Bacterial Infection Elicits Heat Shock Protein 72 Release from Pleural Mesothelial Cells

Heat shock protein 70 (HSP70) has been implicated in infection-related processes and has been found in body fluids during infection. This study aimed to determine whether pleural mesothelial cells release HSP70 in response to bacterial infection in vitro and in mouse models of serosal infection. In addition, the in vitro cytokine effects of the HSP70 isoform, Hsp72, on mesothelial cells were examined. Further, Hsp72 was measured in human pleural effusions and levels compared between non-infectious and infectious patients to determine the diagnostic accuracy of pleural fluid Hsp72 compared to traditional pleural fluid parameters. We showed that mesothelial release of Hsp72 was significantly raised when cells were treated with live and heat-killed Streptococcus pneumoniae. In mice, intraperitoneal injection of S. pneumoniae stimulated a 2-fold increase in Hsp72 levels in peritoneal lavage (p<0.01). Extracellular Hsp72 did not induce or inhibit mediator release from cultured mesothelial cells. Hsp72 levels were significantly higher in effusions of infectious origin compared to non-infectious effusions (p<0.05). The data establish that pleural mesothelial cells can release Hsp72 in response to bacterial infection and levels are raised in infectious pleural effusions. The biological role of HSP70 in pleural infection warrants exploration

“Are we all playing an elaborate game?” A Bourdieusian analysis of children’s participation in decision making in youth justice

There has been a lack of empirical research on children’s involvement in the design and delivery of youth offending services. This PhD investigates the extent and nature of children’s participation in planning, decision making and assessment in youth justice. It seeks to reveal the ‘logic’ and unmask the ‘hidden workings’ of participatory youth justice practice. The PhD involved 15 months of fieldwork, undertaken between 2016-2017 at a youth offending service in England. This involved participant observations and semi-structured interviews with children and young people (n=20) and professionals (n=20). Pierre Bourdieu’s analytical tools: habitus, capital, field and symbolic violence, were utilised to investigate the attitudes and behaviours of practitioners and those under supervision. This original and distinctive study produced new knowledge, uncovering both inclusive and exclusive aspects of practice that either facilitated or foreclosed children’s participation. Opportunities provided to young people to have a say and influence practice were strikingly unequal at the practice level. Involvement in shaping decision making and influencing processes was ostensibly reserved for the non-high risk, especially the ready to conform or those with seemingly malleable personality types. The study found that several young people were seeking to exert minimal energy in order to achieve a type of passive compliance with court order requirements. Professionals were concerned that they were also participating in this type of ‘game playing’. The PhD reveals insight into why agents may not contest the status quo despite experiencing hardship. The PhD presents cogent arguments for involving children more centrally in decision making, unlocking their potential and reversing a system that has traditionally ‘designed out’ opportunities for them to provide a perspective on their care/supervision or devalued the credibility/validity of their experiential knowledge. Peer mentoring was found to be a liberating and enlightening type of practice. Whilst not necessarily denouncing the adult professional voice and perspective, children and young people can be ‘experts by experience’

Youth justice: Past, present and future

In contemporary youth justice in England and Wales, there is too much emphasis on offence- and offender- focused approaches and an insufficient focus on promoting positive outcomes for children in conflict with the law. What is more, since the Crime and Disorder Act 1998, the voices of children embroiled in the Youth Justice System have been marginalised and their participatory rights rendered invalid. Both children and Youth Offending Team workers are finding involvement in the Youth Justice System (e.g. assessment, planning, intervention, supervision and review) to be a disempowering and disengaging experience. In this paper, we outline a number of contemporary tensions and conflicts in relation to youth justice law, policy and practice: the highly political context of youth justice, the criminalising risk, prevention and early intervention agendas and the unique and specialised nature of youth justice services. We also introduce a focus for future developments and 'creative possibilities' for youth justice. Specifically, we advocate for Children First, Offenders Second (CFOS), a progressive and principled model of youth justice that advocates for child sensitive, child appropriate services, diversion and the promotion of positive behaviours and outcomes for children, underpinned by evidence-based partnership working and the engagement of children (and parents) at all stages of the youth justice process

Youth Justice Past Present and Future

In contemporary youth justice in England and Wales, there is too much emphasis on offence- and offender- focused approaches and an insufficient focus on promoting positive outcomes for children in conflict with the law. What is more, since the Crime and Disorder Act 1998, the voices of children embroiled in the Youth Justice System have been marginalised and their participatory rights rendered invalid. Both children and Youth Offending Team workers are finding involvement in the Youth Justice System (e.g. assessment, planning, intervention, supervision and review) to be a disempowering and disengaging experience. In this paper, we outline a number of contemporary tensions and conflicts in relation to youth justice law, policy and practice: the highly political context of youth justice, the criminalising risk, prevention and early intervention agendas and the unique and specialised nature of youth justice services. We also introduce a focus for future developments and 'creative possibilities' for youth justice. Specifically, we advocate for Children First, Offenders Second (CFOS), a progressive and principled model of youth justice that advocates for child sensitive, child appropriate services, diversion and the promotion of positive behaviours and outcomes for children, underpinned by evidence-based partnership working and the engagement of children (and parents) at all stages of the youth justice process

Bacterial infection elicits heat shock protein 72 release from pleural mesothelial cells

Heat shock protein 70 (HSP70) has been implicated in infection-related processes and has been found in body fluids during infection. This study aimed to determine whether pleural mesothelial cells release HSP70 in response to bacterial infection in vitro and in mouse models of serosal infection. In addition, the in vitro cytokine effects of the HSP70 isoform, Hsp72, on mesothelial cells were examined. Further, Hsp72 was measured in human pleural effusions and levels compared between non-infectious and infectious patients to determine the diagnostic accuracy of pleural fluid Hsp72 compared to traditional pleural fluid parameters. We showed that mesothelial release of Hsp72 was significantly raised when cells were treated with live and heat-killed Streptococcus pneumoniae. In mice, intraperitoneal injection of S. pneumoniae stimulated a 2-fold increase in Hsp72 levels in peritoneal lavage (p,0.01). Extracellular Hsp72 did not induce or inhibit mediator release from cultured mesothelial cells. Hsp72 levels were significantly higher in effusions of infectious origin compared to non-infectious effusions (p,0.05). The data establish that pleural mesothelial cells can release Hsp72 in response to bacterial infection and levels are raised in infectious pleural effusions. The biological role of HSP70 in pleural infection warrants exploration

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

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

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

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