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2. Cellular geometry and epithelial-mesenchymal plasticity intersect with PIEZO1 in breast cancer cells

Author

Choon Leng So, Mélanie Robitaille, Francisco Sadras, Michael H. McCullough, Michael J. G. Milevskiy, Geoffrey J. Goodhill, Sarah J. Roberts-Thomson, and Gregory R. Monteith

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Differences in shape can be a distinguishing feature between different cell types, but the shape of a cell can also be dynamic. Changes in cell shape are critical when cancer cells escape from the primary tumor and undergo major morphological changes that allow them to squeeze between endothelial cells, enter the vasculature, and metastasize to other areas of the body. A shift from rounded to spindly cellular geometry is a consequence of epithelial-mesenchymal plasticity, which is also associated with changes in gene expression, increased invasiveness, and therapeutic resistance. However, the consequences and functional impacts of cell shape changes and the mechanisms through which they occur are still poorly understood. Here, we demonstrate that altering the morphology of a cell produces a remodeling of calcium influx via the ion channel PIEZO1 and identify PIEZO1 as an inducer of features of epithelial-to-mesenchymal plasticity. Combining automated epifluorescence microscopy and a genetically encoded calcium indicator, we demonstrate that activation of the PIEZO1 force channel with the PIEZO1 agonist, YODA 1, induces features of epithelial-to-mesenchymal plasticity in breast cancer cells. These findings suggest that PIEZO1 is a critical point of convergence between shape-induced changes in cellular signaling and epithelial-mesenchymal plasticity in breast cancer cells.

Published
2024
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4. 741 TWT-101: a first-in-clinic study of CFI-402411, a hematopoietic progenitor Kinase-1 (HPK1) inhibitor, as single agent or combined with pembrolizumab in subjects with advanced solid malignancies

Author

Omid Hamid, Siqing Fu, Manish Sharma, Anna Spreafico, Kyriakos P Papadopoulos, Erika Hamilton, Alexander Spira, Quincy Chu, Brigette Ma, Emily Roberts-Thomson, Dih-Yih Chen, Judy S Wang, Scott A Laurie, Mark R Bray, and Roger Sidhu

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published
2023
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5. Primary follicular lymphoma of an extraordinarily large prostate: A case report and review of the literature

Author

Isabella S.C. Williams, Samuel Roberts-Thomson, Nathan Lawrentschuk, and Niranjan J. Sathianathen

Subjects
Follicular lymphoma, Prostatic neoplasm, Prostatomegaly, Diseases of the genitourinary system. Urology, RC870-923
Abstract

Primary follicular lymphoma of the prostate is rare. This case report and literature review literature describes a 74-year old male patient who presented with worsening urinary symptoms, and imaging showing prostatomegaly compressing and displacing the rectum. He ultimately underwent a Millen retropubic prostatectomy for a prostate of 692 cc. The histology and immunohistochemistry confirmed the diagnosis as follicular lymphoma. His lymphoma underwent high-grade transformation with leptomeningeal involvement.

Published
2023
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6. Self-efficacy and oral health outcomes in a regional Australian Aboriginal population

Author

Eleanor Jane Parker, Dandara Gabriela Haag, Andrew John Spencer, Kaye Roberts-Thomson, and Lisa Marie Jamieson

Subjects
Self-efficacy, Oral health, Aboriginal, Indigenous, Dentistry, RK1-715
Abstract

Abstract Background Perceived self-efficacy has been associated with psychological well-being, health behaviours and health outcomes. Little is known about the influence of self-efficacy on oral health outcomes for Aboriginal adults in Australia, a population experiencing high levels of oral health conditions. This study examines associations between oral health-related self-efficacy and oral health outcomes in a regional Aboriginal Australian population and investigates whether the associations persist after adjusting for sociodemographic characteristics and other general and oral health-related psychosocial factors. Methods Cross-sectional data were obtained from the baseline questionnaire of the Indigenous Oral Heath Literacy Project, South Australia. Oral health-related self-efficacy was measured using a six item scale, with total sum scores dichotomised into high/low self-efficacy. Oral health outcomes included self-rated oral health and oral health impacts, measured using the Oral Health Impact Profile (OHIP-14). Generalized linear models with a log-Poisson link function were used to estimate Prevalence Ratios (PR) of poor self-rated oral health according to levels of oral health-related self-efficacy. Multivariable linear regressions were used to estimate the association between oral health-related self-efficacy and OHIP-14 scores. Blocks of confounders were subsequently added into the models, with the final model including all factors. Results Complete data were available for 252 participants (63%) aged 18 to 82 years (mean age of 37.6 years). Oral health-related self-efficacy was associated with poor self-rated oral health, with a 43% (PR = 1.43 (95% CI 1.09, 1.88)) greater prevalence of poor self-rated oral health among those with low self-efficacy. Oral health-related self-efficacy was associated with OHIP-14 severity scores, with a score over six points higher for those with low self-efficacy (B = 6.27 95% CI 2.71, 9.83). Although addition of perceived stress into the models attenuated the relationship, associations remained in the final models. Conclusion Lower levels of oral health-related self-efficacy were associated with a higher prevalence of poor self-rated oral health and greater impacts of oral health among Aboriginal adults in regional South Australia. These associations persisted after controlling for sociodemographic and psychosocial confounders, suggesting that increasing self-efficacy may provide an opportunity for improving oral health outcomes for Aboriginal adults.

Published
2022
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8. Is vascular insulin resistance an early step in diet-induced whole-body insulin resistance?

Author

Lauren Carmichael, Michelle A. Keske, Andrew C. Betik, Lewan Parker, Barbara Brayner, Katherine M. Roberts-Thomson, Glenn D. Wadley, D. Lee Hamilton, and Gunveen Kaur

Subjects
Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Abstract There is increasing evidence that skeletal muscle microvascular (capillary) blood flow plays an important role in glucose metabolism by increasing the delivery of glucose and insulin to the myocytes. This process is impaired in insulin-resistant individuals. Studies suggest that in diet-induced insulin-resistant rodents, insulin-mediated skeletal muscle microvascular blood flow is impaired post-short-term high fat feeding, and this occurs before the development of myocyte or whole-body insulin resistance. These data suggest that impaired skeletal muscle microvascular blood flow is an early vascular step before the onset of insulin resistance. However, evidence of this is still lacking in humans. In this review, we summarise what is known about short-term high-calorie and/or high-fat feeding in humans. We also explore selected animal studies to identify potential mechanisms. We discuss future directions aimed at better understanding the ‘early’ vascular mechanisms that lead to insulin resistance as this will provide the opportunity for much earlier screening and timing of intervention to assist in preventing type 2 diabetes.

Published
2022
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9. Quality of life and frailty outcomes following surgical and transcatheter aortic valve replacement

Author

Timothy Luke Surman, John Matthew Abrahams, Jaewon Kim, Hayley Elizabeth Surman, Ross Roberts-Thomson, Joseph Matthew Montarello, James Edwards, Michael Worthington, and John Beltrame

Subjects
Quality of life, Frailty, Depression, Angina, PROMS, Surgery, RD1-811, Anesthesiology, RD78.3-87.3
Abstract

Abstract Background Our objective was to report on the prospective outcomes in the areas of depression, quality of life, angina, and frailty in SAVR and TAVR patients with aortic stenosis undergoing aortic valve intervention. Methods We recruited 300 patients across 3 groups (TAVR, SAVR, and CABG) over 12 months. Depression, quality of life, frailty, and angina were assessed followed by propensity score matching. Results Using logistical regression when all patient factors considered for all patients who had SAVR and TAVR, the only preoperative factors that impacted on 1 year mortality was hypertension and STS score. Quality of life improvements within each group over 12 months was significant (p value = 0.0001). Depression at 12 months between groups (p value = 0.0395) and within each group was significant (p value = 0.0073 for SAVR and 0.0001 for TAVR). Angina was most frequent in TAVR at 12 months in the QL (p = 0.0001), PL (p = 0.0007), and improvement was significant in the QL (SAVR p = 0.0010, TAVR p = 0.0001) and PL (SAVR p = 0.0002), TAVR p = 0.0007) domains in both groups. Frailty at 12 months improved in both groups, but was greatest in TAVR (p value = 0.00126). Conclusions This 12 months follow up of cardiac surgical patients has revealed significant improvement in PROMs and frailty in all groups by 3 months postoperative regardless of surgical or transcatheter approach. Outcome measures of quality of life and frailty could be utilized as a measure of outcome more regularly in patients undergoing aortic valve surgery regardless of approach.

Published
2022
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10. Surgery for rheumatic heart disease in the Northern Territory, Australia, 1997–2016: what have we gained?

Author

Clare Heal, Nadarajah Kangaharan, Marcus Ilton, Andrew Webster, Rosemary Wyber, Bo Remenyi, Zhiqiang Wang, Robert A Baker, Alan Cass, Ross Roberts-Thomson, Nigel Gray, Malcolm McDonald, James Doran, David Canty, Karen Dempsey, Georgie Brunsdon, Colin Royse, Alistair Royse, Jacqueline Mein, Jayme Bennetts, Maida Stewart, Steven Sutcliffe, Benjamin Reeves, Upasna Doran, Patricia Rankine, Richard Fejo, Elisabeth Heenan, Ripudaman Jalota, Jason King, Jonathan Doran, and Joshua Hanson

Subjects
Medicine (General), R5-920, Infectious and parasitic diseases, RC109-216
Abstract

Background Between 1964 and 1996, the 10-year survival of patients having valve replacement surgery for rheumatic heart disease (RHD) in the Northern Territory, Australia, was 68%. As medical care has evolved since then, this study aimed to determine whether there has been a corresponding improvement in survival.Methods A retrospective study of Aboriginal patients with RHD in the Northern Territory, Australia, having their first valve surgery between 1997 and 2016. Survival was examined using Kaplan-Meier and Cox regression analysis.Findings The cohort included 281 adults and 61 children. The median (IQR) age at first surgery was 31 (18–42) years; 173/342 (51%) had a valve replacement, 113/342 (33%) had a valve repair and 56/342 (16%) had a commissurotomy. There were 93/342 (27%) deaths during a median (IQR) follow-up of 8 (4–12) years. The overall 10-year survival was 70% (95% CI: 64% to 76%). It was 62% (95% CI: 53% to 70%) in those having valve replacement. There were 204/281 (73%) adults with at least 1 preoperative comorbidity. Preoperative comorbidity was associated with earlier death, the risk of death increasing with each comorbidity (HR: 1.3 (95% CI: 1.2 to 1.5), p50 mm Hg before surgery (HR 1.9 (95% CI: 1.2 to 3.1) p=0.007) were independently associated with death.Interpretation Survival after valve replacement for RHD in this region of Australia has not improved. Although the patients were young, many had multiple comorbidities, which influenced long-term outcomes. The increasing prevalence of complex comorbidity in the region is a barrier to achieving optimal health outcomes.

Published
2023
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17. Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma

Author

Bart Neyns, Lisa Zimmer, Caroline Robert, Celeste Lebbe, Olivier Michielin, Omid Hamid, Anne Zaremba, Oliver Klein, Ruth Plummer, Joanna Mangana, Paolo A Ascierto, Katharina C Kähler, Georgina V Long, Ryan Sullivan, Grant A McArthur, Michael Weichenthal, Egle Ramelyte, Meghan J Mooradian, Douglas B Johnson, Alexander Shoushtari, Christian U Blank, Judith M Versluis, Prachi Bhave, Claudia Trojanello, Lu Si, Inderjit Mehmi, Tasnia Ahmed, Alexander M Menzies, Adnan Khattak, Severine Roy, Matteo S Carlino, Paul C Lorigan, Clara Allayous, Rachel Roberts-Thomson, Florentia Dimitriou, Kathleen Batty, Thierry Lesimple, Serigne N Lo, Alexandre Wicky, Richard Heywood, Lena Tran, Anna Stansfeld, Julia K Schwarze, Andrea Maurichi, Hui-Ling Yeoh, Mario Santinami, and Andrew M Haydon

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Background Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.Methods Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).Results In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.Conclusion While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.

Published
2022
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18. How did the ancient bacterium, Helicobacter pylori, cause an epidemic of chronic duodenal ulceration?

Author

Ian C Roberts‐Thomson

Subjects
chronic duodenal ulcer, gastric acid secretion, gastritis, Helicobacter pylori, ulcer epidemic, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract The association of Helicobacter pylori with chronic duodenal ulceration was a seminal observation in the short history of gastroenterology. However, H. pylori is now known to be an ancient bacterium, whereas there is persuasive evidence that the epidemic of duodenal ulceration began in the second half of the 19th century and continued into the second half of the 20th century. Possible explanations for the epidemic include genomic changes in the organism and environmental or other influences on the human host. While genomic changes resulted in the appearance of virulence factors, these seem likely to have appeared thousands of years ago with minimal effects on gastritis because of coexisting suppression of gastric immunity. In contrast, the emergence of duodenal ulceration is best explained by a change in the pattern of gastritis from inflammation involving the antrum and body in most individuals to a significant minority (10–20%) with antral gastritis but with relative sparing of the body of the stomach. In the latter group, the increase in serum gastrin (particularly G17) associated with antral gastritis had trophic effects on gastric parietal cells with an increase in the parietal cell mass and hypersecretion of gastric acid. Hypersecretion of acid is seen as the major risk factor for duodenal ulceration with significant contributions from environmental factors including smoking and use of nonsteroidal, anti‐inflammatory drugs. Host factors favoring changes in the pattern of gastritis include delayed acquisition of infection and improved nutrition; both with enhancing effects on mucosal immunity.

Published
2021
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19. Liver alanine catabolism promotes skeletal muscle atrophy and hyperglycaemia in type 2 diabetes

Author

Okun, Jürgen G., Rusu, Patricia M., Chan, Andrea Y., Wu, Yuqin, Yap, Yann W., Sharkie, Thomas, Schumacher, Jonas, Schmidt, Kathrin V., Roberts-Thomson, Katherine M., Russell, Ryan D., Zota, Annika, Hille, Susanne, Jungmann, Andreas, Maggi, Ludovico, Lee, Young, Blüher, Matthias, Herzig, Stephan, Keske, Michelle A., Heikenwalder, Mathias, Müller, Oliver J., and Rose, Adam J.

Published
2021
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20. Blood Pressure Lowering in Patients With Central Hypertension: A Randomized Clinical Trial.

Author

Sharman, James E., Otahal, Petr, Stowasser, Michael, Stanton, Tony, Reid, Christopher M., Nolan, Mark, Roberts-Thomson, Philip, Negishi, Kazuaki, Greenough, Robert, Stewart, Simon, Marwick, Thomas H., and Abhayaratna, Walter P.

Abstract

BACKGROUND: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. METHODS: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. RESULTS: At 24-months, there was a greater reduction in left ventricular mass index (−3.2 [95% CI, −5.0 to −1.3] g/m2; P =0.001) with intervention compared with control. Cuff and central BPs were lowered by a similar magnitude across all BP measurement modes (eg, clinic cuff systolic BP, −6.16 [−9.60 to −2.72] mm Hg and clinic central systolic BP, −4.96 [−8.06 to −1.86] mm Hg; P ≥0.48 all). Secondary analyses found that changes in left ventricular mass index correlated to changes in BP, with the magnitude of effect nearly identical for BP measured by cuff (eg, 24-hour systolic BP, β, 0.17 [0.02–0.31] g/m2) or centrally (24-hour systolic BP, β, 0.16 [0.01–0.32] g/m2). CONCLUSIONS: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729 [ABSTRACT FROM AUTHOR]

Published
2024
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21. NCS‐1 expression is higher in basal breast cancers and regulates calcium influx and cytotoxic responses to doxorubicin

Author

Alice H. L. Bong, Mélanie Robitaille, Michael J. G. Milevskiy, Sarah J. Roberts‐Thomson, and Gregory R. Monteith

Subjects
basal breast cancer, calcium, chemotherapy, NCS‐1, ORAI1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Neuronal calcium sensor‐1 (NCS‐1) is a positive modulator of IP3 receptors and was recently associated with poorer survival in breast cancers. However, the association between NCS‐1 and breast cancer molecular subtypes and the effects of NCS‐1 silencing on calcium (Ca2+) signaling in breast cancer cells remain unexplored. Herein, we report for the first time an increased expression of NCS‐1 in breast cancers of the basal molecular subtype, a subtype associated with poor prognosis. Using MDA‐MB‐231 basal breast cancer cells expressing the GCaMP6m Ca2+ indicator, we showed that NCS‐1 silencing did not result in major changes in cytosolic free Ca2+ increases as a result of endoplasmic reticulum Ca2+ store mobilization. However, NCS‐1 silencing suppressed unstimulated basal Ca2+ influx. NCS‐1 silencing in MDA‐MB‐231 cells also promoted necrotic cell death induced by the chemotherapeutic drug doxorubicin (1 µm). The effect of NCS‐1 silencing on cell death was phenocopied by silencing of ORAI1, a Ca2+ store‐operated Ca2+ channel that maintains Ca2+ levels in the endoplasmic reticulum Ca2+ store and whose expression was significantly positively correlated with NCS‐1 in clinical breast cancer samples. This newly identified association between NCS‐1 and basal breast cancers, together with the identification of the role of NCS‐1 in the regulation of the effects of doxorubicin in MDA‐MB‐231 breast cancer cells, suggests that NCS‐1 and/or pathways regulated by NCS‐1 may be important in the treatment of basal breast cancers in women.

Published
2020
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22. Two-in-one: Combined transcatheter therapy for hypertrophic cardiomyopathy and aortic stenosis

Author

Natalie L. Montarello, Ross L. Roberts-Thomson, Nicholas J. Montarello, Adam J. Nelson, Joseph K. Montarello, and Stephen G. Worthley

Subjects
Aortic stenosis, Hypertrophic cardiomyopathy, Alcohol septal ablation, Transcatheter aortic valve replacement, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Technical advancements together with robust clinical trial evidence continue to extend the reach of transcatheter therapies. Conditions once considered amenable only to surgery, are now treatable percutaneously offering not only safe outcomes, but in some cases, superior results. Whilst ongoing clinical trials will inform which patients are likely to benefit from either approach, safe transcatheter alternatives have been transformative for patients considered unfit for surgery. We present a case from our institution of a septuagenarian with both aortic stenosis and hypertrophic cardiomyopathy deemed unfit for surgery by a porcelain aorta. Alcohol septal ablation (ASA) and transcatheter aortic valve replacement (TAVR) were offered, however in the context of treatment for active malignancy, a previously planned staged intervention had to be performed in a single procedure due to the development of heart failure symptoms. We present the first description of this ‘two-in-one’ intervention and provide background literature review for both ASA and TAVR.

Published
2020
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24. BRAF Signaling Inhibition in Glioblastoma: Which Clinical Perspectives?

Author

Victoria Bouchè, Giovanni Aldegheri, Carmine Antonio Donofrio, Antonio Fioravanti, Samuel Roberts-Thomson, Stephen B. Fox, Francesco Schettini, and Daniele Generali

Subjects
glioblastoma, BRAF V600E, targeted therapy, BRAF-inhibitors, MEK-inhibitors, IDH, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

IDH-wild type (wt) glioblastoma (GB) accounts for approximately 90% of all GB and has a poor outcome. Surgery and adjuvant therapy with temozolomide and radiotherapy is the main therapeutic approach. Unfortunately, after relapse and progression, which occurs in most cases, there are very limited therapeutic options available. BRAF which plays a role in the oncogenesis of several malignant tumors, is also involved in a small proportion of IDH-wt GB. Previous successes with anti-B-Raf targeted therapy in tumors with V600E BRAF mutation like melanoma, combined with the poor prognosis and paucity of therapeutic options for GB patients is leading to a growing interest in the potential efficacy of this approach. This review is thus focused on dissecting the state of the art and future perspectives on BRAF pathway inhibition in IDH-wt GB. Overall, clinical efficacy is mostly described within case reports and umbrella trials, with promising but still insufficient results to draw more definitive conclusions. Further studies are needed to better define the molecular and phenotypic features that predict for a favorable response to treatment. In addition, limitations of B-Raf-inhibitors, in monotherapy or in combination with other therapeutic partners, to penetrate the blood-brain barrier and the development of acquired resistance mechanisms responsible for tumor progression need to be addressed.

Published
2021
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28. The Genomic Landscape of Sporadic Prolactinomas

Author

De Sousa, Sunita M. C., Wang, Paul P. S., Santoreneos, Stephen, Shen, Angeline, Yates, Christopher J., Babic, Milena, Eshraghi, Leila, Feng, Jinghua, Koszyca, Barbara, Roberts-Thomson, Samuel, Schreiber, Andreas W., Torpy, David J., and Scott, Hamish S.

Published
2019
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29. Rationale and design of the IRON-AF study: a double-blind, randomised, placebo-controlled study to assess the effect of intravenous ferric carboxymaltose in patients with atrial fibrillation and iron deficiency

Author

Michael B Stokes, Celine Gallagher, Adrian D Elliott, Dennis H Lau, Prashanthan Sanders, Christopher X Wong, Mehrdad Emami, Kurt C Roberts-Thomson, Samuel J Tu, Nicole Hanna-Rivero, Ricardo S Mishima, Ellen Lyrtzis, Danielle Wlochowicz, and Nicholas AR Clarke

Subjects
Medicine
Abstract

Introduction Atrial fibrillation (AF) is associated with significantly impaired quality-of-life. Iron deficiency (ID) is prevalent in patients with AF. Correction of ID in other patient populations with intravenous iron supplementation has been shown to be a safe, convenient and effective way of improving exercise tolerance, fatigue and quality-of-life. The IRON-AF (Effect of Iron Repletion in Atrial Fibrillation) study is designed to assess the effect of iron repletion with intravenous ferric carboxymaltose in patients with AF and ID.Methods and analysis The IRON-AF study is a double-blind, randomised controlled trial that will recruit at least 84 patients with AF and ID. Patients will be randomised to receive infusions of either ferric carboxymaltose or placebo, given in repletion and then maintenance doses. The study will have follow-up visits at weeks 4, 8 and 12. The primary endpoint is change in peak oxygen uptake from baseline to week 12, as measured by cardiopulmonary exercise testing (CPET) on a cycle ergometer. Secondary endpoints include changes in quality-of-life and AF disease burden scores, blood parameters, other CPET parameters, transthoracic echocardiogram parameters, 6-minute walk test distance, 7-day Holter/Event monitor burden of AF, health resource utilisation and mortality.Ethics and dissemination The study protocol has been approved by the Central Adelaide Local Health Network Human Research Ethics Committee, Australia. The results of this study will be disseminated through publications in peer-reviewed journals and conference presentations.Trial registration number Australian New Zealand Clinical Trials Registry (ACTRN12620000285954).

Published
2021
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31. AKT Regulation of ORAI1-Mediated Calcium Influx in Breast Cancer Cells

Author

Alice Hui Li Bong, Trinh Hua, Choon Leng So, Amelia A. Peters, Mélanie Robitaille, Yin Yi Tan, Sarah J. Roberts-Thomson, and Gregory R. Monteith

Subjects
breast cancer, AKT regulation, calcium signaling, PTEN, GCaMP6, ORAI1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Although breast cancer cells often exhibit both abnormal AKT signaling and calcium signaling, the association between these two pathways is unclear. Using a combination of pharmacological tools, siRNA and CRISPR/Cas9 gene silencing techniques, we investigated the association between PTEN, AKT phosphorylation and calcium signaling in a basal breast cancer cell line. We found that siRNA-mediated PTEN silencing promotes AKT phosphorylation and calcium influx in MDA-MB-231 cells. This increase in AKT phosphorylation and calcium influx was phenocopied by the pharmacological AKT activator, SC79. The increased calcium influx associated with SC79 is inhibited by silencing AKT2, but not AKT1. This increase in calcium influx is suppressed when the store-operated calcium channel, ORAI1 is silenced. The results from this study open a novel avenue for therapeutic targeting of cancer cells with increased AKT activation. Given the association between ORAI1 and breast cancer, ORAI1 is a possible therapeutic target in cancers with abnormal AKT signaling.

Published
2022
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32. Safety of outpatient commencement of sotalol

Author

Kamsani, Suraya H., Middeldorp, Melissa E., Chiang, Glenda, Stefil, Maria, Evans, Shaun, Nguyen, Mau T., Shahmohamadi, Elnaz, Zhang, Jessica Qingying, Roberts-Thomson, Kurt C., Emami, Mehrdad, Young, Glenn D., and Sanders, Prashanthan

Abstract

Inpatient monitoring is recommended for sotalol initiation.

Published
2024
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33. Left atrial, pulmonary vein, and left atrial appendage anatomy in Indigenous individuals: Implications for atrial fibrillation

Author

Nicholas A.R. Clarke, Nadarajah Kangaharan, Benedict Costello, Samuel J. Tu, Nicole Hanna-Rivero, Kim Le, Ian Agahari, Wai Kah Choo, Bradley M. Pitman, Celine Gallagher, Kawa Haji, Kurt C. Roberts-Thomson, Prashanthan Sanders, and Christopher X. Wong

Subjects
Atrial fibrillation, Indigenous, Aboriginal and Torres Strait Islanders, Cardiovascular disease, Computed tomography, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Indigenous Australians experience a greater burden of AF. Whether this is in-part due to differences in arrhythmogenic structures that appear to contribute to AF differences amongst other ethnicities is not known. Methods: We studied forty individuals matched for ethnicity and other AF risk factors. Computed tomography imaging was used to characterise left atrial (LA), pulmonary vein (PV), and left atrial appendage (LAA) anatomy. Results: There were no significant differences in LA diameters or volumes between Indigenous and non-Indigenous Australians. Similarly, we could not detect any consistent differences in PV number, morphology, diameters, or ostial characteristics according to ethnicity. LAA analyses suggested that Indigenous Australians may have a greater proportion of non chickenwing LAA type, and a tendency for eccentric, oval-shaped LAA ostia; however, there were no other differences seen with regards to LAA volume or depth. Indexed values for LA, PV and LAA anatomy corrected for body size were broadly similar. Conclusions: In a cohort of individuals matched for AF risk factors, we could find no strong evidence of ethnic differences in LA, PV, and LAA characteristics that may explain a predisposition of Indigenous Australians for atrial arrhythmogenesis. These findings, in conjunction with our previous data showing highly prevalent cardiometabolic risk factors in Indigenous Australians with AF, suggest that it is these conditions that are more likely responsible for the AF substrate in these individuals. Continued efforts should therefore be directed towards risk factor management in an attempt to prevent and minimise the effects of AF in Indigenous Australians.

Published
2021
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35. ORAI1-Regulated Gene Expression in Breast Cancer Cells: Roles for STIM1 Binding, Calcium Influx and Transcription Factor Translocation

Author

Mélanie Robitaille, Shao Ming Chan, Amelia A. Peters, Limin Dai, Choon Leng So, Alice H. L. Bong, Francisco Sadras, Sarah J. Roberts-Thomson, and Gregory R. Monteith

Subjects
ORAI1, calcium signaling, breast cancer, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

A remodeling of calcium homeostasis, including calcium influx via store-operated calcium entry (SOCE), is a feature of breast cancers. SOCE is critical to maintain calcium balance in the endoplasmic reticulum calcium store and is an important mechanism for calcium signaling in a variety of cell types, including breast cancer cells. The canonical mechanism of SOCE is stromal interacting molecule 1 (STIM1)-mediated activation of ORAI. Elevated ORAI1 expression is a feature of basal breast cancer cells. However, the role of ORAI1 in the regulation of transcription in breast cancer cells of the basal molecular subtype is still unclear. Using CRISPR-Cas9 gene editing, ORAI1 protein expression was disrupted in MDA-MB-231 and MDA-MB-468 basal breast cancer cells. The ORAI1 wild-type and mutants were reintroduced into ORAI1 knockout cells to study the role of ORAI1 in gene transcriptional regulation. In the absence of calcium store depletion, ORAI1 regulated PTGS2 in MDA-MB-231 cells, and this was dependent on ORAI1 pore function and STIM1 binding. The activation of SOCE by thapsigargin resulted in ORAI1-dependent increases in IL6 transcription in MDA-MB-468 cells; this was also dependent on ORAI1 pore function and STIM1 binding and was associated with the translocation of NFAT1. Given the upregulation of ORAI1 in basal breast cancer cells, our results provide further evidence that ORAI1 may contribute to cancer progression through regulation of gene expression.

Published
2022
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36. Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry

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Jitendra PS. Sawhney, Veerappa A. Kothiwale, Vikas Bisne, Rajashekhar Durgaprasad, Praveen Jadhav, Manoj Chopda, Velam Vanajakshamma, Ramdhan Meena, Govindan Vijayaraghavan, Kamaldeep Chawla, Jagan Allu, Karen S. Pieper, A. John Camm, Ajay K. Kakkar, Jean-Pierre Bassand, David A. Fitzmaurice, Samuel Z. Goldhaber, Shinya Goto, Sylvia Haas, Werner Hacke, Lorenzo G. Mantovani, Frank Misselwitz, Alexander G.G. Turpie, Martin van Eickels, Freek W.A. Verheugt, Gloria Kayani, Keith A.A. Fox, Bernard J. Gersh, Hector Lucas Luciardi, Harry Gibbs, Marianne Brodmann, Frank Cools, Antonio Carlos Pereira Barretto, Stuart J. 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Domenech Borras, A. Elorriaga Madariaga, A. Espallargas, M. Fernandez, E. Fernandez Escobar, E. Fernandez Mas, A. Ferrer, J. Fosch, M. Garcia Bermudez, V. Garcia Millan, M. Gavira Saenz, C. Gines Garcia, C. Gomez, Y. Gomez Perez, A. Gonzales Segovia, P. Gonzalez, L. Grigorian, A. Guerrero Molina, M. del C. Gutierrez del Val, B. Herrero Maeso, E. Hevia Rodriguez, A. Iglesias Garcia, M.J. Jimenez Fernandez, B. Jimeno Besa, P. Juan Salvadores, M.B. Lage Bouzamayor, I. Lasuncion, L.E. Lezcano Gort, M. Llobet Molina, M. Lopez, A. Manzanal Rey, J. Mara Guerra, S. Marcus, A. Martin Vila, M. Martinez Mena, P. Mazon, F. Mendez Zurita, G. Millán, M. Molina, P. Montero Alia, D. Montes, M. Moure Gonzalez, R.B. Munoz Munoz, A. Negrete Palma, H.N. Orellana Figueroa, V.M. Ortega, C. Ortiz Cortes, D. Otero Tomera, N. Palomo Merchan, I. Pareja Ibar, E. Pena Garcia, M. Pereda Armayor, M. Perez Carasa, I. Prieto, V. Quintern, R. Renom, L.M. Rincon Diaz, V. Rios, L. Riquelme Sola, R. Rivera, X. Robiro Robiro, M. Roca, C. Roca Saumell, C. Rodrigo, E. Rodriguez, M. Rodriguez Garcia, S. Saez Jimenez, P. Sanchez Calderon, L. Sanchez Mendez, S. Sanchez Parra, C. Santolaya, M.R. Senan Sanz, A. Seoane Blanco, E. Serralvo, N. Sierra, C. Simon Valero, J. Sorribes Lopez, M. Teixido Fontanillas, M. Terns Riera, G. Tobajas, C. Torres, J. Torres Marques, M. Ubeda Pastor, M. Rosenqvist, A. Wirdby, J. Linden, K. Henriksson, M. Elmersson, A. Egilsson, U. Börjesson, G. Svärd, B. Liu, A. Lindh, L.-B. Olsson, M. Gustavsson, Lars Andersson, Lisbeth Andersson, L. Benson, C. Bothin, A. Hajimirsadeghi, K. Kadir, M. Ericsson, A. Ohlsson, H. Lindvall, P. Svensson, K. Thorne, H. Handel, P. Platonov, B. Eriksson, I. Timberg, K. Romberg, M. Crisby, J.-E. Karlsson, S.A. Jensen, A. Andersson, L. Malmqvist, B. Martinsson, F. Bernsten, J. Engdahl, J. Thulin, A. Hot-Bjelac, P. Stalby, H. Aaröe, E. Ahbeck, H. Ahlmark, F. Al-Khalili, G. Bonkowski, S. Dzeletovic, A.-B. Ekstrand, G.-B. Eriksson, K. Floren, C. Grässjö, S. Hahn, P. Jaensson, B. Jansson, J.-H. Jansson, R.-M. Kangert, A. Koch, D. Kusiak, A. Lettenström, A. Lindberg, C.-J. Lindholm, A. Mannermyr, K. Mansson, M. Millborg, C. Nilsson, A.-M. Ohlin, A. Olofsson, A. Osberg, A. Pedersen, K. Risbecker, K. Rosenberg, J. Samuelsson, M. Shayesteh, K. Skoglund, M. Stjernberg, C. Thorsen, J. Steffel, J.H. Beer, J. Debrunner, D. Amstutz, J. Bruegger, G. Elise, A. Grau, A. Guinand, I. Henriette, E. Saga, S. Winnik, A. Parkhomenko, I. Rudyk, V. Tseluyko, O. Karpenko, S. Zhurba, I. Kraiz, I. Kupnovytska, N. Serediuk, Y. Mostovoy, O. Ushakov, O. Koval, I. Kovalskyi, Y. Svyshchenko, O. Sychov, M. Stanislavchuk, O. Kraydashenko, A. Yagensky, S. Tykhonova, I. Fushtey, R. Belegai, G. Berko, L. Burdeuna, O. Chabanna, I. Daniuk, A. Ivanov, E. Kamenska, P. Kaplan, O. Khyzhnyak, S. Kizim, O. Matova, O. Medentseva, V. Mochonyi, M. Mospan, V. Nemtsova, T. Ovdiienko, O. Palamarchuk, M. Pavelko, R. Petrovskyy, D. Plevak, O. Proshak, S. Pyvovar, L. Rasputina, O. Romanenko, O. Romanova, A. Sapatyi, O. Shumakov, R. Stets, L. Todoriuk, V. Varenov, D. Fitzmaurice, N. Chauhan, D. Goodwin, P. Saunders, R. Evans, J. Leese, P.S. Jhittay, A. Ross, M.S. Kainth, G. Pickavance, J. McDonnell, A. Williams, T. Gooding, H. Wagner, S. Suryani, A. Singal, S. Sircar, R. Bilas, P. Hutchinson, A. Wakeman, M. Stokes, N. Paul, M. Aziz, C. Ramesh, P. Wilson, S. Franklin, S. Fairhead, J. Thompson, V. St Joseph, G. Taylor, D. Tragen, D. Seamark, C. Paul, M. Richardson, A. Jefferies, H. Sharp, H. Jones, C. Giles, M. Page, O. Oginni, J. Aldegather, S. Wetherwell, W. Lumb, P. Evans, F. Scouller, N. Macey, Y. Stipp, R. West, S. Thurston, P. Wadeson, J. Matthews, P. Pandya, A. Gallagher, T. Railton, B. Sinha, D. Russell, J.A. Davies, P. Ainsworth, C.P. Jones, P. Weeks, J. Eden, D. Kernick, W. Murdoch, L. Lumley, R.P. Patel, S.W. Wong, M. Saigol, K. Ladha, K. Douglas, D.F. Cumberlidge, C. Bradshaw, G. Van Zon, K.P. Jones, M.J. Thomas, E. Watson, B. Sarai, N. Ahmad, W. Willcock, J. Cairns, S. Sathananthan, N. de Kare-Silver, A. Gilliland, E. Strieder, A. Howitt, B. Vishwanathan, N. Bird, D. Gray, M. Clark, J. Bisatt, J. Litchfield, E. Fisher, T. Fooks, A.R. Kelsall, E. Alborough, J. Wakeling, M. Parfitt, K. Milne, S. Rogers, R. Priyadharshan, J.L. Oliver, E. Davies, S. Abushal, M. Jacobs, C. Hutton, N.I. Walls, R. Thompson, C. Chigbo, S.M.A. Zaidi, M. Howard, K.C. Butter, S. Barrow, H. Little, I.U. Haq, L. Gibbons, S. Glencross, A.J. McLeod, K. Poland, C. Mulholland, A. Warke, P. Conn, G. Burns, R.N. Smith, S. Lowe, R. Kamath, H.S. Dau, J. Webster, I. Hodgins, S. Vercoe, P.C. Roome, H. Pinnock, J.R.A. Patel, A. Ali, N. Hart, R. Davies, E. Stuart, C.A. Neden, M. Danielsen, R. Heath, P. Sharma, S. Galloway, C. Hawkins, R. Oliver, M. Aylward, S. Mannion, M. Braddick, D. Edwards, A.C. Rothwell, A. Sabir, F. Choudhary, S. Khalaque, A. Wilson, S. Peters, W. Coulson, N. Roberts, A. Heer, S. Coates, B. Ward, D. Jackson, S. Walton, D. Shepherd, M. Sterry, T. Wong, M. Boon, R. Bunney, R. Haria-Shah, R.T. Baron, S. Davies, T. Schatzberger, N. Hargreaves, T. Stephenson, H. Choi, R. Batson, L. Lucraft, T. Myhill, S. Estifano, D. Geatch, J. Wilkinson, R. Veale, K. Forshaw, T. Davies, K. Zaman, P. Vinson, C. Liley, M. Bandrapalli, P. McGinty, R. Wastling, P. McEleny, A. Beattie, P. Cooke, M. Wong, J. Gunasegaram, M. Pugsley, S. Ahmad, C. A'Court, J. Ayers, J. Bennett, S. Cartwright, S. Dobson, C. Dooldeniya, A. Flynn, R. Fox, J. Goram, A. Halpin, A. Hay, P. Jacobs, L. Jeffers, L. Lomax, I. Munro, R. Muvva, M. Nadaph, K. Powell, S. Randfield, D. Redpath, R. Reed, M. Rickenbach, G. Rogers, P.B. Saunders, C. Seamark, J. Shewring, P. Simmons, H. Simper, H. Stoddart, A. Sword, N. Thomas, A. Thomson, H. Gibbs, A. Blenkhorn, B. Singh, W. Van Gaal, W. Abhayaratna, R. Lehman, P. Roberts-Thomson, J. Kilian, D. Coulshed, A. Catanchin, D. Colquhoun, H. Kiat, D. Eccleston, J. French, L. Zimmett, B. Ayres, T. Phan, P. Blombery, D. Crimmins, D. O'Donnell, A. Choi, P. Astridge, M. Arstall, N. Jepson, M. Binnekamp, A. Lee, J. Rogers, G. Starmer, P. Carroll, J. Faunt, A. Aggarwala, L. Barry, C. Batta, R. Beveridge, A. Black, M. Bonner, J. Boys, E. Buckley, M. Campo, L. Carlton, A. Connelly, B. Conway, D. Cresp, H. Dimitri, S. Dixon, M. Dolman, M. Duroux, M. Eskandari, R. Eslick, A. Ferreira-Jardim, T. Fetahovic, D. Fitzpatrick, R. Geraghty, J. Gibbs, T. Grabek, M.H. Modi, K. Hayes, M.P. Hegde, L. Hesketh, B. Hoffmann, B. Jacobson, K. Johnson, C. Juergens, I. Kassam, V. Lawlor, M. Lehman, S. Lehman, D. Leung, S. Mackay, M. MacKenzie, C. McCarthy, C. McIntosh, L. McKeon, H. Morrison, C. Mussap, J.-D. Myers, V. Nagalingam, G. Oldfield, V. O'May, J. Palmer, L. Parsons, K. Patching, T. Patching, V. Paul, M. Plotz, S. Preston, H. Rashad, M. Ratcliffe, S. Raynes, J. Rose, L. Sanders, M. Seremetkoska, H. Setio, S. Shone, P. Shrestha, C. Singh, C. Singleton, N. Stoyanov, S. Sutcliffe, K. Swaraj, J. Tarrant, S. Thompson, I.M. Tsay, M. Vorster, A. Waldman, L. Wallis, E. Wilford, K. Wong, S.J. Connolly, A. Spyropoulos, J. Eikelboom, R. Luton, M. Gupta, A.S. Pandey, S. Cheung, R. Leader, P. Beaudry, F. Ayala-Paredes, J. Berlingieri, J. Heath, G. Poirier, M. Du Preez, R. Nadeau, G. Dresser, R. Dhillon, T. Hruczkowski, B. Schweitzer, B. Coutu, P. Angaran, P. MacDonald, S. Vizel, S. Fikry, R. Parkash, A. Lavoie, J. Cha, B. Ramjattan, J. Bonet, K. Ahmad, L. Aro, T. Aves, K. Beaudry, C. Bergeron, J. Bigcanoe, N. Bignell, L. Breakwell, E. Burke, L. Carroll, B. Clarke, T. Cleveland, S. Daheb, P. Dehghani, I. Denis, Z. Djaidani, P. Dorian, S. Douglass, J. Dunnigan, A. Ewert, D. Farquhar, A. Fearon, L. Ferleyko, D. Fournier, B. Fox, M.-C. Grenier, W. Gulliver, K. Haveman, C. Hines, K. Hines, A.M. Jackson, C. Jean, G. Jethoo, R. Kahlon, S. Kelly, R. Kim, V. Korley, J. Kornder, L. Kwan, J. Largy, C. Lewis, S. Lewis, I. Mangat, R. Moor, J. Navratil, I. Neas, J. Otis, R. Otis, M. Pandey, F. Petrie, A. Pinter, M. Raines, P. Roberts, M. Robinson, G. Sas, S. Schulman, L. Snell, S. Spearson, J. Stevenson, T. Trahey, S. Wong, D. Wright, H. Ragy, A. Abd El-Aziz, S.K. Abou Seif, M.G. El Din, S. El Etriby, A. Elbahry, A. El-Etreby, M. Elkhadem, A. Katta, T. Khairy, A. Mowafy, M. Nawar, A. Ohanissian, A. Reda, M. Reda, H. Salem, N. Sami, S. Samir, M. Setiha, M. Sobhy, A. Soliman, N. Taha, M. Tawfik, E. Zaatout, D. Kettles, J. Bayat, H. Siebert, A. Horak, Y. Kelfkens, R. Garda, T. Pillay, M. Guerra, L. van Zyl, H. Theron, A. Murray, R. Louw, D. Greyling, P. Mntla, V. Ueckermann, R. Loghdey, S. Ismail, F. Ahmed, J. Engelbrecht, A. Ramdass, S. Maharajh, W. Oosthuysen, G. Angel, C. Bester, M. Booysen, C. Boshoff, C. Cannon, S. Cassimjee, C. Chami, G. Conway, A. Davids, L. de Meyer, G. Du Plessis, T. Ellis, L. Henley, M. Karsten, E. Loyd, J. Marks, L. Mavhusa, M. Mostert, A. Page, L. Rikhotso, M. Salie, J. Sasto, F. Shaik, A. Skein, L. Smith, G. Tarr, T. Tau, F. van Zyl, W. Al Mahmeed, G. Yousef, A. Agrawal, M. Nathani, M. Ibrahim, E.M. Esheiba, R. Singh, A. Naguib, M. Abu-Mahfouz, M. Al Omairi, A. Al Naeemi, R. Maruthanayagam, N. Bazargani, A. Wassef, R. Gupta, M. Khan, B. Subbaraman, A. Abdul, A. Al Mulla, S. El Bardisy, P. Haridas, S. Jadhav, K. Magdaluyo, M. Makdad, I. Maqsood, R. Mohamed, N. Sharma, R. Sharma, M. Thanzeel, S.Z. Goldhaber, R. Canosa, P. Rama, E. Blumberg, J. Garcia, P. Mullen, V. Wilson, A. Quick, K. Ferrick, W.M. Kutayli, M. Cox, M. Franco, S. Falkowski, R. Mendelson, M. Williams, S. Miller, S. Beach, A. Alfieri, T. Gutowski, I. Haque, R. Reddy, W. Ahmed, P. Delafontaine, D. Diercks, D. Theodoro, K. Remmel, M. Alberts, R. Ison, H. Noveck, P. Duffy, S. Pitta, D. Nishijima, C. Treasure, N. Asafu-Adjaye, K. Ball, M. Bartlett, M. Bentley, S. Bowers, A. Brown, A. Browne, J. Cameron-Watts, M. Canova, D. Cassidy, K. Cervellione, S. Congal, J. DePauw, A. Dickerson, M. Eley, L. Evans, S. Felpel, K. Ferdinand, D. Fielder, P. Gentry, A. Haideri, F. Hakimi, T. Harbour, E. Hartranft, B. Hawkins, M. Headlee, L. Henson, C. Herrick, T. Hicks, S. Jasinski, A. Jones, L. Jones, P. Jones, S. Karl, M. Keeling, J. Kerr, P. Knowles, J. Langdon, M. Lay, J.A. Lee, T. Lincoln, E. Malone, A. Merliss, D. Merritt, J. Minardo, B. Mooso, C. Orosco, V. Palumbo, M. Parker, T. Parrott, S. Paserchia, G. Pearl, J. Peterson, N. Pickelsimer, T. Purcell, J. Raynor, S. Raziano, C. Richard, T. Richardson, C. Robertson, A. Sage, T. Sanghera, P. Shaw, J. Shoemaker, K. Smith, B. Stephanie, A. Thatcher, H. Theobald, N. Thompson, L. Treasure, T. Tripti, C. Verdi, and V. Worthy

Subjects
Surgery, RD1-811, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: The Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. Methods and results: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012–2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P

Published
2018
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37. What factors are associated with dental general anaesthetics for Australian children and what are the policy implications? A qualitative study

Author

John Rogers, Clare Delany, Clive Wright, Kaye Roberts-Thomson, and Mike Morgan

Subjects
Dental caries, Children, Dental general anaesthetics, Potentially preventable dental hospitalisations, Dentistry, RK1-715
Abstract

Abstract Background Dental general anaesthetics undertaken on young children are amongst the most common of all potentially preventable hospitalisations of children in Australia. They are costly for families and the community and entail some risk. The aim of the study was to explore the views of stakeholders about factors associated with children’s dental general anaesthetics in Victoria, Australia and to identify policy implications. Methods Interviews with stakeholders were used to develop a framework of factors. Interview data were subject to qualitative analysis, informed by Interpretative Phenomenological Analysis. Results Eight themes that encompassed 30 main factors were identified through focused discussions with 16 stakeholders. While the safety of dental general anaesthetics has improved and mortality rates are low, side effects are common. Push factors for children’s dental general anaesthetics include a perceived greater ‘child-focus’; preferred models of care; low oral health literacy; parent guilt; convenience; and some dentists reluctance to treat high needs children in the clinic. Factors that may decrease the prevalence of dental general anaesthetics include: prevention of dental caries; using alternative approaches; an appropriate workforce mix; enhancing oral health literacy; and development of guidelines. Conclusion The prevalence of hospitalisation of children to treat dental caries is increasing. Many factors influence the prevalence of paediatric dental general anaesthetics - relating to the child, parent, oral health professional, financial impact, health risk, and accessibility to facilities. There are quality of care and convenience benefits but also high costs and possible health risks. Family, workforce and health system factors have been identified that could decrease the prevalence of paediatric dental general anaesthetics.

Published
2018
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38. A retrospective analysis of eosinophilia as a predictive marker of response and toxicity to cancer immunotherapy

Author

Tharani Krishnan, Yoko Tomita, and Rachel Roberts-Thomson

Subjects
biomarker, cancer, eosinophilia, immune checkpoint inhibitors, response, toxicity, Medicine, Medicine (General), R5-920
Abstract

Aim: To investigate eosinophilia as a potential on-treatment biomarker for patients receiving cancer immunotherapy. Materials & methods: We evaluated the association between eosinophilia and treatment response and toxicity in a retrospective cohort of patients receiving cancer immunotherapy. Results: The study involved 146 patients. Eosinophilia developed in 22%. Patients who developed eosinophilia were more likely to achieve disease control (p = 0.009), with every 0.1 × 109/l rise in eosinophil count, while receiving treatment was associated with a 28% relative increased chance achieving disease control. Although there was a trend toward improved survival, there was no significant association between eosinophilia and improved overall survival (p = 0.136). Patients with eosinophilia were more likely to develop toxicity (p = 0.042). Conclusion: Eosinophilia is a potentially useful biomarker warranting further prospective clinical investigation.

Published
2020
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41. 4.8 Reference Values for Submaximal Exercise Blood Pressure: the EXERcise Stress Test CollaboratION (EXERTION)

Author

Schultz Martin, Ann-Marie Kovacevic, Philip Roberts-Thomson, Tony Stanton, Christian Hamilton-Craig, Sudir Wahi, James Hare, Joseph Selvanayagam, Andrew Maiorana, Alison Venn, and James Sharman

Subjects
Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Exaggerated blood pressure (BP) during submaximal exercise independently predicts cardiovascular mortality and identifies uncontrolled high BP not detected at rest. However, thresholds for submaximal exercise BP during clinical exercise testing have never been defined from a large representative sample, which was the aim of this study. Methods: Records from 13,949 people referred for a clinical exercise stress test (aged 52 ± 13 years, 61% male) using the Bruce treadmill protocol (stages 1 to 4 plus peak) were extracted from 4 Australian hospitals over the years 2000–2018. Exercise records were linked to administrative health datasets (hospital admissions and emergency presentations) to define clinical characteristics, including cardiovascular disease history. Thresholds denoting exaggerated BP were defined as > 90th centile at each exercise stage. Results: SBP and DBP thresholds across all stages were higher in males vs. females (stage-1: 180/90 vs 175/90 mmHg; stage-2: 196/94 vs 190/90 mmHg; stage-3: 204/97 vs 196/91 mmHg; stage-4: 210/100 vs 196/92 mmHg; peak: 215/100 vs 206/95 mmHg). SBP at all stages increased stepwise from the 1st to 4th age quartile (p < 0.05), whilst DBP remained similar (stage-1: 163/90 to 185/92 mmHg; stage-2: 180/90 to 204/95 mmHg; stage-3: 193/90 to 210/95 mmHg, stage-4: 200/91, to 210/96 mmHg; peak: 201/95 to 217/100 mmHg). Results were similar irrespective of cardiovascular disease history. Conclusions: This is the first study to define submaximal exercise BP thresholds during clinical exercise testing. Thresholds were higher in males compared to females and increased with age. These thresholds may help clinicians to identify people at increased high BP-related risk.

Published
2020
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42. P113 The Forgotten Black Box of Blood Pressure: Error in Oscillometric Mean Arterial Pressure is Associated with Cuff Measurement Inaccuracy

Author

Dean Picone, Martin Schultz, Matthew Armstrong, Nathan Dwyer, Philip Roberts-Thomson, Thomas Weber, and James Sharman

Subjects
Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Accurate measurement of cuff systolic BP (SBP) and diastolic BP (DBP) is contingent on the assumption of oscillometric MAP being accurate. If MAP is inaccurate this is likely to impact the accuracy of cuff SBP and DBP, but this has never been determined and was the aim of the study. Methods: In five independent studies, MAP was measured by five unique cuff oscillometric BP devices at the same time as invasive aortic MAP (area under the waveform) by fluid-filled or solid-state catheters among 262 patients (61 ± 11 years, 65% male) during coronary angiography. Cuff SBP and DBP were estimated by device-specific algorithms. Measurement errors were calculated as cuff – invasive aortic BP. Results: For each BP device, MAP error was −2.6 ± 6.1, 0.76 ± 7.2, 1.4 ± 5.5, 1.5 ± 6.7 and 7.1 ± 9.2 mmHg. Corresponding SBP errors were 4.4 ± 8.7, −0.8 ± 11.2, −8.8 ± 10.4, −0.9 ± 10.5 and 1.9 ± 10.8 mmHg, whereas DBP errors were 8.8 ± 5.1, 2.0 ± 7.4, 6.7 ± 7.3, 10.3 ± 9.0 and 13.1 ± 6.4 mmHg. There was a direct relationship between errors in oscillometric MAP and SBP error in four of the five devices (B range = 0.42 to 1.04). However, MAP error was consistently related to DBP error in all devices (B range = 0.48 to 0.97). Across all devices, absolute error in MAP ≥3 mmHg corresponded to absolute error in SBP and DBP ≥5 mmHg in 56–77% and 62–88% of patients. Conclusion: Errors in oscillometric MAP are directly related to cuff SBP and DBP inaccuracy, but the magnitude of error is device-specific. Further work is required to understand algorithms used in oscillometric devices to improve cuff BP accuracy.

Published
2020
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43. P109 The Influence of Sex on Cuff Blood Pressure Accuracy

Author

Elif Stoneman, Dean Picone, Martin Schultz, Matthew Armstrong, Willem Bos, Nathan Dwyer, Peter Lacy, Esben Laugesen, Stefano Omboni, Giacomo Pucci, Philip Roberts-Thomson, George Stouffer, Kenji Takazawa, Thomas Weber, Berend Westerhof, and James Sharman

Subjects
Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Cuff blood pressure (BP) is intended to approximate central aortic BP and accuracy is paramount. Sex differences in BP physiology could influence the accuracy of cuff BP as an estimate of invasive aortic BP, but this has not been explored in-depth and was the aim of this study. Methods: Cuff and invasive aortic BP were measured in 1701 subjects (31.9% female, aged 63 ± 12) during coronary angiography from the INvaSive blood PressurE ConsorTium (INSPECT) database. Cuff accuracy was defined as cuff–invasive BP. In a sub-sample (n = 376, 27% female, aged 63 ± 11), invasive brachial BP was recorded to assess systolic (SBP) amplification (invasive brachial–aortic SBP). Results: Invasive aortic SBP was higher in females compared with males (mean [95% CI]: 141.8 mmHg [137.1, 146.3] versus 132.9 mmHg [129.4, 136.4], p < 0.001). Cuff SBP significantly underestimated invasive aortic SBP in females compared with males (−3.1 mmHg [−5.9, −0.2] versus 1.4 mmHg [−1.1, 4.0], p < 0.001 for difference). Sex differences remained after adjustment for age and height. In the sub-sample, aortic-to-brachial SBP-amplification was lower in females (7.1 mmHg [3.3, 10.8] versus 10.2 mmHg [5.1, 15.4], p = 0.0070). Sex, SBP-amplification, height and age were associated with cuff BP inaccuracy, but only SBP-amplification and age remained associated in multivariable analysis (p < 0.05). Conclusion: Females have greater propensity towards cuff BP inaccuracy through underestimation of aortic SBP. Both age and the magnitude of aortic-to-brachial SBP-amplification are related to cuff BP inaccuracy, which provide greater understanding of sex differences in BP physiology and may help improve the accuracy of cuff BP methods.

Published
2020
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44. P112 Influence of Cuff Blood Pressure Accuracy on Identification of Isolated Systolic Hypertension

Author

Dean Picone, Martin Schultz, Matthew Armstrong, Willem Bos, Nathan Dwyer, Peter Lacy, Esben Laugesen, Stefano Omboni, Giacomo Pucci, Philip Roberts-Thomson, George Stouffer, Kenji Takazawa, Thomas Weber, Berend Westerhof, and James Sharman

Subjects
Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Introduction: Isolated systolic hypertension (ISH) is the most common form of hypertension in older people. However, accurate identification of ISH may be hindered because cuff blood pressure (BP) underestimates systolic BP (SBP) and overestimates diastolic BP (DBP). This study aimed to determine the influence of cuff BP accuracy on the identification of ISH. Methods: Cuff BP and invasive aortic BP were measured simultaneous (or near-simultaneously) in 1737 subjects (63 ± 12 years, 68% male) during coronary angiography. Data was derived from 32 studies, using 20 different cuff BP devices, from the Invasive Blood Pressure Consortium (INSPECT). ISH was defined as ≥140/

Published
2020
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45. P63 Accuracy (Validation) of Central Blood Pressure Measurement Using the Sphygmocor Xcel-cuff Device

Author

Martin Schultz, Dean Picone, Matthew Armstrong, Andrew Black, Nathan Dwyer, Philip Roberts-Thomson, and James Sharman

Subjects
Specialties of internal medicine, RC581-951, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: Numerous devices purport to measure central aortic BP as distinct from conventional brachial BP. This study aimed to determine the accuracy (validation) of the Sphygmocor Xcel-cuff device (AtCor Medical, Sydney, Australia) for measuring central BP. Methods: 330 patients (mean age 61.3 ± 10.6 years) undergoing coronary angiography had simultaneous measurement of invasive aortic BP and non-invasive cuff-derived central BP using the Xcel device (total n = 552 individual comparisons). Methods were undertaken according to Artery Society guidelines and several calibration techniques to derive central SBP were examined. Results: Central SBP was significantly underestimated, and with wide variability, when using the default calibration of brachial cuff SBP/DBP (−7.7 ± 11.0 mmHg). Similar wide variability was observed using other calibration methods (cuff 33% form-factor MAP/DBP, −4.4 ± 11.5 mmHg; cuff 40% form-factor MAP/DBP, 4.7 ± 11.9 mmHg; cuff oscillometric MAP/DBP, −18.2 ± 12.1 mmHg). Only calibration with invasive aortic integrated MAP/DBP resulted in a mean difference ± SD (3.3 ± 7.5 mmHg) within the minimum tolerable error of ≤5 ± ≤8 mmHg. The difference between brachial cuff SBP and invasive aortic SBP was 3.3 ± 10.7 mmHg. A subsample (n = 151) analysis to determine the accuracy of central-to-brachial SBP amplification, showed this to be over-estimated by the Xcel device (4.3 ± 9.1 mmHg, p = 0.02). Conclusion: Irrespective of calibration technique, the Sphygmocor Xcel-cuff device does not pass the Artery Society accuracy (validation) criteria for non-invasive measurement of central BP. Further accuracy refinements of this device are required.

Published
2020
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46. ST‐Segment–Elevation Myocardial Infarction (STEMI) Patients Without Standard Modifiable Cardiovascular Risk Factors—How Common Are They, and What Are Their Outcomes?

Author

Stephen T. Vernon, Sean Coffey, Mario D'Souza, Clara K. Chow, Jens Kilian, Karice Hyun, James A. Shaw, Mark Adams, Philip Roberts‐Thomson, David Brieger, and Gemma A. Figtree

Subjects
atherosclerosis, mortality, risk factor, ST‐segment–elevation myocardial infarction, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background Programs targeting the standard modifiable cardiovascular risk factors (SMuRFs: hypertension, diabetes mellitus, hypercholesterolemia, smoking) are critical to tackling coronary heart disease at a community level. However, myocardial infarction in SMuRF‐less individuals is not uncommon. This study uses 2 sequential large, multicenter registries to examine the proportion and outcomes of SMuRF‐less ST‐segment–elevation myocardial infarction (STEMI) patients. Methods and Results We identified 3081 STEMI patients without a prior history of cardiovascular disease in the Australian GRACE (Global Registry of Acute Coronary Events) and CONCORDANCE (Cooperative National Registry of Acute Coronary Syndrome Care) registries, encompassing 42 hospitals, between 1999 and 2017. We examined the proportion that were SMuRF‐less as well as outcomes. The primary outcome was in‐hospital mortality, and the secondary outcome was major adverse cardiovascular events (death, myocardial infarction, or heart failure, during the index admission). Multivariate regression models were used to identify predictors of major adverse cardiovascular events. Of STEMI patients without a prior history of cardiovascular disease 19% also had no history of SMuRFs. This proportion increased from 14% to 23% during the study period (P=0.0067). SMuRF‐less individuals had a higher in‐hospital mortality rate than individuals with 1 or more SMuRFs. There were no clinically significant differences in major adverse cardiovascular events at 6 months between the 2 groups. Conclusions A substantial and increasing proportion of STEMI presentations occur independently of SMuRFs. Discovery of new markers and mechanisms of disease beyond standard risk factors may facilitate novel preventative strategies. Studies to assess longer‐term outcomes of SMuRF‐less STEMI patients are warranted.

Published
2019
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47. Influence of ethnic background on left atrial markers of inflammation, endothelial function and tissue remodelling

Author

Carlee D. Ruediger, Bobby John, Sathesh Kumar, Han S. Lim, Geetanjali Rangnekar, Kurt C. Roberts-Thomson, Glenn D. Young, David Chase, Prashanthan Sanders, and Scott R. Willoughby

Subjects
Supraventricular tachycardia, Thrombogenesis, Ethnicity, Endothelial function, Inflammation, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract

Background: It has been suggested that ethnicity can make a significant difference to the likelihood of thromboembolic stroke related to atrial fibrillation. Ethnic differences have been shown to alter inflammatory and haemostatic factors; however, this may all be confounded by differences in cardiovascular risk factors between different ethnicity. The impact of different ethnicities on the thrombogenic profile is not known. The aim of this study was to investigate differences in markers of inflammation, endothelial function and tissue remodelling between Caucasian and Indian populations with supraventricular tachycardia (SVT). Methods: Patients with structurally normal hearts undergoing catheter ablation for SVT were studied. This study included 23 Australian (Caucasian) patients from the Royal Adelaide Hospital, Adelaide, Australia and 24 Indian (Indian) patients from the Christian Medical College, Vellore, India. Blood samples were collected from the femoral vein, and right and left atria. Blood samples were analysed for the markers of endothelial function (ADMA, ET-1), inflammation (CD40L, VCAM-1, ICAM-1), and tissue remodelling (MMP-9, TIMP-1) using ELISA. Results: The study populations were well matched for cardiovascular risk factors and the absence of structural heart disease. No difference in the echocardiographic measurements between the two ethnicities was found. In this context, there was no difference in markers of inflammation, endothelial function or tissue remodelling between the two SVT populations. Conclusion: Caucasian and Indian populations demonstrate similar inflammatory, endothelial function or tissue remodelling profiles. This study suggests a lack of an impact of different ethnicity in these populations in terms of thrombogenic risk.

Published
2018
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48. Uncovering the cause of ulcerative colitis

Author

Ian C Roberts‐Thomson, Robert V Bryant, and Samuel P Costello

Subjects
environmental factors, genes, intestinal microbiota, mucosal immunity, ulcerative colitis, Diseases of the digestive system. Gastroenterology, RC799-869
Published
2019
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49. An Emerging Role for Calcium Signaling in Cancer-Associated Fibroblasts

Author

Francisco Sadras, Gregory R. Monteith, and Sarah J. Roberts-Thomson

Subjects
calcium, cancer, cancer-associated fibroblasts, migration, chemoresistance, Biology (General), QH301-705.5, Chemistry, QD1-999
Abstract

Tumors exist in a complex milieu where interaction with their associated microenvironment significantly contributes to disease progression. Cancer-associated fibroblasts (CAFs) are the primary component of the tumor microenvironment and participate in complex bidirectional communication with tumor cells. CAFs support the development of various hallmarks of cancer through diverse processes, including direct cell–cell contact, paracrine signaling, and remodeling and deposition of the extracellular matrix. Calcium signaling is a key second messenger in intra- and inter-cellular signaling pathways that contributes to cancer progression; however, the links between calcium signaling and CAFs are less well-explored. In this review, we put into context the role of calcium signaling in interactions between cancer cells and CAFs, with a focus on migration, proliferation, chemoresistance, and genetic instability.

Published
2021
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50. Hypoxia-induced reactive oxygen species mediate N-cadherin and SERPINE1 expression, EGFR signalling and motility in MDA-MB-468 breast cancer cells

Author

Iman Azimi, Rosalie M. Petersen, Erik W. Thompson, Sarah J. Roberts-Thomson, and Gregory R. Monteith

Subjects
Medicine, Science
Abstract

Abstract One of the hallmarks of the tumour microenvironment is hypoxia resulting from increased oxygen consumption by proliferative cancer cells and altered vasculature. Hypoxic tension initiates various cellular signals and can drive epithelial to mesenchymal transition (EMT), a process important in cancer progression. In this study, using the antioxidant N-acetylcysteine (NAC), we show that hypoxia-induced reactive oxygen species (ROS) in MDA-MB-468 breast cancer cells, selectively regulate hypoxia-induced increases in N-cadherin and SERPINE1, two proteins involved in cell adhesion. Treatment of cells with NAC also attenuated hypoxia-mediated activation of EGFR, but did not have any effect on hypoxia-mediated induction of HIF1α. Exogenous hydrogen peroxide phenocopied the effects of hypoxia on N-cadherin and SERPINE1 expression and EGFR activation, suggesting its possible involvement in these hypoxia-mediated events. Reflective of their effect on cell adhesion proteins and EGFR (associated with migratory phenotypes), NAC also reduced cell migration under hypoxic conditions, a crucial event in metastasis. Our findings suggest a selective role for redox signalling in the regulation of specific components of the responses to hypoxia and induction of EMT in breast cancer cells. This study provides new evidence supporting the potential of targeting ROS as a therapeutic strategy for the control of breast cancer metastasis.

Published
2017
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