Forging an Australasian Region: Trans-Tasman Integration and Interregionalism in the Asia-Pacific

Most commentators view the Australia-New Zealand Closer Economic Relations (CER) agreement as a remarkable example of bilateral integration. CER is not usually regarded, however, as a platform for Australia and New Zealand to jointly engage with third parties. Yet, more than a decade of CER-ASEAN relations culminated, in 2010, in a Free Trade Agreement (the ASEAN-Australia-New Zealand FTA, AANZFTA) between the two regions. This suggests that intra-regional trans-Tasman integration might “spill over” into external cooperation with third parties. Close cooperation and joint approaches have not, however, eventuated in other cases. Australia and New Zealand applied separately to join the interregional Asia-Europe Meeting (ASEM) forum in 2008 and 2009, indicating that their ability to act as a region is not consistent across policy or issue areas. This is an intriguing empirical puzzle, given that most observers of interregionalism elsewhere understand the ability of regions to act in international relations (‘actorness’) as a general, rather than variable, characteristic. Why, then, did Australia and New Zealand negotiate as a single entity with ASEAN on an FTA, but did not coordinate their approach in the ASEM case? This thesis argues that the process of trans-Tasman integration has produced a set of issue-specific institutions, which present Australian and New Zealand policy makers with a ready-made framework for cooperation with third parties in some, but not all, issue areas. Once these institutions were established, it proved a relatively simple step to extend the scope of their operation beyond the trans-Tasman level. This suggests that in the trans-Tasman case, ‘actorness’, understood as the basis on which regions can engage in international relations, may be issue-specific rather than generalised. This thesis makes its case by critically analysing the emergence and evolution of CER-ASEAN relations and by documenting Australia and New Zealand’s separate applications to join ASEM. It draws on extensive archival research and interviews with key actors and decision makers. The thesis adds to the nascent field of interregionalism by offering a new empirical case in which to test and develop theories. It makes a contribution to our understanding of the way institutions shape the scope for regions to “act” in international relations. More broadly, this study provides insights into the relationship between institutional design, individual actors and policy outcomes

A mobile app-based intervention for depression: end-user and expert usability testing Study

BACKGROUND: Despite the growing number of mental health apps available for smartphones, the perceived usability of these apps from the perspectives of end users or health care experts has rarely been reported. This information is vital, particularly for self-guided mHealth interventions, as perceptions of navigability and quality of content are likely to impact participant engagement and treatment compliance. OBJECTIVE: The aim of this study was to conduct a usability evaluation of a personalized, self-guided, app-based intervention for depression. METHODS: Participants were administered the System Usability Scale and open-ended questions as part of a semistructured interview. There were 15 participants equally divided into 3 groups: (1) individuals with clinical depression who were the target audience for the app, (2) mental health professionals, and (3) researchers who specialize in the area of eHealth interventions and/or depression research. RESULTS: The end-user group rated the app highly, both in quantitative and qualitative assessments. The 2 expert groups highlighted the self-monitoring features and range of established psychological treatment options (such as behavioral activation and cognitive restructuring) but had concerns that the amount and layout of content may be difficult for end users to navigate in a self-directed fashion. The end-user data did not confirm these concerns. CONCLUSIONS: Encouraging participant engagement via self-monitoring and feedback, as well as personalized messaging, may be a viable way to maintain participation in self-guided interventions. Further evaluation is necessary to determine whether levels of engagement with these features enhance treatment effects

A mobile app-based intervention for depression: end-user and expert usability testing Study

BACKGROUND: Despite the growing number of mental health apps available for smartphones, the perceived usability of these apps from the perspectives of end users or health care experts has rarely been reported. This information is vital, particularly for self-guided mHealth interventions, as perceptions of navigability and quality of content are likely to impact participant engagement and treatment compliance. OBJECTIVE: The aim of this study was to conduct a usability evaluation of a personalized, self-guided, app-based intervention for depression. METHODS: Participants were administered the System Usability Scale and open-ended questions as part of a semistructured interview. There were 15 participants equally divided into 3 groups: (1) individuals with clinical depression who were the target audience for the app, (2) mental health professionals, and (3) researchers who specialize in the area of eHealth interventions and/or depression research. RESULTS: The end-user group rated the app highly, both in quantitative and qualitative assessments. The 2 expert groups highlighted the self-monitoring features and range of established psychological treatment options (such as behavioral activation and cognitive restructuring) but had concerns that the amount and layout of content may be difficult for end users to navigate in a self-directed fashion. The end-user data did not confirm these concerns. CONCLUSIONS: Encouraging participant engagement via self-monitoring and feedback, as well as personalized messaging, may be a viable way to maintain participation in self-guided interventions. Further evaluation is necessary to determine whether levels of engagement with these features enhance treatment effects

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

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year