Melbourne Medical School Collected Works - Research Publications

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    Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer.
    Ng, T ; Teo, SM ; Yeo, HL ; Shwe, M ; Gan, YX ; Cheung, YT ; Foo, KM ; Cham, MT ; Lee, JA ; Tan, YP ; Fan, G ; Yong, WS ; Preetha, M ; Loh, W-JK ; Koo, S-L ; Jain, A ; Lee, GE ; Wong, M ; Dent, R ; Yap, YS ; Ng, R ; Khor, CC ; Ho, HK ; Chan, A (Oxford University Press (OUP), 2016-02)
    BACKGROUND: Brain-derived neurotrophic factor (BDNF), a neurotrophin that regulates neuronal function and development, is implicated in several neurodegenerative conditions. Preliminary data suggest that a reduction of BDNF concentrations may lead to postchemotherapy cognitive impairment. We hypothesized that a single nucleotide polymorphism (rs6265) of the BDNF gene may predispose patients to cognitive impairment. This study aimed to evaluate the effect of BDNF gene polymorphism on chemotherapy-associated cognitive impairment. METHODS: Overall, 145 patients receiving chemotherapy for early-stage breast cancer (mean age: 50.8 ± 8.8 y; 82.1% Chinese) were recruited. Patients' cognitive functions were assessed longitudinally using the validated Functional Assessment of Cancer Therapy-Cognitive Function (v.3) and an objective computerized tool, Headminder. Genotyping was performed using Sanger sequencing. Logistic regression was used to evaluate the association between BDNF Val66Met polymorphism and cognition after adjusting for ethnicity and clinically important covariates. RESULTS: Of the 145 patients, 54 (37%) reported cognitive impairment postchemotherapy. The Met/Met genotype was associated with statistically significant lower odds of developing cognitive impairment (odds ratio [OR] = 0.26; 95% CI: 0.08-0.92; P = .036). The Met carriers were less likely to experience impairment in the domains of verbal fluency (OR = 0.34; 95% CI: 0.12-0.90; P = .031) and multitasking ability (OR = 0.37; 95% CI: 0.15-0.91; P = .030) compared with the Val/Val homozygote. No associations were observed between Headminder and the BDNF Val66Met polymorphism. CONCLUSIONS: This is the first study to provide evidence that carriers of the BDNF Met allele are protected against chemotherapy-associated cognitive impairment. Further studies are required to validate the findings.
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    Baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF).
    McMurray, JJV ; Anand, IS ; Diaz, R ; Maggioni, AP ; O'Connor, C ; Pfeffer, MA ; Solomon, SD ; Tendera, M ; van Veldhuisen, DJ ; Albizem, M ; Cheng, S ; Scarlata, D ; Swedberg, K ; Young, JB ; RED-HF Committees Investigators, (Wiley, 2013-03)
    AIMS: This report describes the baseline characteristics of patients in the Reduction of Events with Darbepoetin alfa in Heart Failure trial (RED-HF) which is testing the hypothesis that anaemia correction with darbepoetin alfa will reduce the composite endpoint of death from any cause or hospital admission for worsening heart failure, and improve other outcomes. METHODS AND RESULTS: Key demographic, clinical, and laboratory findings, along with baseline treatment, are reported and compared with those of patients in other recent clinical trials in heart failure. Compared with other recent trials, RED-HF enrolled more elderly [mean age 70 (SD 11.4) years], female (41%), and black (9%) patients. RED-HF patients more often had diabetes (46%) and renal impairment (72% had an estimated glomerular filtration rate < 60 mL/min/1.73 m2). Patients in RED-HF had heart failure of longer duration [5.3 (5.4) years], worse NYHA class (35% II, 63% III, and 2% IV), and more signs of congestion. Mean EF was 30% (6.8%). RED-HF patients were well treated at randomization, and pharmacological therapy at baseline was broadly similar to that of other recent trials, taking account of study-specific inclusion/exclusion criteria. Median (interquartile range) haemoglobin at baseline was 112 (106-117) g/L. CONCLUSION: The anaemic patients enrolled in RED-HF were older, moderately to markedly symptomatic, and had extensive co-morbidity.
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    Utility of High-Sensitivity and Conventional Troponin in Patients Undergoing Transcatheter Aortic Valve Replacement: Incremental Prognostic Value to B-type Natriuretic Peptide
    Kobayashi, Y ; Kim, JB ; Moneghetti, KJ ; Fischbein, M ; Lee, A ; Watkins, CA ; Yeung, AC ; Liang, D ; Ozen, MO ; Demirci, U ; Bowen, R ; Fearon, WF ; Haddad, F (NATURE PORTFOLIO, 2019-10-17)
    High-sensitivity Troponin (hs-Tn) has emerged as a useful marker for patients with myocardial injury or heart failure. However, few studies have compared intermediate and hs-Tn in patients undergoing transcatheter aortic valve replacement (TAVR). Moreover, there remains uncertainty of which thresholds are the most useful for discriminating ventricular dysfunction or outcome. In this study we prospectively enrolled 105 patients with severe aortic stenosis (AS) who underwent TAVR as well as blood sampling for high-sensitivity (hs-TnI) and conventional troponin I (EXL-LOCI and RXL) assessment. Patients underwent comprehensive pre-procedure echocardiography. Ventricular dysfunction was defined using left ventricular mass index (LVMI), LV global longitudinal strain (LVGLS) and LV end-diastolic pressure. The mean age was 84.0 ± 8.7 years old and 60% were male sex with mean transaortic pressure gradient of 50.1 ± 16.0 mmHg and AVA of 0.63 ± 0.19 cm2. When using a threshold of 6 ng/L, 77% had positive hs-TnI while 27% had positive hs-TnI using recommended thresholds (16 ng/L for female and 34 ng/L for male). Troponin levels were higher in the presence of abnormal LV phenotypes. The strongest correlate of troponin was LVMI. During median follow-up of 375 days, 21 patients (20%) died. Lower threshold of hs-TnI and EXL-TnI was more discriminatory for overall mortality (Log-rank P = 0.03 for both), while higher threshold of hs-TnI (p = 0.75) and RXL-TnI were not (p = 0.30). Combining hs-TnI and BNP improved to predict long-term outcome (p = 0.004). In conclusion, hs-TnI levels correlated with the degree of LV dysfunction phenotypes. Furthermore, applying a lower threshold for hs-TnI performed better for outcome prediction than a recommended threshold in patients undergoing TAVR. Combining hs-TnI with BNP helped better risk stratification.
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    Approaching Higher Dimension Imaging Data Using Cluster-Based Hierarchical Modeling in Patients with Heart Failure Preserved Ejection Fraction
    Kobayashi, Y ; Tremblay-Gravel, M ; Boralkar, KA ; Li, X ; Nishi, T ; Amsallem, M ; Moneghetti, KJ ; Bouajila, S ; Selej, M ; Ozen, MO ; Demirci, U ; Ashley, E ; Wheeler, M ; Knowlton, KU ; Kouznetsova, T ; Haddad, F (NATURE PUBLISHING GROUP, 2019-07-18)
    Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality, accounting for the majority of heart failure (HF) hospitalization. To identify the most complementary predictors of mortality among clinical, laboratory and echocardiographic data, we used cluster based hierarchical modeling. Using Stanford Translational Research Database, we identified patients hospitalized with HFpEF between 2005 and 2016 in whom echocardiogram and NT-proBNP were both available at the time of admission. Comprehensive echocardiographic assessment including left ventricular longitudinal strain (LVLS), right ventricular function and right ventricular systolic pressure (RVSP) was performed. The outcome was defined as all-cause mortality. Among patients identified, 186 patients with complete echocardiographic assessment were included in the analysis. The cohort included 58% female, with a mean age of 78.7 ± 13.5 years, LVLS of -13.3 ± 2.5%, an estimated RVSP of 38 ± 13 mmHg. Unsupervised cluster analyses identified six clusters including ventricular systolic-function cluster, diastolic-hemodynamic cluster, end-organ function cluster, vital-sign cluster, complete blood count and sodium clusters. Using a stepwise hierarchical selection from each cluster, we identified NT-proBNP (standard hazard ratio [95%CI] = 1.56 [1.17-2.08]) and RVSP (1.37 [1.09-1.78]) as independent correlates of outcome. When adding these parameters to the well validated Get with the Guideline Heart Failure risk score, the Chi-square was significantly improved (p = 0.01). In conclusion, NT-proBNP and RVSP were independently predictive in HFpEF among clinical, imaging, and biomarker parameters. Cluster-based hierarchical modeling may help identify the complementally predictive parameters in small cohorts with higher dimensional clinical data.
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    Improving risk stratification in heart failure with preserved ejection fraction by combining two validated risk scores
    Boralkar, KA ; Kobayashi, Y ; Moneghetti, KJ ; Pargaonkar, VS ; Tuzovic, M ; Krishnan, G ; Wheeler, MT ; Banerjee, D ; Kuznetsova, T ; Horne, BD ; Knowlton, KU ; Heidenreich, PA ; Haddad, F (BMJ PUBLISHING GROUP, 2019-01-01)
    Introduction: The Intermountain Risk Score (IMRS) was developed and validated to predict short-term and long-term mortality in hospitalised patients using demographics and commonly available laboratory data. In this study, we sought to determine whether the IMRS also predicts all-cause mortality in patients hospitalised with heart failure with preserved ejection fraction (HFpEF) and whether it is complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score or N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods and results: We used the Stanford Translational Research Integrated Database Environment to identify 3847 adult patients with a diagnosis of HFpEF between January 1998 and December 2016. Of these, 580 were hospitalised with a primary diagnosis of acute HFpEF. Mean age was 76±16 years, the majority being female (58%), with a high prevalence of diabetes mellitus (36%) and a history of coronary artery disease (60%). Over a median follow-up of 2.0 years, 140 (24%) patients died. On multivariable analysis, the IMRS and GWTG-HF risk score were independently associated with all-cause mortality (standardised HRs IMRS (1.55 (95% CI 1.27 to 1.93)); GWTG-HF (1.60 (95% CI 1.27 to 2.01))). Combining the two scores, improved the net reclassification over GWTG-HF alone by 36.2%. In patients with available NT-proBNP (n=341), NT-proBNP improved the net reclassification of each score by 46.2% (IMRS) and 36.3% (GWTG-HF). Conclusion: IMRS and GWTG-HF risk scores, along with NT-proBNP, play a complementary role in predicting outcome in patients hospitalised with HFpEF.
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    CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma
    Li, Z ; Ju, X ; Lee, K ; Clarke, C ; Hsu, JL ; Abadir, E ; Bryant, CE ; Pears, S ; Sunderland, N ; Heffernan, S ; Hennessy, A ; Lo, T-H ; Pietersz, GA ; Kupresanin, F ; Fromm, PD ; Silveira, PA ; Tsonis, C ; Cooper, WA ; Cunningham, I ; Brown, C ; Clark, GJ ; Hart, DNJ (FERRATA STORTI FOUNDATION, 2018-03-23)
    Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83-T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.
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    What Limits Cardiac Performance during Exercise in Normal Subjects and in Healthy Fontan Patients?
    La Gerche, A ; Gewillig, M (HINDAWI LTD, 2010-01-01)
    Exercise is an important determinant of health but is significantly reduced in the patient with a univentricular circulation. Normal exercise physiology mandates an increase in pulmonary artery pressures which places an increased work demand on the right ventricle (RV). In a biventricular circulation with pathological increases in pulmonary vascular resistance and/or reductions in RV function, exercise-induced augmentation of cardiac output is limited. Left ventricular preload reserve is dependent upon flow through the pulmonary circulation and this requires adequate RV performance. In the Fontan patient, the reasons for exercise intolerance are complex. In those patients with myocardial dysfunction or other pathologies of the circulatory components, it is likely that these abnormalities serve as a limitation to cardiac performance during exercise. However, in the healthy Fontan patient, it may be the absence of a sub-pulmonary pump which limits normal increases in pulmonary pressures, trans-pulmonary flow requirements and cardiac output. If so, performance will be exquisitely dependent on pulmonary vascular resistance. This provides a potential explanation as to why pulmonary vasodilators may improve exercise tolerance. As has recently been demonstrated, these agents may offer an important new treatment strategy which directly addresses the physiological limitations in the Fontan patient.
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    Dendritic cell immunotherapy: clinical outcomes
    Apostolopoulos, V ; Pietersz, GA ; Tsibanis, A ; Tsikkinis, A ; Stojanovska, L ; McKenzie, IFC ; Vassilaros, S (WILEY, 2014-07-01)
    The use of tumour-associated antigens for cancer immunotherapy studies is exacerbated by tolerance to these self-antigens. Tolerance may be broken by using ex vivo monocyte-derived dendritic cells (DCs) pulsed with self-antigens. Targeting tumour-associated antigens directly to DCs in vivo is an alternative and simpler strategy. The identification of cell surface receptors on DCs, and targeting antigens to DC receptors, has become a popular approach for inducing effective immune responses against cancer antigens. Many years ago, we demonstrated that targeting the mannose receptor on macrophages using the carbohydrate mannan to DCs led to appropriate immune responses and tumour protection in animal models. We conducted Phase I, I/II and II, clinical trials demonstrating the effectiveness of oxidised mannan-MUC1 in patients with adenocarcinomas. Here we summarise DC targeting approaches and their efficacy in human clinical trials.
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    Systems Medicine-Complexity Within, Simplicity Without
    Berlin, R ; Gruen, R ; Best, J (SPRINGERNATURE, 2017-06-01)
    This paper presents a brief history of Systems Theory, progresses to Systems Biology, and its relation to the more traditional investigative method of reductionism. The emergence of Systems Medicine represents the application of Systems Biology to disease and clinical issues. The challenges faced by this transition from Systems Biology to Systems Medicine are explained; the requirements of physicians at the bedside, caring for patients, as well as the place of human-human interaction and the needs of the patients are addressed. An organ-focused transition to Systems Medicine, rather than a genomic-, molecular-, or cell-based effort is emphasized. Organ focus represents a middle-out approach to ease this transition and to maximize the benefits of scientific discovery and clinical application. This method manages the perceptions of time and space, the massive amounts of human- and patient-related data, and the ensuing complexity of information.
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    Use and Limitations of E/e' to Assess Left Ventricular Filling Pressure by Echocardiography.
    Park, J-H ; Marwick, TH (Korean Society of Echocardiography, 2011-12)
    Measurement of left ventricular (LV) filling pressure is useful in decision making and prediction of outcomes in various cardiovascular diseases. Invasive cardiac catheterization has been the gold standard in LV filling pressure measurement, but carries the risk of complications and has a similar predictive value for clinical outcomes compared with non-invasive LV filling pressure estimation by echocardiography. A variety of echocardiographic measurement methods have been suggested to estimate LV filling pressure. The most frequently used method for this purpose is the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), which has become central in the guidelines for diastolic evaluation. This review will discuss the use the E/e' ratio in prediction of LV filling pressure and its potential pitfalls.