Human Sialic acid O-acetyl esterase (SIAE) – mediated changes in sensitivity to etoposide in a medulloblastoma cell line

Medulloblastoma (MB), the most common malignant paediatric brain tumour occurs in the cerebellum. Advances in molecular genomics have led to the identification of defined subgroups which are associated with distinct clinical prognoses. Despite this classification, standard therapies for all subgroups often leave children with life-long neurological deficits. New therapeutic approaches are therefore urgently needed to reduce current treatment toxicity and increase survival for patients. GD3 is a well-studied ganglioside which is known to have roles in the development of the cerebellum. Post-partum GD3 is not highly expressed in the brain. In some cancers however GD3 is highly expressed. In MB cells GD3 is largely acetylated to GD3A. GD3 is pro-apoptotic but GD3A can protect cells from apoptosis. Presence of these gangliosides has previously been shown to correlate with resistance to chemotherapy. Here we show that the GD3 acetylation pathway is dysregulated in MB and as a proof-of-principle we show that increased GD3 expression sensitises an MB cell line to etoposide

Adaptation to human locomotion speed

Visual judgments of human movement play an important role in social interactions, but relatively little is known about how retinal motion signals are used to estimate human movement speed. We report a new effect which demonstrates that these judgments are subject to modification by exposure to dynamic images. Participants viewed videos of real scenes depicting either groups of figures walking along a High Street or contestants running in the London Marathon. When video playback was speeded up or slowed down slightly relative to natural speed, participants could readily report whether the figures in each video appeared to be moving unnaturally quickly or slowly. However after adapting to slowed-down walking, natural walking speed appeared too fast, and after adapting to speeded-up walking, natural walking speed appeared too slow. Corresponding effects were found for running videos. Adaptation to natural-speed playback had no effect on apparent locomotion speed. These effects are quite different in a number of respects from those previously reported in studies of retinal velocity adaptation using simple patterns such as gratings. Unlike the stimuli used in most previous studies our videos contained a range of speeds and directions due to the unpredictability of natural scenes. Walkers and runners moved in different directions at different speeds, and at varying distances from the camera. Participants also engaged in free viewing rather than fixation. Furthermore over the range of retinal velocities our stimuli contained, adaptation to simple moving patterns causes a significant reduction in apparent velocity at all test velocities, including at the adapting velocity. Our data are consistent with the operation of a qualitatively different process in judgements of locomotion speed in natural scenes

A comparison of HPV DNA testing and liquid based cytology over three rounds of primary cervical screening: extended follow up in the ARTISTIC trial.

BACKGROUND: The additional sensitivity of HPV testing compared with cytology could permit extended cervical screening intervals. We wished to determine, through a further (third) round of screening in the ARTISTIC trial, the protection provided by a negative baseline HPV screen compared with that of cytology over a 6 year period. METHODS: Cumulative rates of CIN2 or worse (CIN2+) and CIN3 or worse (CIN3+) were correlated with baseline HPV status and cytology. HPV was detected using the Hybrid Capture 2 (Qiagen) assay for high risk types and genotyped using the Linear Array (Roche) and Papillocheck (Greiner) assays. LBC was performed using ThinPrep (Hologic). FINDINGS: Round 3 included 8,873 women of whom 6,337 had been screened in both rounds 1 and 2 and 2,536 had not been screened since round 1. The median duration of follow-up was 72.7 months. The cumulative rate of CIN2+ over three rounds was 3.88% (95%CI 3.59%, 4.17%) overall; 2.39% in round 1, 0.78% in round 2 and 0.74% in round 3. Cumulative rates by baseline status were 20.53% (95%CI 19.04%, 22.08%) for abnormal cytology, 20.12% (95%CI 18.68%, 21.61%) for HPV detection, 1.41% (95%CI 1.19%, 1.65%) for negative cytology and 0.87% (95%CI 0.70%, 1.06%) for a negative HPV test. In HPV negative women aged over 50 the cumulative rate was 0.16% (95%CI 0.07%, 0.34%). Women who were HPV positive/cytology negative at entry had a cumulative CIN2+ rate of 7.73% (95%CI 6.29%, 9.36%) over 6 years, twice the overall rate. INTERPRETATION: A negative HPV test was significantly more protective than normal cytology over three rounds. The findings of this extension of ARTISTIC suggest that the screening interval could be extended to 6 years if HPV testing replaced cytology as the primary screening test

Evidence for norm-based coding of human movement speed

Estimates if the visual speed of human movements such as hand gestures, facial expressions and locomotion are important during social interactions because they can be used to infer mood and intention. However it is not clear how observers use retinal signals to estimate real-world movement speed. We conducted a series of experiments to investigate adaptation-induced changes in apparent human locomotion speed, to test whether the changes show repulsion of similar speeds or global re-normalisation of all apparent speeds. Participants adapted to videos of walking or running figures at various playback speeds, and then judged the apparent movement speed of subsequently presented test clips. Their task was to report whether each test clip appeared to be faster or slower than a ‘natural’ speed. After adaptation to a slow-motion or fast-forward video, psychometric functions showed that the apparent speed of all test clips changed, becoming faster or slower respectively, consistent with global re-normalisation rather than with repulsion of test speeds close to the adapting speed. The adaptation effect depended on the retinal speed of the adapting stimulus but did not require recognizably human movements

Comparing Key Rank Estimation Methods

Recent works on key rank estimation methods claim that algorithmic key rank estimation is too slow, and suggest two new ideas: replacing repeat attacks with simulated attacks (PS-TH-GE rank estimation), and a shortcut rank estimation method that works directly on distinguishing vector distributions (GEEA). We take these ideas and provide a comprehensive comparison between them and a performant implementation of a classical, algorithmic ranking approach, as well as some earlier work on estimating distinguisher distributions. Our results show, in contrast to the recent work, that the algorithmic ranking approach outperforms GEEA, and that simulation based ranks are unreliable

The Open University’s first one day symposium on treatment-emergent neuroendocrine prostate cancer

The Open University's first one-day symposium on treatment-emergent neuroendocrine prostate cancer attracted world-leading figures, early career researchers and industry colleagues. The symposium proved insightful into the ‘real-world’ impact and current problems faced in the diagnosis and treatment of neuroendocrine prostate cancer. It was important for this meeting to take place as the incidence of neuroendocrine prostate cancer is increasing due to the widespread use of next-generation androgen deprivation drugs. The symposium discussions proposed new molecularly driven deadlines to accelerate research and improved the treatment of this deadly and poorly recognized malignancy

Traversing digital-creative perspectives: preparing design and technology students for interdisciplinary work.

The project aim, as stated in the original proposal, was “‘to develop and evaluate a novel collaborative approach using inter-disciplinary curricula to enhance work-readiness of computing and creative advertising undergraduates. The project vehicle is a live brief for the university Computing and Art & Design departments to work with Wycombe District Council to develop a mobile and location-sensitive “Heritage Trail App” to interpret significant sites in High Wycombe”. The overall aim of the project has remained unchanged. However, as a result of the success of the first cycle of project work (undertaken in the 2016-17 academic year), the university was approached by Buckinghamshire County Council and offered an opportunity for a further client partnership to develop a ‘web-app’ to support the delivery of the ‘Safe Places Scheme’, an initiative to provide locations where vulnerable people may seek support when they are out and about in the community. This also allowed the project team to develop and validate the approach with a new student subject and a different year group during the second and final cycle of project work (undertaken in 2017-18). This time final year BSc Computing students worked in partnership with second year BA students reading Graphic Arts, Graphic Design and Illustration. The underpinning project objectives and their mapping to the original themes of ‘Call A’ are also unchanged and are as follows: (1) Align computing and design curricula to develop vocationally relevant collaborative skills. Maps to ‘develop[ing] curriculum innovations from interdisciplinary research, interdisciplinary professional practice …’ (2) Evaluate learning gain arising from an innovative approach to authentically represent interdisciplinary and collaborative digital-creative environments. Maps to ‘respond to employer demands for advanced skills or knowledge’. 5 (3) Analyse engagement metrics to: a) predict/reflect progress in learning and collaboration; b) flag need for supportive interventions; c) use for self-directed learning. Maps to ‘develop use of learner analytics for particular pedagogic purposes’

The long non-coding RNA <i>HORAS5</i> mediates castration-resistant prostate cancer survival by activating the androgen receptor transcriptional program

Prostate Cancer (PCa) is driven by the androgen receptor (AR)-signaling axis. Hormonal therapy often mitigates PCa progression, but a notable number of cases progress to castration-resistant PCa (CRPC). CRPC retains AR-activity and is incurable. Long non-coding RNAs (lncRNAs) represent an uncharted region of the transcriptome. Several lncRNAs have been recently described to mediate oncogenic functions, suggesting that these molecules can be potential therapeutic targets. Here, we identified CRPC-associated lncRNAs by analyzing patient-derived xenografts (PDXs) and clinical data. Subsequently, we characterized one of the CRPC-promoting lncRNAs, HORAS5, in vitro and in vivo. We demonstrated that HORAS5 is a stable, cytoplasmic lncRNA that promotes CRPC proliferation and survival by maintaining AR activity under androgen-depleted conditions. Most strikingly, knockdown of HORAS5 causes a significant reduction in the expression of AR itself and oncogenic AR targets such as KIAA0101. Elevated expression of HORAS5 is also associated with worse clinical outcomes in patients. Our results from HORAS5 inhibition in in vivo models further confirm that HORAS5 is a viable therapeutic target for CRPC. Thus, we posit that HORAS5 is a novel, targetable mediator of CRPC through its essential role in the maintenance of oncogenic AR activity. Overall, this study adds to our mechanistic understanding of how lncRNAs function in cancer progression

Assessment of an ICU-specific, electronic medical summary tool against traditional dictation to reduce communication gaps during ICU-to-inpatient transitions-in-care

&nbsp; Background: Transition from the intensive care unit (ICU) to an inpatient unit is a vulnerable period where communication gaps between medical teams may be associated with preventable adverse events. The transition-in-care (TIC) summary encompasses essential clinical information and facilitates seamless continuity of patient care between sending and receiving healthcare teams. Yet, current dictation practices often produce summaries of suboptimal quality that result in delayed or incomplete information. An electronic TIC summary tool, an alternative method to dictation, standardizes information, which may ensure more timely and complete communication to reduce information breakdowns and delays. Objective: In order to standardize information communicated during ICU-to-inpatient transitions, an ICU-specific, electronic TIC summary tool was implemented in four adult ICUs in the Calgary zone. It is hypothesized that implementation of the electronic summary will improve completeness and timelines of TIC summaries.&nbsp; Methods: A multiple baseline study design was used to evaluate the implementation of the electronic TIC summary. ICUs continued dictation practices for a baseline period, until the electronic tool was implemented sequentially (in a randomized order) to each ICU and evaluated for six months following implementation. Post-implementation, providers had the option to dictate or use the electronic summary. The primary outcome was a binary measure of both completeness of four critical elements and availability of the TIC summary at ICU release. Results: Preliminary results were obtained for two months of baseline (n=48) and post-implementation (n=48) from one ICU. Post-implementation summaries contained four critical elements and were more frequently available at ICU transfer than pre-implementation dictations (73% versus 2%, p&lt;0.001). More post implementation summaries contained completion of essential information (median 88% versus 63%, p&lt;0.001) and had greater availability during transition (90% versus 73%, p=0.04) than pre-implementation dictations. With data collection scheduled to end in June 2019, we anticipate full study results to be available fall 2019. Conclusions: Preliminary results post-implementation suggest greater completion and faster availability for the receiving clinicians. It is anticipated that full study findings will add to the current literature on the effect of computerized tools for reducing communication gaps between ICU and inpatient units during transitions-in-care to ultimately improve patient safety