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Background The Australian BioCommons develops digital capacity, training, and bioinformatics infrastructure to support Australia’s life scientists. So how can we identify the greatest needs of many thousands of geographically dispersed researchers, and also deliver useful infrastructure? Strong user engagement is paramount to understand community needs and direct the deployment and resourcing of appropriate infrastructure to ensure maximum impact. Methods We have developed a five-step process of engagement that maximises community interaction, from initiation to deployment. Results 1/ Identify meaningful communities of manageable scope around focus areas with infrastructure challenges; 2/ Research the community topic area to understand broad needs and challenges to engage members; 3/ Communicate with the broad community, inclusive of everyone from any expertise level or any institution, to identify issues, roadblocks, and solutions/suggestions through electronic surveys, shared discussion boards, and virtual meetings; 4/ Document the challenges and, in discussion with infrastructure specialists, detail conceptual solutions with an endorsement from a subset of practitioners from the community; 5/ Deploy and implement solutions with testing and feedback from the community. Conclusion Through this engagement process, the Australian BioCommons has identified and then coordinated work to deploy essential infrastructure that was previously lacking to support critical communities (e.g. those undertaking genome annotation). Successful outcomes of deployment at this early stage are measured by positive responses from the community (e.g. turning up in large numbers, actively joining the discussion), and active use by early adopters. The method is now being applied to engage a diverse range of communities.&nbsp

Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).

This poster was presented at the eResearch Australasia 2020 virtual conference, 19-23 October 2020. It described the training methodology used by Australian BioCommons, documenting the move to purely online events in response to the COVID-19 pandemic. As part of our mission to help life scientists develop bioinformatics competencies, Australian BioCommons faces challenges relating to Australia’s large size and small, widely-dispersed population. Pre-COVID19, we developed a ‘hybrid’ training method to deliver hands-on bioinformatics workshops to large groups of researchers across the country. The method combined features and benefits of webinar-style delivery from an expert trainer with face-to-face hands-on practical exercises in a classroom setting. Workshops were held concurrently in classrooms at participating sites with trained local researchers acting as facilitators. Since the pandemic has made face-to-face training impossible, we now face different challenges when trying to reach researchers needing our training. When gathering together physically became restricted, we moved our training workshops completely online. In partnership with Pawsey Supercomputing Centre, we augmented the method to utilise ‘breakout rooms’ for personal interactions between small curated groups of trainees with trained facilitators. Despite the delivery of workshops as online presentations, we preserved what makes our training valuable - the provision of hands-on, interactive and tailored learning opportunities. The method has become a key tool for us to ensure scalable and more equitable delivery of short-course bioinformatics training nationally.

Praliciguat, a clinical-stage soluble guanylate cyclase (sGC) stimulator, increases cGMP via the nitric oxide-sGC pathway. Praliciguat has been shown to be renoprotective in rodent models of hypertensive nephropathy and renal fibrosis. In the present study, praliciguat alone and in combination with enalapril attenuated proteinuria in the obese ZSF1 rat model of diabetic nephropathy. Praliciguat monotherapy did not affect hemodynamics. In contrast, enalapril monotherapy lowered blood pressure but did not attenuate proteinuria. Renal expression of genes in pathways involved in inflammation, fibrosis, oxidative stress, and kidney injury was lower in praliciguat-treated obese ZSF1 rats than in obese control rats; fasting glucose and cholesterol were also lower with praliciguat treatment. To gain insight into how tubular mechanisms might contribute to its pharmacological effects on the kidneys, we studied the effects of praliciguat on pathological processes and signaling pathways in cultured human primary renal proximal tubular epithelial cells (RPTCs). Praliciguat inhibited the expression of proinflammatory cytokines and secretion of monocyte chemoattractant protein-1 in tumor necrosis factor-α-challenged RPTCs. Praliciguat treatment also attenuated transforming growth factor-β-mediated apoptosis, changes to a mesenchyme-like cellular phenotype, and phosphorylation of SMAD3 in RPTCs. In conclusion, praliciguat improved proteinuria in the ZSF1 rat model of diabetic nephropathy, and its actions in human RPTCs suggest that tubular effects may contribute to its renal benefits, building upon strong evidence for the role of cGMP signaling in renal health.

This document summarises the high level purposes, goals and approaches the Australian BioCommons will pursue during its establishment phases. The content was developed through a process of national consultation and planning around an investment in bioinformatics research infrastructure in Australia and the text summarises the concepts and considerations motivating the investment, which has now been made. The strategy as set out aims to ensure Australian life science research remains globally competitive, by providing access to the digital tools, methods and training researchers require working in areas such as food security, environmental conservation and disease treatments. High level descriptions of the purpose and organisational structure of the Australian BioCommons, its motivating principles and the key challenges it will address, are included in the text. A focus is defined for the BioCommons service layers and the overall properties of a cloud infrastructure termed the ‘BioCloud’ supporting those services are described. The BioCommons has been initiated over the period 2019 to 2023 by funding from Bioplatforms Australiathrough the Australian Government National Collaborative ResearchInfrastructure Strategy (NCRIS).

Transformative learning experiences can expand individual personal and professional capacity. In this work, the meaning and significance of individual growth is viewed through the lens of public value, focusing on the connection between person and place. This chapter details how Nuffield International Farming Scholars perceive public value contributions stemming from their individual development and subsequent engagement in civic life and community development. Voices of program participants provide insight on capacity building experiences as part of sustainable community development efforts, and how perceived outcomes for individuals such as professional and personal benefits, post-program engagement, and a sense of reciprocity are motivators leading to public value contribution.

Recent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

As for many other research disciplines, rapid advances in digital technologies and methods are proving transformational in life sciences. Internationally, major life sciences infrastructure initiatives are increasingly defining global scale data infrastructures; in particular, the US-based National Institutes of Health through their Data Commons program, and the EU-based ELIXIR program and EBI, are building data infrastructures that are, in many ways, equivalents of the global data-focussed infrastructures driving advances in astronomy and physics - infrastructures like Hubble, LIGO, and the LHC. And, like astronomy and physics, it is clear that world-class life sciences research in Australia and New Zealand will increasingly depend on digital methods and data resources, and communities, that are globally sourced and supported. Therefore, sponsored by Bioplatforms Australia, we have developed a research infrastructure program called the Australian BioCommons that strongly engages the research community, international infrastructure initiatives, and national digital resource providers, recognising that Australia must understand, participate in and contribute to global life science-enabling endeavours as a first class partner, and presenting this as a clear vision of implementable requirements to national providers.ABOUT THE AUTHOR(S)A/Prof Andrew Lonie Director, Australian BioCommons, University of Melbourne.

The current state of much of the Wuhan pneumonia virus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) research shows a regrettable lack of data sharing and considerable analytical obfuscation. This impedes global research cooperation, which is essential for tackling public health emergencies and requires unimpeded access to data, analysis tools, and computational infrastructure. Here, we show that community efforts in developing open analytical software tools over the past 10 years, combined with national investments into scientific computational infrastructure, can overcome these deficiencies and provide an accessible platform for tackling global health emergencies in an open and transparent manner. Specifically, we use all SARS-CoV-2 genomic data available in the public domain so far to (1) underscore the importance of access to raw data and (2) demonstrate that existing community efforts in curation and deployment of biomedical software can reliably support rapid, reproducible research during global health crises. All our analyses are fully documented at https://github.com/galaxyproject/SARS-CoV-2.

BACKGROUND: With decreasing indication for abdominoperineal resection and an increase in sphincter preserving surgery, there is a growing population of patients who suffer from low anterior resection syndrome (LARS). The aim of this study is to use the LARS score to determine the prevalence of LARS at a regional centre in Australia and determine the effect of short- and long-course neoadjuvant therapy, anastomotic technique and interval from surgery will also be assessed. METHODS: Patients who had undergone an anterior resection (high, low or ultralow) at a regional centre over an 11-year period were identified. Eligible patients were contacted to complete a LARS score questionnaire. Results were analysed to determine the rate of major LARS and possible causative roles of certain patient and treatment-related variables. RESULTS: A total of 64 of 76 patients (84%) returned completed questionnaires. The prevalence of major LARS was 37.5%. Short-course neoadjuvant therapy appeared to be more likely to be associated with major LARS compared to long course (odds ratio (OR) = 2.4, 95% confidence interval (CI) 0.37-15.3, P = 0.35); however, this did not reach statistical significance. Rates of major LARS appear to decrease slowly over time and J-pouch colonic anastomosis appears to be slightly protective against major LARS (OR = 0.7, 95% CI 0.12-3.9, P = 0.70); however, neither results were statistically significant. CONCLUSION: The rate of major LARS at this regional centre is 37.5%. Larger prospective multicentre studies are required to determine impact of variables such as type of neoadjuvant therapy, anastomotic techniques and progression of LARS over time.

Aim To summarize the reported prevalence and causative factors of Low Anterior Resection Syndrome (LARS) from studies using the LARS score. Methods A systematic literature search was conducted using Pubmed, Ovid Medline and the Cochrane database. Searches were performed using a combination of MeSH (medical subject headings) terms and key terms. Studies that were included used the LARS score as their primary collection tool. Studies were excluded if initial surgery was not for malignancy, or if the majority of LARS scores were from patients less than 1 year post initial surgery or closure of diverting stoma. Eligible studies were assessed with a validated quality assessment tool prior to performing a meta-analysis with quality effects model. Meta-analysis was conducted with prevalence estimates that had been transformed using the double arcsine method. Results Following the initial search and implementation of inclusion and exclusion criteria 11 studies were deemed suitable for meta-analysis. Meta-analysis found the estimated prevalence of major LARS was 41% (95% CI 34 -48). Where possible outlier studies were excluded, the prevalence was 42% (95%CI 35-48). Radiotherapy and tumour height were the most consistently assessed variables, both showing a consistent negative effect on bowel function. Defunctioning ileostomy was found to have a statically significant negative impact on bowel function in 4 of 11 studies. The majority of reported data has been produced by groups in Denmark and the United Kingdom with limited numbers provided by other locations. Available data is heterogenous with some variables having limited numbers, making meta-analysis of certain variables impossible. Conclusions There is significant prevalence of Low Anterior Resection Syndrome following oncological rectal resection. A low anastomotic height or history of radiotherapy are major risk factors.

Background Pleomorphic dermal sarcoma (PDS) is a rare, poorly defined skin neoplasm with features similar to atypical fibroxanthoma, but with adverse histopathological characteristics indicating metastatic potential such as tumour necrosis, invasion beyond superficial subcutis or vascular and/or perineural infiltration. Optimal treatment for PDS is uncertain and reported outcomes vary due to the rarity of this diagnosis and uncertainty over histopathological categorization. The aim of this study was to review the clinical and histopathological features of PDS in a single Australian centre. Methods A retrospective review of all patients managed at the Peter MacCallum Cancer Centre with PDS between 2003 and 2017 was performed by a search of electronic records and histories reviewed. Results A total of 27 patients were identified, mostly elderly males (85.2%, mean age 79.8 years). Lesions were seen most commonly on the head and neck region (96.3%), predominantly on the scalp (63%). Mean tumour radial surgical excision margin was 12.8 mm. Eighteen patients (66.7%) underwent radiotherapy; 13 adjuvant, three neoadjuvant and two with palliative intent. After median follow-up of 46.4 months, two patients had recurrence (7.4%); both had inadequate deep margins at first excision. There were three all-cause deaths in the cohort. There was one disease-specific mortality with metastatic PDS disease at the time of initial presentation. Conclusion PDS is a rare cutaneous malignancy most commonly found in the head and neck region in elderly men, which is best managed with adequate surgical excision. The role of radiotherapy is undefined and an area for future investigation.

Background Breast cancer risk for BRCA1 and BRCA2 pathogenic mutation carriers is modified by risk factors that cluster in families, including genetic modifiers of risk. We considered genetic modifiers of risk for carriers of high-risk mutations in other breast cancer susceptibility genes. Methods In a family known to carry the high-risk mutation PALB2:c.3113G>A (p.Trp1038*), whole-exome sequencing was performed on germline DNA from four affected women, three of whom were mutation carriers. Results RNASEL:p.Glu265* was identified in one of the PALB2 carriers who had two primary invasive breast cancer diagnoses before 50 years. Gene-panel testing of BRCA1, BRCA2, PALB2 and RNASEL in the Australian Breast Cancer Family Registry identified five carriers of RNASEL:p.Glu265* in 591 early onset breast cancer cases. Three of the five women (60%) carrying RNASEL:p.Glu265* also carried a pathogenic mutation in a breast cancer susceptibility gene compared with 30 carriers of pathogenic mutations in the 586 non-carriers of RNASEL:p.Glu265* (5%) (p