Cancer Research @ UCC - Journal Articles

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All-trans retinoic acid (ATRA)-induced TFEB expression is required for myeloid differentiation in acute promyelocytic leukemia (APL)
(John Wiley & Sons, Inc., 2019-12-06) Orfali, Nina; O'Donovan, Tracey R.; Cahill, Mary R.; Benjamin, Dalyia; Nanus, David M.; McKenna, Sharon L.; Gudas, Lorraine J.; Mongan, Nigel P.; Breakthrough Cancer Research; Haematology Education and Research Trust, Ireland; National Cancer Institute
Objective: In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RAR alpha 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-RAR alpha 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).
An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer
(Nature Publishing Group, 2015-12-17) O'Donnell, Charlotte; Mahmoud, Amr; Keane, Jonathan; Murphy, Carola T.; White, Declan; Carey, Sinead; O'Riordain, Micheal G.; Bennett, Michael W.; Brint, Elizabeth K.; Houston, Aileen M.; Health Research Board; Pathological Society of Great Britain and Ireland
Background: Despite the importance of inflammation in cancer, the role of the cytokine IL-33, and its receptor ST2, in colon cancer is unclear. The aim of this study was to investigate the role of IL-33, and its receptor isoforms (ST2 and ST2L), in colon cancer. Methods: Serum levels of IL-33 and sST2 were determined with ELISA. ST2 and IL-33 expression was detected with quantitative real-time PCR (qRT–PCR), western blotting and immunohistochemistry. ST2 expression in CT26 cells was stably suppressed using ST2-specific shRNA. Cytokine and chemokine gene expression was detected with qRT–PCR. Results: Human colon tumours showed lower expression of ST2L as compared with adjacent non-tumour tissue (P<0.01). Moreover, the higher the tumour grade, the lower the expression of ST2L (P=0.026). Colon cancer cells expressed ST2 and IL-33 in vitro. Functional analyses showed that stimulation of tumour cells with IL-33 induced the expression of chemokine (C–C motif) ligand 2 (CCL2). Knockdown of ST2 in murine colon cancer cells resulted in enhanced tumour growth (P<0.05) in BALB/c mice in vivo. This was associated with a decrease in macrophage infiltration, with IL-33-induced macrophage recruitment reduced by antagonising CCL2 in vitro. Conclusion: The IL-33/ST2 signalling axis may have a protective role in colon carcinogenesis.
Antitumour responses induced by a cell-based Reovirus vaccine in murine lung and melanoma models
(BioMed Central, 2016-07-13) Campion, Ciorsdan A.; Soden, Declan; Forde, Patrick F.; Breakthrough Cancer Research, Ireland; Cork Cancer Research Centre
Background: The ever increasing knowledge in the areas of cell biology, the immune system and the mechanisms of cancer are allowing a new phase of immunotherapy to develop. The aim of cancer vaccination is to activate the host immune system and some success has been observed particularly in the use of the BCG vaccine for bladder cancer as an immunostimulant. Reovirus, an orphan virus, has proven itself as an oncolytic virus in vitro and in vivo. Over 80 % of tumour cell lines have been found to be susceptible to Reovirus infection and it is currently in phase III clinical trials. It has been shown to induce immune responses to tumours with very low toxicities. Methods: In this study, Reovirus was examined in two main approaches in vivo, in mice, using the melanoma B16F10 and Lewis Lung Carcinoma (LLC) models. Initially, mice were treated intratumourally (IT) with Reovirus and the immune responses determined by cytokine analysis. Mice were also vaccinated using a cell-based Reovirus vaccine and subsequently exposed to a tumourigenic dose of cells (B16F10 or LLC). Using the same cell-based Reovirus vaccine, established tumours were treated and subsequent immune responses and virus retrieval investigated. Results: Upregulation of several cytokines was observed following treatment and replication-competent virus was also retrieved from treated tumours. Varying levels of cytokine upregulation were observed and no replication-competent virus was retrieved in vaccine-treated mice. Prolongation of survival and delayed tumour growth were observed in all models and an immune response to Reovirus, either using Reovirus alone or a cell-based vaccine was also observed in all mice. Conclusion: This study provides evidence of immune response to tumours using a cell-based Reovirus vaccine in both tumour models investigated, B16F10 and LLC, cytokine induction was observed with prolongation of survival in almost all cases which may suggest a new method for using Reovirus in the clinic.
Are we sleeping on the job? Insomnia among men with prostate cancer
(PiscoMed Publishing, 2016-04) Drummond, Frances J.
Prostate cancer is one of the most commonly diagnosed cancers in men and almost half of male cancer survivors in the US have had a prostate cancer diagnosis. Insomnia is common among cancer patients and survivors. There is evidence that cognitive behavioural therapy can be used to effectively manage insomnia among women with breast cancer. The aim of this review was to investigate the prevalence, risk factors and management of insomnia among men with prostate cancer. The effect of insomnia on the psychological health and health-related quality of life of these patients and/or survivors is also discussed. Increased awareness and knowledge of this symptom among men with prostate cancer may facilitate improved diagnosis, and management of insomnia in this large population. This in turn may improve the health-related quality of life of these men. Therefore, research into the effective management of insomnia among men with prostate cancer is essential.
Bacteria and tumours: causative agents or opportunistic inhabitants?
(BioMed Central, 2013-03-28) Cummins, Joanne; Tangney, Mark; Health Research Board; European Commission
Associations between different bacteria and various tumours have been reported in patients for decades. Studies involving characterisation of bacteria within tumour tissues have traditionally been in the context of tumourigenesis as a result of bacterial presence within healthy tissues, and in general, dogma holds that such bacteria are causative agents of malignancy (directly or indirectly). While evidence suggests that this may be the case for certain tumour types and bacterial species, it is plausible that in many cases, clinical observations of bacteria within tumours arise from spontaneous infection of established tumours. Indeed, growth of bacteria specifically within tumours following deliberate systemic administration has been demonstrated for numerous bacterial species at preclinical and clinical levels. We present the available data on links between bacteria and tumours, and propose that besides the few instances in which pathogens are playing a pathogenic role in cancer, in many instances, the prevalent relationship between solid tumours and bacteria is opportunistic rather than causative, and discuss opportunities for exploiting tumour-specific bacterial growth for cancer treatment.
Biodiversity: the overlooked source of human health
(Elsevier Inc., 2022-12-28) Linhares, Yuliya; Kaganski, Alexander; Agyare, Christian; Kurnaz, Isil A.; Neergheen, Vidushi; Kolodziejczyk, Bartlomiej; Kędra, Monika; Wahajuddin, Muhammad; El-Youssf, Lahcen; de la Cruz, Thomas Edison; Baran, Yusuf; Pešić, Milica; Shrestha, Uttam; Bakiu, Rigers; Allard, Pierre-Marie; Rybtsov, Stanislav; Pieri, Myrtani; Siciliano, Velia; Flores Bueso, Yensi; Global Young Academy
Biodiversity is the measure of the variation of lifeforms in a given ecological system. Biodiversity provides ecosystems with the robustness, stability, and resilience that sustains them. This is ultimately essential for our survival because we depend on the services that natural ecosystems provide (food, fresh water, air, climate, and medicine). Despite this, human activity is driving an unprecedented rate of biodiversity decline, which may jeopardize the life-support systems of the planet if no urgent action is taken. In this article we show why biodiversity is essential for human health. We raise our case and focus on the biomedicine services that are enabled by biodiversity, and we present known and novel approaches to promote biodiversity conservation.
The burden of healthcare costs associated with prostate cancer in Ireland
(Wichtig: Open Access Journals, 2017-01) Burns, Richéal M.; Leal, Jose; Wolstenholme, Jane; O'Neill, Ciaran; Sullivan, Frank J.; Drummond, Frances J.; Sharp, Linda; Health Research Board
Purpose: With one of the highest incidences across Europe and the rest of the World in 2012, the Republic of Ireland (RoI) has experienced significant increases in prostate cancer (PCa) since 1994. The main driver is the widespread use of PSA testing which is used to detect PCa. This is expected to have significant implications on resource use in the RoI. The focus of this paper was to (i) derive costs for the PCa pathway, from diagnosis to treatment, and (ii) estimate overall healthcare expenditure for PCa in the RoI. Methods: PCa incidence (ICD-10 code: C61), treatment and mortality data during 2007-2010 was obtained from the National Cancer Registry Ireland. Costs associated with diagnosis, treatment, treatment complications, clinical follow-up to year four post-diagnosis and terminal (palliative) care were estimated using sources such as survey data, Irish inpatient costs and published costs.Results: The overall estimated burden of healthcare costs associated with those diagnosed with PCa and receiving care (up to four-year post-diagnosis) or dying from PCa in 2010 was approximately (sic)45.6 million. The overall cost associated with detection, via PSA testing, for those diagnosed with PCa in 2010 (n = 3287) was (sic)366,369. Treatment costs varied considerably with the most expensive treatment being chemotherapy and radical prostatectomy (unit cost (sic)11,278 and (sic)7324, respectively). Conclusions: PCa incidence partly due to high levels of PSA testing has significant resource utilisation implications in the RoI.
Can non-viral technologies knockdown the barriers to siRNA delivery and achieve the next generation of cancer therapeutics?
(Elsevier, 2011-07) Guo, Jianfeng; Bourre, Ludovic; Soden, Declan; O'Sullivan, Gerald C.; O'Driscoll, Caitríona M.; Science Foundation Ireland; Enterprise Ireland; Irish Research Council for Science Engineering and Technology
Cancer is one of the most wide-spread diseases of modern times, with an estimated increase in the number of patients diagnosed worldwide, from 11.3 million in 2007 to 15.5 million in 2030 (www.who.int). In many cases, due to the delay in diagnosis and high increase of relapse, survival rates are low. Current therapies, including surgery, radiation and chemotherapy, have made significant progress, but they have many limitations and are far from ideal. Although immunotherapy has recently offered great promise as a new approach in cancer treatment, it is still very much in its infancy and more information on this approach is required before it can be widely applied. For these reasons effective, safe and patient-acceptable cancer therapy is still largely an unmet clinical need. Recent knowledge of the genetic basis of the disease opens up the potential for cancer gene therapeutics based on siRNA. However, the future of such gene-based therapeutics is dependent on achieving successful delivery. Extensive research is ongoing regarding the design and assessment of non-viral delivery technologies for siRNA to treat a wide range of cancers. Preliminary results on the first human Phase I trial for solid tumours, using a targeted non-viral vector, illustrate the enormous therapeutic benefits once the issue of delivery is resolved. In this review the genes regulating cancer will be discussed and potential therapeutic targets will be identified. The physiological and biochemical changes caused by tumours, and the potential to exploit this knowledge to produce bio-responsive ‘smart’ delivery systems, will be evaluated. This review will also provide a critical and comprehensive overview of the different non-viral formulation strategies under investigation for siRNA delivery, with particular emphasis on those designed to exploit the physiological environment of the disease site. In addition, a section of the review will be dedicated to pre-clinical animal models used to evaluate the stability, safety and efficacy of the delivery systems.
Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?
(Wiley Open Access, 2017) Ní Bhuachalla, Éadaoin B.; Daly, Louise E.; Power, Derek G.; Cushen, Samantha J.; MacEneaney, Peter; Ryan, Aoife M.; Cork Cancer Research Centre; Breakthrough Cancer Research, Ireland
Background: Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis). Methods: A prospective study of ambulatory oncology outpatients presenting for chemotherapy was performed. A detailed survey incorporating clinical, nutritional, biochemical, and quality of life data was administered. Participants were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), and the Nutritional Risk Index (NRI). Computed tomography (CT) assessment of body composition was performed to diagnose CC, sarcopenia, and myosteatosis according to consensus criteria. Results: A total of 725 patients (60% male, median age 64 years) with solid tumours participated (45% metastatic disease). The majority were overweight/obese (57%). However, 67% were losing weight, and CT analysis revealed CC in 42%, sarcopenia in 41%, and myosteatosis in 46%. Among patients with CT-identified CC, the MUST, MST, and NRI tools categorized 27%, 35%, and 7% of them as ‘low nutritional risk’, respectively. The percentage of patients with CT-identified sarcopenia and myosteatosis that were categorised as ‘low nutritional risk’ by MUST, MST and NRI were 55%, 61%, and 14% and 52%, 50%, and 11%, respectively. Among these tools, the NRI was most sensitive, with scores <97.5 detecting 85.8%, 88.6%, and 92.9% of sarcopenia, myosteatosis, and CC cases, respectively. Using multivariate Cox proportional hazards models, NRI score < 97.5 predicted greater mortality risk (hazard ratio 1.8, confidence interval: 1.2–2.8, P = 0.007). Conclusions: High numbers of nutritionally vulnerable patients, with demonstrated abnormal body composition phenotypes on CT analysis, were misclassified by MUST and MST. Caution should be exercised when categorizing the nutritional risk of oncology patients using these tools. NRI detected the majority of abnormal body composition phenotypes and independently predicted survival. Of the tools examined, the NRI yielded the most valuable information from screening and demonstrated usefulness as an initial nutritional risk grading system in ambulatory oncology patients.
CyBorD-DARA is potent initial induction for MM and enhances ADCP: Initial results of the 16-BCNI-001/CTRIAL-IE 16-02 study
(American Society of Hematology, 2019-06-14) O'Dwyer, M.; Henderson, R.; Naicker, S.D.; Cahill, Mary R.; Murphy, P.; Mykytiv, C.; McEllistrim, C.; Krawczyk, J.; Walsh, J.; Lenihan, E.; Kenny, T.; Hernando, A.; Hirakata, G.; Parker, I.; Kinsella, E.; Gannon, G.; Natoni, A.; Lynch, K.; Ryan, A. E.; Science Foundation Ireland; Irish Cancer Society; Janssen Research and Development; National University of Ireland, Galway; European Regional Development Fund; Government of Ireland; Galway University Foundation
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 <10%. On an intention-to-treat basis, 94% achieved ≥very good partial response with ≥complete response in 44% of patients. Among 14 of 15 patients who underwent ASCT and were evaluable for response, all 14 achieved at least very good partial response, with 8 (57%) of 14 achieving complete response. After ASCT, 10 (83%) of 12 patients in whom minimal residual disease analysis was possible were negative at a sensitivity of 10−5 (56% on intention-to-treat/whole study population) according to next-generation sequencing. Flow cytometry analysis of patient samples indicated CyBorD DARA induced activation of macrophage-mediated antibody-dependent cellular phagocytosis. This trial was registered at www.clinicaltrials.gov as #NCT02955810.
Designer bacteria as intratumoural enzyme biofactories
(Elsevier, 2017-09-12) Lehouritis, Panos; Hogan, Glenn; Tangney, Mark; Irish Cancer Society; Science Foundation Ireland; Breakthrough Cancer Research, Ireland
Bacterial-directed enzyme prodrug therapy (BDEPT) is an emerging form of treatment for cancer. It is a biphasic variant of gene therapy in which a bacterium, armed with an enzyme that can convert an inert prodrug into a cytotoxic compound, induces tumour cell death following tumour-specific prodrug activation. BDEPT combines the innate ability of bacteria to selectively proliferate in tumours, with the capacity of prodrugs to undergo contained, compartmentalised conversion into active metabolites in vivo. Although BDEPT has undergone clinical testing, it has received limited clinical exposure, and has yet to achieve regulatory approval. In this article, we review BDEPT from the system designer's perspective, and provide detailed commentary on how the designer should strategize its development de novo. We report on contemporary advancements in this field which aim to enhance BDEPT in terms of safety and efficacy. Finally, we discuss clinical and regulatory barriers facing BDEPT, and propose promising approaches through which these hurdles may best be tackled.
Developing outcome, process and balancing measures for an emergency department longitudinal patient monitoring system using a modified Delphi
(BioMed Central, 2019) Ward, Marie E.; Wakai, Abel; McDowell, Ronald; Boland, Fiona; Coughlan, Eoin; Hamza, Moayed; Browne, John P.; O'Sullivan, Ronan; Geary, Una; McDaid, Fiona; Ní Shé, Éidín; Drummond, Frances J.; Deasy, Conor; McAuliffe, Eilish; Health Research Board; Health Service Executive, Ireland; Royal College of Physicians, Ireland
Early warning score systems have been widely recommended for use to detect clinical deterioration in patients. The Irish National Emergency Medicine Programme has developed and piloted an emergency department specific early warning score system. The objective of this study was to develop a consensus among frontline healthcare staff, quality and safety staff and health systems researchers regarding evaluation measures for an early warning score system in the Emergency Department.
Development of a bioluminescent nitroreductase probe for preclinical imaging
(Public Library of Science, 2015) Vorobyeva, Anzhelika G.; Stanton, Michael; Godinat, Aurelien; Lund, Kjetil B.; Karateev, Grigory G.; Francis, Kevin P.; Allen, Elizabeth; Gelovani, Juri G.; McCormack, Emmet; Tangney, Mark; Dubikovskaya, Elena A.; Intrace Medical SA, Switzerland; Bergen Research Foundation, Norway; Norwegian Cancer Society; Western Norway Regional Health Authority; Science Foundation Ireland; Enterprise Ireland; Health Research Board; Irish Cancer Society; Seventh Framework Programme
Bacterial nitroreductases (NTRs) have been widely utilized in the development of novel antibiotics, degradation of pollutants, and gene-directed enzyme prodrug therapy (GDEPT) of cancer that reached clinical trials. In case of GDEPT, since NTR is not naturally present in mammalian cells, the prodrug is activated selectively in NTR-transformed cancer cells, allowing high efficiency treatment of tumors. Currently, no bioluminescent probes exist for sensitive, non-invasive imaging of NTR expression. We therefore developed a "NTR caged luciferin" (NCL) probe that is selectively reduced by NTR, producing light proportional to the NTR activity. Here we report successful application of this probe for imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. This novel tool should significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where NTR expression is important.
Differential expression of key regulators of Toll-like receptors in ulcerative colitis and Crohn's disease: a role for Tollip and peroxisome proliferator-activated receptor gamma?
(Wiley, 2015-10-14) Fernandes, Philana; MacSharry, John; Darby, Trevor; Shanahan, Fergus; Houston, Aileen M.; Brint, Elizabeth K.; Science Foundation Ireland
The innate immune system is currently seen as the probable initiator of events which culminate in the development of inflammatory bowel disease (IBD) with Toll‐like receptors (TLRs) known to be involved in this disease process. Many regulators of TLRs have been described, and dysregulation of these may also be important in the pathogenesis of IBD. The aim of this study was to perform a co‐ordinated analysis of the expression levels of both key intestinal TLRs and their inhibitory proteins in the same IBD cohorts, both ulcerative colitis (UC) and Crohn's disease (CD), in order to evaluate the potential roles of these proteins in the pathogenesis of IBD. Of the six TLRs (TLRs 1, 2, 4, 5, 6 and 9) examined, only TLR‐4 was increased significantly in IBD, specifically in active UC. In contrast, differential alterations in expression of TLR inhibitory proteins were observed. A20 and suppressor of cytokine signalling 1 (SOCS1) were increased only in active UC while interleukin‐1 receptor‐associated kinase 1 (IRAK‐m) and B cell lymphoma 3 protein (Bcl‐3) were increased in both active UC and CD. In contrast, expression of both peroxisome proliferator‐activated receptor gamma (PPARγ) and Toll interacting protein (Tollip) was decreased in both active and inactive UC and CD and at both mRNA and protein levels. In addition, expression of both PPARγ and A20 expression was increased by stimulation of a colonic epithelial cell line Caco‐2 with both TLR ligands and commensal bacterial strains. These data suggest that IBD may be associated with distinctive changes in TLR‐4 and TLR inhibitory proteins, implying that alterations in these may contribute to the pathogenesis of IBD.
Effect of investigation intensity and treatment differences on prostate cancer survivor's physical symptoms, psychological well-being and health-related quality of life: a two country cross-sectional study
(BMJ Publishing Group Limited, 2016-01) Gavin, Anna T.; Donnelly, David; Donnelly, Conan; Drummond, Frances J.; Morgan, Eileen; Gormley, Gerard J.; Sharp, Linda; Prostate Cancer UK; Health Research Board; Public Health Agency; Research and Development Office, Northern Ireland; National Cancer Control Programme, Ireland
Aim: To investigate effects on men's health and well-being of higher prostate cancer (PCa) investigation and treatment levels in similar populations.Participants PCa survivors in Ireland where the Republic of Ireland (RoI) has a 50% higher PCa incidence than Northern Ireland (NI).Method: A cross-sectional postal questionnaire was sent to PCa survivors 2–18 years post-treatment, seeking information about current physical effects of treatment, health-related quality of life (HRQoL; EORTC QLQ-C30; EQ-5D-5L) and psychological well-being (21 question version of the Depression, Anxiety and Stress Scale, DASS-21). Outcomes in RoI and NI survivors were compared, stratifying into ‘late disease’ (stage III/IV and any Gleason grade (GG) at diagnosis) and ‘early disease’ (stage I/II and GG 2–7). Responses were weighted by age, jurisdiction and time since diagnosis. Between-country differences were investigated using multivariate logistic and linear regression.Results: 3348 men responded (RoI n=2567; NI n=781; reflecting population sizes, response rate 54%). RoI responders were younger; less often had comorbidities (45% vs 38%); were more likely to present asymptomatically (66%; 41%) or with early disease (56%; 35%); and less often currently used androgen deprivation therapy (ADT; 2%; 28%). Current prevalence of incontinence (16%) and impotence (56% early disease, 67% late disease) did not differ between RoI and NI. In early disease, only current bowel problems (RoI 12%; NI 21%) differed significantly in multivariate analysis. In late disease, NI men reported significantly higher levels of gynaecomastia (23% vs 9%) and hot flashes(41% vs 19%), but when ADT users were analysed separately, differences disappeared. For HRQoL, in multivariate analysis, only pain (early disease: RoI 11.1, NI 19.4) and financial difficulties (late disease: RoI 10.4, NI 7.9) differed significantly between countries. There were no significant between-country differences in DASS-21 or index ED-5D-5L score.Conclusions: Treatment side effects were commonly reported and increased PCa detection in RoI has left more men with these side effects. We recommended that men be offered a PSA test only after informed discussion.
Electrochemotherapy causes caspase-independent necrotic-like death in pancreatic cancer cells
(MDPI, 2019-08-14) Fernandes, Philana; O'Donovan, Tracey R.; McKenna, Sharon L.; Forde, Patrick F.; Pancreatic Cancer Research Fund
Pancreatic cancer represents a major challenge in oncology. Poor permeability of the pancreas and resistance to currently available therapies are impediments to improved patient survival. By transiently increasing cell membrane porosity and increasing drug uptake, Electrochemotherapy (ECT) has the potential to overcome these issues. In this study, we have evaluated the response of human and murine pancreatic cancer cells, in vitro, to electroporation in combination with Bleomycin, Cisplatin, or Oxaliplatin (ECT). The cytotoxic actions of all three drugs are potentiated when combined with electroporation in these cells. The biochemical and morphological changes post ECT are associated with immunogenic cell death that occurs with necroptosis rather than apoptosis. Moreover, ECT-induced cell death is rescued by Nec-1 suggesting that necroptosis may play a role in cell death mediated by cancer therapies.
Exploiting somatic alterations as therapeutic targets in advanced and metastatic cervical cancer
(Elsevier Inc., 2021-05-21) Crowley, F. J.; O'Cearbhaill, R. E.; Collins, Dearbhaile C.; National Institutes of Health; National Cancer Institute
It is estimated that 604,127 patients were diagnosed with cervical cancer worldwide in 2020. While a small percentage of patients will have metastatic disease at diagnosis, a large percentage (15–61%) later develop advanced disease. For this cohort, treatment with systemic chemotherapy remains the standard of care, with a static 5-year survival rate over the last thirty years. Data on targetable molecular alterations in cervical cancer have lagged behind other more common tumor types thus stunting the development of targeted agents. In recent years, tumor genomic testing has been increasingly incorporated into our clinical practice, opening the door for a potential new era of personalized treatment for advanced cervical cancer. The interim results from the NCI-MATCH study reported an actionability rate of 28.4% for the cervical cancer cohort, suggesting a subset of patients may harbor mutations which that are targetable. This review sets out to summarize the key targeted agents currently under exploration either alone or in combination with existing treatments for cervical cancer.
Expressional changes in stemness markers post electrochemotherapy in pancreatic cancer cells
(Elsevier B.V., 2018-03-15) Ali, Shahzad; Gill, Kheshwant S.; Saglio, Giuseppe; Cilloni, Daniela; Soden, Declan M.; Forde, Patrick F.; Breakthrough Cancer Research, Ireland; Cork Cancer Research Centre, College of Medicine and Health, University College Cork; Teddy Daly Memorial Fund, Ireland
Pancreatic cancer is one of the most lethal cancers with high metastatic potential and strong chemoresistance. The capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Cancer stem cells exhibit great tumorigenicity and are closely correlated with drug resistance and tumor recurrence. The aim of our study was to illustrate electrochemotherapy as an effective treatment for pancreatic cancer along with the expression change in stemness genes (Nanog, Sox2 and Oct3/4) in pancreatic cancer cells post electrochemotherapy with bleomycin, cisplatin and oxaliplatin. Our results showed the enhanced expression of Nanog and decreased expression level of Oct3/4 after electrochemotherpy. We thus propose that these stemness markerS may have important roles in the initiation and/or recurrence of pancreatic cancer, and consequently may serve as important molecular diagnostics and/or therapeutic targets for the development of novel treatment strategies in pancreatic cancer patients. In conclusion, targeting these stemness factors could potentially improve electrochemotherapy as a treatment and preventing recurrence.
Factors driving inequality in prostate cancer survival: a population based study
(Public Library of Science, 2014-09-09) Burns, Richéal M.; Sharp, Linda; Sullivan, Francis J.; Deady, Sandra E.; Drummond, Frances J.; O'Neill, Ciaran; Scheurer, Michael; Health Research Board; Sanofi-Aventis
As cancer control strategies have become more successful, issues around survival have become increasingly important to researchers and policy makers. The aim of this study was to examine the role of a range of clinical and socio-demographic variables in explaining variations in survival after a prostate cancer diagnosis, paying particular attention to the role of healthcare provider(s) i.e. private versus public status. Data were extracted from the National Cancer Registry Ireland, for patients diagnosed with prostate cancer from 1998-2009 (N = 26,183). A series of multivariate Cox and logistic regression models were used to examine the role of healthcare provider and socio-economic status (area-based deprivation) on survival, controlling for age, stage, Gleason grade, marital status and region of residence. Survival was based on all-cause mortality. Older individuals who were treated in a private care setting were more likely to have survived than those who had not, when other factors were controlled for. Differences were evident with respect to marital status, region of residence, clinical stage and Gleason grade. The effect of socio-economic status was modified by healthcare provider, such that risk of death was higher in those men of lower socio-economic status treated by public, but not private providers in the Cox models. The logistic models revealed a socio-economic gradient in risk of death overall; the gradient was larger for those treated by public providers compared to those treated by private providers when controlling for a range of other confounding factors. The role of healthcare provider and socio-economic status in survival of men with prostate cancer may give rise to concerns that warrant further investigation.
Function2Form Bridge - Towards synthetic protein holistic performance-prediction
(John Wiley & Sons, Inc., 2019-10-07) Yallapragada, V. V. B.; Walker, Sidney P.; Devoy, Ciaran; Buckley, Stephen; Flores, Yensi; Tangney, Mark; Science Foundation Ireland; Health Research Board; Breakthrough Cancer Research, Ireland
Protein engineering and synthetic biology stand to benefit immensely from recent advances in in silico tools for structural and functional analyses of proteins. In the context of designing novel proteins, current in silico tools inform the user on individual parameters of a query protein, with output scores/metrics unique to each parameter. In reality, proteins feature multiple â partsâ /functions, and modification of a protein aimed at altering a given part, typically has collateral impact on other protein parts. A system for prediction of the combined effect of design parameters on the overall performance of the final protein does not exist. Function2Form Bridge (F2F-Bridge), attempts to address this by combining the scores of different design parameters pertaining to the protein being analysed into a single easily interpreted output describing overall performance. The strategy comprises 1. A mathematical strategy combining data from a myriad of in silico tools into an OP-score (a singular score informing on a user-defined overall performance); 2. The F2F-Plot, a graphical means of informing the wetlab biologist holistically on designed construct suitability in the context of multiple parameters, highlighting scope for improvement. F2F predictive output was compared with wetlab data from a range of synthetic proteins designed, built and tested for this study. Statistical/machine learning approaches for predicting overall performance, for use alongside the F2F plot, were also examined. Comparisons between wetlab performance and F2F predictions demonstrated close and reliable correlations. This user-friendly strategy represents a pivotal enabler in increasing accessibility of synthetic protein building and de novo protein design.

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