gene, which lead to impaired retinoid signaling, are implicated in acute promyelocytic leukemia (APL). All-trans-retinoic acid (ATRA), alone and in combination with arsenic trioxide (ATO), restores differentiation in APL cells and promotes degradation of the abnormal oncogenic fusion protein through several proteolytic mechanisms. RARα fusion-protein elimination is emerging as critical to obtaining sustained remission and long-term cure in APL. Autophagy is a degradative cellular pathway involved in protein turnover. Both ATRA and ATO also induce autophagy in APL cells. Enhancing autophagy may therefore be of therapeutic benefit in resistant APL and could broaden the application of differentiation therapy to other cancers. Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies.
- Published
- 2014
34. Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation
- Author
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Mary R. Cahill, Loveena Rishi, Caitriona O'Connor, Jennifer Timoney, Marie Sigurd Hasemann, Karen Keeshan, Joana Campos, Mara Salome, Bo T. Porse, Maura Hannon, and Anne-Katrine Frank
- Subjects
Chromatin Immunoprecipitation ,endocrine system ,Immunology ,Electrophoretic Mobility Shift Assay ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Mice ,hemic and lymphatic diseases ,Animals ,Humans ,E2F1 ,Progenitor cell ,Transcription factor ,Cell Proliferation ,Feedback, Physiological ,Mice, Knockout ,Ccaat-enhancer-binding proteins ,Cell growth ,Intracellular Signaling Peptides and Proteins ,E2F1 Transcription Factor ,3T3 Cells ,Cell Biology ,Hematology ,Cell cycle ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Cell Transformation, Neoplastic ,CCAAT-Enhancer-Binding Proteins ,Cancer research ,biological phenomena, cell phenomena, and immunity - Abstract
The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C/EBPα-p42, and in normal granulocyte/macrophage progenitor cells, we detect C/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.
- Published
- 2014
35. Should Myelodysplastic Syndromes in Very Old Patients be More Actively Managed? Clinical Characteristics, Management and Outcomes for Patients 85 Years and Older
- Author
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Daniel H. Ryan, Laura McDonald, Peter McCarthy, Mohammad Khan, Johnny McHugh, Melanie Strickland, Mary R. Cahill, Vitaliy Mykytiv, Patrick Hogan, Ronan Desmond, Desmond O'Neill, Eileen Kelleher, Philip Murphy, John Quinn, Su Wai Maung, Clodagh Keohane, and Helen Enright
- Subjects
Gastrointestinal bleeding ,Pediatrics ,medicine.medical_specialty ,Cytopenia ,Anemia ,business.industry ,Myelodysplastic syndromes ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Pancytopenia ,Chemotherapy regimen ,Pharmacotherapy ,medicine ,business ,Lenalidomide ,medicine.drug - Abstract
Introduction Myelodysplastic Syndrome (MDS) is classically a disease of older people, with median age at presentation of 70-75 years. The incidence of MDS is estimated at 5-13/100,000/year, but rises to >20/100,000/year in older populations. An increase in diagnosis over the last decades is in part due to improved recognition of MDS, but likely also to an increase in the ageing population. There is very little data on the clinical course, management and outcomes for very old patients (≥85 years of age) with MDS. Patients and Methods: This was a retrospective, multicentre analysis of 84 patients with MDS or Chronic Myelomonocytic Leukemia (CMML) aged ≥85 years at diagnosis from 6 centres in Ireland. Results: We identified 84 patients aged ≥85 years at time of diagnosis of MDS (n= 70) or CMML (n=14), including 47 men (56%) and 37 women (44%). Median age at diagnosis was 87 years (range 85-98). Most patients (93%) were anemic at presentation, including 45/47 men (96%) and 33/37 women (89%). Median hemoglobin (Hb) was 9.5 g/dl (range 5.9 -13.8). Median neutrophil count was 2.4 x109/L (range 0-72). Forty-four patients had thrombocytopenia (median platelet count 144 x 109/L (range 18-624)). Data regarding co-morbidities were available for 75 patients: 69% had hypertension, 36% ischemic heart disease, 39% atrial fibrillation, 31% heart failure, 19% diabetes and 39% renal dysfunction. Ferritin was elevated in 18 (32%) of 57 patients tested. 2006 WHO subgroups were reported for 81 patients: RCMD (32; 40%), CMML (14; 17%), RA (10; 12%), RAEB-1 (10; 12%), RAEB-2 (7; 9%), RARS (2; 3%), t-MDS (2; 3%), Hypoplastic MDS (1; 1%) and 5q- Syndrome (1; 1%). Cytogenetic analysis was performed in 49 patients (58%); results were available for 39 (46%). No patient had molecular studies for MDS-associated mutations or p53 deletions/mutations. Karyotype was normal in 23 patients (59% of those with results available), deletion Y in 5 (13%), Trisomy 8 in 5 (13%), complex in 3 (7.7%), 5q- in 2 (5.2%), and monosomy 7 in 1 (2.5%). Risk stratification by IPSS-R was available for only 37/84 patients, primarily due to lack of cytogenetic testing. Data were available regarding treatment strategies for 81 patients. Thirty-five (43%) received supportive care only. Forty-five patients (57%) were transfused; 29 (34%) became transfusion-dependent during the course of their disease. Of these, only 14 (48%) received erythropoietin (EPO). Of 50 patients with significant anemia likely to cause symptoms (Hb < 10g/dl), only 21 (42%) received EPO. Five patients (6%) received azacitidine (1-18 cycles; median 5), 7 (8%) received G-CSF; none received lenalidomide or iron chelation. Median survival for all patients was 17 months (range 0-147), 16 months for men (range 0-70), and 27 months for women (range 1-147). In 35 patients who had IPSS-R data available, median survival was 49 months for Very Good, 30 months for Good and 13 months for Intermediate category patients. For 4 patients in the Poor and Very Poor categories median survival was 1, 5, 7 and 28 months. Median survival for patients with RA was 28 months (n=10), RCMD 25 months (n=29), CMML 13 months (n= 14), RAEB-1 10 months (n=10) and RAEB-2 19 months (n=7). Six patients (including 3 with RAEB-1, 1 with CMML and 1 with t-MDS) developed Acute Myeloid Leukaemia (7%) at a median of 4.5 months from diagnosis. Median survival for these patients was 9.5 months. Of 84 patients, 60 have died. The main causes of death included marrow failure, sepsis, cardiac events, other malignancies and gastrointestinal bleeding. Conclusions Anemia is the commonest presenting feature of MDS in the very old, and may be the sole cytopenia. Unexplained anemia in the very old should trigger suspicion of underlying MDS, especially if associated with a high MCV. In many patients over 85 years cytogenetic analysis is not performed, precluding accurate prognostic evaluation. MDS in these very old patients is not often actively managed with pharmacological intervention or chemotherapy. Up to 50% of transfusion-dependent patients do not receive erythropoeitin. Azacitidine and lenalidomide are infrequently used. Co-morbidities (especially cardiac and renal disorders) are very common. Survival can be prolonged, especially in patients with low-risk disease. With an ageing population, management of very elderly patients with MDS is becoming more challenging and a more proactive approach should be considered. Figure. Figure. Disclosures Quinn: Janssen: Honoraria.
- Published
- 2018
36. A multi-centre retrospective study of rituximab use in the treatment of relapsed or resistant warm autoimmune haemolytic anaemia
- Author
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Michael O'Dwyer, Maeve Leahy, Oonagh Gilligan, Denis O'Keeffe, Larry Bacon, Irfan Khan, Brian Hennessy, Mary Ryan, Jean Saunders, Matthew Goodyer, Mary R. Cahill, Philip Murphy, Aisling Nee, Suzanne McPherson, Su Wai Maung, Hilary O'Leary, Peter O'Gorman, Helen Enright, Fred Jackson, and Johnny McHugh
- Subjects
Adult ,Male ,safety ,medicine.medical_specialty ,Adolescent ,multicentre ,efficacy ,retrospective ,adult patients ,splenectomy ,Sepsis ,Antibodies, Monoclonal, Murine-Derived ,Young Adult ,rituximab ,Recurrence ,Internal medicine ,medicine ,Humans ,Immunologic Factors ,Initial treatment ,Multi centre ,Complete response ,Aged ,Retrospective Studies ,Aged, 80 and over ,therapy ,business.industry ,Secondary warm autoimmune haemolytic anaemia ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Surgery ,Treatment Outcome ,Female ,autoimmune haemolytic anaemia ,Rituximab ,Anemia, Hemolytic, Autoimmune ,Post treatment ,business ,Ireland ,medicine.drug - Abstract
This retrospective analysis assessed the response, safety and duration of response to standard dose rituximab 375 mg/m(2) weekly for four weeks as therapy for patients with primary or secondary warm autoimmune haemolytic anaemia (WAIHA), who had failed initial treatment. Thirty-four patients received rituximab for WAIHA in seven centres in the Republic of Ireland. The overall response rate was 70 center dot 6% (24/34) with 26 center dot 5% (9/34) achieving a complete response (CR). The time to response was 1 month post-initiation of rituximab in 87 center dot 5% (21/24) and 3 months in 12 center dot 5% (3/24) of patients. The median duration of follow-up was 36 months (range 6-90 months). Of the patients who responded, 50% (12/24) relapsed during follow up with a median time to next treatment of 16 center dot 5 months (range 6-60 months). Three patients were re-treated with rituximab 375 mg/m2 weekly for four weeks at relapse and responded. There was a single episode of neutropenic sepsis. Rituximab is an effective and safe treatment for WAIHA but a significant number of patients will relapse in the first two years post treatment. Re-treatment was effective in a small number of patients, suggesting that intermittent pulse treatment or maintenance treatment may improve long-term response.
- Published
- 2013
37. Induction of autophagy by Imatinib sequesters Bcr-Abl in autophagosomes and down-regulates Bcr-Abl protein
- Author
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Sharon L. McKenna, Michelle J. Nyhan, Lisa C. Crowley, Baukje M. Elzinga, Tracey R. O’Donovan, and Mary R. Cahill
- Subjects
Proteasome Endopeptidase Complex ,medicine.drug_class ,GABARAP ,Fusion Proteins, bcr-abl ,Down-Regulation ,Biology ,Transfection ,Piperazines ,Tyrosine-kinase inhibitor ,Mice ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Phagosomes ,hemic and lymphatic diseases ,Autophagy ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Protein Kinase Inhibitors ,neoplasms ,Adenine ,Membrane Proteins ,Imatinib ,Hematology ,Cell biology ,Pyrimidines ,Imatinib mesylate ,Gene Knockdown Techniques ,Benzamides ,Imatinib Mesylate ,Cancer research ,Beclin-1 ,Signal transduction ,Apoptosis Regulatory Proteins ,K562 Cells ,Tyrosine kinase ,Signal Transduction ,medicine.drug ,K562 cells - Abstract
Chronic Myeloid Leukemia (CML) is a disease of hematopoietic stem cells which harbor the chimeric gene Bcr-Abl. Expression levels of this constitutively active tyrosine kinase are critical for response to tyrosine kinase inhibitor treatment and also disease progression, yet the regulation of protein stability is poorly understood. We have previously demonstrated that imatinib can induce autophagy in Bcr-Abl expressing cells. Autophagy has been associated with the clearance of large macromolecular signaling complexes and abnormal proteins, however, the contribution of autophagy to the turnover of Bcr-Abl protein in imatinib treated cells is unknown. In this study, we show that following imatinib treatment, Bcr-Abl is sequestered into vesicular structures that co-localize with the autophagy marker LC3 or GABARAP. This association is inhibited by siRNA mediated knockdown of autophagy regulators (Beclin 1/ATG7). Pharmacological inhibition of autophagy also reduced Bcr-Abl/LC3 co-localization in both K562 and CML patient cells. Bcr-Abl protein expression was reduced with imatinib treatment. Inhibition of both autophagy and proteasome activity in imatinib treated cells was required to restore Bcr-Abl protein levels to those of untreated cells. This ability to down-regulate Bcr-Abl protein levels through the induction of autophagy may be an additional and important feature of the activity of imatinib.
- Published
- 2013
38. A novel 33-Gene targeted resequencing panel provides accurate, clinical-grade diagnosis and improves patient management for rare inherited anaemias
- Author
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Helene Dreau, Doug Higgs, Jonathan O. Cullis, Avery Mixon, Joaquin Sanchez Garcia, Brenda Gibson, Mary Morgan, Edward A. Wilson, Christian Babbs, Juliana Teo, Joanne Mason, Amrana Qureshi, Shirley Henderson, Ulf Tedgård, Irene Roberts, Peter Carey, Noémi B. A. Roy, Anna Schuh, Wale Atoyebi, Katherine Wray, Georgina W. Hall, David Roberts, Steven Okoli, Nongnuch Sirachainan, Melanie Proven, David J. P. Ferguson, Julie Curtin, and Mary R. Cahill
- Subjects
Male ,Congenital dyserythropoietic anaemia ,medicine.medical_specialty ,next‐generation sequencing ,Bioinformatics ,Polymorphism, Single Nucleotide ,Workflow ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Rare Diseases ,Molecular genetics ,congenital dyserythropoietic anaemia ,Medicine ,Humans ,Red Cells and Iron ,Genetic Predisposition to Disease ,Genetic Testing ,Medical diagnosis ,Gene ,Genetic Association Studies ,Sanger sequencing ,pyruvate kinase deficiency ,business.industry ,Diagnostic test ,Computational Biology ,Disease Management ,High-Throughput Nucleotide Sequencing ,Infant ,Reproducibility of Results ,Clinical grade ,Anemia ,Hematology ,Patient management ,inherited anaemia ,030220 oncology & carcinogenesis ,molecular genetics ,Mutation ,symbols ,next-generation sequencing ,business ,Research Paper ,030215 immunology - Abstract
Summary Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next‐generation‐sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical‐grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically‐reliable diagnostic test and minimize false‐negative results we developed an open‐source tool (CoverMi) to accurately determine base‐coverage and the ‘discoverability’ of known mutations for every sample. We validated our 33‐gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS‐based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.
- Published
- 2016
39. Current Practice in the Treatment of Haemophilia
- Author
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Mary R. Cahill and B. T. Colvin
- Subjects
Pediatrics ,medicine.medical_specialty ,Evidence-based practice ,business.industry ,Current practice ,hemic and lymphatic diseases ,medicine ,Hematology ,business ,Haemophilia ,medicine.disease ,Intensive care medicine - Abstract
Haematologists are long standing proponents of evidence based practice-well exemplified among professionals who care for patients with haemophilia. The rapidly expanding range of therapeutic products and the numerous accompanying clinical trials are swiftly interpreted and translated into clinical practice. This translation is formalised by frequently updated quidelines issued by the United Kingdom Haemophilia Centre Directors' Organisation (UKHCDO) and relevant to all doctors involved in the care of patients with haemophilia. In the last five years eight sets of guidelines have been issued in the UK alone relating to the treatment of haemophilia and its complications [1-8]. Against this background we aim to review current practice in the treatment of haemophilia.
- Published
- 2016
40. The effectiveness of interventions to improve laboratory requesting patterns among primary care physicians: a systematic review
- Author
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Colin P Bradley, John Browne, Sharon L Cadogan, and Mary R. Cahill
- Subjects
Inservice Training ,REMINDER MESSAGES ,UNCERTAINTY ,Cochrane Library ,Laboratory testing ,Practice Patterns, Physicians' ,Interventions ,Diagnostic Techniques and Procedures ,Medicine(all) ,education.field_of_study ,Health Policy ,Health services research ,Behaviour change ,General Medicine ,11 Medical And Health Sciences ,RANDOMIZED CONTROLLED-TRIAL ,GENERAL-PRACTITIONERS ,Primary care ,Systematic review ,Policy ,Practice Guidelines as Topic ,Health Policy & Services ,Life Sciences & Biomedicine ,medicine.medical_specialty ,Referral ,STRATEGIES ,Formative Feedback ,Reminder Systems ,Population ,Health Informatics ,Physicians, Primary Care ,medicine ,Humans ,education ,EDUCATION-PROGRAM ,08 Information And Computing Sciences ,Science & Technology ,DIAGNOSTIC-TESTS ,FEEDBACK ,business.industry ,Clinical study design ,Primary care physician ,Public Health, Environmental and Occupational Health ,Evidence-based medicine ,Healthcare interventions ,Health Care Sciences & Services ,Family medicine ,HEALTH-CARE ,Systematic Review ,AUDIT ,business - Abstract
Background Laboratory testing is an integral part of day-to-day primary care practice, with approximately 30 % of patient encounters resulting in a request. However, research suggests that a large proportion of requests does not benefit patient care and is avoidable. The aim of this systematic review was to comprehensively search the literature for studies evaluating the effectiveness of interventions to improve primary care physician use of laboratory tests. Methods A search of PubMed, Cochrane Library, Embase and Scopus (from inception to 09/02/14) was conducted. The following study designs were considered: systematic reviews, randomised controlled trials (RCTs), controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series analysis (ITSs). Studies were quality appraised using a modified version of the Effective Practice and Organisation of Care (EPOC) checklist. The population of interest was primary care physicians. Interventions were considered if they aimed to improve laboratory testing in primary care. The outcome of interest was a volume of laboratory tests. Results In total, 6,166 titles and abstracts were reviewed, followed by 87 full texts. Of these, 11 papers were eligible for inclusion in the systematic review. This included four RCTs, six CBAs and one ITS study. The types of interventions examined included education, feedback, guidelines, education with feedback, feedback with guidelines and changing order forms. The quality of included studies varied with seven studies deemed to have a low risk of bias, three with unclear risk of bias and one with high risk of bias. All but one study found significant reductions in the volume of tests following the intervention, with effect sizes ranging from 1.2 to 60 %. Due to heterogeneity, meta-analysis was not performed. Conclusions Interventions such as educational strategies, feedback and changing test order forms may improve the efficient use of laboratory tests in primary care; however, the level of evidence is quite low and the quality is poor. The reproducibility of findings from different laboratories is also difficult to ascertain from the literature. Some standardisation of both interventions and outcome measures is required to enable formal meta-analysis. Electronic supplementary material The online version of this article (doi:10.1186/s13012-015-0356-4) contains supplementary material, which is available to authorized users.
- Published
- 2015
41. Can mean platelet component be used as an index of platelet activity in stable coronary artery disease?
- Author
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John Cooke, Eugene P. McFadden, Mary R. Cahill, Mairead O'Reilly, and Tracy Murphy
- Subjects
Blood Platelets ,Male ,medicine.medical_specialty ,Acute coronary syndrome ,Coronary Artery Disease ,Coronary Angiography ,Coronary artery disease ,immune system diseases ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Platelet activation ,Prospective cohort study ,Hematology ,Platelet Count ,Vascular disease ,business.industry ,Case-control study ,Middle Aged ,Flow Cytometry ,Platelet Activation ,medicine.disease ,Thrombosis ,P-Selectin ,Case-Control Studies ,Cardiology ,Female ,business - Abstract
Acute coronary syndrome is associated with intracoronary thrombosis secondary to platelet activation. Previous groups have investigated platelet activation in both stable and unstable vascular disease. Most measures of platelet activation are not routinely available or easily adaptable to large scale clinical use. Recently, measurement of the mean platelet component (MPC) has become part of the routine data provided by an automated full blood count analyser, the Advia 120. MPC measures platelet density which changes on platelet activation. Our objectives were to determine if platelet activation, as measured by MPC, is increased in patients with stable coronary artery disease (CAD) and to determine if MPC could be useful in differentiating people with stable CAD from controls on an everyday clinical basis. Three hundred and forty-five consecutive patients attending for elective coronary angiography had full blood count analysis and MPC measurement performed using an ADVIA-120 analyser. Three hundred and twenty-four were analysed in our final dataset. Two hundred and fifty-three (78%) had CAD. Patients with CAD were significantly (p
- Published
- 2009
42. Smoking as an independent risk factor for macrocytosis in middle-aged adults: a population-based observational study
- Author
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Maeve A, O'Reilly, Seán R, Millar, Claire M, Buckley, Janas M, Harrington, Ivan J, Perry, and Mary R, Cahill
- Subjects
Erythrocyte Indices ,Male ,Erythrocytes ,Smoking ,Erythrocytes, Abnormal ,Middle Aged ,Hematologic Diseases ,Vitamin B 12 ,Cross-Sectional Studies ,Folic Acid ,Risk Factors ,Humans ,Female ,Anemia, Macrocytic ,Aged - Published
- 2015
43. Induction of autophagy is a key component of all-trans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacological modulation
- Author
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Sharon L. McKenna, Michelle J. Nyhan, Mary R. Cahill, Lorraine J. Gudas, Nina Orfali, Adrian Britschgi, Nigel P. Mongan, Mario P. Tschan, and Tracey R. O’Donovan
- Subjects
Acute promyelocytic leukemia ,Cancer Research ,Myeloid ,Cellular differentiation ,Antineoplastic Agents ,HL-60 Cells ,Tretinoin ,Ubiquitin-Activating Enzymes ,Protein degradation ,Biology ,Differentiation, Autophagy, Myeloid Leukemia, ATRA, Promyelocytic Leukemia ,Autophagy-Related Protein 7 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Leukemia, Promyelocytic, Acute ,hemic and lymphatic diseases ,Genetics ,medicine ,Autophagy ,Humans ,610 Medicine & health ,Molecular Biology ,neoplasms ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,Adenine ,Microfilament Proteins ,Myeloid leukemia ,Cell Differentiation ,Chloroquine ,Cell Biology ,Hematology ,Autophagy-Related Protein 8 Family ,medicine.disease ,Cell biology ,Neoplasm Proteins ,Leukemia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Antirheumatic Agents ,Microtubule-Associated Proteins ,Granulocytes - Abstract
Acute myeloid leukemia (AML) is characterized by the accumulation of immature blood cell precursors in the bone marrow. Pharmacologically overcoming the differentiation block in this condition is an attractive therapeutic avenue, which has achieved success only in a subtype of AML, acute promyelocytic leukemia (APL). Attempts to emulate this success in other AML subtypes have thus far been unsuccessful. Autophagy is a conserved protein degradation pathway with important roles in mammalian cell differentiation, particularly within the hematopoietic system. In the study described here, we investigated the functional importance of autophagy in APL cell differentiation. We found that autophagy is increased during all-trans-retinoic acid (ATRA)-induced granulocytic differentiation of the APL cell line NB4 and that this is associated with increased expression of LC3II and GATE-16 proteins involved in autophagosome formation. Autophagy inhibition, using either drugs (chloroquine/3-methyladenine) or short-hairpin RNA targeting the essential autophagy gene ATG7, attenuates myeloid differentiation. Importantly, we found that enhancing autophagy promotes ATRA-induced granulocytic differentiation of an ATRA-resistant derivative of the non-APL AML HL60 cell line (HL60-Diff-R). These data support the development of strategies to stimulate autophagy as a novel approach to promote differentiation in AML.
- Published
- 2015
44. Detection of Aspirin Resistance by PFA-100: Prevalence and Aspirin Compliance in Patients with Chronic Stable Angina
- Author
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Mary R. Cahill, Syed Abbas, Jacob de Haan, Brendan Meany, and Basil H. Crowe
- Subjects
Adult ,Male ,medicine.medical_specialty ,Time Factors ,Platelet Function Tests ,Myocardial Infarction ,Angina Pectoris ,Reference Values ,Internal medicine ,Prevalence ,medicine ,Humans ,cardiovascular diseases ,Platelet activation ,Myocardial infarction ,Stroke ,Aged ,Aged, 80 and over ,Aspirin ,Nitrates ,Unstable angina ,business.industry ,PFA-100 ,Hematology ,Middle Aged ,medicine.disease ,Salicylates ,Surgery ,Coronary arteries ,medicine.anatomical_structure ,Case-Control Studies ,Concomitant ,Cardiology ,Patient Compliance ,Female ,Cardiology and Cardiovascular Medicine ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Most acute coronary syndromes result from a platelet-rich occlusion of the coronary arteries. Antiplatelet drugs are of proven efficacy in preventing myocardial infarction, unstable angina, and stroke. However, not all patients on aspirin (ASA) benefit. We studied the phenomenon of aspirin resistance with a simple and reliable platelet function analyzer--the PFA-100. Studying 31 patients with unstable angina and 105 controls, we found aspirin resistance in 42% of patients, most of whom were shown to be compliant utilizing concomitant salicylate levels.
- Published
- 2005
45. Duration of increased bleeding tendency after cessation of aspirin therapy
- Author
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Damien Ryan, H. Paul Redmond, G. McGreal, Basil H. Crowe, Brian J. Manning, Ronan A. Cahill, and Mary R. Cahill
- Subjects
Adult ,Male ,Bleeding Time ,Platelet Function Tests ,Placebo ,Double-Blind Method ,Bleeding time ,Humans ,Medicine ,Prospective Studies ,Antipyretic ,Elective surgery ,Volunteer ,Hemostasis ,Aspirin ,medicine.diagnostic_test ,business.industry ,Discontinuation ,Anesthesia ,Female ,Surgery ,business ,Platelet Aggregation Inhibitors ,medicine.drug - Abstract
Background Aspirin has a significant effect on hemostasis, so it is often recommended that patients taking aspirin discontinue treatment before elective surgery. While off aspirin, these patients may be at risk of thrombosis. The optimum period of time that aspirin should be withheld is controversial. The aim of this study was to establish the duration of the antihemostatic effect of prolonged aspirin therapy. Study design In a prospective study, 51 healthy volunteers were randomly assigned into 3 groups, each receiving an identical tablet for 14 days. One group received a placebo tablet; individuals in the other two groups received either 75 mg or 300 mg of aspirin once a day. Template bleeding times and specific platelet function testing (using the PFA-100; Dade Behring) were carried out on subjects before therapy and again after its completion until they returned to baseline. Results Thirty-eight volunteers complied sufficiently with the protocol to provide useful results. All bleeding times normalized within 96 hours and all platelet function tests within 144 hours after stopping aspirin. There was no demonstrable hemostatic defect in any volunteer persisting by or beyond the sixth day after treatment cessation. There was no apparent difference in duration of effect between those taking either 75 mg or 300 mg of aspirin. Conclusions This study uses sensitive measures of platelet function to demonstrate the duration of increased bleeding tendency after withdrawal of aspirin therapy. It supports discontinuation of aspirin therapy 5 days before elective surgery (with the operation being performed on the sixth day).
- Published
- 2005
46. Haemophagocytic lymphohistiocytosis presenting as HELLP syndrome: a diagnostic and therapeutic challenge
- Author
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Mary R. Cahill, Raymond Michael Kelly, Robert N. Kerley, and Louise C. Kenny
- Subjects
Adult ,HELLP Syndrome ,Pediatrics ,medicine.medical_specialty ,Abdominal pain ,HELLP syndrome ,medicine.medical_treatment ,Lymphohistiocytosis, Hemophagocytic ,Article ,Diagnosis, Differential ,03 medical and health sciences ,Fatal Outcome ,0302 clinical medicine ,Pregnancy ,hemic and lymphatic diseases ,Biopsy ,medicine ,Humans ,Etoposide ,Bone Marrow Transplantation ,Chemotherapy ,030219 obstetrics & reproductive medicine ,medicine.diagnostic_test ,business.industry ,General Medicine ,medicine.disease ,Haemolysis ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Female ,Bone marrow ,medicine.symptom ,business ,Rare disease ,medicine.drug - Abstract
Haemophagocytic lymphohistiocytosis (HLH) is a rare, potentially fatal, haematological disorder, which can be clinically challenging to diagnose and manage. We report a case of HLH in a previously healthy 33-year-old primigravida. The patient presented at 22 weeks gestation with dyspnoea, abdominal pain, anaemia, thrombocytopenia and elevated liver enzymes suggestive of HELLP syndrome.HELLP, a syndrome characterised by haemolysis, elevated liver enzymes and low platelets is considered a severe form of pre-eclampsia. Despite delivery of the fetus, her condition deteriorated over 3–4 days with high-grade fever, worsening thrombocytopenia and anaemia requiring transfusion support. A bone marrow biopsy showed haemophagocytosis and a diagnosis of HLH was made. Partial remission was achieved with etoposide-based chemotherapy and complete remission following bone marrow transplantation. Eleven months post-transplant, the disease aggressively recurred, and the patient died within 3 weeks of relapse.
- Published
- 2017
47. Minimal Residual Disease (MRD) Status in FCR-Treated CLL Patients at the End of Treatment Influences Progression Free Survival (PFS), Results of the Ctrial-IE (ICORG) 07-01/ CLL Ireland Study, with Mutational Analysis Providing Additional Insight
- Author
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Gerard Crotty, Elisabeth A. Vandenberghe, David O'Brien, Kathleen Scott, Niamh Appleby, Mary R. Cahill, Johanna Kelly, Hilary O'Leary, Brian Hennessy, Michael O'Dwyer, Amjad Hayat, Smyth Liam, Helen Enright, Andrew J. Hodgson, Fiona Quinn, Imelda Parker, and Maeve Leahy
- Subjects
medicine.medical_specialty ,Chronic lymphocytic leukemia ,Immunology ,Gene mutation ,Biochemistry ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Median follow-up ,hemic and lymphatic diseases ,Internal medicine ,Medicine ,Progression-free survival ,Cytopenia ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Minimal residual disease ,Fludarabine ,Surgery ,Regimen ,030220 oncology & carcinogenesis ,business ,030215 immunology ,medicine.drug - Abstract
Fludarabine, cyclophosphamide and rituximab (FCR) therapy results in a complete remission (CR) rate of 72% and a median progression free survival (PFS) of 80 months in non-del (17P) CLL1. Achieving an MRD negative (MRD-ve) CR after completing therapy is an early surrogate marker for overall survival (OS) and PFS2. Specific genetic CLL subtypes determined by fluorescent in-situ hybridisation (FISH) analysis, immunoglobulin mutation IgVH, NOTCH1 and SF3B1 status determine response to chemotherapy3,4. We completed a multi-centre prospective study between 2008 and 2012, with a median follow up of 62.6 months using MRD status to determine length of therapy. Patients who achieved an MRD-veCR after 4 courses of FCR received no further therapy and the remaining patients completed 6 cycles of FCR. MRD status was tracked 6 monthly in patients who became MRD-veuntil MRD was detected. The genetic subtype was also analysed but did not influence treatment. Fifty-two patients {35M;17F, median age 61years (range 37-73)} were enrolled. Forty-six patients completed the MRD assessment after 4 cycles. Eleven patients discontinued assigned FCR therapy for the following reasons: prolonged cytopenia (4); non-compliance (1); autoimmune haemolytic anaemia (2); renal impairment (1); pleural effusion (1); not recorded (2). Eighteen (34.6%) patients achieved an MRD-veCR after 4 cycles and a further11 after 6cycles resulting in 29/52 (55.8%) MRD-veCRs in total. The median PFS was 72.3 months (95% Confidence Interval 61.3-84.1 months) and the median OS has not been reached. Patients who attained an MRD-veversusMRD+vestatus had a prolonged PFS (81.1 vs 46.2 months, p FISH results were available for 48 patients; del(13q) in 16/48 (33%), del(11q) in 15/48 (31%) no abnormality in 12/48 (25%), trisomy 12 in 4 (8%) and other abnormality in 1 patient. The IgVH status was unfavourable in 34/52 (65%), SF3B1 mutations were detected in 5/51 (9.8%) and NOTCH1 mutations in 10/52(19.2%) patients respectively, comparable to published studies of first-line treatment in CLL3,4. The median PFS for patients with good risk IgVH was not reached. Del(11q) did not impact on PFS (median PFS 66.5 vs 78.9 months, p=0.7301). SF3B1 and NOTCH1 mutated patients had a shortened PFS (median PFS 38.4 vs 71.1 months, p=0.038 and median PFS 62.4 vs 82.2 months p=0.0302, respectively). In conclusion abbreviated FCR therapy is effective for patients achieving MRD-veremission after 4 cycles. SF3B1 and NOTCH1 mutated patients had a short PFS and may benefit from alternative first-line treatment. This finding emphasizes the role mutational profiling will play in optimising and personalising therapy in CLL in the future. Reference: Tam C, O'Brien S, WierdaW, et al. “Long-term results of the fludarabine, cyclophosphamide and rituximab regimen as initial therapy of chronic lymphocytic leukemia” Blood 2008 Aug 15;112(4):975-80 Böttcher S, Ritgen M, Fischer K, et al. "Minimal Residual Disease Quantification is an Independent Predictor of Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia: A Multivariate Analysis From the Randomized GCLLSG CLL8 Trial" J Clin Onc 2012 Mar 20; 30(9):980-8. StilgenbauerS,SchnaiterA,PaschkaP, et al. "Gene mutations and treatment outcome in chronic lymphocyticleukemia: results from the CLL8 trial" Blood 2014 May 22;123(21):3247-54 Chiaretti S, Marinelli M, Del Giudice I, et al."NOTCH1, SF3B1, BIRC3 and TP53 mutations in patients with chronic lymphocytic leukaemia undergoing first-line treatment: correlation with biological parameters and response to treatment"LeukLymphoma 2014 Dec; 55(12):2785-92 Figure 1 Patient outcomes by MRD status in ICORG 07-01 Trial Figure 1. Patient outcomes by MRD status in ICORG 07-01 Trial Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Crotty: BMS, Takeda, Novartis, Janssen, Roche: Honoraria. O'Dwyer:Glycomimetics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.
- Published
- 2016
48. The effects of ropivacaine hydrochloride on platelet function: an assessment using the platelet function analyser (PFA-100)
- Author
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J. M. Porter, Mary R. Cahill, George D. Shorten, and Basil H. Crowe
- Subjects
Epidural blood patch ,Local anesthetic ,medicine.drug_class ,Ropivacaine ,business.industry ,PFA-100 ,medicine.medical_treatment ,Epidural space ,Dose–response relationship ,Anesthesiology and Pain Medicine ,medicine.anatomical_structure ,Anesthesia ,Fibrinolysis ,medicine ,Platelet ,business ,medicine.drug - Abstract
Amide local anaesthetics impair blood clotting in a concentration-dependent manner by inhibition of platelet function and enhanced fibrinolysis. We hypothesised that the presence of ropivacaine in the epidural space could decrease the efficacy of an epidural blood patch, as this technique requires that the injected blood can clot in order to be effective. Ropivacaine is an aminoamide local anaesthetic used increasingly for epidural analgesia during labour. The concentration of local anaesthetic in blood achieved in the epidural space during the performance of an epidural blood patch is likely to be the greatest which occurs (intentionally) in any clinical setting. This study was undertaken to investigate whether concentrations of ropivacaine in blood, which could occur: (i) clinically in the epidural space and (ii) in plasma during an epidural infusion of ropivacaine, alter platelet function. A platelet function analyser (Dade PFA-100, Miami) was employed to assess the effects of ropivacaine-treated blood on platelet function. The greater concentrations of ropivacaine studied (3.75 and 1.88 mg x ml(-1)), which correspond to those which could occur in the epidural space, produced significant inhibition of platelet aggregation. We conclude that the presence of ropivacaine in the epidural space may decrease the efficacy of an early or prophylactic epidural blood patch.
- Published
- 2001
49. Smoking as an independent risk factor for macrocytosis in middle-aged adults: A population-based observational study
- Author
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Mary R. Cahill, Seán R. Millar, Janas M. Harrington, O'Reilly M, Claire M. Buckley, and Ivan J. Perry
- Subjects
business.industry ,Environmental health ,medicine ,Observational study ,Hematology ,Macrocytosis ,Population based ,Risk factor ,medicine.disease ,business - Published
- 2015
50. Protein A immunoadsorption in chronic refractory ITP reverses increased platelet activation but fails to achieve sustained clinical benefit
- Author
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Marion G. Macey, James D. Cavenagh, Adrian C. Newland, and Mary R. Cahill
- Subjects
Autoimmune disease ,medicine.medical_specialty ,P-selectin ,business.industry ,medicine.medical_treatment ,Hematology ,medicine.disease ,Gastroenterology ,Endocrinology ,Refractory ,Internal medicine ,medicine ,Platelet ,Plasmapheresis ,Platelet activation ,Immunoadsorption ,business ,Whole blood - Abstract
Adults with chronic relapsing ITP present a difficult therapeutic challenge. The ongoing antibody-mediated platelet destruction in this group might be expected to be associated with increased expression of platelet surface membrane activation antigens. We have studied a group of 10 patients with refractory ITP and 35 healthy controls. Using an immediate, sensitive, unfixed, whole blood, flow cytometric method to detect platelet surface P-selectin and GP53, we have detected markedly increased platelet activation in the ITP group compared with the controls (P-selectin; patient median 24.5% v control median 2.0%. GP53 median 6.5% v 2.1%, P < 0.01 for both). Five patients underwent protein A immunoadsorption therapy. The effect of protein A immunoadsorption on platelet activation before, during and after 18 treatments in these patients was studied and patients were followed-up to assess clinical outcome. Platelet-associated immunoglobulin measurements were made before and at the end of six treatments. Platelet activation decreased after immunoadsorption. P-selectin expression fell significantly; pre- and post-treatment median values differed by 15.5%, P < 0.01, for GP53 the difference was 2.5%, P = NS. A reduction in both platelet-associated IgG (median reduction of 11.8 ng/10(6) platelets, P = 0.08) and IgM (7.6 ng/10(6) platelets, P = 0.06) was recorded.
- Published
- 1998
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