Grand designs, grim reality : political representation, competition and equity in regional Victoria

This work brings new understanding to the subtle ways in which the ability of one rural community to change is curtailed by self-reinforcement of an ideology not entirely of their own making. In a political environment where economic returns and population growth appear to be the true indicators of value and success, the struggle of some rural communities to change a long term and seemingly intractable trajectory of decline is well documented. The historical importance of rural communities as a place where food and fibre are grown has been challenged by market forces, climatic conditions and the relative growth of cities and service-based industries over the last three decades. To people in rural areas experiencing population stasis or decline, the situation appears to be a competition that is not being won at a local level. This thesis employs critical ethnography to understand a layered investigation of the ideological paradigms internalised by leaders in this community in a place-based setting to explore how this influences political advocacy and action. The work focusses on the Wimmera Southern Mallee region in Victoria, Australia with a particular emphasis on the city of Horsham as the major regional centre. The purpose of this work is to understand how ideology and behaviours are used to reinforce a system of power that is dominated by prestige leadership. The work also considers how external political and ideological influences may further reinforce on to leaders in the region a set of values and expectations which negatively impact on action and outcomes. The findings of this work have implications for rural community engagement, regional development, place-based initiatives and regional advocacy.Doctor of Philosoph

Understanding and addressing digital disadvantage in Wimmera Southern Mallee :Research report

The Understanding and addressing digital disadvantage in Wimmera Southern Mallee Project (the project) explored the challenges Wimmera Southern Mallee residents, focusing on low-income individuals and families, small/micro businesses and migrant groups have in accessing and effectively engaging with digital technology to help guide future regional actions. The project team interviewed 31 people from across five Local Government areas in the Wimmera Southern Mallee (Hindmarsh, West Wimmera, Northern Grampians, Horsham Rural City and Yarriambiack) who have low engagement with digital technology and/or limited internet access, as well as a representative sample of those who work to support those with low digital literacy. Ethnographic research was undertaken to understand the factors that impact on digital engagement and accessibility across the three key demographic groups in the study area. The research investigated people’s access to hardware (e.g. computers, phones and tablets) as well as networks (internet plans and connections – broadband, satellite, mobile etc.). Understanding the challenges in engaging with and interpreting digital technology will help inform future advocacy and policy responses for this region. The research will also facilitate better targeting of information and support to Wimmera Mallee residents to actively improve uptake, access, and engagement. This is important, as the region has been identified as having the lowest digital literacy of any area in Victoria (Australian Digital Inclusion Index 2020)

Unlocking aspiration, outcomes and equity by unpacking childcare issues in the Wimmera Southern Mallee

The Unlocking Aspiration, Outcomes and Equity by unpacking childcare issues in the Wimmera Southern Mallee Project (the project) explored issues in childcare provision and access across four rural local government areas (Hindmarsh, West Wimmera, Yarriambiack and Northern Grampians) within the Wimmera Southern Mallee. The intent of this work was to inform the ByFive Wimmera Southern Mallee (WSM) Early Years initiative (ByFive), a place-based community collaboration. ByFive was initiated by the WSM regional partnership in 2018, after the community nominated early childhood as their highest priority. The Victorian Government provides funding to ByFive to work together to redesign and improve early years’ service delivery within the WSM. Through this work the ByFive collaboration seeks to overcome disadvantage and inform whole of government system change to address a range of issues impacting the social, health and developmental outcomes of children by the age of five in the Wimmera Southern Mallee Region

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Protein ubiquitination is a dynamic and reversibleprocess of adding single ubiquitin molecules orvarious ubiquitin chains to target proteins. Here,using multidimensional omic data of 9,125 tumorsamples across 33 cancer types from The CancerGenome Atlas, we perform comprehensive molecu-lar characterization of 929 ubiquitin-related genesand 95 deubiquitinase genes. Among them, we sys-tematically identify top somatic driver candidates,including mutatedFBXW7with cancer-type-specificpatterns and amplifiedMDM2showing a mutuallyexclusive pattern withBRAFmutations. Ubiquitinpathway genes tend to be upregulated in cancermediated by diverse mechanisms. By integratingpan-cancer multiomic data, we identify a group oftumor samples that exhibit worse prognosis. Thesesamples are consistently associated with the upre-gulation of cell-cycle and DNA repair pathways, char-acterized by mutatedTP53,MYC/TERTamplifica-tion, andAPC/PTENdeletion. Our analysishighlights the importance of the ubiquitin pathwayin cancer development and lays a foundation fordeveloping relevant therapeutic strategies