Posttranscriptional regulation of PARG mRNA by HuR facilitates DNA repair and resistance to PARP inhibitors

The majority of pancreatic ductal adenocarcinomas (PDAC) rely on the mRNA stability factor HuR (ELAV-L1) to drive cancer growth and progression. Here, we show that CRISPR-Cas9–mediated silencing of the HuR locus increases the relative sensitivity of PDAC cells to PARP inhibitors (PARPi). PDAC cells treated with PARPi stimulated translocation of HuR from the nucleus to the cytoplasm, specifically promoting stabilization of a new target, poly (ADP-ribose) glycohydrolase (PARG) mRNA, by binding a unique sequence embedded in its 30 untranslated region. HuR-dependent upregulation of PARG expression facilitated DNA repair via hydrolysis of polyADP-ribose on related repair proteins. Accordingly, strategies to inhibit HuR directly promoted DNA damage accumulation, inefficient PAR removal, and persistent PARP-1 residency on chromatin (PARP-1 trapping). Immunoprecipitation assays demonstrated that the PARP-1 protein binds and posttranslationally modifies HuR in PARPi-treated PDAC cells. In a mouse xenograft model of human PDAC, PARPi monotherapy combined with targeted silencing of HuR significantly reduced tumor growth compared with PARPi therapy alone. Our results highlight the HuR–PARG axis as an opportunity to enhance PARPi-based therapies. ©2017 AACR

Increase in the flock prevalence of lameness in ewes is associated with a reduction in farmers using evidence-based management of prompt treatment : a longitudinal observational study of 154 English sheep flocks 2013–2015

Since 2006, farmers in England have received new recommendations on best practice to manage lameness in sheep through a range of knowledge exchange activities. The adoption of each recommendation varied, but in 2013 approximately 50% of farmers reported treating all lame sheep within 3 days of onset of lameness (prompt treatment), 41% did not practice routine foot trimming, 50% culled sheep that had been lame and 14% vaccinated against footrot; all recommended best practices. The aim of this study was to investigate the prevalence of lameness in ewes in England from 2013 to 2015 and to identify changes in practice to manage lameness between 2013 and 2015 and the population attributable fraction for these managements. A longitudinal study with a cohort of 154 English sheep farmers was run for three years, farmers completed questionnaires on lameness in their flock for the previous 12 months in 2013, 2014 and 2015. The geometric mean prevalence of lameness in ewes was 4.1% in 2015, significantly higher than 3.3% and 3.2% for the same 128 farmers who provided data in both 2013 and 2014. Between 2013 and 2015 there was a significant reduction in farmers practising prompt treatment (50.6%–28.6%) but an increase in not practising routine foot trimming (40.9%–79.2%), culling sheep that had been lame (49.4%–81.8%), and vaccinating against footrot (14.3%–29.2%). Not practising prompt treatment, ≥5% of sheep feet bleeding during routine foot trimming, vaccinating ewes for 5 years, not treating lame sheep promptly, ≥5% of sheep feet bleeding during routine foot trimming, and mixing of flocks were 34.5%, 25.3%, 2.9% and 2.4%. In 2013, when 50% of farmers used prompt treatment, the PAF for not using prompt treatment was only 13.3%. We conclude that the change in practice by these farmers towards flock-level managements and a reduction in individual prompt treatment of lame sheep negatively impacted the prevalence of lameness in sheep. This change occurred despite the evidence that prompt treatment of lame sheep is highly effective at reducing the prevalence of lameness in sheep flocks and is an example of cognitive dissonance

Angiography-based superficial wall strain of de novo stenotic coronary arteries:serial assessment of vessels treated with bioresorbable scaffold or drug-eluting stent

Objectives: This study sought to present an angiography-based computational model for serial assessment of superficial wall strain (SWS, dimensionless) of de-novo coronary stenoses treated with either bioresorbable scaffold (BRS) or drug-eluting stent (DES). Background: A novel method for SWS allows the assessment of the mechanical status of arteries in-vivo, which may help for predicting cardiovascular outcomes. Methods: Patients with arterial stenosis treated with BRS (n = 21) or DES (n = 21) were included from ABSORB Cohort B1 and AIDA trials. The SWS analyses were performed along with quantitative coronary angiography (QCA) at pre-PCI, post-PCI, and 5-year follow-up. Measurements of QCA and SWS parameters were quantified at the treated segment and adjacent 5-mm proximal and distal edges. Results: Before PCI, the peak SWS on the ‘to be treated’ segment (0.79 ± 0.36) was significantly higher than at both virtual edges (0.44 ± 0.14 and 0.45 ± 0.21; both p &lt; 0.001). The peak SWS in the treated segment significantly decreased by 0.44 ± 0.13 (p &lt; 0.001). The surface area of high SWS decreased from 69.97mm2 to 40.08mm2 (p = 0.002). The peak SWS in BRS group decreased to a similar extent (p = 0.775) from 0.81 ± 0.36 to 0.41 ± 0.14 (p &lt; 0.001), compared with DES group from 0.77 ± 0.39 to 0.47 ± 0.13 (p = 0.001). Relocation of high SWS to device edges was often observed in both groups after PCI (35 of 82 cases, 41.7 %). At follow-up of BRS, the peak SWS remained unchanged compared to post-PCI (0.40 ± 0.12 versus 0.36 ± 0.09, p = 0.319). Conclusion: Angiography-based SWS provided valuable information about the mechanical status of coronary arteries. Device implantation led to a significant decrease of SWS to a similar extent with either polymer-based scaffolds or permanent metallic stents.</p

Failure patterns in resected pancreas adenocarcinoma: lack of predicted benefit to SMAD4 expression.

OBJECTIVE: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA). BACKGROUND: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection. METHODS: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (\u3c12 \u3emonths) or long-term (\u3e30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined. RESULTS: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15). CONCLUSIONS: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA

Long-term clinical outcomes of everolimus-eluting bioresorbable scaffolds versus everolimus-eluting stents:final five-year results of the AIDA randomised clinical trial

Background: Absorb bioresorbable vascular scaffold (BVS)-related events have been reported between 1 and 3 years – the period of active scaffold bioresorption. Data on the performance of the Absorb BVS in daily clinical practice beyond this time point are scarce. Aims: This report aimed to provide the final five-year clinical follow-up of the Absorb BVS in comparison with the XIENCE everolimus-eluting stent (EES). In addition, we evaluated the effect of prolonged dual antiplatelet therapy (DAPT) administration on events in the scaffold group. Methods: AIDA was a multicentre, investigator-initiated, non-inferiority trial, in which 1,845 unselected patients with coronary artery disease were randomly assigned to either the Absorb BVS (n=924) or the XIENCE EES (n=921). Target vessel failure (TVF), a composite of cardiac death, target vessel myocardial infarction or target vessel revascularisation, was the primary endpoint. Scaffold thrombosis cases were matched with controls and tested for the effect of prolonged DAPT. Results: Up to five-year follow-up, there was no difference in TVF between the Absorb BVS (17.7%) and the XIENCE EES (16.1%) (hazard ratio [HR] 1.31, 95% confidence interval [CI]: 0.90-1.41; p=0.302). Definite or probable device thrombosis (DT) occurred in 43 patients (4.8%) in the scaffold group compared to 13 patients (1.5%) in the stent group (HR 3.32, 95% CI: 1.78-6.17; p<0.001). DT between 3 and 4 years occurred six times in the Absorb arm versus three times in the XIENCE arm. Between 4 and 5 years, the incidence was three versus two, respectively. Of those three DT in the scaffold group, two occurred in XIENCE EES-treated lesions. The odds ratio of scaffold thrombosis in patients on DAPT compared to off DAPT throughout five-year follow-up was 0.36 (95% CI: 0.15-0.86). Conclusions: The excess risk of the Absorb BVS on late adverse events, in particular device thrombosis, in routine PCI continues up to 4 years and seems to plateau afterwards

A Comparison of Neural Decoding Methods and Population Coding Across Thalamo-Cortical Head Direction Cells

Head direction (HD) cells, which fire action potentials whenever an animal points its head in a particular direction, are thought to subserve the animal’s sense of spatial orientation. HD cells are found prominently in several thalamo-cortical regions including anterior thalamic nuclei, postsubiculum, medial entorhinal cortex, parasubiculum, and the parietal cortex. While a number of methods in neural decoding have been developed to assess the dynamics of spatial signals within thalamo-cortical regions, studies conducting a quantitative comparison of machine learning and statistical model-based decoding methods on HD cell activity are currently lacking. Here, we compare statistical model-based and machine learning approaches by assessing decoding accuracy and evaluate variables that contribute to population coding across thalamo-cortical HD cells

Parallel processes:Getting it write?

This paper offers a critical reflection on the processes surrounding the writing of a book aimed at foster carers and residential workers. By utilising the concept of parallel process as well as the four modes of reflection identified by Ruch (2000), we explore the ways in which the wider context of both direct works with children and reflective practice have been impacted by the tensions between relationally based, child-centred practice and wider managerialist imperatives. The paper draws parallels between these practice tensions and those currently in play within the academy. By employing a dialogical and reflective analysis of the process and interactions surrounding the writing of a practitioner-targeted book, the paper demonstrates the ways in which critical and process reflection post-event took place, considering the heretofore unexplored parallel processes between writing for practice, and practice. In so doing, it identifies the ways in which the authors mirrored practitioners in relation to the management of anxiety, a sense of constrained autonomy and confidence, and an avoidance of recognising and challenging structural and political context. Implications for the creation of practice literature and for the academy are considered.Output Status: Forthcoming/Available Onlin

Assessing secondary attack rates among household contacts at the beginning of the influenza A (H1N1) pandemic in Ontario, Canada, April-June 2009: A prospective, observational study

<p>Abstract</p> <p>Background</p> <p>Understanding transmission dynamics of the pandemic influenza A (H1N1) virus in various exposure settings and determining whether transmissibility differed from seasonal influenza viruses was a priority for decision making on mitigation strategies at the beginning of the pandemic. The objective of this study was to estimate household secondary attack rates for pandemic influenza in a susceptible population where control measures had yet to be implemented.</p> <p>Methods</p> <p>All Ontario local health units were invited to participate; seven health units volunteered. For all laboratory-confirmed cases reported between April 24 and June 18, 2009, participating health units performed contact tracing to detect secondary cases among household contacts. In total, 87 cases and 266 household contacts were included in this study. Secondary cases were defined as any household member with new onset of acute respiratory illness (fever or two or more respiratory symptoms) or influenza-like illness (fever plus one additional respiratory symptom). Attack rates were estimated using both case definitions.</p> <p>Results</p> <p>Secondary attack rates were estimated at 10.3% (95% CI 6.8-14.7) for secondary cases with influenza-like illness and 20.2% (95% CI 15.4-25.6) for secondary cases with acute respiratory illness. For both case definitions, attack rates were significantly higher in children under 16 years than adults (25.4% and 42.4% compared to 7.6% and 17.2%). The median time between symptom onset in the primary case and the secondary case was estimated at 3.0 days.</p> <p>Conclusions</p> <p>Secondary attack rates for pandemic influenza A (H1N1) were comparable to seasonal influenza estimates suggesting similarities in transmission. High secondary attack rates in children provide additional support for increased susceptibility to infection.</p

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes