Considerations for Evaluating the Introduction of New Cancer Screening Technology: Use of Interval Cancers to Assess Potential Benefits and Harms

This framework focuses on the importance of the consideration of the downstream intermediate and long-term health outcomes when a change to a screening program is introduced. The authors present a methodology for utilising the relationship between screen-detected and interval cancer rates to infer the benefits and harms associated with a change to the program. A review of the previous use of these measures in the literature is presented. The framework presents other aspects to consider when utilizing this methodology, and builds upon an existing framework that helps researchers, clinicians, and policy makers to consider the impacts of changes to screening programs on health outcomes. It is hoped that this research will inform future evaluative studies to assess the benefits and harms of changes to screening programs

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The overexpression of Bax produces cell death upon induction of the mitochondrial permeability transition

Stably transfected Jurkat T cells were produced in which Bax expression is inducible by muristerone A. The cell death resulting from induction of the overexpresion of Bax was prevented by inhibition of the mitochondrial permeability transition (MPT) with cyclosporin A (CyA) in combination with the phospholipase A2 inhibitor aristolochic acid (ArA). The caspase-3 inhibitor Z-Asp-Glu-Val aspartic acid fluoromethylketone (Z-DEVD-FMK) had no effect on the loss of viability. The MPT was measured as the CyA plus ArA- preventable loss of the mitochondrial membrane potential (ΔΨ(m)). The MPT was accompanied by the release of cytochrome c from the mitochondria, caspase-3 activation in the cytosol, cleavage of the nuclear enzyme poly(ADP- ribose)polymerase (PARP), and DNA fragmentation, all of which were inhibited by CyA plus ArA. Z-DEVD-FMK had no effect on the loss of ΔΨ(m) and the redistribution of cytochrome c but did prevent caspase-3 activation, PARP cleavage, and DNA fragmentation. It is concluded that Bax induces the MPT, a critical event in the loss of cell viability. In addition to the cell death, the MPT mediates other typical manifestations of apoptosis in this model, namely release of cytochrome c, caspase activation with PARP cleavage, and DNA fragmentation

81 Has the transition to digital mammography in breast cancer screening resulted in real benefits?

Most breast screening programmes worldwide have replaced Screen-Film mammography (SFM) with Full-field Digital Mammography (FFDM). While FFDM provides significant technical and practical advantages over SFM in the provision of population screening programs, whether this move has had beneficial effects on health outcomes remains unclear. An increase in screen-detection rates is only beneficial if the additional cancers detected would have otherwise presented at a later stage and caused morbidity and premature mortality. An indirect measure of this is an observed decrease in the interval cancer rate. The objective of this study is to compare health outcomes before, during and after the transition from SFM to FFDM in women in NSW, Australia. To do this, we will use linked data to capture women’s journeys from screened/unscreened to cancer diagnosis/no cancer diagnosis to treatment/no treatment and to dead/alive. For the period 1988 to _, a cohort of women with records from Breastscreen NSW, and a second, but substantially overlapping, cohort of all women diagnosed with breast cancer will have their data linked with records in the NSW Central Cancer Registry, NSW Admitted Patient Data Collection, and the NSW Mortality Data

Functional consequences of the sustained or transient activation by Bax of the mitochondrial permeability transition pore

The overexpression of Bax kills cells by a mechanism that depends on induction of the mitochondrial permeability transition (MPT) (Pastorino, J. G., Chen, S.-T., Tafani, M., Snyder, J. W., and Farber, J. L. (1998) J. Biol Chem. 273, 7770-7775). In the present study, purified, recombinant Bax opened the mitochondrial permeability transition pore (PTP). Depending on its concentration, Bax had two distinct effects. Al a concentration of 125 nM, Bax caused the release of the intermembranous proteins cytochrome c and adenylate kinase and the release from the matrix of sequestered calcein, effects prevented by the inhibitor of the PTP cyclosporin A (CSA), AL this concentration of Bax, there was no detectable mitochondrial swelling or depolarization. These effects of low Bax concentrations are interpreted as the consequence of transient, non-synchronous activation of the PTP followed by a prompt recovery of mitochondrial integrity, By contrast, Bax concentrations between 250 nM and 1 mu M caused a sustained opening of the PTP with consequent persistent mitochondrial swelling and deenergization (the MPT). CSA prevented the RIFT induced by fax, Increasing concentrations of calcium caused a greater proportion of the mitochondrial to undergo the MPT in the presence of Bax. Importantly, two known mediators of apoptosis, ceramide and GD3 ganglioside, potentiated the induction by Bax of the MPT, The data imply that Bax mediates the opening of the mitochondrial PTP with the resultant release of cytochrome c from the intermembranous space