Practising social justice: Community organisations, what matters and what counts

This thesis investigates the situated knowing-in-practice of locally-based community organisations, and studies how this practice knowledge is translated and contested in inter-organisational relations in the community services field of practices. Despite participation in government-led consultation processes, community organisations express frustration that the resulting policies and plans inadequately take account of the contributions from their practice knowledge. The funding of locally-based community organisations is gradually diminishing in real terms and in the competitive tendering environment, large nationally-based organisations often attract the new funding sources. The concern of locally-based community organisations is that the apparent lack of understanding of their distinctive practice knowing is threatening their capacity to improve the well-being of local people and their communities. In this study, I work with practitioners, service participants and management committee members to present an account of their knowing-in-practice, its character and conditions of efficacy; and then investigate what happens when this local practice knowledge is translated into results-based accountability (RBA) planning with diverse organisations and institutions. This thesis analyses three points of observation: knowing in a community of practitioners; knowing in a community organisation and knowing in the community services field of practices. In choosing these points of observation, the inquiry explores some of the relations and intra-actions from the single organisation to the institutional at a time when state government bureaucracy has mandated that community organisations implement RBA to articulate outcomes that can be measured by performance indicators. A feminist, performative, relational practice-based approach employs participatory action research to achieve an enabling research experience for the participants. It aims to intervene strategically to enhance recognition of the distinctive contributions of community organisations’ practice knowledge. This thesis reconfigures understandings of the roles, contributions and accountabilities of locally-based community organisations. Observations of situated practices together with the accounts of workers and service participants demonstrate how community organisations facilitate service participants’ struggles over social justice. A new topology for rethinking social justice as processual and practice-based is developed. It demonstrates how these struggles are a dynamic complex of iteratively-enfolded practices of respect and recognition, redistribution and distributive justice, representation and participation, belonging and inclusion. The focus on the practising of social justice in this thesis offers an alternative to the neo-liberal discourse that positions community organisations as sub-contractors accountable to government for delivering measurable outputs, outcomes and efficiencies in specified service provision contracts. The study shows how knowing-in-practice in locally-based community organisations contests the representational conception of knowledge inextricably entangled with accountability and performance measurement apparatus such as RBA. Further, it suggests that practitioner and service participant contributions are marginalised and diminished in RBA through the privileging of knowledge that takes an ‘expert’, quantifiable and calculative form. Thus crucially, harnessing local practice knowing requires re-imagining and enacting knowledge spaces that assemble and take seriously all relevant stakeholder perspectives, diverse knowledges and methods

A Novel Long Range Spin Chain and Planar N=4 Super Yang-Mills

We probe the long-range spin chain approach to planar N=4 gauge theory at high loop order. A recently employed hyperbolic spin chain invented by Inozemtsev is suitable for the SU(2) subsector of the state space up to three loops, but ceases to exhibit the conjectured thermodynamic scaling properties at higher orders. We indicate how this may be bypassed while nevertheless preserving integrability, and suggest the corresponding all-loop asymptotic Bethe ansatz. We also propose the local part of the all-loop gauge transfer matrix, leading to conjectures for the asymptotically exact formulae for all local commuting charges. The ansatz is finally shown to be related to a standard inhomogeneous spin chain. A comparison of our ansatz to semi-classical string theory uncovers a detailed, non-perturbative agreement between the corresponding expressions for the infinite tower of local charge densities. However, the respective Bethe equations differ slightly, and we end by refining and elaborating a previously proposed possible explanation for this disagreement.Comment: 48 pages, 1 figure. v2, further results added: discussion of the relationship to an inhomogeneous spin chain, normalization in sec 3 unified, v3: minor mistakes corrected, published versio

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy

Search for the Xb and other hidden-beauty states in the π+π−ϒ(1S) channel at ATLAS

This Letter presents a search for a hidden-beauty counterpart of the X(3872) in the mass ranges of 10.05–10.31 GeV and 10.40–11.00 GeV, in the channel Xb→π+π−ϒ(1S)(→μ+μ−), using 16.2 fb−1 of pp   collision data collected by the ATLAS detector at the LHC. No evidence for new narrow states is found, and upper limits are set on the product of the Xb cross section and branching fraction, relative to those of the ϒ(2S), at the 95% confidence level using the CLS approach. These limits range from 0.8% to 4.0%, depending on mass. For masses above 10.1 GeV, the expected upper limits from this analysis are the most restrictive to date. Searches for production of the ϒ(13DJ), , and states also reveal no significant signals

Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis

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

Although the MYC oncogene has been implicated in cancer, a systematic assessment of alterations of MYC, related transcription factors, and co-regulatory proteins, forming the proximal MYC network (PMN), across human cancers is lacking. Using computational approaches, we define genomic and proteomic features associated with MYC and the PMN across the 33 cancers of The Cancer Genome Atlas. Pan-cancer, 28% of all samples had at least one of the MYC paralogs amplified. In contrast, the MYC antagonists MGA and MNT were the most frequently mutated or deleted members, proposing a role as tumor suppressors. MYC alterations were mutually exclusive with PIK3CA, PTEN, APC, or BRAF alterations, suggesting that MYC is a distinct oncogenic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such as immune response and growth factor signaling; chromatin, translation, and DNA replication/repair were conserved pan-cancer. This analysis reveals insights into MYC biology and is a reference for biomarkers and therapeutics for cancers with alterations of MYC or the PMN. We present a computational study determining the frequency and extent of alterations of the MYC network across the 33 human cancers of TCGA. These data, together with MYC, positively correlated pathways as well as mutually exclusive cancer genes, will be a resource for understanding MYC-driven cancers and designing of therapeutics

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

Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context

Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics

The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing

The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Renal cell carcinoma(RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival