Melbourne Medical School Collected Works - Research Publications

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    First-In-Human Phase I Study of the OX40 Agonist MOXR0916 in Patients with Advanced Solid Tumors
    Kim, TW ; Burris, HA ; Luken, MJDM ; Pishvaian, MJ ; Bang, Y-J ; Gordon, M ; Awada, A ; Camidge, DR ; Hodi, FS ; McArthur, GA ; Miller, WH ; Cervantes, A ; Chow, LQ ; Lesokhin, AM ; Rutten, A ; Sznol, M ; Rishipathak, D ; Chen, S-C ; Stefanich, E ; Pourmohamad, T ; Anderson, M ; Kim, J ; Huseni, M ; Rhee, I ; Siu, LL (AMER ASSOC CANCER RESEARCH, 2022-08-15)
    PURPOSE: OX40, a receptor transiently expressed by T cells upon antigen recognition, is associated with costimulation of effector T cells and impairment of regulatory T-cell function. This first-in-human study evaluated MOXR0916, a humanized effector-competent agonist IgG1 monoclonal anti-OX40 antibody. PATIENTS AND METHODS: Eligible patients with locally advanced or metastatic refractory solid tumors were treated with MOXR0916 intravenously once every 3 weeks (Q3W). A 3+3 dose-escalation stage (0.2-1,200 mg; n = 34) was followed by expansion cohorts at 300 mg (n = 138) for patients with melanoma, renal cell carcinoma, non-small cell lung carcinoma, urothelial carcinoma, and triple-negative breast cancer. RESULTS: MOXR0916 was well tolerated with no dose-limiting toxicities observed. An MTD was not reached. Most patients (95%) experienced at least one adverse event (AE); 56% of AEs, mostly grade 1-2, were related to MOXR0916. Most common treatment-related AEs included fatigue (17%), diarrhea (8%), myalgia (7%), nausea (6%), decreased appetite (6%), and infusion-related reaction (5%). Pharmacokinetic (PK) parameters were dose proportional between 80 and 1,200 mg and supported Q3W administration. The recommended expansion dose based on PK and OX40 receptor saturation was 300 mg Q3W. Immune activation and upregulation of PD-L1 was observed in a subset of paired tumor biopsies. One renal cell carcinoma patient experienced a confirmed partial response. Overall, 33% of patients achieved stable disease. CONCLUSIONS: Although objective responses were rarely observed with MOXR0916 monotherapy, the favorable safety profile and evidence of tumor immune activation in a subset of patients support further investigation in combination with complementary agents such as PD-1/PD-L1 antagonists.
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    Medication reviews and deprescribing as a single intervention in falls prevention: a systematic review and meta-analysis
    Seppala, LJ ; Kamkar, N ; van Poelgeest, EP ; Thomsen, K ; Daams, JG ; Ryg, J ; Masud, T ; Montero-Odasso, M ; Hartikainen, S ; Petrovic, M ; van der Velde, N (OXFORD UNIV PRESS, 2022-09-02)
    BACKGROUND: our aim was to assess the effectiveness of medication review and deprescribing interventions as a single intervention in falls prevention. METHODS: DESIGN: systematic review and meta-analysis. DATA SOURCES: Medline, Embase, Cochrane CENTRAL, PsycINFO until 28 March 2022. ELIGIBILITY CRITERIA: randomised controlled trials of older participants comparing any medication review or deprescribing intervention with usual care and reporting falls as an outcome. STUDY RECORDS: title/abstract and full-text screening by two reviewers. RISK OF BIAS: Cochrane Collaboration revised tool. DATA SYNTHESIS: results reported separately for different settings and sufficiently comparable studies meta-analysed. RESULTS: forty-nine heterogeneous studies were included. COMMUNITY: meta-analyses of medication reviews resulted in a risk ratio (RR) of 1.05 (95% confidence interval, 0.85-1.29, I2 = 0%, 3 studies(s)) for number of fallers, in an RR = 0.95 (0.70-1.27, I2 = 37%, 3 s) for number of injurious fallers and in a rate ratio (RaR) of 0.89 (0.69-1.14, I2 = 0%, 2 s) for injurious falls. HOSPITAL: meta-analyses assessing medication reviews resulted in an RR = 0.97 (0.74-1.28, I2 = 15%, 2 s) and in an RR = 0.50 (0.07-3.50, I2 = 72% %, 2 s) for number of fallers after and during admission, respectively. LONG-TERM CARE: meta-analyses investigating medication reviews or deprescribing plans resulted in an RR = 0.86 (0.72-1.02, I2 = 0%, 5 s) for number of fallers and in an RaR = 0.93 (0.64-1.35, I2 = 92%, 7 s) for number of falls. CONCLUSIONS: the heterogeneity of the interventions precluded us to estimate the exact effect of medication review and deprescribing as a single intervention. For future studies, more comparability is warranted. These interventions should not be implemented as a stand-alone strategy in falls prevention but included in multimodal strategies due to the multifactorial nature of falls.PROSPERO registration number: CRD42020218231.
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    Multi-Omic analyses characterize the ceramide/sphingomyelin pathway as a therapeutic target in Alzheimer's disease.
    Baloni, P ; Arnold, M ; Buitrago, L ; Nho, K ; Moreno, H ; Huynh, K ; Brauner, B ; Louie, G ; Kueider-Paisley, A ; Suhre, K ; Saykin, AJ ; Ekroos, K ; Meikle, PJ ; Hood, L ; Price, ND ; Alzheimer’s Disease Metabolomics Consortium, ; Doraiswamy, PM ; Funk, CC ; Hernández, AI ; Kastenmüller, G ; Baillie, R ; Han, X ; Kaddurah-Daouk, R (Springer Science and Business Media LLC, 2022-10-08)
    Dysregulation of sphingomyelin and ceramide metabolism have been implicated in Alzheimer's disease. Genome-wide and transcriptome-wide association studies have identified various genes and genetic variants in lipid metabolism that are associated with Alzheimer's disease. However, the molecular mechanisms of sphingomyelin and ceramide disruption remain to be determined. We focus on the sphingolipid pathway and carry out multi-omics analyses to identify central and peripheral metabolic changes in Alzheimer's patients, correlating them to imaging features. Our multi-omics approach is based on (a) 2114 human post-mortem brain transcriptomics to identify differentially expressed genes; (b) in silico metabolic flux analysis on context-specific metabolic networks identified differential reaction fluxes; (c) multimodal neuroimaging analysis on 1576 participants to associate genetic variants in sphingomyelin pathway with Alzheimer's disease pathogenesis; (d) plasma metabolomic and lipidomic analysis to identify associations of lipid species with dysregulation in Alzheimer's; and (e) metabolite genome-wide association studies to define receptors within the pathway as a potential drug target. We validate our hypothesis in amyloidogenic APP/PS1 mice and show prolonged exposure to fingolimod alleviated synaptic plasticity and cognitive impairment in mice. Our integrative multi-omics approach identifies potential targets in the sphingomyelin pathway and suggests modulators of S1P metabolism as possible candidates for Alzheimer's disease treatment.
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    Stroke genetics informs drug discovery and risk prediction across ancestries.
    Mishra, A ; Malik, R ; Hachiya, T ; Jürgenson, T ; Namba, S ; Posner, DC ; Kamanu, FK ; Koido, M ; Le Grand, Q ; Shi, M ; He, Y ; Georgakis, MK ; Caro, I ; Krebs, K ; Liaw, Y-C ; Vaura, FC ; Lin, K ; Winsvold, BS ; Srinivasasainagendra, V ; Parodi, L ; Bae, H-J ; Chauhan, G ; Chong, MR ; Tomppo, L ; Akinyemi, R ; Roshchupkin, GV ; Habib, N ; Jee, YH ; Thomassen, JQ ; Abedi, V ; Cárcel-Márquez, J ; Nygaard, M ; Leonard, HL ; Yang, C ; Yonova-Doing, E ; Knol, MJ ; Lewis, AJ ; Judy, RL ; Ago, T ; Amouyel, P ; Armstrong, ND ; Bakker, MK ; Bartz, TM ; Bennett, DA ; Bis, JC ; Bordes, C ; Børte, S ; Cain, A ; Ridker, PM ; Cho, K ; Chen, Z ; Cruchaga, C ; Cole, JW ; de Jager, PL ; de Cid, R ; Endres, M ; Ferreira, LE ; Geerlings, MI ; Gasca, NC ; Gudnason, V ; Hata, J ; He, J ; Heath, AK ; Ho, Y-L ; Havulinna, AS ; Hopewell, JC ; Hyacinth, HI ; Inouye, M ; Jacob, MA ; Jeon, CE ; Jern, C ; Kamouchi, M ; Keene, KL ; Kitazono, T ; Kittner, SJ ; Konuma, T ; Kumar, A ; Lacaze, P ; Launer, LJ ; Lee, K-J ; Lepik, K ; Li, J ; Li, L ; Manichaikul, A ; Markus, HS ; Marston, NA ; Meitinger, T ; Mitchell, BD ; Montellano, FA ; Morisaki, T ; Mosley, TH ; Nalls, MA ; Nordestgaard, BG ; O'Donnell, MJ ; Okada, Y ; Onland-Moret, NC ; Ovbiagele, B ; Peters, A ; Psaty, BM ; Rich, SS ; Rosand, J ; Sabatine, MS ; Sacco, RL ; Saleheen, D ; Sandset, EC ; Salomaa, V ; Sargurupremraj, M ; Sasaki, M ; Satizabal, CL ; Schmidt, CO ; Shimizu, A ; Smith, NL ; Sloane, KL ; Sutoh, Y ; Sun, YV ; Tanno, K ; Tiedt, S ; Tatlisumak, T ; Torres-Aguila, NP ; Tiwari, HK ; Trégouët, D-A ; Trompet, S ; Tuladhar, AM ; Tybjærg-Hansen, A ; van Vugt, M ; Vibo, R ; Verma, SS ; Wiggins, KL ; Wennberg, P ; Woo, D ; Wilson, PWF ; Xu, H ; Yang, Q ; Yoon, K ; COMPASS Consortium, ; INVENT Consortium, ; Dutch Parelsnoer Initiative (PSI) Cerebrovascular Disease Study Group, ; Estonian Biobank, ; PRECISEQ Consortium, ; FinnGen Consortium, ; NINDS Stroke Genetics Network (SiGN), ; MEGASTROKE Consortium, ; SIREN Consortium, ; China Kadoorie Biobank Collaborative Group, ; VA Million Veteran Program, ; International Stroke Genetics Consortium (ISGC), ; Biobank Japan, ; CHARGE Consortium, ; GIGASTROKE Consortium, ; Millwood, IY ; Gieger, C ; Ninomiya, T ; Grabe, HJ ; Jukema, JW ; Rissanen, IL ; Strbian, D ; Kim, YJ ; Chen, P-H ; Mayerhofer, E ; Howson, JMM ; Irvin, MR ; Adams, H ; Wassertheil-Smoller, S ; Christensen, K ; Ikram, MA ; Rundek, T ; Worrall, BB ; Lathrop, GM ; Riaz, M ; Simonsick, EM ; Kõrv, J ; França, PHC ; Zand, R ; Prasad, K ; Frikke-Schmidt, R ; de Leeuw, F-E ; Liman, T ; Haeusler, KG ; Ruigrok, YM ; Heuschmann, PU ; Longstreth, WT ; Jung, KJ ; Bastarache, L ; Paré, G ; Damrauer, SM ; Chasman, DI ; Rotter, JI ; Anderson, CD ; Zwart, J-A ; Niiranen, TJ ; Fornage, M ; Liaw, Y-P ; Seshadri, S ; Fernández-Cadenas, I ; Walters, RG ; Ruff, CT ; Owolabi, MO ; Huffman, JE ; Milani, L ; Kamatani, Y ; Dichgans, M ; Debette, S (Springer Science and Business Media LLC, 2022-11)
    Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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    A new technique for assessing arterial pressure wave forms and central pressure with tissue Doppler.
    Haluska, BA ; Jeffriess, L ; Mottram, PM ; Carlier, SG ; Marwick, TH (Springer Science and Business Media LLC, 2007-01-31)
    BACKGROUND: Non-invasive assessment of arterial pressure wave forms using applanation tonometry of the radial or carotid arteries can be technically challenging and has not found wide clinical application. 2D imaging of the common carotid arteries is routinely used and we sought to determine whether arterial waveform measurements could be derived from tissue Doppler imaging (TDI) of the carotid artery. METHODS: We studied 91 subjects (52 men, age 52 +/- 14 years) with and without cardiovascular disease. Tonometry was performed on the carotid artery simultaneously with pulsed wave Doppler of the LVOT and acquired digitally. Longitudinal 2D images of the common carotid artery with and without TDI were also acquired digitally and both TDI and tonometry were calibrated using mean and diastolic cuff pressure and analysed off line. RESULTS: Correlation between central pressure by TDI and tonometry was excellent for maximum pressure (r = 0.97, p < 0.0001). The mean differences between central pressures derived by TDI and tonometry were minimal (systolic 5.36 +/- 5.5 mmHg; diastolic 1.2 +/- 1.2 mmHg). CONCLUSION: Imaging of the common carotid artery motion with tissue Doppler may permit acquisition of a waveform analogous to that from tonometry. This method may simplify estimation of central arterial pressure and calculation of total arterial compliance.
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    Neurocognitive trajectory and proteomic signature of inherited risk for Alzheimer's disease.
    Paranjpe, MD ; Chaffin, M ; Zahid, S ; Ritchie, S ; Rotter, JI ; Rich, SS ; Gerszten, R ; Guo, X ; Heckbert, S ; Tracy, R ; Danesh, J ; Lander, ES ; Inouye, M ; Kathiresan, S ; Butterworth, AS ; Khera, AV ; He, Z (Public Library of Science (PLoS), 2022-09)
    For Alzheimer's disease-a leading cause of dementia and global morbidity-improved identification of presymptomatic high-risk individuals and identification of new circulating biomarkers are key public health needs. Here, we tested the hypothesis that a polygenic predictor of risk for Alzheimer's disease would identify a subset of the population with increased risk of clinically diagnosed dementia, subclinical neurocognitive dysfunction, and a differing circulating proteomic profile. Using summary association statistics from a recent genome-wide association study, we first developed a polygenic predictor of Alzheimer's disease comprised of 7.1 million common DNA variants. We noted a 7.3-fold (95% CI 4.8 to 11.0; p < 0.001) gradient in risk across deciles of the score among 288,289 middle-aged participants of the UK Biobank study. In cross-sectional analyses stratified by age, minimal differences in risk of Alzheimer's disease and performance on a digit recall test were present according to polygenic score decile at age 50 years, but significant gradients emerged by age 65. Similarly, among 30,541 participants of the Mass General Brigham Biobank, we again noted no significant differences in Alzheimer's disease diagnosis at younger ages across deciles of the score, but for those over 65 years we noted an odds ratio of 2.0 (95% CI 1.3 to 3.2; p = 0.002) in the top versus bottom decile of the polygenic score. To understand the proteomic signature of inherited risk, we performed aptamer-based profiling in 636 blood donors (mean age 43 years) with very high or low polygenic scores. In addition to the well-known apolipoprotein E biomarker, this analysis identified 27 additional proteins, several of which have known roles related to disease pathogenesis. Differences in protein concentrations were consistent even among the youngest subset of blood donors (mean age 33 years). Of these 28 proteins, 7 of the 8 proteins with concentrations available were similarly associated with the polygenic score in participants of the Multi-Ethnic Study of Atherosclerosis. These data highlight the potential for a DNA-based score to identify high-risk individuals during the prolonged presymptomatic phase of Alzheimer's disease and to enable biomarker discovery based on profiling of young individuals in the extremes of the score distribution.
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    Macrophage polarization as a potential therapeutic target for atherosclerosis: a dynamic stochastic modelling study.
    Liu, M ; Cai, Y ; Pan, J ; Peter, K ; Li, Z (The Royal Society, 2022-08)
    We proposed a dynamic stochastic mathematical model to evaluate the role of macrophage polarization in plaque development. The dynamic process of macrophages from proliferation to death was simulated under different lipid microenvironments. The probability of macrophage phenotypic switching was described using a Bernoulli distribution where the stochastic variable was determined by the local lipid level. Moreover, the interactions between macrophages and microenvironmental factors vary with macrophage phenotype. We investigated the distribution of key microenvironmental factors, the dynamics of macrophage polarization and its influence on foam cell formation. M1 macrophages were found to predominate in advanced plaque corresponding to the exacerbated inflammation observed in mice experiments. The imbalance between the deposition of oxidized low-density lipoprotein and phagocytic effects of macrophages governed the formation of foam cells. Furthermore, we simulated targeted therapies by either directly inhibiting the polarization probability to M1 macrophages or indirectly regulating macrophage polarization due to high-density lipoprotein levels. Comparison of simulation results with experimental findings in both therapies indicated that the intervention and regulation of macrophage polarization could influence plaque microenvironment and subsequently induce plaque regression, especially in the early stage. The proposed modelling system can facilitate the evaluation of novel therapies targeting macrophage polarization.
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    Transferability of genetic loci and polygenic scores for cardiometabolic traits in British Pakistani and Bangladeshi individuals.
    Huang, QQ ; Sallah, N ; Dunca, D ; Trivedi, B ; Hunt, KA ; Hodgson, S ; Lambert, SA ; Arciero, E ; Wright, J ; Griffiths, C ; Trembath, RC ; Hemingway, H ; Inouye, M ; Finer, S ; van Heel, DA ; Lumbers, RT ; Martin, HC ; Kuchenbaecker, K (Springer Science and Business Media LLC, 2022-08-09)
    Individuals with South Asian ancestry have a higher risk of heart disease than other groups but have been largely excluded from genetic research. Using data from 22,000 British Pakistani and Bangladeshi individuals with linked electronic health records from the Genes & Health cohort, we conducted genome-wide association studies of coronary artery disease and its key risk factors. Using power-adjusted transferability ratios, we found evidence for transferability for the majority of cardiometabolic loci powered to replicate. The performance of polygenic scores was high for lipids and blood pressure, but lower for BMI and coronary artery disease. Adding a polygenic score for coronary artery disease to clinical risk factors showed significant improvement in reclassification. In Mendelian randomisation using transferable loci as instruments, our findings were consistent with results in European-ancestry individuals. Taken together, trait-specific transferability of trait loci between populations is an important consideration with implications for risk prediction and causal inference.
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    One-year mortality after hip fracture surgery: urban-rural differences in the Colombian Andes
    Duque-Sanchez, J-D ; Toro, L-A ; Gonzalez-Gomez, F-I ; Botero-Baena, S-M ; Duque, G ; Gomez, F (SPRINGER LONDON LTD, 2022-12-01)
    To determine urban-rural differences influencing mortality in patients with hip fracture in Colombian Andes Mountains over a 1-year period. PURPOSE: To identify the urban-rural differences of sociodemographic variables, fracture-related characteristics, and preoperative and postoperative clinical factors associated with 1-year mortality in patients over 60 years old who underwent hip fracture surgery in the Andes Mountains. METHODS: A total of 126 patients with a fragility hip fracture during 2019-2020 were admitted to a tertiary care hospital. They were evaluated preoperatively and followed up until discharge. Those who survived were contacted by telephone at 1, 3, and 12 months. Univariate, bivariate, and Kaplan-Meier analyses with survival curves were performed. Relative risk was calculated with a 95% confidence interval. RESULTS: A total of 32.5% of the patients died within 1 year after surgery, with a significant difference between those who resided in rural areas (43.1%) and those who resided in urban areas (23.5%) (RR 1.70; 95% CI, 1.03 to 2.80, p = 0.036). In the multivariate analysis, anemia (hemoglobin level ≤ 9.0 g/dL during hospitalization) (RR 6.61; 95% CI, 1.49-29.37, p = 0.003), a blood transfusion requirement (RR 1.47; 95% CI, 1.07 to 2.01, p = 0.015), the type of fracture (subtrochanteric fracture (RR = 4.9, 95% CI = 1.418-16.943, p = 0.005)), and postoperative acute decompensation of chronic disease (RR 1.60; 95% CI, 1.01 to 2.53, p = 0.043) were found to be independent predictive factors of 1-year mortality after surgery. CONCLUSIONS: There was a difference in 1-year mortality between patients from rural and urban areas. More studies must be conducted to determine whether rurality behaves as an independent risk factor or is related to other variables, such as the burden of comorbidities and in-hospital complications.
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    Phylogeny-Aware Analysis of Metagenome Community Ecology Based on Matched Reference Genomes while Bypassing Taxonomy.
    Zhu, Q ; Huang, S ; Gonzalez, A ; McGrath, I ; McDonald, D ; Haiminen, N ; Armstrong, G ; Vázquez-Baeza, Y ; Yu, J ; Kuczynski, J ; Sepich-Poore, GD ; Swafford, AD ; Das, P ; Shaffer, JP ; Lejzerowicz, F ; Belda-Ferre, P ; Havulinna, AS ; Méric, G ; Niiranen, T ; Lahti, L ; Salomaa, V ; Kim, H-C ; Jain, M ; Inouye, M ; Gilbert, JA ; Knight, R ; Sharpton, TJ (American Society for Microbiology, 2022-04-26)
    We introduce the operational genomic unit (OGU) method, a metagenome analysis strategy that directly exploits sequence alignment hits to individual reference genomes as the minimum unit for assessing the diversity of microbial communities and their relevance to environmental factors. This approach is independent of taxonomic classification, granting the possibility of maximal resolution of community composition, and organizes features into an accurate hierarchy using a phylogenomic tree. The outputs are suitable for contemporary analytical protocols for community ecology, differential abundance, and supervised learning while supporting phylogenetic methods, such as UniFrac and phylofactorization, that are seldom applied to shotgun metagenomics despite being prevalent in 16S rRNA gene amplicon studies. As demonstrated in two real-world case studies, the OGU method produces biologically meaningful patterns from microbiome data sets. Such patterns further remain detectable at very low metagenomic sequencing depths. Compared with taxonomic unit-based analyses implemented in currently adopted metagenomics tools, and the analysis of 16S rRNA gene amplicon sequence variants, this method shows superiority in informing biologically relevant insights, including stronger correlation with body environment and host sex on the Human Microbiome Project data set and more accurate prediction of human age by the gut microbiomes of Finnish individuals included in the FINRISK 2002 cohort. We provide Woltka, a bioinformatics tool to implement this method, with full integration with the QIIME 2 package and the Qiita web platform, to facilitate adoption of the OGU method in future metagenomics studies. IMPORTANCE Shotgun metagenomics is a powerful, yet computationally challenging, technique compared to 16S rRNA gene amplicon sequencing for decoding the composition and structure of microbial communities. Current analyses of metagenomic data are primarily based on taxonomic classification, which is limited in feature resolution. To solve these challenges, we introduce operational genomic units (OGUs), which are the individual reference genomes derived from sequence alignment results, without further assigning them taxonomy. The OGU method advances current read-based metagenomics in two dimensions: (i) providing maximal resolution of community composition and (ii) permitting use of phylogeny-aware tools. Our analysis of real-world data sets shows that it is advantageous over currently adopted metagenomic analysis methods and the finest-grained 16S rRNA analysis methods in predicting biological traits. We thus propose the adoption of OGUs as an effective practice in metagenomic studies.