Are people with negative diabetes screening tests falsely reassured? Parallel group cohort study embedded in the ADDITION (Cambridge) randomised controlled trial

Objective To assess whether receiving a negative test result at primary care based stepwise diabetes screening results in false reassurance

Revisiting spin ice physics in the ferromagnetic Ising pyrochlore Pr2_2Sn2_2O7_7

Pyrochlore materials are characterized by their hallmark network of corner-sharing rare-earth tetrahedra, which can produce a wide array of complex magnetic ground states. Ferromagnetic Ising pyrochlores often obey the "two-in-two-out" spin ice rules, which can lead to a highly-degenerate spin structure. Large moment systems, such as Ho$_2$Ti$_2$O$_7$ and Dy$_2$Ti$_2$O$_7$, tend to host a classical spin ice state with low-temperature spin freezing and emergent magnetic monopoles. Systems with smaller effective moments, such as Pr$^{3+}$-based pyrochlores, have been proposed as excellent candidates for hosting a "quantum spin ice" characterized by entanglement and a slew of exotic quasiparticle excitations. However, experimental evidence for a quantum spin ice state has remained elusive. Here, we show that the low-temperature magnetic properties of Pr$_2$Sn$_2$O$_7$ satisfy several important criteria for continued consideration as a quantum spin ice. We find that Pr$_2$Sn$_2$O$_7$ exhibits a partially spin-frozen ground state with a large volume fraction of dynamic magnetism. Our comprehensive bulk characterization and neutron scattering measurements enable us to map out the magnetic field-temperature phase diagram, producing results consistent with expectations for a ferromagnetic Ising pyrochlore. We identify key hallmarks of spin ice physics, and show that the application of small magnetic fields ($\mu_0 H_c \sim$0.75T) suppresses the spin ice state and induces a long-range ordered magnetic structure. Together, our work clarifies the current state of Pr$_2$Sn$_2$O$_7$ and encourages future studies aimed at exploring the potential for a quantum spin ice ground state in this system

Protocol for population testing of an Internet-based Personalised Decision Support system for colorectal cancer screening

Extent: 8p.Background: Australia has a comparatively high incidence of colorectal (bowel) cancer; however, population screening uptake using faecal occult blood test (FOBT) remains low. This study will determine the impact on screening participation of a novel, Internet-based Personalised Decision Support (PDS) package. The PDS is designed to measure attitudes and cognitive concerns and provide people with individually tailored information, in real time, that will assist them with making a decision to screen. The hypothesis is that exposure to (tailored) PDS will result in greater participation in screening than participation following exposure to non-tailored PDS or resulting from the current non-tailored, paper-based approach. Methods/design: A randomised parallel trial comprising three arms will be conducted. Men and women aged 50-74 years (N = 3240) will be recruited. They must have access to the Internet; have not had an FOBT within the previous 12 months, or sigmoidoscopy or colonoscopy within the previous 5 years; have had no clinical diagnosis of bowel cancer. Groups 1 and 2 (PDS arms) will access a website and complete a baseline survey measuring decision-to-screen stage, attitudes and cognitive concerns and will receive immediate feedback; Group 1 will receive information 'tailored' to their responses in the baseline survey and group 2 will received 'non-tailored' bowel cancer information. Respondents in both groups will subsequently receive an FOBT kit. Group 3 (usual practice arm) will complete a paper-based version of the baseline survey and respondents will subsequently receive 'non-tailored' paper-based bowel cancer information with accompanying FOBT kit. Following despatch of FOBTs, all respondents will be requested to complete an endpoint survey. Main outcome measures are (1) completion of FOBT and (2) change in decision-to-screen stage. Secondary outcomes include satisfaction with decision and change in attitudinal scores from baseline to endpoint. Analyses will be performed using Chi-square tests, analysis of variance and log binomial generalized linear models as appropriate. Discussion: It is necessary to restrict participants to Internet users to provide an appropriately controlled evaluation of PDS. Once efficacy of the approach has been established, it will be important to evaluate effectiveness in the wider at-risk population, and to identify barriers to its implementation in those settings.Carlene J Wilson, Ingrid HK Flight, Ian T Zajac, Deborah Turnbull, Graeme P Young, Stephen R Cole, Tess Gregor

Suppression of adenine nucleotide translocase-2 by vector-based siRNA in human breast cancer cells induces apoptosis and inhibits tumor growth in vitro and in vivo

INTRODUCTION: Adenine nucleotide translocator (ANT) 2 is highly expressed in proliferative cells, and ANT2 induction in cancer cells is known to be directly associated with glycolytic metabolisms and carcinogenesis. In addition, ANT2 repression results in the growth arrest of human cells, implying that ANT2 is a candidate for cancer therapy based on molecular targeting. METHODS: We utilized an ANT2-specific RNA interference approach to inhibit ANT2 expression for evaluating its antitumor effect in vitro and in vivo. Specifically, to investigate the therapeutic potential of ANT2 repression, we used a DNA vector-based RNA interference approach by expressing shRNA to knockdown ANT2 in breast cancer cell lines overexpressing ANT2. RESULTS: ANT2 shRNA treatment in breast cancer cell line MDA-MB-231 repressed cell growth as well as proliferation. In addition, cell cycle arrest, ATP depletion and apoptotic cell death characterized by the potential disruption of mitochondrial membrane were observed from the ANT2 shRNA-treated breast cancer cells. Apoptotic breast cancer cells transfected with ANT2 shRNA also induced a cytotoxic bystander effect that generates necrotic cell death to the neighboring cells. The intracellular levels of TNFalpha and TNF-receptor I were increased in ANT2 shRNA transfected cells and the bystander effect was partly blocked by anti-TNFalpha antibody. Ultimately, ANT2 shRNA effectively inhibited tumor growth in vivo. CONCLUSION: These results suggest that vector-based ANT2 RNA interference could be an efficient molecular therapeutic method for breast cancer with high expression of ANT2.This work was supported in part by the grants from the Cancer Research Center, and the Korean Science & Engineering Foundation through the Tumor Immunity Medical Research Center at Seoul National University College of Medicine

Transcription elongation factors represent in vivo cancer dependencies in glioblastoma

Glioblastoma is a universally lethal cancer with a median survival of approximately 15 months1. Despite substantial efforts to define druggable targets, there are no therapeutic options that meaningfully extend glioblastoma patient lifespan. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology2–4 for use in orthotopic patient-derived xenograft (PDX) models, creating a high-throughput negative selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators necessary for cell survival in vivo are non-overlapping with those required in vitro. We identified transcription pause-release and elongation factors as one set of in vivo-specific cancer dependencies and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause-release, promoting cell survival specifically in vivo. Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, supporting targeting the transcription elongation machinery as a therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of ‘cancer dependencies’ not identified by previous in vitro approaches, which could supply untapped opportunities for therapeutic intervention